BIPARATOPNYE POLYPEPTIDES - ANTAGONISTS OF SIGNAL TRANSMISSION OF WNT IN TUMOR CELLS
BIPARATOPNYE POLYPEPTIDES - ANTAGONISTS OF SIGNAL TRANSMISSION OF WNT IN TUMOR CELLS The present invention relates to new polypeptides, binding like receptor low density lipoprotein protein 5 (LRP5) and like receptor low density lipoprotein protein 6 (LRP6). The invention also relates to nucleic acids, encoding such polypeptides; methods of manufacture of such polypeptides; cells - host, which express or are able to express such polypeptides; compositions, containing such polypeptides; and also applications of such polypeptides or such compositions, in particular, in therapeutic purposes in the field of cancer diseases. Activation signal path of WNT requires binding extracellular of WNT-and-ligands with receptor Frizzled and byby LRP5 (number of access: UniProtKB -075197/lrp5_human) or its close related homologue LRP6 (number of access: UniProtKB - 075581/lrp6 human being). In cells of mammals there is 19 proteins of WNT and 10 receptors Frizzled. In the absence of of WNT ligand cytoplasmic beta - catenin phosphorylated protein complex, consisting of frame proteins Axin and activated protein C, as well as kinases gsk3 - 6eta and sk1a. Followed by recognition of beta - tgsr - ubikvitinligazoi leads to ubiquitin - mediated degradation of beta - katenina. In the presence of of WNT ligand binding of WNT with Frizzled and LRP5 or LRP6 leads to to fish cytoplasmic of the effector protein Dvl and phosphorylation cytoplasmic tail LRP5 or LRP6, that provides site for connection Axin. Sequestration Axin by means of LRP5 or LRP6 leads to inactivation of complex Axin-and-American Power-and-GSK3-and-6eta, and it, to stabilization and accumulation of intracellular beta - katenina. So, level of beta - katenina in cytoplasm grows, and beta - catenin moves to nucleus, forming complexes with terms of family transcription factors tkletochnogo factor (Taverage)/factor, binds lymphoid enhancer (LEF). Then mechanism are basal transcription and transcription the coactivators, including protein (CREB-and-optional binding protein, SZRU), which binds with protein, binding with cAMP - sensitive element (cAMP of Response the Element-and-optional binding protein, CREB), or its homologue rzoo, which leads to expression of different target genes, including Axin2, cyclin d1 and with - the ICC. Additional level of ligand - dependent regulation of track of WNT mediated ez - by the ligase RNF43 and its close related homologue ZNRF3, and also secreted proteins of r-spondinami (the de Lau 28 (4): 305 - 16). RNF43 is intermediary in ubikvitinirovanii receptor complex Frizzled/LRP5 or LRP6 cell surface, results its degradation and so suppressing ligand - dependent activity track of WNT. Activity of RNF43 counteract family members of r-spondinov (Rspondinovye ligands 1 - 4). In the presence of R spondinovogo ligand it eliminates RNF43 with cell surface, it possible accumulation of complex Frizzled/LRP5 or LRP6 and amplification of WNT-and-signalinga in the presence of of WNT-and-ligands. LRP5 and LRP6 act as gatekeepers ligand - dependent activation of signal path of WNT and, consequently, can considered targets for achievement of full block track, all mediated 19 - th ligands of WNT and 10 - second receptors Frizzled, and also amplified of r-spondinovymi ligands. In particular, of WNT-and-ligands can be divide into classes and WntlWnt3a, each of which for signal transmission binds with different epitopes/sections LRP5 and LRP6. An extracellular domain LRP5 and LRP6 has four repeating beta - propeller element, connected with EGFR-and-similar domain, behind them follow three LDLR-and-repetition type. integration structural and functional analysis of LRP5 and LRP6 makes assume, that Wntl (ligand class Wntl) binds with fragment of LRP6, which contains beta - the propellers 1 and 2, a of Wnt3a binds with fragment, which contains beta - the propellers 3 and 4. present in known moment only image extracellular domain of LRP6, containing beta - propeller sections 1 - 4, in low solving (Ahn Giperaktivatsiya signal path of WNT receives participate in pathogenesis of various types of cancer. In some types of cancer frequent mutations in molecules signal descending tract promote constitutive activation of track of WNT (nair ., mutations activated protein C at of colorectal cancer; activated beta - catenin mutation at pechenochnokletochnoi carcinoma). Opposite, at three times negative breast cancer (tnrmzh), nemelko cellular cancer light (nmkrl), to the adenocarcinoma pancreatic, and also subset colorectal crayfish (operation switch) and endometrialnykh crayfish activation signal path of WNT is actuated ligand - dependent mechanism (T. e ., autokrinnoi/parakrinnoi activation of WNT), detectable by endocellular accumulation of beta - katenina. At nmkrl, tnrmzh and to the adenocarcinoma pancreatic ligand - dependent activation of WNT mediated multiple mechanisms, including to increase the nnuyu expression of WNT-and-ligands and/or receptors LRP5 and LRP6, or same silencing negative regulator LRP5 and lrp6 - dkk1 (tnrmzh: Liu Khramtsov Nakashima From level of technology are known some molecules, binding LRP5 or LRP6 and capable to modulate signal path of WNT: Dickkopf-and-1 (DKK1) - this inhibitor LRP5 and LRP6. DKK1 binds with both byby of WNT, LRP5 and 6, and also transmembrane protein Kremen, suppresses of WNT-and-signaling and leads to rapid internalization LRP5 and LRP6. Was it is shown, that DKK1 suppresses as Wntl -, and Wnt3aoposredovannuyu signal transmission. Examination by structural modeling have shown, that separate molecule DKK1 cooperative and binds with elongated section extracellular domain of LRP6 (from 1 - th to 3 - of beta - propeller). Structural analysis predict interaction DKK1 and LRP6 by principle of cooperative binding, with initial binding with 3 - m beta - propeller section, which facilitates the interaction/bonding with 1 - m and 2 m - beta - propeller sections, since changes conformation extracellular domain of LRP6. However, as already mentioned, specific epitopes in domains 1 - of, 2 - of and 3 - of beta - propellers, receiving participate in binding DKK1 and LRP6, not clarified from - the low-resolution reconstructions structure complete extracellular domain of LRP6, coupled with DKK1. Was it is shown, that treatment DKK1 2012; 113 (1): 31 - 8). Therefore doubts arise in, that inhibitors of LRP5 and LRP6 or do which - or inhibitors of signal path of WNT (Wntl and Wnt3a) can be used in therapeutic purposes, nair ., may go in development as agent against cancer. W02009/056634 relates to molecules, binding with LRP6, which may antagonistically or agonisticheski interact with signal by Wntl or with signal by wnt3/3a, and which may be used in diagnosis or for treatment of "disorders, associated with signal by of WNT", such as osteoarthritis, polycystic kidney or cancer. In this document not mentioned which - or specific examples similar binding molecules, certain by their amino acid sequences. In wo2011/138391 and wo2011/138392 invention describes multivalent antibodies, binding LRP6. In wo2011/138391 invention claims antibodies, blocking one of signal tracts of WNT (Wntl or Wnt3), not enhancing at that other path (respectively Wnt3 or Wntl). In wo2011/138392 among other things presented antibodies or fragments of antibodies, reinforcing signal of WNT by formation of receptor clusters LRP6. In wo2011/138391 explained, that for desired effect molecules, binding LRP6, should be adjusted to format full of IgG antibodies. Examples are given biparatopnykh molecules LRP6, including molecule of IgG with the first specificity binding, connected with single-chain chain Fv-and-section with the second specificity binding. Some formats are described as having considerably WiFi client continuously nnoi thermal stability (Tiel from 50 to 52 theoretically). Fn-and-section can to molecule of IgG effector function, such as complement - dependent cytotoxicity of (kzts) or antitelozavisimayakletochnooposredovannaya cytotoxicity of (azkts). Β-wo2013/067355 invention describes binding LRP6biparatopnye immunoglobulin scFv antibody-and-constructs with prolonged period half-, obtained from molecules of IgG, described in wo2011/138391. In wo2011/119661 there described are antibodies, binding with LRP6 and suppress signal transmission through first to the isoform of WNT, especially through Wnt3 or Wnt3a, but reinforcing transmission signal through the second to the isoform of WNT, which can be isoform Wntl, 2, 2, 4, 6, 7a, 7 [7 [], 8a, 9a, 9 [9 [], 10a or 10 [10 []. Invention describes bispecific molecules, binding with E1 - E2 - section LRP6, as well as with ez - E4 - section LRP6. For production of bispecific antibodies used technology "projections - in - cavity". Epitopes binding (defined amino acid residues within the extracellular domain of/beta - propeller sections LRP6), receiving participate in binding LRP6 with antibodies, not identified neither in w02009/056634, neither in wo2011/138391 or wo2013/067355, and only partially identified in wo2011/119661. In particular, binding LRP6 antibodies are able to suppress signal transmission of WNT by means of alternative mechanisms, corresponding binding with different sections LRP6, including direct competition with Wnts or inhibition of formation of triple receptor complexes (of WNT-and-LRP6-and-Frizzled), as other amplified signal transmission, it is possible, by formation of receptor clusters (Ahn Nevertheless, neither one of described in the level of equipment binding molecules until that has not been committed members health care to use as a medicinal agent for treatment of any of - or disease. Speaking more specifically, like application requires very special binding properties of, correct specificity, to such molecules not attributed, have not activated or not inhibited other target (Eg ., results of undesirable activation or inhibition of other signal tracts, or same insufficient activation or inhibition of relative to target to the isoform), in case of biilimultispetsifichnykh agents - overlying balance of two or more the specificities binding, proper pharmacokinetic and pharmacodynamic properties of, acceptable toxicological profile and, end same, efficiency of In light of above contained there is demand for new therapeutic agents, providing effective treatment of various types of cancer diseases and tumors. So, the invention is provision similar pharmacologically active agents, which may be used in treatment of row cancer diseases, including nmkrl and tnrmzh. In particular, the invention is provision similar pharmacologically active agents, compositions and/or methods of treatment, which have certain advantages as compared with used and/or known from the equipment on moment agents, compositions and/or methods. These advantages include efficiency According to the first aspect, present invention polypeptides are provided, which specifically bound with LRP5 or LRP6, like the polypeptide according to the invention has first separate immunoglobulin variable domain (and), selected from the group of separate up immunoglobulin variable domains from (1) to (of III), determined the presence of the following CDR--sequences: (I): CDR1: TYTVG (=SEQ N0:1) CDR2: AIRRRGSSTYYADSVKG (=SEQ N0:2) CDR3: DTRTVALLQYRYDY (=SEQ N0:3) (II): CDR1: SYAMG (=SEQ N0:4) CDR2: AIRRSGRRTYYADSVKG (=SEQ N0:5) CDR3: ARRVRSSTRYNTGTWWWEY (=SEQ N0:6) (III): CDR1: RYTMG (=SEQ N0:7) CDR2: AIVRSGGSTYYADSVKG (=SEQ N0:8) CDR3: DRRGRGENYILLΥSSGRYEΥ (=SEQ N0:9), and second immunoglobulin separate variable domain (b), selected from the group of separate up immunoglobulin variable domains (of IV) and (V-), determined the presence of the following CDR--sequences: (IV): CDR1: SYAMG (=SEQ N0:10) CDR2: AISWSGGSTYYADSVKG (=SEQ N0:11) CDR3: SPIPΥGSLLRRRNNYDΥ (=SEQ N0:12) (V): CDR1: SYAMG (=SEQ N0:13) CDR2: AISWRSGSTYYADSVKG (=SEQ N0:14) CDR3: DPRGYGVAYVSAYYEY (=SEQ N0:15). Terms "first" and "second" relative to this separate immunoglobulin variable domains are intended only for the designations, that these domains are two different domains (as they at least contain different CDR--sequence) .data therefore terms should not be understood as indicating accurate order or sequence domains in similar polypeptide chain. Polypeptides according to the invention optionally contain third immunoglobulin separate variable domain, especially such, as albuminsvyazyvayushchii separate immunoglobulin variable domain, as is - domain Alb 11, containing the following CDR-: CDRl (Albll): SFGMS (=SEQ n0:16) CDR2 (Albl 1): SISGSGSDTLYADSVKG (=SEQ n0:17) CDR3 (Albl 1): GGSLSR (=SEQ n0:18). According to more specific version of polypeptides according to the invention include separate immunoglobulin variable domains, which are domains VHH, preferably humanized domains VHH. According to more specific version of polypeptides according to the invention contain the first separate immunoglobulin variable domain (and), selected from the group of separate up immunoglobulin variable domains from (1) to (of III), which have the following sequence: AVQLVESGGGLVQPGGSLRLSCAASGRTFSTYTVGWFRQAPGKEREFV AAIRRRGSSTYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTAVYYCAADTRTVALLQYRYDYWGQGTLVTVSS (=SEQ N0:19) (II): A OF OF V QL THE VE S-GGGL OF V QUANTIZATION GGSLRL OF C S-A-A-S-S-S-GGTFΥAMGWFRQ Α-P GKEREF OF V AAIRRSGRRTΥΥ AD OF S-VKGRFTISRDNSKNTVYLQMNSLRPEDTAVYY OF C AAARRVRSSTRYNTGTWWWEYWGQGTL VT CIRCUITS VS OF S- (=SEQ N0:20) (III): AVQLVESGGGLVQPGGSLRLSCAASGLTFSRYTMGWFRQAPGKEREF VAAIVRSGGSTYYADSVKGRFTISRDNSKNTVYFQMNSFRPEDTAVYYCAADRRGRGENYIFFYSSGRYEYWGQGTF VT CIRCUITS VS OF S- (=SEQ N0:21), and second immunoglobulin separate variable domain (b), selected from the group, consisting of separate up immunoglobulin variable domains (of IV) and (V-), which have the following sequence: (IV): E OF V QF THE VE S-GGGE OF V QUANTIZATION GGS THE FRF S WITH A-A-S-S-S-GRTFΥAMGWFRQ AP GKEREF OF V A OF THE AIS OF W SGGSTYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTAVYYCAASPIPYGSLLRRRNNYDYWGQGTLVTVS S- (=SEQ n0:22), and (V): E OF V QL THE VE S-GGGL OF V QUANTIZATION GGSLRL OF C S-A-A-S-S-S-GGTFΥAMGWFRQ Α-P GKEREFVAAISWRSGSTYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTAVYYCAADPRGYGVAYVS HBSAG AY YEYWGQGTLVTVS S- (=SEQ N0:23). According to especially preferable alternative polypeptides involves additionally fragment, drives enhanced half, said fragment, drives enhanced half, is covalently bound with said polypeptide and optionally is selected from the group, consisting of albuminsvyazyvayushchego fragment, such as albuminsvyazyvayushchii peptide or albuminsvyazyvayushchii immunoglobulin domain, preferably albuminsvyazyvayushchii separate immunoglobulin variable domain, more preferably domain Alb 11, transferrinsvyazyvayugtsego fragment, such as antitransferrinovyi immunoglobulin domain, molecules of polyethylene glycol, human serum albumin, and also fragment of human serum albumin. Especially preferable are polypeptides, which in addition to two separate immunoglobulin variable domains (and) and (b) according to the description above contain domain a1y1, having the following sequence: EVQLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSS ISGSGSDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVTVSS (=SEQ N0:24) According to the next version of the invention specific polypeptides, containing or consisting of any of the following three polypeptide chains: F13500575 with sequence SEQ ID n0:25, F13500571 with sequence SEQ ID n0:26, and F13500720 with sequence SEQ ID n0:27. According to further aspects the invention concerns nucleic acid molecules, expression vectors, cells - host, and also methods of production of, used for manufacture of invented polypeptide. Nucleic acid molecules, encoding polypeptides according to the invention, in separated form can be used for construction of corresponding expression vectors, which are then can be transferred by transfection into cells - hosts, used for biopharmaceutical production of polypeptides according to the invention. Similar methods of manufacturing, as a rule, include stages culturing cells - host in the conditions, expression of polypeptide, isolation of polypeptide and its cleaning known in the field of methods. Further aspects, versions, application and methods, are used in which polypeptides according to the invention, will be clear from below of the following detailed description of the invention and of the formula applied. Invention presented new molecules, which make possible more efficient treatment of various types of cancer, such as tnrmzh, operation switch and nmkrl, with smaller number of side effects. Polypeptides according to the invention provide unexpected therapeutic effect (T. e ., the validity) in treatment of cancer patients patients, consists in, that they are able to cause regression of tumor, which to the full patomorfologicheskomu response (CSPs). Expected, that this in its turn leads to considerable improvement of survival rate without progressing and common survival rate, especially in case of large unsold medical demand, such, as, nair ., at breast cancer. So, polypeptides according to the invention provide new therapeutic possibility for treatment of row types of cancer, in particular the, where detected razregulirovannyi signal path of WNT and beta - katenina. Moreover, polypeptides according to the invention easily to, they have high stability and low antigenicity, and also is opened a number of capabilities relative to ways of introduction, apart from injections and infusions. On Figure 1 it is shown schematic image of biparatopnykh polypeptides - antagonists of signal transmission Wntl and Wnt3a. They consist of three domains, two of which are with certain epitopes LRP5 and LRP6 (blocking agent and WntlWnt3a) and one serves for extending half-time (domain, binding with human serum albumin). On Figure 2 it is shown absence of correlation between analyses binding by methods FACS and is preferable for representative amount of LRP6-binding VHH, obtained in immunization Lamas. Panel VHH under number "1" is characterised by high affinity to cells, expressing LRP6 on plasma membrane, the detected by means of analysis of binding FACS (along axis shown in value MCF). Panel VHH under number "2" is characterised by high affinity to recombinant extracellular domain of human LRP6 (rhLRP6-and-fn), the detected by means of analysis of binding is preferable (X axis shown value od405). On Figure 3 it is shown binding three biparatopnykhperekrestnoreaktivnykh by lrp5/lrp6 VHH-and-constructs with prolonged period with half-LRP5 (figure behind) and LRP6 (figure of members), which they are supered-express in cell lines [nek 293, as compared with negative control, consisting of nenatselennogosvyazyvatelya (VHH-construct, binding with bacterial protein, which in cells [nek 293 not is expressed). On Figure 4 is indicated complete competition three biparatopnykhperekrestnoreaktivnykh by lrp5/lrp6 VHH-and-constructs with prolonged period with half-DKK1 behind binding as with human LRP5 (Figure 4 and), and human LRP6 (Figure 4 in), which they are supered-express in cell lines [nek 293, detected in analysis DKK1-and-competition of based on FACS. On Figure 5 it is shown complete inhibition track Wntl and Wnt3a three biparatopnymiperekrestnoreaktivnymi by lrp5/lrp6 VHH-and-by the constructs with prolonged period half-(Figure 5 and) and comparison with other molecules, coupling LRP6 (Figure 5 β-: Knob ns yw2 10.09 and MOR08168IgGlLALA 6475 scFv antibody; Figure 5 with: 802t) in combined analysis of gene - to the reporter and WntlWnt3a. On Figure 6 demonstrated is inhibition of WNT-and-signalinga in cancer cells, detectable inhibition of relative mRNA expression Axin2 (Figure 6 and), and also cell proliferation (Figure 6 in), used for the WiFi client continuously by agreed to percent (%) viable cells, after treatment three biparatopnymiperekrestnoreaktivnymi by lrp5/lrp6 VHH-and-by the constructs with prolonged half-period (in final concentration of 1 mm) and after treatment of 802t, as compared with f013500571 and untreated (control) cells (of left and right sides figure 6B); for treatment of one biparatopnym lrp5/lrp6 construct with prolonged period half-(Figure 6 with) and 802t (Figure 6 d of) shown curves dependence response from dose. On Figure 7 is indicated efficiency biparatopnykhperekrestnoreaktivnykh by lrp5/lrp6 VHH-and-constructs with prolonged half-period On Figure 8 demonstrated is inhibition track of WNT in tumors, treated biparatopnymiperekrestnoreaktivnymi by lrp5/lrp6 VHH-and-by the constructs with prolonged period half-f013500571 and f013500720, was that WiFi client continuously detectable level of expression of mRNA Axin2 in the control group. On Figure 9 it is shown the effect of suppression of the \ up13a - signalinga on release of generating TNF-alpha - dendritic cells (Figure 9 and), and influence on activation of T - cells, revealed release interferon - gamma, after treatment biparatopnymperekrestnoreaktivnym by lrp5/lrp6 VHH-and-construct with prolonged half-period. Each symbol means separate donor dendritic cells (DC). Given data standardised to level of TNF-alpha - in shape of the control (Figure 9 and), and each symbol means unique donor pair for DC and T - cells (panel in). Set out above and other aspects of and versions of the invention will be clear from given then description, in which: and) if not as indicated or not is determined or other, all used terms have usual for the given area value, which obviously skilled. For example, present refer on standard aid, such as Sambrook and others ., "MolecularCloning: a of Laboratory and manuallymanual" (2 - E of 2 yr.), T. 1 - 3, the Cold of Spring Harbor framework Laboratory and Press Books (1989); Lewin, "Genes of IV", the Oxford University of Press Books, herpex - York, (1990), Roitt b) if not as indicated or other, terms " in) term g) term Immunoglobulin domains characterized in that is stored characteristic for molecules antibodies immunoglobulin laying, representing 2 - sloinyi "sandwich" from approximately seven antiparallel beta - threads, laid in two beta - sheet, optionally stabilized conservative disulfide bond. d) term So, common structure or sequence of the variable domain of immunoglobulin may be displayed to in the following form: fr1 - cdr1 - fr2 - cdr2 - fr3 - cdr3 - fr4. namely immunoglobulin variable domain (s -) gives antibody specificity by antigen, since on it is antigen-binding section. E) term " In light of above contained of determining antigen-binding domain common 4 - chaining antibodies (such, as molecule of IgG, of IgM, of IgA, IgD or IgE; are known from level of technology) or of Fab-and-fragment, P (a ') 2 - fragment, fv [fragmentafv, such as it is disulfide cross-linked fv [ilifv scFv antibody-fragment, or diatela (all are known from level of technology), from functioning like common 4 - chaining antibodies, as a rule, will not be considered separate immunoglobulin variable domain, as in these cases binding with corresponding epitope of the antigen usually is not at use of only one (separate) immunoglobulin domain, but requires pair (combined) up immunoglobulin domains, such as variable domains of light and heavy chain, T. e ., pairs of the VH-to other State up immunoglobulin domains, which jointly bound with epitope corresponding antigen. the El) Hamers-and-Casterman with, Atarhouch T, Muyldermans s-, the Robinson of G, Hamers of c, Songa preservation of the, Bendahmanν, Hamers R: "Naturallyoccurringantibodies devoid ones care Emitting chains"; Nature 363, 446 - 448 (1993)). Term "VHH-and-domain" was selected, to distinguish such variable domains from variable domains of heavy chain, available in ordinary 4 - chained antibodies (which hereinafter marked as "OS - domains" or "the VH-and-domains") and from variable light chain domains, available in ordinary 4 - chained antibodies (which hereinafter marked as "u - domains" or "VL-and-domains"). VHH-and-domains are capable of specifically binding with epitope without additional antigen-binding domain (as distinct from vh [ilivh VL-and-domains common 4 - chaining antibodies, in case of which vl [ivl the VH-and-domains recognize epitope together). VHH-and-domains are small, stable and effective antigenraspoznayushchimi units, formed by separate immunoglobulin domain. In a context of the present invention terms VHH-and-domain, VHH, VHH-and-domain, VHH-fragment antibody, VHH-antibody, and also "Nanobody®" and "Nanobody® - flOMeH" ("Nanobody" is trade mark company AblynxN.V.; Ghent; Belgium) are used interchangeably and designated representatives separate up immunoglobulin variable domains (having structure fr1 - cdr1 - fr2 - cdr2 - fr3 - cdr3 - fr4 and binding specifically with epitope, without dependence for this purpose in the presence of the second immunoglobulin variable domain of), which also can be discrimination between from the VH-and-domains by so-"distinctive remnants of" according to the determination of, nair ., w02009/109635, Figure 1. Amino acid residues of VHH-and-domain numbered on general system numbering OS - domains, developed Rabat Methods from 231, 25 - 38 (1999). According to this system numbering - Fr1 consists of amino acid residues in positions 1 - 30, - CDR1 consists of amino acid residues in positions 31 - 35, - Fr2 consists of amino acid residues in positions 36 - 49, - CDR2 consists of amino acid residues in positions 50 - 65, - Fr3 consists of amino acid residues in positions 66 - 94, - CDR3 consists of amino acid residues in positions 95 - 102, - Fr4 consists of amino acid residues in positions 103 - 113. However it should be mentioned - and this well known for OS - domains and for VHH-and-domains - that total number of amino acid residues in each CDR-can vary and may not correspond to the total amount of the amino acid residues, numbering carbonator by Rabat (namely, one or more positions according to numbering by Rabat in real sequences may not be busy, or same real sequence can more than amino acid residues, than is system Rabat). This it, that as a whole numeration by Rabat may correspond to or not correspond to real numbering amino acid residues in real sequence. From level of technology are known alternative methods of numbering amino acid residues OS - domains, which may similar manner be used and to VHH-and-domains. Nevertheless, if not as indicated or other, the present description, formula and on shapes is used numeration by Rabat, applied to VHH-and-domains according to the description above. The total number of amino acid residues in VHH-and-domain, as a rule, is in the range from 110 to 120, frequently between 112 and 115. Should be, however, noted, that for described here targets can approach and more short and long sequence. Further structural characteristics and functional properties VHH-and-domains and containing their polypeptides can be summarized as follows: VHH-and-domains ("designed" nature for functional binding with the antigen without presence of variable domain of the light chain and without any - or interaction with it) are able function as separate, relative to small functional antigen-binding structural unit, domain or polypeptide. This differs VHH-and-domains from vh [ivh VL-and-domains common 4 - chaining antibodies, which alone, as a rule, not are suitable to be practical use as separate of antigen-binding proteins or separate up immunoglobulin variable domains, but require the combination of the in the or other form of, to provide functional antigen-binding unit (as, for example, in ordinary fragments of antibodies, such as of Fab fragments; in scFv antibody, consisting of the VH-and-domain, covalently connected with VL-and-domain). Due to this unique properties field VHH-and-domains separately or as part of larger polypeptide - has a row of considerable advantages as compared with using normal vh [ivh VL-and-domains, scFv or normal antibody fragments (such, as fab [ilifab p (a ') 2 - fragments): - for high affinity and high-selective binding antigen is required only one domain, so that there is no necessity in presence of two separate domain, and also certified in correct spatial conformation and configuration of these two domains (T. e ., by means of special linkers, as in case of scFv antibody). - VHH-and-domains can expressed one gene and do not require posttranslational laying or modifications; - VHH-and-domains can be easily built in multivalent and multispecific formats (about than states then); - VHH-and-domains soluble and do not show tendency to aggregation (as murine antigen-binding domains, the described dollpage 544 - 546 (1989)); - VHH-and-domains very resistant to effect of temperature, pH of, proteases and other denaturating agents or conditions, and therefore may be made of, be store or without using refrigerating equipment, thereby saving finance, time and preventing consequences for the environment; - VHH-and-domains relative to simple and .5 cl to be made, even in industrial scale. For example, VHH-and-domains and containing their polypeptides can be produced by culturing microbial (nair ., according to description below), not using expression systems mammals, required, for example, for normal antibody fragments; - VHH-and-domains as compared with conventional 4 - chain antibodies and their antigensvyazyvayushchimi fragments relative to small (approximately 15 kDa, or 10 times less than, than usual of IgG), and therefore - better penetrate tissue and - may be introduced in more high doses than common 4 - chain antibodies and binding fragments thereof; - VHH-and-domains can an so called properties of the mandarin binding (among other things due to elongated as compared to ordinary the VH-and-domains loop their CDR3), and therefore are accessible to them also target and epitopes, inaccessible for normal 4 - chained antibodies and their antigen-binding fragments. Methods for preparing VHH-and-domains, binding with specific antigen or epitope, have been described previously, Eg ., in w02006/040153 and wo2006/122786. Also in this document detail described is, that VHH-and-domains camelids can be "humanize", replacing one or more amino acid residues in amino acid sequence original VHH-sequence one or more amino acid residues, which are in the same positions the VH-and-domain common 4 - chaining human antibody. Humanized VHH-and-domain can contain one or more fully human sequences frame sections, and in more specific version of realisation can contain human sequence frame sections, obtained from of DP-29, of DP-47, of DP-51, or their parts, optionally combined with sequences JH, such as jh5. ℮2) Blast antibodies in fact correspond to vh [ilivh VL-and-domains mammals, that are not verblyudovymi, in particular, human 4 - chained antibodies. That it may be to bind epitope as separate antigen-binding domain, T. e ., not in pair with corresponding vl [ilivl the VH-and-domain, is required special withdrawal by such portions properties, Eg ., by means of libraries sequences separate human vh [ilivh VL-and-domains. Blast antibodies, as VHH, have molecular mass from approximately 13 to approximately 16 kDa, and if obtained from fully human sequences, then do not require for humanization, nair ., therapeutic application article on. As in case of VHH-and-domains, they well expression of in prokariotnykh systems expression, that provides considerable reduction common production costs. Blast antibodies, as VHH-and-domains, can be subjected affinnomu ageing, introducing in amino acid sequence of one or more CDR-change, which lead to improved affinity of the obtained separate immunoglobulin variable domain to its corresponding antigen as compared with corresponding parent molecule. Subjected affinnomu ageing molecules separate up immunoglobulin variable domains according to the invention can be produced from known level of technology methods, for example, described in the Marks ℮3) in addition, skilled in this area also will be clearly testify, which can be "transplants" one or more of above mentioned CDR-to other "frames", including, but not by them, frames of human origin or nonimmunoglobulin frames. Suitable frames and procedures for similar transplantation CDR-are known from level of technology. solid) terms " Part of binding molecules (such, as usual antibody or polypeptide according to the invention), which recognizes epitope, called 3) term " and) polypeptide (such, as immunoglobulin, antibody, immunoglobulin separate variable domain, polypeptide according to the invention or antigen-binding molecule or its fragment in common understanding), capable of " to) as a whole term " As a rule, antigen-binding proteins (such, as polypeptides according to the invention) have binding dissociation constant (Kd of) from 10E - 5 to 10E - 14 mole/liter (m) or less, preferably from 10E - 7 to 10E - 14 mole/liter (m) or less, more preferably from 10E - 8 to 10E - 14 mole/liter, more preferably from 10E - 11 to 10E - 13 (measured, nair ., analysis Kinexa; is known from level of technology), and/or association constant (kDa) at least 10e7 IU - 1, preferably at least 10 [e10 8 IU - 1, more preferably at least 10 [e10 9 IU - 1, such as at least 10e11 IU - 1. Any value Kd of the above 10E - 4 m, as a rule, accepted pointing at nonspecific binding. Preferably polypeptide according to the invention binds with desired antigen with Kd of at, than 500 nm, preferably at, than 200 nm, more preferably at, than 10 nm, such, as less than 500 PM. Specificity binding antigen-binding protein with antigen or epitope can be determined by any suitable known l) term " m) amino acid residues of designated standard trigraphic or single-letter codes amino acids, know to and generally accepted in this area. At comparison of two amino acid sequences term -Asp, Asn-, GIUs and Gin; (of III) polar, positively charged residues: His-, of Arg and Lys-; (of IV) large aliphatic, polar residues: met polypeptide, -Leu, not, -Val Cys; and (of V) aromatic residues: Phe-, tug and flows of gas solutions. Especially preferable are the following conservative amino acid replacement: On-Ala-Gly or on Ser-; Of Arg Lys-on; Asn-on Gin or on-His; Asp-on GIUs; Cys at Ser-; Gin on Asn-; GIUs Asp; On-Gly Ala or on of Pro; On His-Asn-or on Gin; lie on-Leu or on-Val; -Leu on lie or on-Val; Lys-on of Arg, on Gin or on GIUs; Met polypeptide on-Leu, on tug or on not; On Phe-met polypeptide, on-Leu or on tug; Ser-on of Thr; Of Thr on Ser-; Of flows of gas solutions on tug; Tug on flows of gas solutions or on Phe-; On-Val not or on-Leu. and) nucleic acid molecule or polypeptide is considered to be about)" Polypeptides according to the invention are specific by LRP5 and LRP6, in sense, that contain immunoglobulin separate variable domains, specifically binding with epitopes, nalichestvuyushchimi in both of these molecules (molecules, perekrestnoreaktivno binding lrp5/lrp6). Molecules according to the invention bound with human forms of LRP5 and LRP6, and preferably also with their analogs in other types of, having value for development of drugs, τ. ℮ ., LRP5 and LRP6 Javanese macaque and mouse. In the same wide sense invention are provided new pharmacologically active agents for treatment of cancer diseases. Agents according to the invention to belong to a new class of binding molecules, namely to biparatopnymperekrestnoreaktivnym by lrp5/lrp6 polypeptides, which contain two or more separate up immunoglobulin variable domains, binding with LRP5 and/or LRP6 by different epitopes. Terms "perekrestnoreaktivnyi" and "biparatopnyi" explained above, so that biparatopnyeperekrestnoreaktivnye by lrp5/lrp6 molecules can be determined as molecules, capable to bind with LRP5 along two different epitopes, contained in protein LRP5, and also capable to bind with LRP6 along two corresponding epitopes, contained in protein LRP6. More specifically polypeptides according to the invention contain: - the first immunoglobulin separate variable domain, capable of specifically to bind and with LRP5, and with LRP6 (perekrestnoreaktivnyi by lrp5/lrp6) by epitope/so, which leads to suppression signal path Wntl, suppressing activated Wntl transcription gene - target, and - the second immunoglobulin separate variable domain, capable of specifically to bind and with LRP5, and with LRP6 (perekrestnoreaktivnyi by lrp5/lrp6) by epitope/so, which leads to suppression signal path Wnt3a, suppressing activated Wnt3a transcription gene - target. Due to two separate immunoglobulin variable domains in the similar polypeptide, the two domain are with different epitopes (having ratio to transfer signal Wntl/Wnt3a), these molecules are biparatopnymi coupling molecules. This mode biparatopnogo binding schematised shown on figure 1. In connection with this it should be mentioned, that supposed, that polypeptides according to the invention can be connected to a separate one molecule LRP5 or LRP6 both its 1l^r5/1l^r6 - binding domains, as shown on Figure 1 (mode intramolecular binding). Nevertheless, may have place and other modes of binding. Finally, supposed, that polypeptides according to the invention are able compete with DKK1 - natural ligand LRP5 and LRP6, preventing Wntl - and wntza-and-cignalingy - the binding with LRP5 and LRP6, thus by inhibiting signal track Wntl and Wnt3a. Nevertheless, this theory also should not be understood as limits volume of invention. More specifically polypeptides according to the invention specifically bound with LRP5 or LRP6, the like polypeptides contain the first separate immunoglobulin variable domain (and), selected from the group of separate up immunoglobulin variable domains from (1) to (of III), determined the presence of the following CDR--sequences: (I): CDR1: TYTVG (=SEQ N0:1) CDR2: AIRRRGSSTYYADSVKG (=SEQ N0:2) CDR3: DTRTVALLQYRYDY (=SEQ N0:3) [=CDR-domain Wntl-and-333E06mod] (II): CDR1: SYAMG (=SEQ N0:4) CDR2: AIRRSGRRTYYADSVKG (=SEQ N0:5) CDR3: ARRVRSSTRYNTGTWWWEY (=SEQ N0:6) [=CDR-domain Wntl-and-333g06] (III): CDR1: RYTMG (=SEQ N0:7) CDR2: AIVRSGGSTYYADSVKG (=SEQ N0:8) CDR3:DRRGRGENYILLΥS-SGRYEΥ (= SEQ N0:9) [=CDR-domain Wntl-and-332D03mod], and second immunoglobulin separate variable domain (b), selected from the group of separate up immunoglobulin variable domains (of IV) and (V-), determined the presence of the following CDR--sequences: (IV): CDR1: SYAMG (=SEQ N0:10) CDR2: AISWSGGSTYYADSVKG (=SEQ N0:11) CDR3: SPIPΥGSLLRRRNNYDΥ (=SEQ N0:12) [=CDR-domain wnt3a - 093a01] (V): CDR1: SYAMG (=SEQ N0:13) CDR2: AISWRSGSTYYADSVKG (=SEQ N0:14) CDR3: DPRGYGVAYVSAYYEY (=SEQ N0:15) [=CDR-domain wnt3a - 367b10], Field of terms "first" and "second" relative to this separate immunoglobulin variable domains is intended only for the designations, that these domains are different domains, as they contain different CDR--sequence and are with different epitopes. However data terms should not be understood as indicating accurate order or sequence domains in similar polypeptide chain. Other words, above of the mandate separate immunoglobulin variable domains (and) and (b) in polypeptide according to the invention can be arranged in order of (and)- (b) or in order of (b)- (and). Term "specifically bound with LRP5 or LRP6" should be understood as then, that separate immunoglobulin variable domains (and) and (b) are perekrestnoreaktivnymi relative to LRP5 and LRP6. A itself, binding properties of such molecules are determined their (CDR-) sequences, so that outlined above and in the formula of the feature of "specifically bound with LRP5 or LRP6" is intended only for illustration practical application of the invention, but not for limiting its volume. Separate immunoglobulin variable domains, as a rule, have in fact of four frame sections (fr1-and-fr4, respectively) and of three sections, complementarity determining (CDR1-and-CDR3, respectively). To reside in one polypeptide or polypeptide chain, said first and second separate immunoglobulin variable domains should be covalently are connected, or directly, or through peptide - linker. Therefore common structure molecules according to the invention may also be portray as: Of Fr (a of) - L-CDR-(of a) - L-of Fr (of a) 2 - CDR-(of a) 2 - of Fr (of a) 3 - CDR-(of a) 3 - of Fr (of a) 4 - [peptide - linker] - of Fr (6) 1 - CDR-(6) 1 - of Fr (6) 2 - CDR-(6) 2 - of Fr (6) 3 - CDR-(6) 3 - of Fr (6) 4 where Of Fr (of a) means frame section of the first separate immunoglobulin variable domain, Of Fr (6) means frame section of the second separate immunoglobulin variable domain, CDR-(of a) means of the first CDR-separate immunoglobulin variable domain, CDR-(6) means of the second CDR-separate immunoglobulin variable domain, [peptide - linker] means optionally nalichestvuyushchii peptide - linker, the CDR-have defined above sequence. Again - still should be understand, that (and) and (b) can vary points, T. e ., molecules with common structure Of Fr (6) 1 - CDR-(6) 1 - of Fr (6) 2 - CDR-(6) 2 - of Fr (6) 3 - CDR-(6) 3 - of Fr (6) 4 - [peptide - linker] - of Fr (of a) - L-CDR-(of a) - L-of Fr (of a) 2 - CDR-(of a) 2 - of Fr (of a) 3 - CDR-(of a) 3 - of Fr (of a) 4 also are embraced by present invention. Peptide - linker optionally contains third domain or consists of it, such, as albuminsvyazyvayushchii separate immunoglobulin variable domain, as is - domain a1y1, containing the following CDR-: CDR-(Albl 1) 1: SFGMS (=SEQIDNO: 16) CDR-(Albl 1) 2: SISGSGSDTLYADSVKG (=SEQ n0:17) CDR-(Alb 11) 3: GGSLSR (=SEQ n0:18) Hence group of polypeptides according to the invention with the general structure: Of Fr (a of) - L-CDR-(of a) - L-of Fr (of a) 2 - CDR-(of a) 2 - of Fr (of a) 3 - CDR-(of a) 3 - of Fr (of a) 4 - [peptide - linker] - of Fr (Alb 11) 1cdr (Alb 11) 1fr (Alb 11) 2cdr (Alb 11) 2fr (Alb 11) 3-and-CDR-(Albll) 3 - of Fr (Albll) 4 - [peptide - linker] - of Fr (6) 1 - CDR-(6) 1 - of Fr (6) 2 CDR-(6) 2 - of Fr (6) 3 - CDR-(6) 3 - of Fr (6) 4. Again - still, order of three separate up immunoglobulin variable domains (and), (b) and Alb 11 is not fixed, opposite to, polypeptides with the following sequence above said domains: (b)- Alb 11 - (and) also are embraced. Moreover, invention also are embraced by polypeptides, in which domain Alb 11 is HaNili with - end of polypeptide (Eg ., Alb 11 - (and)- (b), Alb 11 - (b)- (and), (and)- (b)- Alb 11, or (b)- (and)- Alb 11). In three preferable versions realization polypeptides according to the invention contain separate immunoglobulin variable domains, certain as follows: The first preferable version of realisation: polypeptides, containing the first separate immunoglobulin variable domain with the following sequences of CDR-: CDR1: TYTVG (=SEQ N0:1) CDR2: AIRRRGSSTYYADSVKG (=SEQ N0:2) CDR3: DTRTVALLQYRYDY (=SEQ N0:3) and second immunoglobulin separate variable domain with the following sequences of CDR-: CDR1: SYAMG (=SEQ N0:10) CDR2: AISWSGGSTYYADSVKG (=SEQ N0:11) CDR3: SPIPΥGSLLRRRNNYDΥ (=SEQ N0:12). The second preferable version of realisation: polypeptides, containing the first separate immunoglobulin variable domain with the following sequences of CDR-: CDR1: SYAMG (=SEQ N0:4) CDR2: AIRRSGRRTYYADSVKG (=SEQ N0:5) CDR3: ARRVRSSTRYNTGTWWWEY (=SEQ N0:6) and second immunoglobulin separate variable domain with the following sequences of CDR-: CDR1: SYAMG (=SEQ N0:13) CDR2: AISWRSGSTYYADSVKG (=SEQ N0:14) CDR3: DPRGYGVAYVSAYYEY (=SEQ N0:15). Third preferable version of realisation: polypeptides, containing the first separate immunoglobulin variable domain with the following sequences of CDR-: CDR1: RYTMG (=SEQ N0:7) CDR2: AIVRSGGSTYYADSVKG (=SEQ N0:8) CDR3: DRRGRGENYILLΥSSGRYEΥ (=SEQ N0:9) and second immunoglobulin separate variable domain with the following sequences of CDR-: CDR1: SYAMG (=SEQ N0:13) CDR2: AISWRSGSTYYADSVKG (=SEQ N0:14) CDR3: DPRGYGVAYVSAYYEY (=SEQ N0:15). Of course, outlined above versions - τ. ℮ ., optionally containing peptides - linkers and/or additional domains, in particular domain a1y1, with different sequence of separate up immunoglobulin variable domains can be used and to these three preferable versions of realization. In especially preferable version albuminsvyazyvayushchii separate immunoglobulin variable domain is located between two eer5yaler6 - coupling separate immunoglobulin variable domains. Therefore three especially preferred alternatives of can be imagine as follows: The first especially preferable version of realisation: Polypeptides, containing the first (eer5yaler6 - binding) separate immunoglobulin variable domain with the following sequences of CDR-: CDR1: TYTVG (=SEQ N0:1) CDR2: AIRRRGSSTYYADSVKG (=SEQ N0:2) CDR3: DTRTVALLQYRYDY (=SEQ n0:3) albuminsvyazyvayushchii separate immunoglobulin variable domain with the following sequences of CDR-: CDR1: SFGMS (=SEQ N0:16) CDR2: SISGSGSDTLYADSVKG (=SEQ N0:17) CDR3: GGSLSR (=SEQ N0:18); and second (eer5yaler6 - binding) separate immunoglobulin variable domain with the following sequences of CDR-: CDR1: SYAMG (=SEQ N0:10) CDR2: AISWSGGSTYYADSVKG (=SEQ N0:11) CDR3: SPIPΥGSLLRRRNNYDΥ (=SEQ N0:12); or in set out order, or with altered sequence above said domains. The second especially preferable version of realisation: polypeptides, containing the first (eer5yaler6 - binding) separate immunoglobulin variable domain with the following sequences of CDR-: CDR1: SYAMG (=SEQ N0:4) CDR2: AIRRSGRRTYYADSVKG (=SEQ N0:5) CDR3: ARRVRSSTRYNTGTWWWEY (=SEQ n0:6); albuminsvyazyvayushchii separate immunoglobulin variable domain with the following sequences of CDR-: CDR1: SFGMS (=SEQ N0:16) CDR2: SISGSGSDTLYADSVKG (=SEQ N0:17) CDR3: GGSLSR (=SEQ N0:18); and second (eer5yaler6 - binding) separate immunoglobulin variable domain with the following sequences of CDR-: CDR1: SYAMG (=SEQ N0:13) CDR2: AISWRSGSTYYADSVKG (=SEQ N0:14) CDR3: DPRGYGVAYVSAYYEY (=SEQ N0:15); or in set out order, or with altered sequence above said domains. Third especially preferable version of realisation: polypeptides, containing the first (eer5yaler6 - binding) separate immunoglobulin variable domain with the following sequences of CDR-: CDR1: RYTMG (=SEQ N0:7) CDR2: AIVRSGGSTYYADSVKG (=SEQ N0:8) CDR3: drrgrgenyillυssgryeυ (=SEQ n0:9); albuminsvyazyvayushchii separate immunoglobulin variable domain with the following sequences of CDR-: CDR1: SFGMS (=SEQ N0:16) CDR2: SISGSGSDTLYADSVKG (=SEQ N0:17) CDR3: GGSLSR (=SEQ N0:18); and second (eer5yaler6 - binding) separate immunoglobulin variable domain with the following sequences of CDR-: CDR1: SYAMG (=SEQ N0:13) CDR2: AISWRSGSTYYADSVKG (=SEQ N0:14) CDR3: DPRGYGVAYVSAYYEY (=SEQ N0:15); or in set out order, or with altered sequence above said domains. Above said sequence CDR-are brought in Tables la, 1b and Ib table la: sequence CDR-separate up immunoglobulin variable domains, preventing transmission of signal Wntl: Table head module: sequence CDR-separate up immunoglobulin variable domains, preventing transmission of signal Wnt3a: CDR3SPIPΥGSLLRRRNNYD OF Y DPRGY OF G OF V OF A Υ V-S-A-ΥYEΥ (SEQ N0:12) (SEQ N0:15) TABLE LB: Sequence CDR-separate up immunoglobulin variable domains, binding with serum albumin (domain A1Sh: In addition to above installed sequences CDR-separate immunoglobulin variable domains, contained in polypeptides according to the invention, have sequences up immunoglobulin frame sections (of Fr). These sequences preferably are not immunogenic for people, and therefore are preferably human or humanized FRposledovatelnostyami. acceptable human or humanized FRposledovatelnosti are known from level of technology. Particularly preferred sequence of Fr can be find in shown below versions, complete describing separate immunoglobulin variable domains, and it, and sequence CDR-and fr. According to more specific version of polypeptides according to the invention include separate immunoglobulin variable domains, which are domains VHH, preferably humanized domains VHH. According to more specific version of polypeptides according to the invention contain the first separate immunoglobulin variable domain (and), selected from the group of separate up immunoglobulin variable domains from (1) to (of III), which have the following sequence: AVOLVESGGGLVOPGGSLRLSCAASGRTFSTYTVGWFROAPGKEREFVAAIRRRGSSTYYADSVKGRFTISRDNSKNTVYLOMNSLRPEDTAVYYCAADTRTVALLOYRYD ROTATIONGOGTL VT CIRCUITS VS OF S- [=domain Wntl-and-333E06mod;=SEQ n0:19] (III) AVOLVESGGGLVOPGGSLRLSCAASGLTFSRYTMGWFROAPGKEREFVAAIVRSGGSTYYADSVKGRFTISRDNSKNTVYLOMNSLRPEDTAVYYCAADRRGRGENYILLYSSGRYE OF YWGOGTLVTVSS and second immunoglobulin separate variable domain (b), selected from the group, consisting of separate up immunoglobulin variable domains (of IV) and (V-), which have the following sequence: (IV) EVOLVESGGGLVOPGGSLRLSCAASGRTFSSYAMGWFROAPGKEREFVAAISWSGGSTYYADSVKGRFTISRDNSKNTVYLOMNSLRPEDTAVYYCAASPIPYGSLLRRRNNYD OF YWGOGTLVTVS S- [=domain Wnt3a-and-093α01;=SEQ n0:22], and SH E OF V OL THE VE S-GGGL V OF THE OP GGSLRL S WITH A-A-S-S-GGTFS-ΥAMGWFRO AP GKEREF OF V AND AISWRSGSTYYADSVKGRFTISRDNSKNTVYLOMNSLRPEDTAVYYCAADPRGYGVAYVS HBSAG AY YEYWGOGTL VT CIRCUITS VS OF S- [=domain wnt3a - 367b10;=SEQ n0:23]. Preferable of the methods are polypeptides, containing - the first immunoglobulin separate variable domain with amino acid sequence according to SEQ n0:19 and second immunoglobulin separate variable domain with amino acid sequence according to SEQ n0:22; or - the first immunoglobulin separate variable domain with amino acid sequence according to yet SEQ of n0:20 and second immunoglobulin separate variable domain with amino acid sequence according to SEQ n0:23; or - the first immunoglobulin separate variable domain with amino acid sequence according to yet SEQ of n0:21 and second immunoglobulin separate variable domain with amino acid sequence according to yet SEQ of n0:23. So, above described versions can be schematised portray as iovd (and)- [peptide - linker] - iovd (b), where "iovd" means corresponding separate immunoglobulin variable domain, and the rest of determining and versions remain the same, and above that, especially with respect to presence of optional peptides - linkers and/or additional domains, especially domain a1y1, and also with respect to different orders of separate up immunoglobulin variable domains. According to specific versions above realization said polypeptides can additionally contain fragment, drives enhanced half, said fragment, drives enhanced half, is covalently bound with said polypeptide and optionally is selected from the group, consisting of albuminsvyazyvayushchego fragment, such as albuminsvyazyvayushchii peptide or albuminsvyazyvayushchii immunoglobulin domain, preferably albuminsvyazyvayushchii separate immunoglobulin variable domain, more preferably domain Alb 11, transferrinsvyazyvayushchego fragment, such as antitransferrinovyi immunoglobulin domain, molecules of polyethylene glycol, serum albumin, preferably human serum albumin, and also fragment (human) serum albumin. Sequence above of said separate immunoglobulin variable domain of the Alb 11 next: EVOLVESGGGLVOPGNSLRLSCAASGFTFSSFGMSWVROAPGKGLEWVSSISGSGSDTbYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSRSSOGTLVTVSS (=domain Albll;=SEQ n0:24) Further examples of separate up immunoglobulin variable domains, binding with human serum albumin, are known from level of technology and are described in detail, Eg ., international patent publications wo2006/122787 and w02008/028977. Other peptides, binding with human serum albumin, are described, nair ., in w02008/068280, wo2009/127691 and wo2011/095545. So, three preferable specific of the methods of invention are: The first preferable a specific version of realisation: Polypeptides, containing - the first (eer5yaler6 - binding) separate immunoglobulin variable domain with amino acid sequence according to SEQ n0:19; - albuminsvyazyvayushchii separate immunoglobulin variable domain with amino acid sequence according to SEQ n0:24; - second (eer5yaler6 - binding) separate immunoglobulin variable domain with amino acid sequence according to SEQ n0:22; or in set out order, or with altered sequence above said three domains. The second preferable a specific version of realisation: Polypeptides, containing - the first (eer5yaler6 - binding) separate immunoglobulin variable domain with amino acid sequence according to SEQ n0:20; - albuminsvyazyvayushchii separate immunoglobulin variable domain with amino acid sequence according to SEQ n0:24; - second (yarb/yarb - binding) separate immunoglobulin variable domain with amino acid sequence according to yet SEQ of n0:23; or in set out order, or with altered sequence above said three domains. Third preferable a specific version of realisation: Polypeptides, containing - the first (yarb/yarb - binding) separate immunoglobulin variable domain with amino acid sequence according to yet SEQ of n0:21; - albuminsvyazyvayushchii separate immunoglobulin variable domain with amino acid sequence according to SEQ n0:24; - second (eyarbyalerb - binding) separate immunoglobulin variable domain with amino acid sequence according to yet SEQ of n0:23; or in set out order, or with altered sequence above said three domains. In more preferable specific versions of the albuminsvyazyvayushchii separate immunoglobulin variable domain is located between two eyarbyalerb - coupling separate immunoglobulin variable domains. Sequence mentioned above separate up immunoglobulin variable domains are brought in Tables Pa, PB and cooler: Table Pa: sequence of separate up immunoglobulin variable domains, preventing transmission of signal Wntl: Table PB: sequence of separate up immunoglobulin variable domains, preventing transmission of signal Wnt3a: Table cooler: separate up immunoglobulin sequence variable domains, binding with serum albumin (domain A1Sh: As is installed above, (at least two) separate up immunoglobulin variable domain in polypeptide according to the invention can be connected with each other directly, without using linker, or same through linker. Linker is preferably peptide linker and, according to the invention, formulas so, to make possible binding of at least two separate up immunoglobulin variable domains each from their epitopnykh targets. Suitable linkers So, suitable linkers may contain amino acid sequence, Eg ., length in 9 or more amino acids, preferably at least 17 amino acids, as - is approximately 20 - 40 amino acids. Sequence linker can be found in nature or not found in nature. In case of use in therapeutic purposes linker preferably is not immunogenic for subject, which polypeptide is introduced according to the invention. One of suitable groups of linker sequences are linkers, obtained from hinge section heavily chained antibodies, according to description in wo1996/34103 and wo1994/04678. Other example are polialaninovyelinkernye sequence, such, as-Ala-Ala-Ala-. Further preferable examples of linker sequences are linkers-Gly/Ser-of different length, such, as linkers (-Glyof X ser-of Y )Z of , including, nair ., (-Gly4 ser-)3 , (-Gly4 ser-)5 , (-Gly4 ser-)7 , (-Gly3 ser-)3 , (-Gly3 ser-)5 , (-Gly3 ser-) of V, (-Gly3 ser-2 )3 , (-Gly3 ser-2 )5 And (-Gly3 ser-2 )7 . Alternatively or additionally to polypeptide to the linker at least two separate up immunoglobulin variable domain in polypeptide according to the invention can be connected with each other by means other fragment, such as other polypeptide, which in preferable, but not single version can be additional separate immunoglobulin variable domain, according to already given above determination of. Such fragment can be in fact inactive or can and as a biological effect, such as improved desired properties of polypeptide, or same can be due to polypeptide one or more additional desired property. As already presented above, preferable additional polypeptide domain extends the half polypeptide, being such, as domain, binding with (human) serum albumin, such as domain a1y1. Therefore according to the next version of the invention especially embraces polypeptides, containing any of below the following sequences, the accurate amino acid sequences can be take from table III below: Yet SEQ of n0:25 (=sequence of polypeptide f013500575), Yet SEQ of n0:26 (=sequence of polypeptide f013500571), Yet SEQ of n0:27 (=sequence of polypeptide f013500720). According to more specific version of polypeptides according to the invention are selected from the following group molecules: Polypeptide f013500575 with sequence SEQ ID n0:25, polypeptide f013500571 with sequence SEQ ID n0:26, and polypeptide f013500720 with sequence SEQ of n0:27. Table III: Sequence of three specific versions of realization of polypeptides according to the invention As explained earlier, if not as indicated or other, the polypeptides according to the invention may contain further fragments and/or additional polypeptide domains, if only such additional fragment or domain does not prevent their bonding with lrp5/lrp6. Polypeptides according to the invention may additionally include modification, such as glikozilnye residues or modified amino acid side chain, and also can pegilirovatsya in order for extending half-time and other properties of similar molecules. Methods and reagents for pegylation biparatopnykh structures separate up immunoglobulin variable domains can be find, nair ., in wo2011/107507. Polypeptides according to the invention may have modified HaNkontse sequence, Eg ., with removal of one or more of n-end amino acids, or with the replacement of Eg ., the first of n-final amino acids (Eg ., glutamate on alanine), for the purpose of optimization of molecules for expression in certain systems expression (such, as specific vectors or cell - hosts), or for expression of as inclusion bodies or in soluble form, or for the secretion in medium or periplazmaticheskoe space or for holding in a cell, or for production of more homogeneous product. Polypeptides according to the invention may have modified on with - end of sequence, Eg ., with additional alanine (as shown for three versions of realisation in the table III above) and/or with additional amino acid substitutes in with - end part or in other installed positions of any frame sections, according to the purpose of further improving stability or WiFi client continuously ny immunogenicity of such polypeptides. In addition, half polypeptides according to the invention can be prolongation addition of albumin domain, T. e ., having transformed them in albumin fusion proteins. Examples suitable albumin fragments and methods of their addition to binding molecules are described, nair ., in w02001/079271 and w02003/059934. Preferably polypeptides according to the invention have values binding (copepod), analysis of measured binding FACS, described in example 7.1 below, in the range of 10"6 mole/liter or less, more preferably 10"9 mole/liter or less, still more preferably in the range from th "10 to 10"13 mole/liter, or have value ic50, measured combined analysis of gene - to the reporter and WntlWnt3a, described in example 7.3 below, 10"9 mole/liter or less, more preferably in the range from 5 X th "10 mole/liter to 10"12 mole/liter. Polypeptides according to the invention is possible more effective treatment of number of types of cancer, such as tnrmzh, operation switch and nmkrl. In them improved In particular, as shown In the same experiments So, polypeptides according to the invention actually provide new therapeutic possibility for treatment of cancer diseases, especially in case of large unsold medical demand, such, as, nair ., at (three times negative) breast cancer. As neither strange, inventors came to such decision by not traditional track, T. e ., trying to develop inhibitors or binding molecules with high specificity/selectivity one a certain target, such as LRP6 (referred to as a target for treatment of "diseases, mediated by signal transmission of WNT", nair ., in w02009/056634). Vice versa, inventors have developed molecules, targeting simultaneously on two related protein - LRP6 and LRP5 - and so reached above described considerably improved effects Molecular mechanism, in the base such advantages, not completely clear, however can be assume - not having intentions limited specific theory - that such perekrestnoreaktivnye molecules can possess additional, and therefore more strong effect on very muddled signal cascade of signal path of WNT. Described above keep advantage effects additionally illustrated examples below and available in them comparative data. Moreover, polypeptides according to the invention are simple in manufacturing and better are dissolved, that means, that their can be stored and/or introduce in more high in comparison with common antibodies concentrations. They are stable at room temperature and longer remain stable even at extreme values of pH of, so that may be made of, stored and/or be transported without using refrigerating equipment, thereby saving finance, time and preventing consequences for the environment. Due to above set out, and also its low immunogenicity, they additionally opened a number of capabilities relative to ways of introduction, apart from injections and infusions, and also relative to introduction of protocols and use of specific devices. According to further aspects the invention relates to molecules nucleic acids and expression vectors, encoding polypeptides according to the invention, and also to expressing their cells - host. These nucleic acids, vectors and cells - hosts are useful in manufacture of polypeptides according to the invention, and their additional aspects and versions will be learn more are described below in correlation with outlining methods of production of polypeptides according to the invention. Owing to their biological properties polypeptides according to the invention are useful for treatment of diseases, characterized by excessive or abnormal cell proliferation, such as cancer and idiopathic pulmonary fibrosis (ilf). For example, polypeptides according to the invention can be to treat the following cancers, tumor and other proliferative diseases, not limited by them: Cancer of head and neck; lung cancer, such as, nair ., nemelko cell lung cancer (nmkrl) and small cell lung cancer (mkrl); neoplasm mediastinum, such as, nair ., neurogenic tumor and mesenchymal tumor; Cancer gastro - intestinal tract (gastrointestinal tract), such as, nair ., cancer esophagus, stomach, pancreas, liver and bile ducts (including, nair ., pechenochnokletochnuyu carcinoma (Framework)), and also of thin and thick intestines (including, nair ., colorectal cancer); prostate cancer; testicular cancer; Gynecological types of cancer, such as, nair ., ovarian cancer; cancer, such as, nair ., mammary gland carcinoma, hormone - retseptorpolozhitelnyi cancer, [neg 2 - positive breast and three times negative cancer; cancer endocrine system; Sarcoma of soft tissues, such as, nair ., fibrosarcoma, rhabdomyosarcoma, angiosarcoma, sarcoma sarcoma; sarcoma bones, such as, nair ., myeloma, osteosarcoma, tumor sarcoma, fibrosarcoma, the osteochondroma, osteoblastoma and khondroblastoma; mesothelioma; Skin cancer, such as, nair ., carcinoma basal cells, flat cell carcinoma, carcinoma cells merkelya and melanoma; neoplasm of central nervous system and brain, such as, Eg ., astrocytoma, glioblastoma, glioma, the neuroblastoma and retinoblastoma; lymphoma and leukemia, such, as, nair ., in - cell nekhodzhkinskie lymphoma (NHL), T - cell nekhodzhkinskie lymphoma, chronic in - cell lymphocytic leukosis (in - khll), chronic T - cell lymphocytic leukosis (T - khll), disease s lymphoma (bkh), leukosis with large granular lymphocytes (bgl), chronic myelogenous leukosis (khml), acute myelogenous/myeloid leucosis (UML), acute lymphatic/lymphoblastic leucosis (oll), multiple tier myeloma (mm), plasmacytoma and myelodysplastic syndromes (mmf); and also tumor unknown primary localization. Implied, that all above said cancer disease, tumor, neoplasm and T. d ., lithology specific localization of/point of origin in body of, include as primary tumor, and taking place from them metastatic tumor. More specifically polypeptides according to the invention useful in treatment of such diseases, in particular cancer diseases, at which abnormal proliferation cells induced anomalous (activated) of WNT-and-signalingom, or it receives in it participation. Therefore polypeptides according to the invention are particularly useful for the treatment of solid tumors, more specifically for treatment of lung cancer, liver, colon, brain, thyroid gland, pancreas, breast, ovarian and prostate, more and more specifically for treatment of nemelko cellular lung cancer (nmkrl), three times negative breast cancer (tnrmzh) and colorectal cancer (operation switch). In particular, polypeptides according to the invention can be used for treatment of patients with locally or of metastatic tnrmzh, patients with metastatic nmkrl or locally or of metastatic operation switch, as single agent or in combination, to prolongation survival rate without progressing (vbp) and common survival rate (s). In addition, polypeptides according to the invention can be used as neoadjuvant therapy for patients with breast cancer for the purpose of achieving complete pathomorphological response (CSPs; is determined as absence of residual of invasive cancer and cancer Polypeptides according to the invention can be used in therapeutic protocols in a context of the first line, second line or any further line treatment. Polypeptides according to the invention can be used for prophylaxis, short-term or long-term treatment of above mentioned diseases, optionally in combination with radiation therapy and/or surgery. Also polypeptides according to the invention especially are useful for treatment of other diseases, caused by abnormal cell proliferation, in which receives participation of signal path of WNT, such as idiopathic pulmonary fibrosis (ilf). (Konigshoff In addition, polypeptides according to the invention especially are useful for treatment of retinopathies, especially for treatment of diabetic retinopathy from - the abnormal activation of WNT in cells inner retina, which causes intensified is anomalous formation of blood vessels of retina, that leads to the development and progressing diabetic retinopathy (-chen of Y. "The activation care of The of WNT pathwayplays a of pathogenic the Role in diabeticretinopathy in vitro humans and sort animalmodels" "ElevatedLRP6 the Levels correlate Hotel With vascularendothelial growth options factor pluggable in vitro of The vitreous care proliferativediabeticretinopathy" And finally, since it is shown, that signal suppression of tract Wntl/Wnt3a may also influence on dendritic cells (DC) and function of dendritic cells, polypeptides according to the invention can be useful for treatment of immune and infectious diseases, as well as for influence on the micro-environment tumor at various cancer diseases from number of listed above. Tumor actively inhibit antitumor immunity, and DC stabilize the important role in mechanism deviation from cancer immunity. In particular, investigating have shown, that of WNT-and-ligands in the microenvironment of the tumor are able also initiate parakrinnyisignaling in immune cells and to regulate antitumor immunity host (the Hong 2015 ; 75 (4): 656 - 65). Of course, above the described covers usage of polypeptides according to the invention in different methods of treatment above of said diseases by administration of therapeutically effective dose to the patient, requiring that, as is equal to and application of these polypeptides for preparing drugs for treatment of such diseases, as is equal to and pharmaceutical compositions, containing such polypeptides according to the invention, as is equal to and preparation of and/or manufacture of medicinal agents, including such polypeptides according to the invention, and T. d. and T. U. Polypeptides according to the invention can be used in alone or in combination with other pharmacologically active substances, such as substance best practices level or standard treatment, such as, nair ., cytostatic or the cytotoxic substance, inhibitors of cell proliferation, antiangiogenic substance, steroids, immunomodulators/inhibitors of control points and T. U. Cytostatic and/or the cytotoxic active substances, which may be introduced in combination with compounds according to the invention, include, not limited by them, hormones, analogs of hormones and the antihormones, inhibitors of aromatase, agonists and lhrh antagonists, inhibitors of growth factors (such growth factors, as, for example, growth factor platelet (PDGE), fibroblast growth factor (of FGF), factor vascular endothelial growth (of VEGF), epidermal growth factor (EGFR), -like growth factors (of IGF), epidermal growth factor human (of HER, nair ., the HER2, HER3, HER4) and growth factor hepatocytes (of HGF)), where inhibitors are, for example, antibodies against growth factor, antibodies against growth factor receptor and inhibitors of tyrosine kinase, such as, for example, cetuximab, gefitinib, afatinib, nintedanib, obtain imatinib, lapatinib, bosutinib and trastuzumab; antimetabolites (nair ., antifolaty, such as methotrexate, raltitreksed, pyrimidine analogs, such as 5 - fluorouracil (5 - fu), capecitabine and gemcitabine, purine and adenosine analogs, such as azathioprine, thioguanine, kladribin and pentostatin, cytarabine (Agha with), fludarabine); antitumor antibiotics (nair ., anthracyclines); derivatives of platinum (nair ., cisplatin, oxaliplatin, Mytomicin); alkylating agents (nair ., estramustine, mechlorethamine, melfalan, chlorambucil, busulfan, dakarbazin, cyclophosphamide, ifosfamid, controlled release, nitrosourea, such as, for example, carmustine and lomustin, tiotepa); antimitotic agents (nair ., alkaloids Vinca, such as, for example, vinblastine, vindesine, vinorelbin and vincristine; and also taxanes, such as paclitaxel, docetaxel); inhibitors of angiogenesis, inhibitors of tubulin; inhibitors of DNA synthesis, parp inhibitors, inhibitors of topoisomerase (for example, epipodofillotoksiny, such as, for example, etopozide and etopofos, teniposide, amsacrine, topotecan, irinotekan, cytostatic mitoxantrone), serine/threoninekinase (nair ., inhibitors of PDK1, inhibitors of staining RAF, inhibitors of a-- staining RAF, inhibitors of b of - staining RAF, inhibitors of c - staining RAF, inhibitors of mTOR, inhibitors of mTORCl/2, inhibitors of pi3k, inhibitors of ρ13κ of α, double inhibitors of mTOR/pi3k, inhibitors of STK33, inhibitors act, inhibitors of PLK1 (such as volasertib), inhibitors of CDK, the Aurora kinase inhibitors), tyrosine kinase inhibitors (nair ., inhibitors of PTK2/FAK), inhibitors of protein - protein interaction, inhibitors of MEK, inhibitors of ERK, inhibitors of FLT3, inhibitors of BRD4, inhibitors of IGF - 1r, agonists TRAILR2, inhibitors of showing Bcl - the XL, inhibitors of the Bel - 2, inhibitors of showing Bcl - 2/showing Bcl - the XL, inhibitors of receptor egv, inhibitors of bcr - abl kinase, inhibitors of abl kinase, inhibitors of Src of, rapamycin analogs (for example, everolimus, temzirolimus, ridaforolimus, sirolimus), inhibitors of synthesis of androgen, inhibitors of receptors androgen, inhibitors of DNMT, inhibitors of HDAC, inhibitors of ang1/2, inhibitors of Sur 17, radiopharmaceutical preparations, immunotherapeutic agents, such as inhibitors of immune of control points (nair ., molecules/immunoglobulins, binding CTLA4, pd1, of Pd - L1 of, LAG3 and TIM3, such as ipilimumab, nivolumab, pembrolizumab), anticancer vaccine, such as traditional tumor vaccine (cell vaccine, Eg ., Sipuleucel - T for of prostate cancer treatment), personalized neoantigennye vaccine and onkoliticheskie viruses, as well as various chemotheraputic agents, such as amiphostin, anagrelide, clodronate, filgrastin, interferon, interferon - alpha, leucovorin, rituximab, prokarbazin, levamisole, Meena, mitotan, pamidronate and porfimer. Especially preferable are methods for treatment, including use of polypeptides according to the invention in combination with medicinal agent, selected from a group, consisting of: (I) antibodies against of VEGF (bevacizumab and other antiangiogenic substance), with or without combination with chemotherapy (including combination of doxorubicin/cyclophosphamide and/or combination of capecitabine/docetaxel by neoadjuvant circuit; protocol taxane/platinum for the first and pozdneishikh treatment of lines) for patients with breast cancer; (Ii) ITC EGFR is for nmkrl, mutant by EGFR is, or krizotiniba for nmkrl with adjustment of alk, with or without combination with chemotherapy (the cytotoxic combined therapy platinum medications, including gemcitabine/cisplatin therapy as the first line; docetaxel or pemetreksed as second line therapy for patients with with lung cancer; (Iii) antibodies against EGFR is (cetuximab and panitumumab for tumors with (Iv) immunotherapeutic agents, including agents against of Pd-and-1, such as pembrolizumab and nivolumab, agents against of Pd-and-l1, agents against CTLA4, agents against BTLA, agents against LAG3 and agents against TIM3, such as antibodies against PDL1 and T. d ., nair ., for treatment of patients with breast cancer, lung and operation switch. (V) chemotherapeutic agents, such as anti-neoplastic preparations based on platinum, or same in combination with chemotherapeutic protocol FOLFOX, including folinovuyu acid, 5 '- fluorouracil and oxaliplatin, or same in combination with chemotherapeutic protocol FOLFOXIRI, including folinovuyu acid, 5' - fluorouracil, oxaliplatin and irinotekan, nair ., for treatment of patients with breast cancer and operation switch. If two or more substance or principle of action is used as part of the combination chemotherapy protocol, then their may be introduced by the same or different tracks, in fact one and the same time (T. e ., simultaneously, in parallel) or in different times (nair ., in series, running, alternately, according to order of or in any other form of alternating mode). If substance or on principles of is introduced simultaneously one and the same by, then can be introduced in the form of different pharmaceutical preparations or compositions or as part of combined pharmaceutical preparation or composition. In addition, if two or more substance or principle is used as part of the combination chemotherapy protocol, then each substance or principle may be introduced in the same amount and along the same protocol, which are used for single use of the compound of or principle of, and such combined use may have synergistic effect or not have its. However if combined application of two or more active substances leads to synergistic effect, then can be reduced amount of one, several or all introduced substances or principles, preserving the desired therapeutic effect. This may be useful for, for example, to avoid, limiting or reducing any - or undesired by-effects, associated with application of one or more substances or principles in ordinary amounts, preserving the desired pharmacological or therapeutic effect. Of course, above described are embraced by manufacture of and methods of making polypeptides according to the invention for combined application with above said combination partners. Are embraced by also manufacture and methods for manufacturing said above of combination partners for combined application with polypeptides according to the invention. So, invention are provided, nair ., methods of using or manufacturing for use immunomodulator/inhibitor of control points, such as antibodies against pd1, such as pembrolizumab or nivolumab, for introduction in combination with polypeptide according to the invention, and more specifically for introduction in as component of the combined therapeutic protocol with polypeptide according to the invention. Moreover, invention also are embraced by sets of, included in at least one polypeptide according to the invention and one or more other components, selected from the group, consisting of other medicinal agents, used for treatment of diseases and disorders according to the description above, and also devices according to description below. Polypeptides according to the invention and/or compositions containing them may be introduced to the patient, requiring in this, by any method, depending on particular used pharmaceutical preparation or composition. So, polypeptides according to the invention and/or compositions containing them may be introduced, for example, intravenously (in. in.), subcutaneously (U. to.), intramuscularly (in. m.), intraperitoneally (in. b.), through skin, orally, sublingually (Eg ., in the form of sublingual tablets, spray or drops, placed under tongue and adsorb through mucous membrane in sternohyoid capillary network), (inside -) nasally (Eg ., in the form of nasal spray and/or aerosol), surface, by means of suppository, inhalation or any other suitable method in the effective amount or dose. Polypeptides according to the invention and/or compositions containing them is introduced according to protocol of treatment of, suitable for treatment and/or relief of disease, disorder or condition, to be treatment or relief. Doctor, as a rule, can determine suitable protocol treatment of depending on such factors, as disease, disorder or state, subject to treatment or relief, disease severity, the severity degree of its symptoms, a specific used polypeptide according to the invention, a specific path administration and used pharmaceutical preparation or composition, age, field, weight, power supply mode, patient s general state and the like factors, well known a doctor. As a rule, protocol includes introduction of one or more polypeptides according to the invention or one or more containing their compositions in therapeutically effective amounts or doses. As a rule, for treatment and/or relief of mentioned here diseases, disorders and conditions, depending on particular subject to treatment of diseases, disorder or condition, a specific force used polypeptide according to the invention, used a specific track administration and a specific pharmaceutical preparation or composition polypeptides according to the invention in common is introduced in an amount from 0.005 to 20.0 mg per kg of body weight and dose, preferably from 0.05 to 10.0 mg/kg/dose, more preferably from 0.5 to 10 mg/kg/dose, or continuously (Eg ., infusion), or, that more preferably, in the form of separate doses (such as, Eg ., received twice per week, a week, time per month; cm. below), but all this may significantly differ, especially depending on the above mentioned parameters. Therefore in some cases sufficient may be dose is less than said here minimum dose, while in other cases it may exceed upper boundary. At introduction of large amounts of their split is recommended on a number of smaller doses, received during the day. Depending on particular polypeptide according to the invention, and its specific pharmacokinetic and other properties of, its may be introduced once a day, every second, third, fourth, fifth or sixth day, a week, time per month and T. U. Introduction of protocol may imply term weekly treatment. Under "term" there is in type of duration of at least two weeks, preferably months or years. The validity of polypeptides according to the invention, and also containing their compositions can be verified by any suitable known Preferably polypeptides according to the invention have better characteristics, than common known antibodies (such, as binding LRP6, described in partition "level of equipment" above), in at least one of these analysis or models, and preferably in one or more models For pharmaceutical use polypeptides according to the invention may be introduced into composition of pharmaceutical preparation, including (1) at least one polypeptide according to the invention and (of II) at least one pharmaceutically acceptable carrier, diluent, auxiliary substance, adjuvant and/or stabilizer, and also (of III) optionally one or more additional pharmacologically active polypeptides or compounds. Under "pharmaceutically acceptable" should be understand material, not showing any - or biological or other undesirable effects at introduction to an individual and not interacting detrimentally with any from other components pharmaceutical composition (such as, nair ., pharmaceutically active ingredient), which contains corresponding material. Specific examples can be find in standard Benefits, such as, nair ., Remington's the PharmaceuticalSciences, 18 - E of 2 yr ., Mack Publishing by the COMPANY, USA (1990). For example, polypeptides according to the invention can be retseptirovat and introduce by any method, known Pharmaceutical preparations for parenteral administration, such as intravenous, intramuscular, hypodermic injection or intravenous infusion, can, for example, be sterile solutions, suspensions, variances, emulsions or powders, which contain active substance and can be used, optionally after additional dissolution step or dilution, for injection or infusion. Suitable carriers or diluents for similar preparations include, for coded and not for limiting, sterile water and pharmaceutically acceptable aqueous buffers and solutions, such as physiological phosphate - salt solution, Ringer solution, dextrose solution and solution khenka; oil with water; glycerol; ethanol; glycols, such as propylene glycol, and mineral oil, animal oil and vegetable oils, for example, peanut oil, soya oil and suitable their mixture. Solutions of polypeptides according to the invention may also contain preservative for preventing growth of microorganisms, such, as antibacterial and antifungal substance, for example, U - hydro ksibenzoaty, parabens, chlorobutanol, phenol, sorbic acid, thiomersal, ethylenediaminetetraacetic acid (and its salts with alkaline metals) and T. U. In many cases preferably include isotonic agents, for example, sugar, buffers or sodium chloride. Optionally can be used emulsifiers and/or dispersers. Adequate fluidity may be maintained, for example, formation of liposomes, maintenance of the required particle size in case of dispersions and use of surface - active substances. May also be added other substances, delay absorption, for example, aluminum monostearate and gelatin. Solutions can be of teeming in injection vials, ampoule, bottle for infusions and T. U. In any case final medicinal form should be sterile, liquid and stable during production and in storage. Sterile injection solutions is made connection of an active substance in required amount of appropriate solvent, when required with different other components from mentioned above of, with sterilizing filtration following. In case of sterile powders for preparing sterile injection solutions preferable methods of manufacturing methods are vacuum drying and freezing-out, making it possible to produce the powder of active substance and any desired additional ingredient from their solution, preliminarily passed sterilizing filtration. Usually prefer aqueous solutions or suspension. As a rule, suitable preparations for therapeutic proteins, such as polypeptides according to the invention, are buffered solutions of proteins, such as solutions, containing protein in a suitable concentration (such, as from 0.001 to 400 mg/ml, preferably from 0.005 to 200 mg/ml, more preferably from 0.01 to 200 mg/ml, more preferably 1.0 - 100 mg/ml, such, as 1.0 mg/ml (in. in. introduction) or 100 mg/ml (and. to. introduction) and aqueous buffer, such as: - phosphate - salt solution, pH of 7.4, - acetate buffers, pH of 3.2 - 7.5, preferably pH of 4.8 - 5.5 - gistidinovye buffers, pH of 5.5 - 7.0, - succinate buffers, pH of 3.2 - 6.6, and - citrate buffers, pH of 2.1 - 6.2, and, optionally, salt (Eg ., of NaCl) and/or sugar (Eg ., sucrose and trehalose) and/or other polyols (Eg ., mannitol and glycerol) for providing isotonic solution. Preferable buffered solutions of proteins are solutions, containing approximately 0.05 mg/ml polypeptide according to the invention, dissolved in 25 mm phosphate buffer, pH of 6.5, adjusted with addition of 220 mm trehalose byby. Additionally similar solutions may contain other agents, such as detergents, Eg ., 0.02% Nonidet-and-20 or Nonidet-and-80. Preparations for subcutaneous application may contain considerably large concentration of polypeptide according to the invention, such, as to 100 mg/ml or even above 100 mg/ml. However skilled in this area will be clearly testify, that above the indicated components and amount of are only one, preferable from capabilities. Skilled will be immediately evident, or same easily vyvodimy from above contained, their alternative to and versions. Also as compared to ordinary antibodies or fragments of antibodies one from large advantages application polypeptides according to the invention is, that their can be easily introduced tracks, different from parenteral administration, and easily developing their product for such introduction. For example, as described in international patent application w02004/041867, like polypeptides can be retseptirovat as preparations for oral, intranasal, RR and transdermal administration. According to the next aspect of the polypeptide according to the invention can be used in combination with device, lumps for introduction of polypeptide, such as syringe, handle - injector, micro or other device. Invention also presented methods for the production of polypeptide according to the invention, the such methods as a whole include stages: - cultivation of cells - host, containing nucleic acid, encoding polypeptide according to the invention (hereinafter: "nucleic acid according to the invention") in conditions, expression of polypeptide according to the invention; and - separation or isolation of polypeptide, of expressed byby, from culture; and - optionally further cleaning and/or modification and/or retseptirovaniya polypeptide according to the invention. Nucleic acid according to the invention can, nair ., be DNA molecule, containing coding sequence, and also regulatory sequence and optionally natural or artificial the nitrons, or can be molecule cDNA. It may have their initial codons or optimized codons, specially adapted for expression in supposed cell - or host organism - host. According to one of Embodiment of the Invention nucleic acid according to the invention is in in fact separated form according to determination of above. Nucleic acid according to the invention may also be in the form of, be present in and/or be part of vector, such as, for example, plasmid, or kosmidaYAC, which again - still may be in in fact separated form. Vector may be in fact expression vector, T. e ., vector, capable to provide expression of polypeptide Nucleic acids according to the invention can be made or allows known According to another version of the invention relates to host or cell - host, expressing or that is to express polypeptide according to the invention; and/or which contains nucleic acid, encoding polypeptide according to the invention. According to especially preferable alternative of the mandate cells - hosts are bacterial cells, yeast cells, fungal cells or cells of mammals. For production of in industrial scale preferred heterologous hosts for (industrial) production of separate up immunoglobulin variable domains - containing polypeptides and their protein drugs include strains Polypeptides according to the invention, unusable in a cell according to the description above, can developed or vnutrikletochno (nair ., in cytosol, periplasm or the harvest) followed by isolation from cells - host and optional further cleaning; or they can be produced extracellularly (secreted in medium, where cultivated cells - hosts) followed by isolation from cultural medium and optional further cleaning. Additional methods and reagents, used for recombinant production of polypeptides, such, as suitable expression vectors, methods of transformation or transfection, selection markers, methods of induction of expression of protein, culturing conditions and T. U. are known from level of technology. The same way skilled are known equipment of isolation and purification of protein, suitable for method for production of polypeptide according to the invention. Production of polypeptides according to the invention fermentation in suitable recombinant organisms - host, such as For identification of perekrestnoreaktivnykh by lrp5/lrp6 VHH-and-domains binding it is necessary was to develop and translate the row of protocols immunization Lamas: first Lamas immunized the recombinant extracellular domains proteins LRP6 and LRP5 (from human and mouse). However functional evaluation of above of said recombinant protein LRP5 shows, that only epitope binding class Wntl was is laid appropriately. And vice versa, nothing indicated on adequate laying of domain binding class lrp5 - wnt3a. Therefore for development of suitable for immunization antigens has been practiced additional operation. As bypass track Lamas immunized cells [nek 293, stable transfected human LRP5 or human LRP6. However and then can be to achieve only very weak expression of human LRP5, as at time, and at stable transfection, and also with use of different cell lines (cells [nek 293, cho and NIH-and-3t3). Therefore for achievement of sufficient expression LRP5 has been practiced more additional operation. At the end of ends, after a certain amount of unsuccessful samples and errors, this makes it developed to achieve protocol, implying stable to - transfection cells η ε-κ293MesDC-and-2, shaperonom, which should increase exogenous expression of LRP5. But even in this case, T. e ., after koekspressiiMesDC-and-2 during creation of stable transfectant LRP5 cell line, repeatedly observed instability expression of protein. This drug problem: expression LRP5 during immunization and selection could be lost. To solve this additional problem, number of passages cells, expressing LRP5, restricted as little as possible and fulfil additional sorting cells to enrichment cells, expressing LRP5. Lamas additionally immunized DNA, encoding LRP5, and DNA, encoding LRP6, with and without chaperone hMesDC-and-2 on opposite ends. Several lamam introduced additional stimuli in an attempt to enhance perekrestnoreaktivnyi immune response, to to increase chances identification perekrestnoreaktivnykh by lrp5/lrp6 VHH-and-domains. Through regular time intervals took samples immunized blood (CRC), determine serological response and prepared from isolated CRC common RNA. After immunization recombinant protein observed average serological response to LRP6, as distinct from weak serological response to LRP5. Average immune response to LRP5 observed in Lamas, immunized DNA. And vice versa, for immunizations cells observed very weak immune response. Additionally investigated synthetic library. The not to the grain, at the end of ends makes it to achieve sufficient variety of repertoire for the advancement of the next stage, as set out in example 2. Example 2: isolation of monovalent VHH-and-domains gunn), binding LRP5 and LRP6 Immediately after selection immune tissues allocate common RNA, affirmed integrity and concentration of RNA. Of these preparations RNA did samples cDNA. Nucleotide sequences, encoding VHH, amplifitsirovali from samples of cDNA a single-WS - PCR. Amplicons by 700 U. about ., specially amplified from cDNA present in sample IgG2 and of IgG3, allocate from agarose gel and subsequently used as template for "socket" PCR. Then products PCR split p α-χ50 - this expression vector, obtained from pUC119, containing a gene of resistance to ampicillin and promoter/Ac, which is followed by sequence encoding signal peptide rsh - protein in one reading frame with further site insertion VHH-and-domain. In reading frame with sequence, encoding VHH-and-domain, vector encodes with - final ICC, geksagistidinovuyu mark and rsh - protein kolifaga. After infection library clones Withdrawal of: For taking created and used library VHH-and-blast furnace fagmid. Taking into account very high interspecies homology proteins (LRP5 and LRP6 human and Lama), was unclear, provides caused by whether in Lam immune response sufficient variety of VHH-and-domains. Therefore during taking in parallel with immune libraries used two synthetic library. During taking used the following different strategy: - Change obtained from LRP5 and LRP6 tools, so to chans to detect perekrestnoreaktivnye by lrp5/lrp6 VHH-and-domains, nair ., in selecting libraries from immunized LRP5 Lamas by means of obtained from LRP6 proteins, or field and LRP5, and LRP6 during taking by synthetic libraries. - Type of change - source for taking human/murine perekrestnoreaktivnykh by lrp5/lrp6 VHH-and-domains (cross with mice reactivity such antagonists LRP5 and LRP6 allows to evaluate efficiency of, T. e ., suppression of tumor growth, and profile safety, necessary for evaluating therapeutic window in the same pre-clinical models (T. e ., in ksenotransplantatnykh models tumors mice)). - Withdrawal of "in solution" by means of recombinant proteins, to hold epitopes in natural conformation: additional obstacle was in, that recombinant proteins LRP5 and LRP6 at direct application on boards is preferable for binding lose adequate laying. Therefore recombinant proteins biotinilirovali and, confirming adequate laying of functional analyses, used for taking "in solution". - Withdrawal by means of cells, overexpressing LRP5 or LRP6, to to provide natural conformation receptors. Unexpectedly, but this present important intake, especially required for improvement of selection of domains, binding with domain LRP5 class Wnt3a, since functional data on recombinant protein have shown is insufficient correct laying of the \ up13a - binding epitope. Example 3: screening monovalent VHH After taking clones in density of 96 - them having agglutination with deep holes (volume 1 ml) and induced expression of VHH addition of iptg. According to standard procedure, produced, nair ., in wo2011/107507, prepared periplazmaticheskie extracts separate clones was carried out and their screening on binding with human LRP6 and LRP5. Initially screening periplazmaticheskikh extracts was binding analysis is preferable with the recombinant LRP6 and LRP5, which is sensitive, by interference-resistive and high-producing analysis as compared with analysis of binding based on FACS. After cleaning VHH, identified analyses is preferable, gave additional characteristic by means of analysis of binding FACS, to confirm binding of purified VHH with receptors LRP6 and LRP5 in their natural conformation. Usually expected good correlation analyses of binding by methods is preferable and FACS. However in this case VHH, preferably binding with LRP6 and LRP5 in analysis is preferable (τ. ℮ ., with high affinity to recombinant extracellular domain LRP6 or LRP5), expressed not necessarily any or very weak binding with human LRP6 and LRP5 in analysis of binding FACS, that shown on figure 2 on panel binding substances "2". Field different buffers coating (phosphate - salt buffer dulbekko and bicarbonate buffer) and blocking solutions at setting is preferable (the Marvel and BSA) avert not observed divergence. Instead was, that very weak according to is preferable svyazyvateli have shown high affinity to LRP5 and LRP6 in binding FACS using cells, expressing LRP5 and LRP6, as shown on figure 2 on panel binding substances "2". These additional data and experiments done possible withdrawal of high affine binding substances, of recognising natural conformation of two receptors. The above, has been confirmed by, that these high affine binding substance recognized in proteins LRP5 and LRP6 depending on conformation epitope, and not linear epitope. These additional irregular data and experiments done possible withdrawal of therapeutically important substances, binding LRP5 and LRP6, which should possess high affinity to LRP5 and LRP6, expressible on plasma membrane in its natural conformation. Therefore, notwithstanding on (1) low productivity analyses of binding FACS, (of II) less than noise-immune setting analysis and (of III) complexity described above, during loading from - losses of the expression of the recombinant protein at passivating cells, overexpressing LRP5, these analysis all same used for subsequent selection and characteristics of high affine VHH-and-svyazyvatelei. If briefly, cells incubated with by the breedings purified VHH (serial dilution 1:5 from 1 μμ to 1 PM in final concentration) during 1.5 hours at 4 theoretically on tablet shaker. After 5 - multiple cells washing buffer FACS, consisting of ix phosphate - salt buffer (PRF)+ 10% embryonic bull serum (ebs) + 0.05% sodium azide, their incubated on length from 30 minutes to 1 hour at 4 theoretically with polyclonal murine antibody, binding with frame section VHH, and it, binding with all Check svyazyvatelyamiLRP5 and/or LRP6. After of triple washing cells buffer FACS their incubated on length from 30 minutes to 1 hour at 4 theoretically with labelled secondary antibody (protivomyshinoe, FE) followed by threefold washing buffer FACS. Fluorescence measured by means of FACS the Array (of bd). On the basis of data about binding FACS and analysis of sequences in immune libraries and libraries synthetic origin identified in common hundred perekrestnoreaktivnykh by lrp5/lrp6 families/clusters VHH. Examples their representatives shown and are determined its sequence below. VHH expressed in If expression in Total expression of VHH in Encoding sequence inserted in expression vector rakhyuo and expressed in Cells Total expression of VHH in Encoding sequence inserted in expression vector p α-χ159 and expressed in Purification of VHH: With VHHgeksagistidinovoi mark cleaned on the Tecan EVO150 affinity chromatography with an metal (RoboColumns 100ul NickelSepharose™ 6 FF of, Atoll), eluted with column 250 mm - imidazole and then desalted to fsbd. Integrity and purity of VHH affirmed SDS-polyacrylamide gel-and--PAGE and/immunoenzymometric or western blotting - with by the detection antibodies against the ICC and VHH. Example 4: 4.1 Force binding with LRP5 and LRP6. cross-reactivity: analysis competition of with DKK1 based on FACS During characteristics perekrestnoreaktivnykh by lrp5/lrp6 monovalent VHH observed, that obtained in analysis of binding FACS data are not always correlated with force, observed in analysis gene - to the reporter and WntlWnt3a, peer the whole, from - the high speed dissociation of some VHH. Therefore there necessity in development of this additional analysis (τ. ℮ ., FACS for competition of with DKK1), which proved a more reliable with respect to selectivity and of determining force of binding, and also comparison binding with LRP5 and LRP6. Was to selection of functional VHH, binding with LRP5 and LRP6 with the same force, to one and the same concentration to achieve blockade of both receptors. Therefore identified functional VHH to Wntl and Wnt3a characterized FACS for competition of with DKK1 as follows: For analysis of competition of with DKK1 based on FACS used cells [nek 293 with stable caused human LRP5 or human LRP6. Human recombinant DKK1 (rhDKKl - of R&d of the Systems, Part Number 5439-and-Dc/the CF) added to the to cells in constant final concentration 1 nm. Cells incubated with rhDKKl and LRP5i/or 1ler6 - svyazyvatelyami (serial dilution of purified VHH 1:5) during 1.5 hour at 4 theoretically on tablet shaker. After of triple washing cells buffer FACS their incubated with biotinylated kozlinym antibody against human DKK1 (of R&d of the Systems, art. BAF1096) during 30 minutes at 4 theoretically on tablet shaker. After of triple washing cells buffer FACS their incubated with streptavidin FE (of bd Biosciences, art. 554061) on length from 30 minutes to 1 hour at 4 theoretically on tablet shaker in darkness. Cells twice washed buffer FACS, measured fluorescence by means of FACS the Array (of bd) and marked value MCF. Expected, that perekrestnoreaktivnye by lrp5/lrp6 VHH will be compete with human DKK1 behind binding with [nek 293, supering-express human LRP5, as is equal to and behind binding with [nek 293, supering-express human LRP6. Opposite to, by specific LRP5VHH would compete with human DKK1 behind binding with [nek 293, supering-express human LRP5, but not the binding with [nek 293, supering-express human LRP6 (or compete would, but very slightly (>200 [nm200) (and vice versa, the same relates to specific by LRP6VHH). As a result of this experiment dapsone displayed a, that present perekrestnoreaktivnye by lrp5/lrp6 VHH compete with human DKK1 behind binding with [nek 293, supering-express human LRP5, as is equal to and with [nek 293, supering-express human LRP6 (T. e ., WiFi client continuously tracks the value MCF at to increase the NII concentration svyazyvatelya, where complete suppression DKK1-and-binding at highest proven complies with concentration value MCF < 60). 4.2 Interspecies cross-reactivity: of a mouse and a javanese macaque to determine, whether is capable extracted panel perekrestnoreaktivnykh by lrp5/lrp6 VHH to bind with LRP5 and LRP6 from mouse and Javanese macaque, fulfil the following FACS for competition of with DKK1: Serial dilution VHH incubated with cells of [nek 293, stably expressing LRP5 mouse, LRP5 macaque, LRP6 mouse or LRP6 macaque in the presence of 1 and 0.3 nm hDKKl (concentration below copepod for mouse and macaque respectively). Binding DKK1 with cells of identify by means of biotinylated antibodies against DKK1 with streptavidin - FE as secondary detector, according to the description above. As a result have been able to demonstrate such cross reactivity. 4.3 Epitope - specific sorting Experiments by sorting fulfil for of the most strong blocking Wntl-and-signalingperekrestnoreaktivnykh by lrp5/lrp6 VHH, to determine different epitopic group. In particular, separate VHH tested ability to compete with other biotinilirovannymiVHH (T. consumed. standard VHH) the binding with receptors LRP5 and LRP6 by means of analysis based on FACS. Serial dilution separate VHH incubated on the cells [nek 293, stably expressing human LRP5 or LRP6, together with 200 PM or 500 PM biotinylated reference VHH (concentration value below value of copepod). Binding of biotinylated reference VHH with cells of determined by means of streptavidine - FE. Competition VHH with standard VHH behind binding with LRP5 and LRP6 WiFi client continuously effect was that fluorescence, measured FACS the Array. As a result of these experiments blockers Wntlpodrazdelili on three groups. More low affinity VHH not dimension owing to carry out experiments by epitopspetsificheskoi sorting for blockers of Wnt3a. 4.4 Analysis gene - to the reporter and WntlWnt3a Capacity perekrestnoreaktivnykh by lrp5/lrp6 VHH suppress of WNT-and-signaling tested functional analysis and WntlWnt3a. In this is impossible with respect to was to use installed protocol, had to make several attempts of, to be set biochemical functional analysis, such as analysis blocking Wntl/wnt3a - lrp5/lrp6: to all complexity with the recombinant proteins LRP5 and LRP6 (cm. an example 1), no functional recombinant Wntl ligand (including available in sale). Proteins of WNT contain much conserved cysteine and modified by monounsaturated fatty acid (palmitinoleinovoi acid), connected to conservative to the serine. These posttranslational modification necessary for effective signalinga and the secretion of WNT. Structural analysis have shown, that one of domains, containing lipid palmitinoleinovuyu acid, is required for binding with receptor Frizzled, results to change of conformation, routine possible interaction of WNT-and-ligands with LRP5 and LRP6 on cellular surface. Present, such that posttranslational modification necessary for functional investigations with this protein, but at the same time similar lipid posttranslational modification of very highly complicated expression and purification of these proteins (from - due to bad solubility). This therefore to become large barrier for biochemical analysis. Therefore for characteristics of purified VHH was developed functional analysis on cellular based: analysis of WNT gene - to the reporter beta - lactamase. In particular, for suppressing track Wntl cells CellSensorLEF/TCF-and-bla bar FreeStyle 293f (Invitrogen, art. κ1677) transfected human Wntl and selected clones with stable caused human Wntl. For checking suppression of track Wnt3a created cells CellSensorLEF/TCF-and-bla bar FreeStyle 293f with stable caused human Wnt3a. Cell line CellSensor® LEF/TCF - bla bar FreeStyle™ 293 has reporter gene beta - lactamase under control of induced of WNT promoter LEF/TCF, which stable is built in cells FreeStyle™ 293 (Invitrogen). So, expression of Wntl or Wnt3a in these cells leads to constitutive expression, and it, and to enzymatic activity of beta - lactamase. Therefore treatment of functional perekrestnoreaktivnymi by lrp5/lrp6 VHH should cause suppression track Wntl and Wnt3a, which will lead to suppression of enzymatic activity of beta - lactamase. For analysis of 1e06/ml cells with caused Wntl or Wnt3a seeded on 384 - alveolar plotting board for tissue cultures and incubated during night at 37 theoretically. Next day prepared serial dilution of various perekrestnoreaktivnykh by lrp5/lrp6 VHH and added to the to cells in presence of LiCl in final concentration of 10 nm. As positive control to cells added to the DKK1 in final concentration of 200 nm. Treatment DKK1 led to the full suppression track Wntl and Wnt3a and therefore to the full suppression of enzymatic activity of beta - lactamase. Cells incubated during night at 37 theoretically. Next day enzymatic activity beta - lactamase measured according to instructions of a manufacturer of (Invitrogen, art. k1085). For fluorescent emission obtained value at 460 nm and 530 nm by means of standard fluorescent tablet Rieder, and ratio of emission at 460/530 nm applied on graph relative to said treatment. Efficiency expected relative to positive control (DKK1 in final concentration of 200 nm). The whole selected twelve perekrestnoreaktivnykh by lrp5/lrp6 blockers of Wntl, complete efficiency and force of which was larger, than 50 nm. Identified fourteen perekrestnoreaktivnykh blockers of Wnt3a, mainly weak. Only one blocker Wnt3a proved good force (below 5 nm). 4.5 Analysis of phosphorylation of Wntl and Wnt3a Construction of the powerful and effective samples from each group of blockers of Wntl, and also construction of the powerful and effective blockers Wnt3a further tested in analysis of phosphorylation of LRP5 and LRP6, dependent from Wntl and Wnt3a. In analysis of phosphorylation of used cells CellsensorLEF/TCF 293f from Invitrogen (art. k1677), to - transfected expression vectors, coding items or Wntl, or Wnt3a. As formation of complex of WNT-and-Frizzled-and-LRP5 or - LRP6 leads to phosphorylation LRP5 or LRP6 and subsequent descending transmission of signal, for measuring such transmission can be used quantitative determination of phosphorylation of. To produce specific by LRP5 and LRP6 readings, cells subjected lysis and fulfil the immunoprecipitation by means of antibodies, selective by LRP5 or LRP6 (directed against intracellular domain of two receptors). Phosphorylated LRP5 or LRP6 identify Western - blotting using polyclonal antibodies against phospho - 1ltr6 (serl490) (the Cell Signaling the Technology), vyyavlyayushchego phosphorylated proteins and LRP5, and LRP6. Sampled panel purified VHH, blocking Wntl and Wnt3a, containing at least one representative VHH from each group, tested in final concentrations from 10 to 100 nm. In particular, cells incubated during night in the presence of blocking VHH before lysis cells and by the immunoprecipitation LRP5 and LRP6. Efficiency VHH, blocking Wntl and Wnt3a, at freezing of phosphorylation of LRP5 and LRP6 expected quantitative evaluation strips Western - blotting as compared with positive control (DKK1, final concentration 1 mcm). Perekrestnoreaktivnym by lrp5/lrp6 VHH-and-domains gave further evaluation of expression and cleaning in Thermal stability monovalent perekrestnoreaktivnykh by lrp5/lrp6 VHH determined fluorescent analysis of thermal shift (exchange) by means of Lightcycler (Roche Airport). VHH incubated at different values of pH in the presence of the Orange Sypro, of a temperature gradient. After deployment the laying, caused by heat, strip down hydro fobnye sections proteins, with which binds Sypro the Orange, that leads to agreed to to increase the intensity of fluorescence (vozb/EM=465/580 nm). Bending point on the first derivative curve of fluorescence intensity serves as measure of melting point (Tf). In all VHH Tf at enhanced to increase the NII pH and it was equalized at pH 6, which is the typical for VHH circuit Tf. For perekrestnoreaktivnykh by lrp5/lrp6 VHH-and-blockers of Wntl and VHH-and-blockers of Wnt3a received average value of 82 theoretically at pH 7. By method of analytical exclusion chromatography of investigated potential possibility of aggregation and multimerization of VHH to LRP5 and LRP6. For this purpose 8 mcg of purified sample VHH in concentration of 0.5 mg/ml injected with the aid of equipment Dionex the Ultimate 3000 in column Agilent the SEC-and-3. The mobile phase applied of L-argininovyi buffer (10 mm phosphate, 300 mm-Arg of HCl, pH of 6.0) on flow rate 1 ml/min. Neither of VHH to LRP5 and LRP6 not that large problems with thrombicytes during ekhanaliza: profiles pointed to more than 95% monomers in most specimens. Perekrestnoreaktivnye by lrp5/lrp6 VHH for Wntl and Wnt3a used as building blocks for creating biparatopnogo construct, pictured on figure 1. as method for extending half-time used genetic fusion with VHH, binding with serum albumin. Three building unit (Wntl-blocking agent-, Wnt3ablokator and albuminsvyazyvayushchii) unite the flexible linker. VHH formulated in The best results tangent force by combined analysis gene - to the reporter and WntlWnt3a received at insertion into VHH, binding human serum albumin/HAS, in the middle of. Used 35-and-GSlinker, and VHH-blockers and WntlWnt3a placing the in preferable order. With the aim of selecting optimal VHH-and-svyazyvatelei and combinations of svyazyvatelei created library, in which VHH, binding human serum albumin/HAS, placed between lrp5/lrp6 Wntl-and-Wnt3ablokatorami. In particular, in library used panel high affine svyazyvatelei with large force and effectiveness according to analysis or WntlWnt3a (analysis gene - to the reporter and phosphorylation), to create biparatopnye constructs with prolonged period half-, designed, as shown on figure 1. after expression in Analysis gene - to the reporter and WntlWnt3a: Analysis gene - to the reporter and WntlWnt3a fulfil according to the description in example 4.4, in the presence of final concentration HAS 30 mcm. Purified biparatopnye by lrp5/lrp6 constructs tested 12 dilutions, starting from 2.5 mcm. Most constructs shown high force - from 1.7 nm to 0.16 nm and complete efficiency in both reporter analysis, that reflected in the table IV below. Sequence installed there individual VHH-and-domains, inhibiting Wntl and Wnt3a, are given in table V below: Table IV: Force and essektivnost selected biparatopnykhperekrestnoreaktivnykh by lrp5/lrp6 unn - constructs with prolonged period in half-analysis gene - to the reporter in the presence of HAS Table of V: Sequence VHH-and-domains. given in table IV (. Example 6: optimization of sequences VHH and VHH -constructs Optimization of sequences - this process, in which the parent sequence is subjected to mutations, to make its more similar with human embryonic consensus sequence IGHV3-and-IGHJ. For example, specific amino acids frame sections (except for so called distinguishing residues) are replaced with their human analogs so, to preserve structure, activity and stability of the protein. These mutations may be divided into the following category : 1. Standard: optimization of sequences in these positions should not substantially change stability, activity or affinity VHH, therefore their all is changed simultaneously, to produce base version. 2. Unique: unknown, as optimization of sequences in these positions affect on stability, activity or affinity VHH, therefore their examined individually on the basis of base versions. Known, that are the critical residues important for stability, activity and affinity VHH, therefore their is not changed. In addition, amino acids CDR-, for which there is experimental confirmation the, that they sensitive to posttranslational modifications (PEJ), discoloration so, to inactivate the site PEJ, it before ever touching the structure, activity and stability of the protein. Most frequently posttranslational modification, described for antibodies and VHH, listed in the table VI below. Sensitivity VHH to posttranslational modifications analyzed by research with forced load, of a row of standard conditions, including treatment of H2 Exhaust gases for evaluating oxidation of methionine, high temperature, high pH and for long-term storage for evaluating dezamidirovaniya asparagine and isomerization of aspartate. Percentage share of oxidation, dezamidirovaniya and isomerization of measured according to standard procedures and compared with reference samples (VHH, stored at -20 theoretically). For determination of potentially sensitive residues fulfil analysis of integral proteins by reversed - phase chromatography (ofkh) and mapping peptides by mass - spectrometry (ms). If after stress - dough VHH postoperative period posttranslational modification, corresponding to (- MR) amino acid (s -) subjected mutations. Table VI of: Potential posttranslational modification and potentially launching their motives As a result described above constructs introduced several mutations, the report among other things three construct, shown in the table III above, selected for further characteristics Example 7: After optimization of sequences VHH three biparatopnykhperekrestnoreaktivnykh by lrp5/lrp6 VHH-construct with prolonged period half-it is recombinant expressed and cleaned, after which characterized by means of row functional and biophysical analysis, described below. Binding with human LRP5 and LRP6 determined on the cells FACS analysis, as shown on shapes behind and of members. In particular, binding with human LRP5 tested on cells [nek 293 with stable caused human LRP5. For binding with human LRP6 used cells [nek 293 with stable caused human LRP6. Cells incubated with by the breedings LRP5ievrb - svyazyvatelei (serial dilution svyazyvatelei 1:5, corresponding final concentration of, indicated on shapes behind and of members) during 1.5 hour at 4 theoretically on tablet shaker. After 5 - multiple cells washing buffer FACS, consisting of ix PRF (Invitrogen, art. 141190 - 094) + 10% ebs (the Sigma, art. F7524) + 0.05% sodium azide, their incubated during 1 hour at 4 theoretically with polyclonal murine antibody, binding with frame section VHH. After of triple washing cells buffer FACS their incubated during 1 hour at 4 theoretically with labelled secondary antibody (protivomyshinoe, FE (115 - 116 - 071)) followed by threefold washing buffer FACS. Fluorescence measured by means of FACS the Array (of bd). Bonding with human LRP5 and LRP6 at highest concentration of proven value complies MCF > 600. Negative control consisted of nenatselennogosvyazyvatelya (VHH-construct, binding with bacterial protein, which in cells [nek 293 not is expressed). As shown respectively on figure behind and figure of members, bonding with human LRP5 and LRP6 value complies MCF > 600 and > 1600, at highest concentration of proven three biparatopnykhperekrestnoreaktivnykh by lrp5/lrp6 VHH-and-constructs with prolonged half-period. These data is confirmed, that formatted biparatopnye binding molecules with optimized sequence in its natural conformation in system analysis on cells are as with human LRP5, and with human LRP6. Value copepod binding with hLRP5 and hLRP6 are given in table VII below. Table of VII: Value eszo binding with human LRP5 and LRP6. Force and efficiency three biparatopnykhperekrestnoreaktivnykh by lrp5/lrp6 VHH-and-constructs additionally analyzed analysis competition of with DKK1 based on FACS, described in example 4.1. [Nek 293 cells with stable caused human LRP5 or human LRP6 incubated with serial by the breedings perekrestnoreaktivnykh by lrp5/lrp6 VHH-and-constructs (serial dilution 1:5, corresponding final concentration of, indicated on shapes 4a and 4B). Perekrestnoreaktivnye by lrp5/lrp6 VHH compete with human DKK1 behind binding with cells [nek 293, supering-express human LRP5, as is equal to and behind binding with cells [nek 293, supering-express human LRP6, as shown respectively on shapes 4a and 4B. Complete suppression of binding DKK1 reached at the highest checked concentrations (>10 nm), that corresponds to values of MCF < 60. Opposite to, by specific LRP5VHH would compete with human DKK1 behind binding with [nek 293, supering-express human LRP5, but not the binding with [nek 293, supering-express human LRP6 (or compete would, but very slightly (>200 nm) (and vice versa, the same relates to specific by LRP6VHH). As a result of this experiment dapsone displayed a, that present perekrestnoreaktivnye by lrp5/lrp6 VHH compete with human DKK1 behind binding with [nek 293, supering-express human LRP5, as is equal to and with [nek 293, supering-express human LRP6 (T. e ., WiFi client continuously tracks the value MCF at to increase the NII concentration svyazyvatelya, where complete suppression DKK1-and-binding at highest proven complies with concentration value MCF < 60). Value ic50 for competition of DKK1 behind binding with hLRP5 and hLRP6 with three perekrestnoreaktivnymi by lrp5/lrp6 VHH-and-by the constructs are given in the table VIII below. These data is confirmed binding three perekrestnoreaktivnykh by lrp5/lrp6 VHH-and-constructs with human LRP5 and with human LRP6, and shown very similar affinity (here as determined by values of 1c 50 in the analysis of competition of with DKK1) of two receptors. Moreover, data are strengthened by position, that formatted biparatopnye binding molecules with optimized sequence in its natural conformation are as with human LRP5, and with human LRP6. Table of VIII: Value IC^nDKK1 with competition of the binding with human LRP5 and LRP6. certain analysis of binding FACS analysis of competition of with DKK1 f013500571 f013500575 f013500720 7.3 Combined analysis of gene - to the reporter and WntlWnt3a Force and efficiency formatted biparatopnykh binding molecules with optimized sequence analyzed by combined analysis gene - to the reporter and WntlWnt3a, to provide functional check of blockers of Wntl and Wnt3a in one analysis. Combined analysis of gene - to the reporter and WntlWnt3a is based on described in example 4.4 analysis, changes with the following protocol. 1E06/ml cells with caused Wntl seeded on 384 - alveolar plotting board for tissue cultures and treated recombinant human Wnt3a (rivers. cel. Wnt3a: of R&d of #5036-and-Wn/the CF), after that cells are incubated during night at 37 theoretically. Next day prepared serial dilution of various biparatopnykhperekrestnoreaktivnykh by lrp5/lrp6 VHH and added to the to cells in presence of LiCl in final concentration of 10 nm. As positive control to cells added to the DKK1 in final concentration of 200 nm. Treatment DKK1 led to the full suppression combined track Wntl and Wnt3a and therefore to the full suppression of enzymatic activity of beta - lactamase. Cells incubated during night at 37 theoretically. Next day measured enzymatic activity beta - lactamase according to the instructions of a manufacturer. As specified in example 4.4, for fluorescent emission obtained value at 460 nm and 530 nm by means of standard fluorescent tablet Rieder, and ratio of emission at 460/530 nm applied on graph relative to said treatment. The ratio value fluorescence [460/535nm], designated on figure 5a as "base line", corresponds to complete inhibition of track Wntl and Wnt3a, a certain treatment with positive control (DKK1 in final concentration of 200 nm). The ratio value fluorescence [460/535nm], designated as "Wntl", corresponds to activation of only track Wntl, defined by cells, sverkhekspressiruyushchimWntl (τ. ℮ ., not treated recombinant human Wnt3a). The ratio value fluorescence [460/535nm], designated as "Wntl + Wnt3a", corresponds to combined activation of tracts and WntlWnt3a, certain by treatment of cells, overexpressing Wntl, recombinant human Wnt3a. As shown on figure 5a, complete suppression of (T. e ., ratio of fluorescence [460/535nm], corresponding to base line) achieved by treatment of three perekrestnoreaktivnymi by lrp5/lrp6 formatted biparatopnymi coupling binding molecules with optimized sequence. In addition, was also considerable force, as shown in table IX below at values ic50. Table of IX: Value MPP suppression of tracts and WntlWnt3a in combined analysis and WntlWnt3a gene - to the reporter Then force and efficiency perekrestnoreaktivnykh by lrp5/lrp6 formatted biparatopnykh binding molecules with optimized sequence compared with known first of molecules, coupling LRP6, mentioned in wo2011/138391 and wo2011/119661: In wo2011/138391 have been described are multivalent antibodies, binding with LRP6 and inhibiting interaction with ligand as propeller 1 (nair ., Wntl), and propeller 3 (nair ., Wnt3). These multivalent antibodies, binding with LRP6, are biparatopnymi molecules, coupling LRP6, consisting of antibodies of IgG as the first binding receptor domain and fragment scFv antibody as the second binding receptor domain, the antibody IgG and scFv antibody fragment are connected linker. In wo2011/138391 communicates, that all binding LRP6 molecules have approximately equal force through reporternomu analysis and WntlWnt3a (Figure 18 wo2011/138391). Therefore for comparative experiments can be to select any of these multivalent molecules, binding with LRP6. As therefore first connection for comparing was classified to use construct "901" (denoted MOR08168IgGlLALA 6475 scFv antibody; also shown on Figure 27 wo2011/138391). In wo2013/067355 shown derivatives of this construct "901". More specifically invention describes compounds 801t and 802t (cm. information on temperature control system. 132 description), having two yarb - binding domain scFv antibody fragment plus, drives enhanced half. As, along the whole visibility, 801t and 802t have the same force and biophysical characteristics in vitro of, for the experiments described below took only one of them - version 802t. In wo2011/119661 invention describes antibodies bispecific, binding with LRP6 and suppress transmission signal by many to the isoform of WNT. These bispecific antibodies against LRP6 are with two different sections LRP6 and inhibit signal transmission, inducible isoforms of WNT, among them Wntl and Wnt3a. For producing said bispecific antibodies against LRP6 used construction according to principle of "projections - vovpadiny" (Atwell Table Of X: value IC^n suppression of tracts and WntlWnt3a in analysis Wntland Wnt3a gene - to the reporter Force and efficiency biparatopnykhperekrestnoreaktivnykh by lrp5/lrp6 VHH-and-constructs with prolonged period half-compared with biparatopnoi molecule MOR08168IgGlLALA 6475 scFv antibody, binding LRP6, with of bispecific molecule Knob ns yw2 10.09 against LRP6 and with of bispecific molecule 802t against LRP6, using combined analysis of gene - to the reporter and WntlWnt3a. As shown on figure V, complete suppression of (T. e ., ratio of fluorescence [460/535nm], corresponding to base line on figure V) achieved by treatment of Knob ns yw2 10.09 (bispetsificheskim hybrid antibody of IgG byby heavy chain yw211.31.62 and yw2 10.09) also, as perekrestnoreaktivnoi by lrp5/lrp6 formatted biparatopnoi binding molecule with optimized sequence f013500571. However f013500571 proved greater force, as indicated in the table of the XI below. At the same time biparatopnye molecules MOR08168IgGlLALA 6475 scFv and 802t, binding LRP6, have shown is insufficient complete suppression of Wntl and Wnt3a (T. e ., ratio of fluorescence [460/535ημ] considerably above base line on figure V and on figure 5c, respectively). These data indicate then, that both biparatopnye molecules MOR08168IgGlLALA 6475 scFv and 802t, binding LRP6, have considerably smaller efficiency at suppression Wntl and Wnt3a as compared with f013500571. Therefore described for further experiments Table of the XI: Value ICsn suppression of tracts and WntlWnt3a in combined analysis and WntlWnt3a gene - to the reporter Capacity biparatopnykhperekrestnoreaktivnykh by lrp5/lrp6 unn - constructs with prolonged period half-suppress active of WNT-and-signaling additionally described by means of cell lines with active of WNT-and-signalingom, described earlier (Bafico 28 (21): 2163 - 72). If briefly, line of cancer cells with active of WNT-and-signalingom, Pa - 1 and PA-TU-and-8988s, seeded on 12 - lunkovye boards and treated by perekrestnoreaktivnymi lrp5/lrp6 VHH-and-by the constructs in final concentration of 1 mcm on throughout two days. Capacity suppress of WNT-and-signaling identify by inhibition of mRNA expression Axin2, endogenic gene - target of WNT. Analysis of expression kptsr fulfil using standard techniques RNA: RNA recovery was by means of QIAGENRNeasy the Mini KIT is according to protocol of QIAGEN; synthesis of cDNA by means of SuperscriptVILOcDNASynthesis KIT is (Invitrogen, art. 11754050) and kptsr - by means of TaqManGene expression command Assay with primers/probes Axin2TaqMan (Hs00610344_mlAxin2 for FAM, the Life Technologies for) and also of c eucaryotic 18s endogenic control the VIC-and-MGB (4319413 ε-- 1307061, AutoMARK Biosystems). As shown on figure 6a, and cancer cells the PA-te18988s, and Pa - 1 in treatment of three biparatopnymiperekrestnoreaktivnymi by lrp5/lrp6 VHH-and-by the constructs with prolonged period half-have shown considerable WiFi client continuously tracks the relative levels of mRNA Axin2 (τ. ℮ ., of normalized by endogenous control) as compared with untreated (control) cells. These data show ability of biparatopnykhperekrestnoreaktivnykh by lrp5/lrp6 VHH-and-constructs with prolonged period half-suppress of WNT-and-signaling in cell lines with active of WNT-and-signalingom. In addition, investigated the effect of blockade of WNT-and-signalinga on viability of cells of cancer cell lines the PA-tu8988s and YAPC, about which earlier reported, that their proliferation depends on active of WNT-and-signalinga (Jiang offer In addition, for f013500571 as compared with 802t on lines of cancer cells the PA-tu8988s (Figure 6 with) and YAPC (Figure 6 d of) appreciated dependence of viability of cells from dose. In treatment of f013500571 identified dose-dependent WiFi client continuously tracks the cell viability. Unlike it, in treatment of comparison compound 802t influence on viability of cells not discovered in one of lines of cancer cells the PA-tu8988s and YAPC. These data demonstrate, that biparatopnyeperekrestnoreaktivnye of NO lrp5/lrp6 VHH-and-constructs with prolonged period half-have best effect as compared with 802t. Perekrestnoreaktivnye by lrp5/lrp6 biparatopnyeVHH-and-constructs/binding molecules with prolonged period half-additionally described Implemented conducts experiments, designed to determine, whether suppress these binding molecules growth of tumor Transgenic expression of WNT-and-ligands by means of LTR--and-enhancer of virus of breast tumor mice (promoter MMTV) in mice leads to extensive hyperplasia ducts with subsequent by the adenocarcinoma of mammary gland in transgenic (Tg) mice to 6 - month age. These mammary gland tumor called induced glucocorticoids caused of WNT-and-ligands and by their indices similar tnrmzhopukholyam, including expression of epithelial and mesenchymal markers (like basal phenotype) and active of WNT-and-signaling, assessed by intracellular localization of beta - katenina. In particular, breast tumor in transgenic mice MMTV-and-of WNT-and-1 depend on Wntl. In the same art, reported, that blocking activity of WNT by means of soluble receptor of WNT, including cysteine-rich domain (btsd) Frizzled8, fused with human fn-and-domain (f8crdhfc) (DeAlmeida Perekrestnoreaktivnye by lrp5/lrp6 biparatopnyeVHH-and-constructs with prolonged period half-1.20 mice twice per week, but in higher doses, T. e ., 30 and 45 mg/kg (Figure 7 with), from - the data, obtained for this compound in experiments described above Table khpa:Essektivnost f013500571 Table khpb:Essektivnost f013500720 Table khpv:EssektivnostKnob ns yw2 10.09 introduction of twice per week. Results of this experiment shown also on Figure 7c. As can be understand by figures 7a - 7c and tables khpa - khpv, treatment biparatopnymiperekrestnoreaktivnymi by lrp5/lrp6 VHH-and-by the constructs with prolonged period half-(f013500571 in a dose of 4 and 10 mg/kg and f013500720 in a dose of 1 mg/kg by the curve 2p/week) actually resulted tumor regression (T. e ., suppression of growth tumor (pro) > 100%, which corresponds to reduction of tumor; decreased volume of the tumor at the end of experience by efficiency of as compared with tumor volume at the beginning of experience), the are not found significant changes of body mass (<10%) and on histopathological analysis of gastrointestinal tract are not found features. Is important, that unlike it, in treatment of ytrb - specific svyazyvatelemKnob ns yw2 10.09 not observed any regress tumors, even in maximum introduced mice by plot To additionally it possible to study observed in efficiency of difference experiment described above Table XIID:EssektivnostKnob ns yw2 10.09 introduction of twice or three times a week, soglazno said. As seen by data, given in the table XIID, in this setting also not reached considerable amplification effect in plan pro. Other words, these experiments, data and results clearly indicate more high efficiency biparatopnykhVHH-and-constructs with prolonged half-period as compared with Knob ns yw2 10.09, and also unprecedented ability of polypeptides according to the invention not only release growth of tumor, but even cause its reduced. Reduced tumor (T. e ., regress tumor) is, outside deserves the doubts, desirable therapeutic effect (T. e ., effectiveness) in treatment of cancer patients patients. In the same art, in clinical investigations drug, causing regression of tumor, which to the full patomorfologicheskomu response (CSPs), positively lead to considerable improvement of survival rate without progressing and common survival rate in case of large unsold medical demand, such, as at breast cancer. Described above comparative examples also demonstrate, that perekrestnoreaktivnye by lrp5/lrp6 biparatopnyeVHH-and-constructs with prolonged period half-not only are better by their indices binding, such as affinity or value of to, but they also have large advantages and better characteristics in conditions of Then studied, can whether soedineniemszh081681§shaa 6475 scFv antibody to provide the same effect. For this purpose fulfilled the following examination tolerance in vivo in mice: compound MOR08168IgGlLALA 6475 scFv antibody 1.20 So, biparatopnyeperekrestnoreaktivnye by lrp5/lrp6 VHH-and-constructs with prolonged period half-have the advantage with respect to therapeutic window; T. e ., they cause regression of tumor without significant changes of body mass (<10%) and without features, which would identified histopathological analysis of gastrointestinal tract. To additionally evaluate influence of perekrestnoreaktivnykh by lrp5/lrp6 biparatopnykhVHH-and-constructs/binding molecules with prolonged period of half-on of WNT-and-signaling, at the end of as described example 9 experience by efficiency of allocate tumor. In particular, tumor allocate through 16 hours after the last injection of compounds or control treatment. Suppression of WNT-and-signalinga determined by WiFi client continuously agreed to mRNA expression Axin2 in tumors, analyzed according to the description in example 8. ratio change mRNA expression Axin2 relative to control group is indicated on figure 8a for efficiency of f013500571 Table XIIIA: WiFi client continuously tracks the mRNA expression Axin2 in tumors in treatment of F013500571, data field figures 7a and 8a, Table khshb: WiFi client continuously tracks the mRNA expression Axin2 in tumors in treatment of F013500720. Data field figures 7B and 8B, As seen by figures 8a and 8B, and also tables khsha and khshb, in tumors, treated molecules, perekrestnoreaktivno coupling lrp5/lrp6, the postoperative period considerable WiFi client continuously tracks and dose-dependent reduction of (in particular, for treatment of f013500571) mRNA expression Axin2 in the control group. These results are make assume, that molecules, perekrestnoreaktivno binding lrp5/lrp6, actually are able to suppress growth of tumor, suppressing of WNT-and-signaling in tumor cells. And. and of Bentley w ε-.: to Monitoring GFP--and-operon the Fusion protein expression command during the High the cell densitycultivation care of Escherichia coli the Using the AN of an line the Optical the Sensor. Biotechnology and sort Bioengineering, 65:54 - 64. (1999)) or are equivalent to them. Nevertheless, addition medium such amino acids, as isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine, or complex components, such as soya peptone or yeast extract, can be useful. Enzymatic process fulfil semicontinuous method. Conditions: temperature 30 - 40 theoretically, pH of 6 - 7, 5, dissolved oxygen is more than 20%. After consumption of initial carbon source culture fuel above this (or equivalent) nutrient medium. At accumulation in fermenter 40 - 90 g/l of dry weight of cells culture induced adequately inductor, corresponding used promotory system (nair ., iptg, lactose, arabinozoi). Induction can be performed complete pulse induction or as partial induction, by delivering corresponding inductor in fermenter for prolonged time. Phase production should last not less than 4 hours. Cells separated by centrifugation in rotor centrifuges, tubular centrifuges or plate separators, culture supernatant is poured off. Any of above described biparatopnykh polypeptide constructs according to the invention can be selected for production of pharmaceutical preparation for subcutaneous administration following composition of: Medicinal substance: 100 mg/ml (from 1 to 3 nmol/ml) acetate buffer: 25 mm Trehalose: 220 mm Ammonium-and-20: 0.02% Medicinal substance is introduced in solution composition above said composition, sterilized and stored at 2 - 8 theoretically. Example 13: pharmaceutical application article on Manufactured in example 11.2 solution is introduced to the patient, requiring in this, such as a man, patient cancer, sensitive to inhibitors of WNT-and-signalinga, by intravenous infusion (in a dose of from 100 to 200 mg) with interval of from two to four weeks. Example 14: effect of suppression of the \ ¥ U! 3a - signalinga on release of pro-inflammatory cytokines dendritic cells in analysis Human dendritic cells of origin (Mo - DC) created as follows: mkpk cultured on medium-x-vivo of with addition of 50 ng/ml of GM-CSF and 50 ng/ml of IL-and-4. After 24 h of culturing supernatant carefully selected and substituted medium-x-vivo of with addition of the same of GM-CSF and IL-and-4. On the fourth day supernatant carefully selected and substituted medium-x-vivo of only in presence of lps or in combination with human Wnt3a or with human Wnt3a and molecules, perekrestnoreaktivno coupling lrp5/lrp6. Next day supernatants collected and subjected analysis TNF-alpha - by method is preferable according to the instructions of a manufacturer. As earlier reported (Oderup These data demonstrate, that formatted biparatopnye binding molecules with optimized sequence are able to restore secretion of TNF-alpha - treated in Wnt3a dendritic cells, thereby suppressing inhibitory effect of WNT on dendritic cells. It should be mentioned, that blocking track of WNT in dendritic cells of the microenvironment of the tumor may be potential therapeutic approach to disturbance opukholeoposredovannogo suppression of immunity and of addition antitumor immunity. That it possible to study the effect of DC on T - cells (effector T - cells), pretreated Wnt3a DC, with or without molecules, binding perekrestnoreaktivno lrp5/lrp6, cultured together with T - cells, isolated from mkpk, as described earlier (Oderup and others. "The Canonical and sort noncanonical of WNT proteins the Program dendritic the Cell responses for Laptops tolerance". Of j Immunol. 2013; 190 (12): 6126 - 34). Through 3 days joint cultivation DC/T - cells collected supernatants and subjected their analysis on IFN - gamma by method is preferable according to the instructions of a manufacturer. Secretion IFN - gamma is a marker activation of T - cells. As shown on figure 0.9B, the \ up13a - mediated suppression of DC leads to WiFi client continuously nnoi secretion IFN - gamma T - cells (suppression of function of T - cells), which fully is reduced by treatment of molecules, perekrestnoreaktivno coupling lrp5/lrp6. In this these data show, molecules that, perekrestnoreaktivno binding lrp5/lrp6, inhibit inhibitory effect of WNT on dendritic cells, results restoration of function of T - cells. Known, that constant activation/stimulation of T - cells causes final differentsiirovanie, leading to istoshchennomu phenotype T - cells, progressive loss of function of T - cells. Therefore is provided, that influence of molecules, binding perekrestnoreaktivno lrp5/lrp6, on T - cells, mediated activation of DC, can be limited by depletion T - cells. Expected therefore, that combined treatment, in which introduction of molecules, binding perekrestnoreaktivno lrp5/lrp6, merged with by administration of inhibitor of immune of control points, blocking exhausted T - cells, should help to activate and maintain function T - cells, thereby changing the micro-environment tumour and maintaining therapeutic effect molecules according to the invention. <110> BERINGER INGELHEIM GOLDEN SANDS RESORT GMBH <120> BIPARATOPNYEPOLIPEPTTHE IDES - ANTAGONISTS OF SIGNAL TRANSMISSION OF WNT IN TUMOR CELLS <130> P12-AND-0401/WO/1 <160> 47 <170> BiSSAP 1.2 <210> 1 <211> 5 <212> Protein <213> Artificial sequence <22 0> <223> CDRlWntl-and-333E06mod <400> 1 Of Thr tug of Thr-Val-Gly 1 5 <210> 2 <211> 17 <212> Protein <213> Artificial sequence <22 0> <223> CDR2Wntl-and-333E06mod <400> 2 -Ala lie of Arg Arg-Gly Ser-Ser-of Thr-Tyr-Tyr-Ala-Asp-Val-Gly Ser-Lys-15 10 15 <210> 3 <211> 14 <212> Protein <213> Artificial sequence <22 0> <223> CDR3Wntl-and-333E06mod <400> 3 Asp-of Thr Arg of of Thr-Val-Ala-Leu-Leu-Tyr-Tyr-Tyr-Asp Arg of Gin 15 10 <210> 4 <211> 5 <212> Protein <213> Artificial sequence <22 0> <223> CDRlWntl-and-333g06 <400> 4 Ser-met polypeptide-Gly-Tyr-Ala 1 5 <210> 5 <212> Protein <213> Artificial sequence <22 0> <223> CDR2Wntl-and-333g06 <400> 5 lie-Ala Arg Ser--Gly Arg of Thr-Tyr-Tyr-Ala-Asp-Val-Gly Ser-Lys-15 10 15 <210> 6 <211> 19 <212> Protein <213> Artificial sequence <22 0> <223> CDR3Wntl-and-333g06 <400> 6 -Ala Arg-Val Arg of Ser-Ser-of Thr Arg of Tyr-Asn-of Thr-Gly of Thr teterapeptide Trp teterapeptide Trp 15 10 15 teterapeptide Trp Glu-Tyr- <210> 7 <211> 5 <212> Protein <213> Artificial sequence <22 0> <223> CDRlWntl-and-332D03mod <400> 7 Of Arg-Tyr met polypeptide of Thr-Gly 1 5 <210> 8 <211> 17 <212> Protein <213> Artificial sequence <22 0> <223> CDR2Wntl-and-332D03mod <400> 8 lie-Ala-Val Arg of Ser--Gly-Gly Ser-of Thr-Tyr-Tyr-Ala-Asp-Val-Gly Ser-Lys-15 10 15 <210> 9 <211> 20 <212> Protein <213> Artificial sequence <22 0> <223> CDR3Wntl-and-332D03mod <400> 9 Asp-Arg-Gly of Arg-Gly-Glu-Asn-Tyr lie-Leu-Leu-Tyr Ser-Ser--Gly 15 10 15 Of Arg tug Glu-tug 20 1 5 <400> 11 -Ala lie Ser-teterapeptide Trp Ser--Gly-Gly Ser-of Thr-Tyr-Tyr-Ala-Asp-Val Ser-Lys-1 5 10 15 Ser-of Pro lie of Pro-Tyr-Gly-Leu-Leu Ser-Arg Arg of Asn-Asn-Tyr-Asp-1 5 10 15 Ser-met polypeptide-Gly-Tyr-Ala 1 5 <400> 14 -Ala lie Ser-teterapeptide Trp Arg of Ser-Ser-of Thr-Tyr-Tyr-Gly-Ala-Asp-Val-Gly Ser-Lys-15 10 15 <210> 15 <211> 16 <212> Protein <213> Artificial sequence <22 0> <223> CDR3Wnt3a-and-3 67 β-10 <400> 15 Of Pro-Asp of Arg-Tyr-Gly-Gly-Val-Ala-Tyr-Val-Ala-Tyr-Tyr Ser-Glu-Tyr-15 10 15 <210> 16 <211> 5 <212> Protein <213> Artificial sequence <22 0> <223> CDRlAlbll <400> 16 Ser-Phe-met polypeptide of Ser-Gly 1 5 <210> 17 <211> 17 <212> Protein <213> Artificial sequence <22 0> <223> CDR2Albll <400> 17 Ser-lie of Ser-Gly-Gly Ser-Ser-Asp-of Thr-Leu-Tyr-Ala-Asp-Val-Gly Ser-Lys-15 10 15 <210> 18 <211> 6 <212> Protein <213> Artificial sequence <22 0> <223> CDR3Albll <400> 18 -Gly-Gly-Leu Ser-Ser-of Arg 1 5 <210> 19 <211> 123 <212> Protein <213> Artificial sequence <22 0> <223> VHH-and-domain Wntl-and-333E06mod <210> 20 <211> 128 <212> Protein <213> Artificial sequence <22 0> <223> VHH-and-domain Wntl-and-333g06 <210> 21 <211> 129 <212> Protein <213> Artificial sequence <22 0> <223> VHH-and-domain Wntl-and-332D03mod <400> 21 Gin-Ala-Val-Leu-Val-Gly-Gly-Gly-Leu Glu-Ser-Gin-Val Gly-Gly 1 5 10 15 Ser-of Arg-Leu-Leu Ser-is Cys-Ala-Ala-Gly-Leu Ser-of Thr Phe-Ser-of Arg-Tyr 20 25 30 Of Thr met polypeptide-Gly teterapeptide Trp Phe-Arg of Gin-Ala Gly Lys-Arg-Glu-Phe--Val 35 40 45 lie-Ala-Ala-Val Arg of Ser--Gly-Gly Ser-of Thr-Tyr-Tyr-Ala-Asp-Val Ser- 50 55 60 Of Arg-Gly Lys-Phe-of Thr lie Ser-of Arg Asp-Asn-Ser-Lys-Asn-of Thr-Val-Tyr 65 70 75 80 -Leu Gin met polypeptide Ser-Asn-Leu is of Arg of Pro Glu-Asp-of Thr-Ala-Val-Tyr-Tyr is Cys 85 90 95 -Ala-Ala-Asp Arg-Gly of Arg-Gly-Glu-Asn-Tyr-Leu-Leu-Tyr Ser-lie 100,105,110 Of Ser-Gly Arg of Tyr-Glu-Tyr-teterapeptide Trp-Gly Gin of Thr-Gly-Leu-Val-Val Ser- 115,120,125 Ser- <210> 22 <211> 126 <212> Protein <213> Artificial sequence <22 0> <223> VHH-and-domain wnt3a - 093a01 <400> 22 <210> 23 <211> 125 <212> Protein <213> Artificial sequence <22 0> <223> VHH-and-domain wnt3a - 367b10 <400> 23 <210> 24 <212> Protein <213> Artificial sequence <223> VHH-and-domain Albll <400> 24 -Val Ser-Ser- 115 <210> 25 <211> 435 <212> Protein <213> Artificial sequence <22 0> <223> VHH-construct f013500575 <400> 25 <210> 27 <211> 440 <212> Protein <213> Artificial sequence <22 0> <223> VHH-construct f013500720 <210> 28 <211> 149 <212> Protein <213> Artificial sequence <22 0> <223> VHH-and-domain f0129093a01 <400> 28 <210> 29 <211> 151 <212> Protein <213> Artificial sequence <223> VHH-and-domain f0130333g06 <400> 29 <213> Artificial sequence <22 0> <223> VHH-and-domain f0130333e06 <210> 34 <211> 149 <212> Protein <213> Artificial sequence <22 0> <223> VHH-and-domain f0130378b05 <400> 34 145 <210> 35 <211> 147 <212> Protein <213> Artificial sequence <22 0> <223> VHH-and-domain f0130378a04 <400> 35 Glu-Gin-Val-Leu-Val-Gly-Gly-Gly-Leu Glu-Ser-Gin-Val Gly-Gly 1 5 10 15 Ser-of Arg-Leu-Leu Ser-is Cys-Ala-Ala-Gly Ser-of Arg of Thr Phe-Ser-Ser-Tyr- 20 25 30 Met polypeptide-Ala-Gly teterapeptide Trp Phe-Arg of Gin-Ala Gly Lys-Arg-Glu-Phe--Val 35 40 45 <210> 36 <211> 150 <212> Protein <213> Artificial sequence <22 0> <223> VHH-and-domain f013 0372c08 <400> 36 <210> 37 <211> 462 <212> Protein <213> Artificial sequence <22 0> <223> VHH-construct f013500016 <400> 37 <210> 38 <211> 463 <212> Protein <213> Artificial sequence <22 0> <223> VHH-construct f013500018 <400> 38 Glu-Gin-Val-Leu-Val-Gly-Gly-Gly-Leu Glu-Ser-Gin-Val Gly-Gly 1 5 10 15 Ser-of Arg-Leu-Leu Ser-is Cys-Ala-Ala-Gly-Leu Ser-of Thr Phe-Ser-of Arg-Tyr 20 25 30 Of Thr met polypeptide-Gly teterapeptide Trp Phe-Arg of Gin-Ala Gly Lys-Arg-Glu-Phe--Val 35 40 45 <210> 39 <211> 461 <212> Protein <213> Artificial sequence <22 0> <223> VHH-construct f013500021 <400> 39 Glu-Gin-Val-Leu-Val-Gly-Gly-Gly-Leu Glu-Ser-Gin-Val Gly-Gly 15 10 15 <210> 40 <211> 456 <212> Protein <213> Artificial sequence <22 0> <223> VHH-construct f013500026 <210> 41 <211> 461 <212> Protein <213> Artificial sequence <22 0> <223> VHH-construct f013500030 <400> 41 <212> Protein <213> Artificial sequence <22 0> <223> VHH-construct f013500032 <400> 42 -Val-Val Ser-Ser--Gly-Ala-Ala Glu-Gin Lys-Leu is lie Ser-Glu-Glu- 435,440,445 Asp-Asn--Gly-Ala-Leu-Ala-His-His-His-His-His-His 450,455,460 <210> 43 <211> 462 <212> Protein <213> Artificial sequence <22 0> <223> VHH-construct f013500033 Of Thr-Asp-Ala-Val-Tyr-Tyr is Cys-Ala-Ala-Ala-Arg-Val Arg of Ser-Ser- 405,410,415 Of Thr Arg of Tyr-Asn-of Thr-Gly of Thr teterapeptide Trp teterapeptide Trp teterapeptide Trp Glu-Tyr-teterapeptide Trp-Gly-Gly Gin 420,425,430 Of Thr-Leu-Val-Val Ser-Ser--Gly-Ala-Ala Glu-Lys-Leu is lie Ser-Gin 435,440,445 Glu-Glu-Asp-Asn--Gly-Leu-Ala-Ala-His-His-His-His-His-His 450,455,460 <210> 44 <211> 456 <212> Protein <213> Artificial sequence <22 0> <223> VHH-construct f013500039 <210> 45 <211> 463 <212> Protein <213> Artificial sequence <22 0> <223> VHH-construct f013500046 <210> 46 <211> 457 <212> Protein <213> Artificial sequence <22 0> <223> VHH-construct f013500047 <210> 47 <211> 462 <212> Protein <213> Artificial sequence <22 0> <223> VHH-construct f013500053 The invention provides novel biparatopic LRP5/LRP6 cross-reactive binding polypeptides, and more specifically novel biparatopic LRP5/LRP6 cross-reactive immunoglobulin single variable domain constructs which can inhibit Wnt signaling pathways. The invention also relates to specific sequences of such polypeptides, methods of their production, and methods of using them, including methods of treatment of diseases such as cancer. E polypeptide, specifically binding with LRP5 or LRP6, containing - the first immunoglobulin separate variable domain, selected from the group of separate up immunoglobulin variable domains (I)- (of III), determined the presence of the following CDR--sequences: (I): CDR1: TYTVG (=SEQ N0:1) CDR2: AIRRRGSSTYYADSVKG (=SEQ N0:2) CDR3: DTRTVALLQYRYDY (=SEQ N0:3) (II): CDR1: SYAMG (=SEQ N0:4) CDR2: AIRRSGRRTYYADSVKG (=SEQ N0:5) CDR3: ARRVRSSTRYNTGTWWWEY (=SEQ N0:6) (III): CDR1: RYTMG (=SEQ N0:7) CDR2: AIVRSGGSTYYADSVKG (=SEQ N0:8) CDR3: DRRGRGENYILLΥSSGRYEΥ (=SEQ N0:9), and - the second immunoglobulin separate variable domain, selected from the group of separate up immunoglobulin variable domains (of IV) and (V-), determined the presence of the following CDR--sequences: (IV): CDR1: SYAMG (=SEQ N0:10) CDR2: AISWSGGSTYYADSVKG (=SEQ N0:11) CDR3: SPIPΥGSLLRRRNNYDΥ (=SEQ N0:12) (V): CDR1: SYAMG (=SEQ N0:13) CDR2: AISWRSGSTYYADSVKG (=SEQ N0:14) CDR3: DPRGYGVAYVSAYYEY (=SEQ N0:15). 2. Polypeptide by and. 1, differs, that - said first separate immunoglobulin variable domain contains the following sequence CDR-: CDR1: TYTVG (=SEQ N0:1) CDR2: AIRRRGSSTYYADSVKG (=SEQ N0:2) CDR3: DTRTVALLQYRYDY (=SEQ N0:3) and where - specified second separate immunoglobulin variable domain contains the following sequence CDR-: CDR1: SYAMG (=SEQ N0:10) CDR2: AISWSGGSTYYADSVKG (=SEQ N0:11) CDR3: SPIPΥGSLLRRRNNYDΥ (=SEQ N0:12). 3. Polypeptide of NO of π. 1, differs, that - said first separate immunoglobulin variable domain contains the following sequence CDR-: CDR1: SYAMG (=SEQ N0:4) CDR2: AIRRSGRRTYYADSVKG (=SEQ N0:5) CDR3: ARRVRSSTRYNTGTWWWEY (=SEQ N0:6) and where - specified second separate immunoglobulin variable domain contains the following sequence CDR-: CDR1: SYAMG (=SEQ N0:13) CDR2: AISWRSGSTYYADSVKG (=SEQ N0:14) CDR3: DPRGYGVAYVSAYYEY (=SEQ N0:15). 4. Polypeptide of NO of π. 1, differs, that - said first separate immunoglobulin variable domain contains the following sequence CDR-: CDR1: RYTMG (=SEQ N0:7) CDR2: AIVRSGGSTYYADSVKG (=SEQ N0:8) CDR3: DRRGRGENYILLΥSSGRYEΥ (=SEQ N0:9) and where - specified second separate immunoglobulin variable domain contains the following sequence CDR-: CDR1: SYAMG (=SEQ N0:13) CDR2: AISWRSGSTYYADSVKG (=SEQ N0:14) CDR3: DPRGYGVAYVSAYYEY (=SEQ N0:15). 5. Polypeptide according to any of the and. and. 1 - 4, characterized in that said immunoglobulin separate variable domains are domains VHH, preferably humanized domains VHH. 6. Polypeptide by and. 1, differs, that - said first separate immunoglobulin variable domain is selected from group of separate up immunoglobulin variable domains (1) - (of III) with the following sequences: (I): AVQLVESGGGLVQPGGSLRLSCAASGRTFSTYTVGWFRQAPGKEREFV AAIRRRGS ST-ΥΥ AD OF S-VKGRFTISRDNSKNTVYLQMNSLRPEDTAVYYCAADTRTVALLQYRYDYWGQGTLVTVSS (=SEQ N0:19), (II): AVQLVESGGGLVQPGGSLRLSCAASGGTFSSYAMGWFRQAPGKEREFVAAIRRSGRRTYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTAVYYCAAARRVRS ST-RYNTGTWWWEYWGQGTL VT CIRCUITS OF V S-S- (=SEQ N0:20), (III): AVQLVESGGGLVQPGGSLRLSCAASGLTFSRYTMGWFRQAPGKEREFV AAIVRSGGSTΥΥ THE ADS VKGRFTISRDNSKNTVYLQMNSLRPEDTAVYYCAADRRGRGENYILLΥ S-S-THE GR YE ROTATION GQGTLVTV S-S- (=SEQ N0:21), and where - specified second separate immunoglobulin variable domain is selected from the group, consisting of separate up immunoglobulin variable domains (of IV) and (V-) with the following sequences: EVQLVE S-GGGLVQPGGSLRLS OF C OF A AS OF GRTF S-S-ΥAMGWFRQAPGKEREFVAAISWSGGSTYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTAVYYCAASPI P YGSLLRRRNNYDYWGQGTLVT VS OF S- (=SEQ N0:22), (V): Ε-OF V QL THE VE S-GGGL OF V QUANTIZATION GGSLRL OF C S-A-A-S-S-S-GGTFΥAMGWFRQ Α-P GKEREF OF V A OF THE AIS OF W RSGSTΥΥ AD OF S-VKGRFTISRDNSKNTVYLQMNSLRPEDTAVYYCAADPRGYGVAYVSAYYEYWGQGTLVTVSS (=SEQ N0:23). 7. Polypeptide of NO of π. 1 or of π. 2, differs, that - said first separate immunoglobulin variable domain has amino acid sequence according to SEQ n0:19, and - specified second separate immunoglobulin variable domain has amino acid sequence according to SEQ n0:22. 8. Polypeptide according to Claim 1 or U. 3, differs, that - said first separate immunoglobulin variable domain has amino acid sequence according to SEQ n0:20, and - specified second separate immunoglobulin variable domain has amino acid sequence according to SEQ n0:23. 9. Polypeptide according to Claim 1 or U. 4, differs, that - said first separate immunoglobulin variable domain has amino acid sequence according to SEQ n0:21, and - specified second separate immunoglobulin variable domain has amino acid sequence according to SEQ n0:23. 10. Polypeptide according to any of claims U. 1 - 9, characterized in that said first and second separate immunoglobulin variable domains covalently are connected peptide - linker, where indicated peptide - linker optionally contains third immunoglobulin separate variable domain or consists of it. 11. Polypeptide according to any of claims U. 1 - 9, characterized in that additionally contains polypeptide fragment, drives enhanced half, said fragment, drives enhanced half, is covalently bound with said polypeptide and optionally is selected from the group, consisting of albuminsvyazyvayushchego fragment, such as albuminsvyazyvayushchii peptide or albuminsvyazyvayushchii immunoglobulin domain, transferrinsvyazyvayushchego fragment, such as antitransferrinovyi immunoglobulin domain, molecules of polyethylene glycol, human serum albumin, and also fragment of human serum albumin. 12. Polypeptide by and. 11, characterized in that said fragment, drives enhanced half, is albuminsvyazyvayushchim separate immunoglobulin variable domain, preferably domain Alb 11, determined by SEQ n0:24. 13. Polypeptide, selected from the group of polypeptides, containing or consisting of SEQ n0:25, SEQ n0:26 and SEQ n0:27. 14. Nucleic acid molecule, preferably in isolated form, encoding polypeptide according to any of claims U. 1 - 13. 15. Expression vector, which contains nucleic acid by and. 14. 16. Cell - host, carrying expression vector by and. 15. 17. Method of production of polypeptide according to any of claims U. 1 - 13, including stages - cultivation of cells - by host and. 16 in conditions, expression of polypeptide according to any of claims U. 1 - 13; and - isolation of said polypeptide. 18. The method and. 17, additionally including stage - purification of the said polypeptide. 19. Pharmaceutical composition, containing (1) as an active substance polypeptide according to any of the and. and. 1 - 13 and (of II) a pharmaceutically acceptable carrier, and also optionally (of III) diluent, auxiliary substance, adjuvant and/or stabilizer. 20. Polypeptide according to any of the and. and. 1 - 13 for use as a medicinal agent in method for treatment, prophylaxis or relief of disease, disorder or condition in human or animal. 21. Polypeptide according to any of the and. and. 1 - 13 for using in cancer treatment, preferably breast cancer, lung cancer, pancreas cancer, colorectal cancer, sarcoma, ovarian cancer or pechenochnokletochnoi carcinoma, or for use in the treatment of idiopathic pulmonary disease, or for use in the treatment of retinopathy, caused by abnormal signal transmission of WNT. 22. Polypeptide according to any of the and. and. 1 - 13 for use in the treatment three times negative breast cancer (tnrmzh). 23. Polypeptide according to any of the and. and. 1 - 13 for application in combination with chemotherapeutic agents, therapeutically active compound, suppresses angiogenesis, track signal transduction inhibitor, inhibitor of EGFR is, immunomodulator, immune inhibitor of control points or means for hormonal therapy. 24. Therapeutic agent, selected from the group, consisting of chemotherapeutic agents, therapeutically active compounds, suppress angiogenesis, inhibitors of track signal transduction, inhibitors of EGFR is, immunomodulators, inhibitors of immune of control points and the means for hormonal therapy, for application in combination with polypeptide according to any of the and. and. 1 - 13. 25. Method for treating cancer, idiopathic pulmonary disease or retinopathy in patient, in need, including introduction of to the indicated patient the effective amount of polypeptide according to any of claims U. 1 - 13 or pharmaceutical composition according to Claim 19. 26. Polypeptide, containing - the first immunoglobulin binding protein, which is capable of specifically to bind and with LRP5, and with LRP6 ("perekrestnoreaktivnyi by lrp5/lrp6") and suppresses caused Wntl transcription gene - target, and - - the second immunoglobulin binding protein, which is capable of specifically to bind and with LRP5, and with LRP6 ("perekrestnoreaktivnyi by lrp5/lrp6") and suppresses caused Wnt3a transcription gene - target. 27. Polypeptide according to Claim 26, characterized in that said first and second immunoglobulin binding proteins are separate immunoglobulin variable domains. 28. Use of polypeptide according to any of claims U. 1 - 13, 26 or 27 for modification of the microenvironment of the tumor by suppression caused by Wntl and Wnt3a gene transcription - target in dendritic cells. 29. Polypeptide according to any of claims U. 1 - 13, 26 or 27dlya application in treatment of cancer. 3 0. Polypeptide according to any of claims U. 1 - 13, 26 or 27dlya application in treatment of cancer in combination with immune inhibitor of control points, selected from a group, consisting of antibodies against of Pd-and-1, antibodies against of Pd-and-l1, antibodies against CTLA4, antibodies against BTLA, antibodies against LAG3 and antibodies raised against TIM3, or same in combination with anticancer vaccine.TECHNICAL FIELD
BACKGROUND OF THE INVENTION
BRIEF DESCRIPTION OF THE INVENTION
BRIEF DESCRIPTION OF GRAPHIC MATERIALS
OVERHEAT DESCRIPTION OF INVENTION
Wntl-and-333E06mod Wntl-and-333g06 Wntl-and-332d03 mode CDR1 TYTVG SYAMG RYTMG (SEQ N0:1) (SEQ N0:4) (SEQ N0:7) CDR2 AIRRRGS S-ΤΥΥ AD OF S- AIRRSGRRTYYADSV AIVRSGGSTYYADS VKG THE KG VKG (SEQ N0:2) (SEQ N0:5) (SEQ N0:8) CDR3 DTRTVALLQYRYD ARRVRSSTRYNTGTW DRRGRGENYILLΥ S- Υ WWEY SGRYEY (SEQ N0:3) (SEQ N0:6) (SEQ N0:9) Wnt3a - 093a01 Wnt3a - 367b10 CDR1 SYAMG (SEQ N0:10) SYAMG (SEQ N0:13) CDR2 AISWSGGSTYYADSVKG (SEQ N0:11) AISWRSGSTYYADSVKG (SEQ N0:14) Albl 1 domain CDR1 SFGMS (SEQ N0:16) CDR2 SISGSGSDTLYADSVKG (SEQ N0:17) CDR3 GGSLSR (SEQ N0:18) VHH OF ID SEQ ID N0: FR1 CDR1 FR2 CDR2 FR3 CDR3 FR4 Wntl-and-333ε06 mode SEQ N0:19 AVQLVESGGGLVQPGGSLRLSCAASGRTFS TYTVG WFRQAPGKEREFV A OF AIRRRGSSTYYADSVKG RFTISRDNSKNTVYLQMNSLRPEDTAVYYCAA DTRTVALLQYRYDY WGQGTLVTVSS Wntl-and-333g06 SEQ N0:20 AVQLVESGGGLVQPGGSLRLSCAASGGTFS SYAM OF G WFRQAPGKEREFV A OF AIRRSGRRTYYADSVKG RFTISRDNSKNTVYLQMNSLRPEDTAVYYCAA ARRVRSSTRYNTGTWWWEΥ WGQGTLVTVSS VHH OF ID SEQ ID N0: FR1 CDR1 FR2 CDR2 FR3 CDR3 FR4 Wntl-and-332d03 mode SEQ N0:21 AVQLVESGGGLVQPGGSLRLSCAASGLTFS RYTM OF G WFRQAPGKEREFV A OF AIVRSGGSTYYADSVKG RFTISRDNSKNTVYLQMNSLRPEDTAVYYCAA DRRGRGENYILLYSSGRYEY WGQGTLVTVSS VHH OF ID SEQ ID N0: FR1 CDR1 FR2 CDR2 FR3 CDR3 FR4 Wnt3a-and-093α01 SEQ N0:22 EVQLVESGGGLVQPGGSLRLSCAASGRTFS SYAM OF G WFRQAPGKEREFV A OF AISWSGGSTYYADSVKG RFTISRDNSKNTVYLQMNSLRPEDTAVYYCAA SPIPYGSLLRRRNNYDY WGQGTLVTVSS Wnt3a-and-367β10 SEQ N0:23 EVQLVESGGGLVQPGGSLRLSCAASGGTFS SYAM OF G WFRQAPGKEREFV A OF AISWRSGSTYYADSVKG RFTISRDNSKNTVYLQMNSLRPEDTAVYYCAA DPRGYGVAYVSAYY Ε-Υ WGQGTLVTVSS VHH OF ID SEQ ID N0: FR1 CDR1 FR2 CDR2 FR3 CDR3 FR4 Alb 11 SEQ N0:24 EVQLVESGGGLVQPGNSLRLSCAASGFTFS SFGMS WVRQAPGKGLEW VS OF SISGSGSDTLYADSVKG L-RFTISRDNAKTTYLQMNSLRPEDTAVYYCTI GGSLS OF R SSQGTLVTVSS OF ID SEQ ID N0: Amino acid sequence of (sequence CDR-underlined) F013500575 SEQ N0:25 AVOLVESGGGLVOPGGSLRLSCAASGRTFSTYTVGWFROAPGK EREFVAAIRRRGSSTYYADSVKGRFTISRDNSKNTVYLOMNSLR PEDTAVYYCAADTRTVALLOYRYDYWGOGTLVTVSSGGGGSG GGGSGGGGSGGGGSGGGGSGGGGSGGGGSE OF V QLVESGGGL OF V OF Q PGNSLRLSCAASGFTFSSFGMSWVROAPGKGLEWVSSISGSGSDTLYADSVKGRFTISRDNAKTTLYLOMNSLRPEDTAVYYCTIGGS LSRSSQGTLVTVSSGGGGSGGGGSGGGGSGGGGSGGGGSGGGG S-GGGGSE OF V OL THE VE S-GGGL V OF THE OP GGSLRL OF C S-A-A-S-S-S-GRTFΥAMGWFROAPGKEREFVAAISWSGGSTYYADSVKGRFTISRDNSKNTVYLOMNSLRPEDTAVYYCAASPIPYGSLLRRRNNYDYWGOGTLVTV THE SSA F013500571 SEQ N0:26 AVOLVESGGGLVOPGGSLRLSCAASGGTFSSYAMGWFROAPGKEREFVAAIRRSGRRTYYADSVKGRFTISRDNSKNTVYLOMNSLRPEDT A OF OF V ΥYC A OF A OF ARRVRS S-ECO RI ΥΝΤGTWWWE ROTATION GOGTL VT CIRCUITS OF V S-S-OF G GGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSEVQLVES OF G GGL OF V OPGNSLRLSCAASGFTF S-OF FRONTAL CROSS GMS OF W VROAPGKGLEW OF V S-STEROL GSGSDTLYADSVKGRFTISRDNAKTTLYLOMNSLRPEDTAVYYC TIGGSLSRSSOGTLVTVSSGGGGSGGGGSGGGGSGGGGSGGGGS GGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGGTFSSYA MGWFROAPGKEREFVAAISWRSGSTYYADSVKGRFTISRDNSK NT-VYLOMNSLRPEDTAVYY OF C AADPRGYGVAYVSAYYEYW CO GTLVTVSSA OF ID SEQ ID N0: Amino acid sequence of (sequence CDR-underlined) F013500720 SEQ N0:27 AVOLVESGGGLVOPGGSLRLSCAASGLTFSRYTMGWFROAPGK EREFVAAIVRSGGSTYYADSVKGRFTISRDNSKNTVYLOMNSLRPEDΤ A OF OF V ΥΥ OF C OF A ADRRGRGENYILLΥ S-S-THE GR YEΥ OF W CO THE GTL VT CIRCUITS OF V S-S-OF G GGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSEVQLVES OF G GGL OF V OPGNSLRLSCAASGFTF S-OF FRONTAL CROSS GMS OF W VROAPGKGLEW OF V S-STEROL GSGSDTLYADSVKGRFTISRDNAKTTLYLOMNSLRPEDTAVYYC TIGGSLSRSSOGTLVTVSSGGGGSGGGGSGGGGSGGGGSGGGGS GGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGGTFSSYA MGWFROAPGKEREFVAAISWRSGSTYYADSVKGRFTISRDNSK NT-VYLOMNSLRPEDTAVYY OF C AADPRGYGVAYVSAYYEYW CO GTLVTVSSA EXAMPLES
Example 1: immunization Lamas LRP5 and LRP6 to induction of humoral immune response
Creation of library:
4.6 Biophysical properties
Example 5: creation and characteristic biparatopnykh constructs with prolonged half-period
Reporter analysis Wntl Reporter analysis Wnt3a Construct Of n-end of With - end of THE IC50 (M) % ING. THE IC50 (M) % ING. F013500053 F0129093 [A 01 F0130333G06 2, 3 Ε-- 10 102 4, 1 Ε-- 10 97 F013500039 F0129093 [A 03 F0130333E06 1, 7 Ε-- 09 102 1, 6 Ε-- 09 82 F013500046 F0130332D03 F0129093 [A 01 5, 1 Ε-- 10 102 6, 0 Ε-- 10 96 F013 500016 F0130332D03 F0130367B10 3, 1 Ε-- 10 102 2, 7 Ε-- 10 99 F013 500018 F0130332D03 F0130378B05 7, 4 Ε-- 10 102 1, 3 Ε-- 09 98 F013500047 F0130333E06 F0129093 [A 01 8, 8 Ε-- 10 102 9, 1 Ε-- 10 94 F013500026 F0130333E06 F0130367B10 3, 3 Ε-- 10 102 2, 6 Ε-- 10 100 F013500021 F0130333G06 F0130367B10 1, 6 Ε-- 10 102 1, 8 Ε-- 10 102 F013500032 F0130378A04 F0130333G06 2, 4 Ε-- 10 102 4, 3 Ε-- 10 94 F013500033 F0130378B05 F0130333G06 1, 8 Ε-- 10 102 2, 5 Ε-- 10 88 F013500030 F0130378B05 F0130372C08 1, 4 Ε-- 09 102 1, 3 Ε-- 09 96 VHH specificity of ID Amino acid sequence of SEQ ID N0: F0129093 [a 01 Wnt3a Ε-OF V QL THE VE S-GGGL OF V QUANTIZATION GGSLRL OF C S-A-A-S-S-S-GRTFΥ A OF MGWFRQAPGKEREFVAAISWSGGSTYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTAVYYCAASPIPΥGSLLRRRNNYD ROTATION GOGTL VT CIRCUITS OF V S-S-Α-Α-Α-Ε-ΟKLISEEDLN OF G A OF Α-ΗΗΗΗΗΗ 28 F0130333g06 Wntl EVQLVESGGGLVQPGGSLRLSCAASGGTFSSYAMGWFRQAPGKEREFVAAIRRSGRRTYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTAVYYCAAARRVRSSTRYNTGTWWWEYWGQGTL VT CIRCUITS OF V S-S-A-A-Α-Ε-OKLISEEDLN OF G A OF Α-ΗΗΗΗΗΗ 29 F0129093 α 03 Wnt3a Ε-OF V QL THE VE S-GGGL OF V QUANTIZATION GGSLRL OF C S-A-A-S-S-GRTFΤΥ OF V MGWFRQAPGKEREFVAAINWSGSRTYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTAVYYCAA OF SRS S-YAGRTYYELYDYWGOGTL VT CIRCUITS VS OF S-Α-Α-Α-Ε-ΟKLISEEDLNG A OF Α-ΗΗΗΗΗΗ 30 F0130333e06 Wntl EVQEVESGGGEVQPGGSERESCAASGRTFSTYTVGWFRQAPGKEREFVAAIRRRGSSTYYSDSVKGRFTISRDNSKNTVYLQMNSLRPEDTAVYY OF C PAAD TRTVALLOYRYDYWGOGTLVTVSSAAAEOKLISEEDLN OF G A OF Α-ΗΗΗΗΗΗ 31 F0130332d03 Wntl EVQLVESGGGLVQPGGSLRLSCAASGLTFSRYTMGWFRQ Α-P GKEREF OF V OF A AINRSGGSTYYSDS VK OF GRFTISRDNSKNTVYLQMNSLRPEDTAVYYCAADRRGRGENΥSLLΥ S-SNRYE ROTATION GQGTLVTV S-S-A-A-Α-Ε-OKL LI EEDLNG A OF Α-ΗΗΗΗΗΗ 32 F0130367b10 Wnt3a Ε-VQL THE VE S-GGGL ANY VQP GGSLRL OF C S-A-A-S-S-S-GGTFΥ A OF MGWFRQ Α-P GKEREFVAAISWRSGSTYY AD OF S-VK OF GRFTISRDNSKNTVYLQMNSLRPEGTAVYYCAADPRGY GV CHIPSETS A OF Υ VS OF A OF ΥYE ROTATION GOGTLVTV S-S-GA AND Α-Ε-OKLISEEDLNGAAHHHHHH 33 F0130378b05 Wnt3a EVQLVESGGGLVQPGGSLRLSCVASGRTFSSYAMGWFRQAPGKEREFVAAISRSGGRTYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTAVYYCAADRRVYSTLPPTTSRYNYWGOGTLVTVSSAAAEOKLISEEDLNG A OF Α-ΗΗΗΗΗΗ 34 F0130378a04 Wnt3a Ε-OF V QL THE VE S-GGGL OF V QUANTIZATION GGSLRL OF C S-A-A-S-S-S-GRTFΥ A OF MGWFRQAPGKEREFVAAITRTGRRTΥΥ AD OF S-VK OF GRFTISRDNSKNTVYLQMNSLRPEDTAVYYCAADRRGYYYYDSSFYDYWGOGTL VT CIRCUITS VS OF SAAAEOKLISEEDLNGAAHHHHHH 35 VHH specificity of ID Amino acid sequence of SEQ ID N0: F0130372c08 Wntl Ε-OF V QL THE VE S-GGGL OF V QUANTIZATION GGSLRL OF C S-A-A-S-GRTF OF SD SUBJECT MGWFRQAPGKEREFVAAISWSGGRTYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTAVYYCAAKRRGRGSVSPNS S-SRYNYWGQGTL VT CIRCUITS VS OF S-THE AAA EOKLISEEDLNGAAHHHHHH 36 F013500016 EVQLVESGGGLVQPGGSLRLSCAASGLTFSRYTMGWFRQ Α-P GKEREF OF V OF A AINRSGGSTYYSDS VK OF GRFTISRDNSKNTVYLQMNSLRPEDTAVYYCAADRRGRGENYSLLΥ S-SNRYEYWGQGTL VT CIRCUITS OF V S-THE SG GGGSGGGGSGGGGSGGGGSGGGGSGGGGS GG IS GGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYY OF C TIGGSLSRSSQGTLVTVSSGGGGSGGGGSGGGG S-GGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGGTFSSYAMGWFRQAPGKEREFVAAISWRSGSTYYADSVKGRFTISRDNSK NT-OF V YLQMNSLRPEGTAVYY OF C OF A ADPRGY GV CHIPSETS HBSAG AY V-S-A-ΥYE ROTATION GOGTL VT CIRCUITS OF V S-S-GA AND AEOKLISEEDLN OF G 37 Α-Α-ΗΗΗΗΗΗ F013500018 EVQLVESGGGLVQPGGSLRLSCAASGLTFSRYTMGWFRQ Α-P GKEREF OF V OF A AINRSGGSTYYSDS VK OF GRFTISRDNSKNTVYLQMNSLRPEDTAVYYCAADRRGRGENYSLLYSSNRYE ROTATION GQGTLVTVSSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGS GG IS GGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVTVSSGGGGSGGGGSGGGG S-GGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCVASGRTFSSYAMGWFRQAPGKEREFVAAISRSGGRTYYADSVKGRFTISRDNSKNΤVYLQMNSLRPEDTAVYY OF C AADRRVYSTLPPTTSRYNYWGOGTLVTVSSGAAEOKLISEEDLNGA Α-ΗΗΗΗΗΗ 38 VHH specificity of ID Amino acid sequence of SEQ ID N0: F013500021 EVQLVESGGGLVQPGGSLRLSCAASGGTFSSYAMGWFRQAPGKEREFVAAIRRSGRRTYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTAVYYCAAARRVRSSTRYNTGTWWWEYWGQGTL VT CIRCUITS OF V S-THE SG GGGSGGGGSGGGGSGGGGSGGGGSGGGGS GG IS GGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYY OF C TIGGSLSRSSQGTLVTVSSGGGGSGGGGSGGGG S-GGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGGTFSSYAMGWFRQAPGKEREFVAAISWRSGSTYYADSVKGRFTISRDNSK NT-OF V YLQMNSLRPEGTAVYY OF C OF A ADPRGY GV CHIPSETS HBSAG AY V-S-A-ΥYE ROTATION GOGTL VT CIRCUITS OF V S-S-GA AND AEOKLISEEDLN OF G Α-Α-ΗΗΗΗΗΗ 39 F013500026 EVQLVESGGGLVQPGGSLRLSCAASGRTFSTYTVGWFRQAPGKEREFVAAIRRRGSSTYYSDSVKGRFTISRDNSKNTVYLQMNSLRPEDTAVYY OF C PAAD TRTVALLQYRYD ROTATION GQGTLVTVSSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSEVQL OF V ESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSRS S-QGTL VT CIRCUITS VS OF S-GGGGSGGGGSGGGGSGGGGS GG IS GGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGGTFSSYAMGWFRQAPGKEREFVAAISWRSGSTYYADSVKGRFTISRDNSKNTVYLQMNSLRPEGTAVYY OF C OF A ADPRGY OF G OF V OF A Υ V-S-A-ΥYE ROTATION GOGTL VT CIRCUITS VS OF SGAAEOKLISEEDLNGAAHHHHHΗ 40 F013500030 EVQLVESGGGLVQPGGSLRLSCVASGRTFSSYAMGWFRQAPGKEREFVAAISRSGGRTYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTAVYYCAADRRVYSTLPPTTSRYNYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSE OF V QL THE VE S-GGGL OF V QPGNSLRL S-OF C OF A GF AS OF THE TF S-OF FRONTAL CROSS OF GM S-WVRQAPGKGLEWVSSISGSGSDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSRS S-QGTL VT CIRCUITS VS OF S-GGGGSGGGGSGGGGSGGGG S-GGGGSGGGGSGGGGSEVQL THE VE S-GGGLVQPGGSLRLSCAASGRTFSDYGMGWFRQAPGKEREFVAAIS OF W SGGRTΥΥ AD OF S-VKGRFTISRDNSKNTVYLQMNSLRPEDTAVYYCAAKRRGRGSVSPN S-S-SRYNYWGOGTLVTV S-S-GAAEOKLISEEDLNGAAHHΗΗΗΗ 41 VHH specificity of ID Amino acid sequence of SEQ ID N0: F013500032 EVQLVESGGGLVQPGGSLRLSCAASGRTFSSYAMGWFRQ AP GKEREF OF V OF A AITRTGRRTΥΥ AD OF S-VK OF GRFTISRDNSKNTVYLQMNSLRPEDTAVYYCAADRRGYΥΥYD S-OF FRONTAL CROSS YD ROTATION GQGTL VT CIRCUITS OF V S-S-GGGGS OF G GGGSGGGGSGGGGSGGGGSGGGGSGGGGSE OF V OF Q LVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLS RS-S-QGTL VT CIRCUITS VS OF S-GGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGGTFSSYAMGWFRQAPGKEREFVAAIRRSGRRTYYADSVKGRFTISRDNSKNTVYLQΜΝSLRPEDΤ A OF OF V ΥΥ OF C A OF A OF ARRVRS S-ECO RI ΥΝΤ GF OF W WWEYWGQGTLVTV S-S-GAAEOKLISEEDLNGAA 42 ΗΗΗΗΗΗ F013500033 EVQLVESGGGLVQPGGSLRLSCVASGRTFSSYAMGWFRQAPGKEREFVAAISRSGGRTYYADS VK OF GRFTISRDNSKNTVYLQMNSLRPEDTAVYY WITH Α Α-DRRVYSTLPPTTSRYNYWGQGTLVTV S-SGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSE OF V QL THE VE S-GGGL OF V QPGNSLRL S-OF C OF A GF AS OF THE TF S-OF FRONTAL CROSS OF GM S-WVRQAPGKGLEWVSSISGSGSDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSRS S-QGTL VT CIRCUITS VS OF S-GGGGSGGGGSGGGGSGGGG S-GGGGSGGGGSGGGGSEVQLVE S-GGGLVQPGGSLRL S-OF C OF A AS OF GGTF S-S-ΥAMGWFRQAPGKEREF OF V OF A AIRRSGRRTYYADSVKGRFTISRDNSKNTVYLQΜΝSLRPEDΤAVYY OF C A OF A OF ARRVRS S-ECO RI ΥΝΤ GF OF W WWEYWGQGTLVTVSSGAAEOKLISEEDLNGAA 43 ΗΗΗΗΗΗ F013500039 EVQLVESGGGLVQPGGSLRLSCAASGRTFSTYVMGWFRQAPGKEREFVAAINWSGSRTYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTAVYYCAA OF SRS S-YAGRTYYELYD ROTATION GQGTLVTV S-SGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSE OF V QL THE VE S-GGGL OF V QPGNSLRL S-OF C OF A GF AS OF THE TF S-OF FRONTAL CROSS OF GM S-WVRQAPGKGLEWVSSISGSGSDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSRS S-QGTL VT CIRCUITS VS OF S-GGGGSGGGGSGGGGSGGGG S-GGGGSGGGGSGGGGSEVQLVE S-GGGLVQPGGSLRLSCAASGRTFSTYTVGWFRQAPGKEREF OF VA AIRRRGS S-ΤΥΥ OF SD SVKGRFTISRDNSKNT OF V YLQMNSLRPEDTAVYYCAADTRTVALLQYRYDYWGOGTLVTVSSGAAEOKLISEEDLNGAAHHHHHΗ 44 VHH specificity of ID Amino acid sequence of SEQ ID N0: F013500046 EVQLVESGGGLVQPGGSLRLSCAASGLTFSRYTMGWFRQ Α-P GKEREF OF V OF A AINRSGGSTYYSDS VK OF GRFTISRDNSKNTVYLQMNSLRPEDTAVYYCAADRRGRGENΥSLLΥ S-SNRYE ROTATION GQGTL VT CIRCUITS OF V S-S-OF G GGGSGGGGSGGGGSGGGGSGGGGSGGGGS GG IS GGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYY OF C TIGGSLSRSSQGTLVTVSSGGGGSGGGGSGGGG S-GGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGRTFSSYAMGWFRQAPGKEREFVAAISWSGGSTYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTAVYYCAASPIPYGSLLRRRNNYD ROTATION GOGTL VT CIRCUITS OF V S-S-GA AND AEOKLISEEDLN OF G Α-Α-ΗΗΗΗΗΗ 45 F013500047 EVQLVESGGGLVQPGGSLRLSCAASGRTFSTYTVGWFRQAPGKEREFVAAIRRRGSSTYYSDSVKGRFTISRDNSKNTVYLQMNSLRPEDTAVYY OF C PAAD TRTVALLQYRYD ROTATION GQGTLVTVSSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSEVQL OF V ESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSRS S-QGTL VT CIRCUITS VS OF S-GGGGSGGGGSGGGGSGGGGS GG IS GGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGRTFSSYAMGWFRQAPGKEREFVAAISWSGGSTΥΥADSVKGRFTISRDNSKNTVYLQMNSLRPEDTAVYYCAASPIPYGSLLRRRNNYDYWGOGTLVTVSSGAAEOKLISEEDLNGAAHHHHHH 46 F013500053 Ε-OF V QL THE VE S-GGGL OF V QUANTIZATION GGSLRL OF C S-A-A-S-S-S-GRTFΥ A OF MGWFRQAPGKEREFVAAISWSGGSTYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTAVYYCAASPIPΥGSLLRRRNNYD ROTATION GQGTLVTV S-SGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSE OF V QL THE VE S-GGGL OF V QPGNSLRL S-OF C OF A GF AS OF THE TF S-OF FRONTAL CROSS OF GM S-WVRQAPGKGLEWVSSISGSGSDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSRS S-QGTL VT CIRCUITS VS OF S-GGGGSGGGGSGGGGSGGGG S-GGGGSGGGGSGGGGSEVQL THE VE S-GGGLVQPGGSLRL S-OF C OF A AS OF GGTF S-S-ΥAMGWFRQAPGKEREF OF V OF A AIRRSGRRTYYADSVKGRFTISRDNSKNTVYLQΜΝSLRPEDΤAVYY OF C A OF A OF ARRVRS S-ECO RI ΥΝΤ GF OF W WWEYWGOGTLVTV S-S-GAAEOKLISEEDLN GA AND Α-ΗΗΗΗΗΗ 47 Motif Modification of M Oxidation of met polypeptide OF N-S-/ G/H/N/A Deamidization Asn- -D-S-/ G/H Isomerization of Asp- OF N-X S-/ T OF-X- Asn-glycosylation (X ≠ Λ2 P) Q/E piroglutamat 7.1 Binding analysis FACS
certain binding FACS analysis
Binding analysis based on FACS F013500571 F013500575 F013500720 hLRP5, eszo (nm) 0.01 0.001 0.02 hLRP6, Eszo (nm) 0.02 0.01 0.02 7.2 Analysis of competition of with DKK1 based on FACS
Analysis of competition of with DKK1 F013500571 F013500575 F013500720 hLRP5, 1c50 (nm) 0.03 0.03 0.3 hLRP6, 1c50 (nm) 0.01 OD 0.2 Combined analysis of Wntl and Wnt3a gene - to the reporter F013500571 F013500575 F013500720 1C50 (nm) 0.05 0.2 0.06 Reporter analysis of WNT Knob ns yw2 10.09 Knob ns yw211.31.62 Wntl, the IC50 (nm) 4.8 4.6 Wnt3a, the IC50 (nm) 0.7 0.9 Combined analysis of Wntl and Wnt3a gene - to the reporter F013500571 Knob ns yw2 10.09 MOR08168IgGlLALA 6475 scFv antibody 802Τ 1C50 (nm) 0.05 1.15 0.19 0.01 Example 8: influence of three biparatopnykhperekrestnoreaktivnykh by lrp5/lrp6 unn - constructs with prolonged period half-transmission signal of WNT and viability of cancer cell lines
Example 9: efficiency
Dose [mg/kg] PRO [%] Regressov [X/7] Lethality [X/7] G istopatologicheskaya evaluation of gastrointestinal tract Control Gistidinovyi buffer - - - - F013500571 10 128 7 0 Without features of 4 113 7 0 Without features of 2 61 0 0 not ODA. Dose [mg/kg] PRO [%] Regressov [X/7] Lethality [X/7] G istopatologicheskaya evaluation of gastrointestinal tract Control Gistidinovyi buffer - - - - F013500720 1 128 7 0 Without features of 0.4 60 0 0 Without features of 0.2 17 0 0 not ODA. Dose [mg/kg] PRO [%] Regressov [X/7] Lethality [X/7] G istopatologicheskaya evaluation of gastrointestinal tract Control Citrate buffer - - - - Knob ns yw2 10.09 30 80 0 0 - 45 85 0 0 Without features of Dose [mg/kg] Graph PRO [%] Regressov [X/5] Lethality [X/5] Control Tsitratn th buffer Three times a week Knob ns yw2 10.09 45 Twice per week 55 1 0 90 Twice per week 85 0 0 90 Three times a week 87 0 0 Example 10: suppression of track of WNT
Dose [mg/kg] PRO [%] WiFi client continuously tracks Axin2 (%) Control Gistidinovyi buffer - F013500571 10 128 83 4 113 77 2 61 35 Dose [mg/kg] PRO [%] WiFi client continuously tracks Axin2 (%) Control Gistidinovyi buffer - F013500720 1 128 92 0.4 60 -21 0.2 17 35 Example 11: method of industrial production of
Example 12: pharmaceutical preparation for U. to. introduction
LIST OF SEQUENCES
<210> <211> <212> <213> 10 5 Protein artificial sequence <22 0> <223> CDRl wnt3a - 093a01 <400> 10 <210> <211> <212> <213> 11 17 Artificial protein sequence <22 0> <223> CDR2 wnt3a - 093a01 1-Gly 5 10 15 <210> <211> <212> <213> 12 17 Artificial protein sequence <22 0> <223> CDR3 wnt3a - 093a01 <400> 12 1 Tug 5 10 15 <210> <211> <212> <213> 13 5 Protein artificial sequence <22 0> <223> CDRlWnt3a-and-3 67 β-10 <400> 13 <210> <211> <212> <213> 14 17 Artificial protein sequence <22 0> <223> CDR2Wnt3a-and-3 67 β-10 -Ala -Val Gin -Leu -Val Glu- Ser- -Gly -Gly -Gly -Leu -Val Gin Of Pro -Gly -Gly 1 5 10 15 Ser- -Leu Of Arg -Leu Ser- Is Cys -Ala -Ala Ser- -Gly Of Arg Of Thr Phe- Ser- Of Thr Tyr- 20 25 30 Of Thr -Val -Gly Teterapeptide Trp Phe- Of Arg Gin -Ala Of Pro -Gly Lys- Glu- Of Arg Glu- Phe- -Val 35 40 45 -Ala -Ala lie Of Arg Of Arg Of Arg -Gly Ser- Ser- Of Thr Tyr- Tyr- -Ala Asp- Ser- -Val 50 55 60 Lys- -Gly Of Arg Phe- Of Thr lie Ser- Of Arg Asp- Asn- Ser- Lys- Asn- Of Thr -Val Tyr- 65 70 75 80 -Leu Gin Met polypeptide Asn- Ser- -Leu Of Arg Of Pro Glu- Asp- Of Thr -Ala -Val Tyr- Tyr- Is Cys 85 90 95 -Ala -Ala Asp- Of Thr Of Arg Of Thr -Val -Ala -Leu -Leu Gin Tyr- Of Arg Tyr- Asp- Tyr- 100 105 110 Teterapeptide Trp -Gly Gin -Gly Of Thr -Leu -Val Of Thr -Val Ser- Ser- 115 120 -Ala 1 -Val Gin -Leu -Val 5 Glu- Ser- -Gly -Gly -Gly 10 -Leu -Val Gin Of Pro -Gly 15 -Gly Ser- -Leu Of Arg Leu is 20 Ser- Is Cys -Ala -Ala Ser-25 -Gly -Gly Of Thr Phe- Ser-30 Ser- Tyr- -Ala Met polypeptide -Gly 35 Teterapeptide Trp Phe- Of Arg Gin -Ala 40 Of Pro -Gly Lys- Glu- Arg of 45 Glu- Phe- -Val -Ala -Ala 50 lie Of Arg Of Arg Ser- -Gly 55 Of Arg Of Arg Of Thr Tyr- Tyr-60 -Ala Asp- Ser- -Val Lys-65 -Gly Of Arg Phe- Of Thr lie 70 Ser- Of Arg Asp- Asn- Ser-75 Lys- Asn- Of Thr -Val Tyr-80 -Leu Gin Met polypeptide Asn- Ser-85 -Leu Of Arg Of Pro Glu- Asp-90 Of Thr -Ala -Val Tyr- Tyr-95 Is Cys -Ala -Ala -Ala Arg of 100 Of Arg -Val Of Arg Ser- Ser-105 Of Thr Of Arg Tyr- Asn- Of Thr 110 -Gly Of Thr Teterapeptide Trp Teterapeptide Trp Teterapeptide Trp 115 Glu- Tyr- Teterapeptide Trp -Gly Gin 120 -Gly Of Thr -Leu -Val Of Thr 125 -Val Ser- Ser- Glu- -Val Gin -Leu -Val Glu- Ser- -Gly -Gly -Gly -Leu -Val Gin Of Pro -Gly -Gly 1 5 10 15 Ser- -Leu Of Arg -Leu Ser- Is Cys -Ala -Ala Ser- -Gly Of Arg Of Thr Phe- Ser- Ser- Tyr- 20 25 30 -Ala Met polypeptide -Gly Teterapeptide Trp Phe- Of Arg Gin -Ala Of Pro -Gly Lys- Glu- Of Arg Glu- Phe- -Val 35 40 45 -Ala -Ala lie Ser- Teterapeptide Trp Ser- -Gly -Gly Ser- Of Thr Tyr- Tyr- -Ala Asp- Ser- -Val 50 55 60 Lys- -Gly Of Arg Phe- Of Thr lie Ser- Of Arg Asp- Asn- Ser- Lys- Asn- Of Thr -Val Tyr- 65 70 75 80 -Leu Gin Met polypeptide Asn- Ser- -Leu Of Arg Of Pro Glu- Asp- Of Thr -Ala -Val Tyr- Tyr- Is Cys 85 90 95 -Ala -Ala Ser- Of Pro lie Of Pro Tyr- -Gly Ser- -Leu -Leu Of Arg Of Arg Of Arg Asn- Asn- 100 105 110 Tyr- Asp- Tyr- Teterapeptide Trp -Gly Gin -Gly Of Thr -Leu -Val Of Thr -Val Ser- Ser- 115 120 125 Glu- -Val Gin -Leu -Val Glu- Ser- -Gly -Gly -Gly -Leu -Val Gin Of Pro -Gly -Gly 1 5 10 15 Ser- -Leu Of Arg -Leu Ser- Is Cys -Ala -Ala Ser- -Gly -Gly Of Thr Phe- Ser- Ser- Tyr- 20 25 30 -Ala Met polypeptide -Gly Teterapeptide Trp Phe- Of Arg Gin -Ala Of Pro -Gly Lys- Glu- Of Arg Glu- Phe- -Val 35 40 45 -Ala -Ala lie Ser- Teterapeptide Trp Of Arg Ser- -Gly Ser- Of Thr Tyr- Tyr- -Ala Asp- Ser- -Val 50 55 60 Lys- -Gly Of Arg Phe- Of Thr lie Ser- Of Arg Asp- Asn- Ser- Lys- Asn- Of Thr -Val Tyr- 65 70 75 80 -Leu Gin Met polypeptide Asn- Ser- -Leu Of Arg Of Pro Glu- Asp- Of Thr -Ala -Val Tyr- Tyr- Is Cys 85 90 95 -Ala -Ala Asp- Of Pro Of Arg -Gly Tyr- -Gly -Val -Ala Tyr- -Val Ser- -Ala Tyr- Tyr- 100 105 110 Glu- Tyr- Teterapeptide Trp -Gly Gin -Gly Of Thr -Leu -Val Of Thr -Val Ser- Ser- 115 120 125 Glu-1 -Val Gin -Leu -Val 5 Glu- Ser- -Gly -Gly -Gly 10 -Leu -Val Gin Of Pro -Gly 15 Asn- Ser- -Leu Of Arg Leu is 20 Ser- Is Cys -Ala -Ala Ser-25 -Gly Phe- Of Thr Phe- Ser-30 Ser- Phe- -Gly Met polypeptide Ser-35 Teterapeptide Trp -Val Of Arg Gin -Ala 40 Of Pro -Gly Lys- -Gly Leu is 45 Glu- Teterapeptide Trp -Val Ser- Ser-50 lie Ser- -Gly Ser- -Gly 55 Ser- Asp- Of Thr -Leu Tyr-60 -Ala Asp- Ser- -Val Lys-65 -Gly Of Arg Phe- Of Thr lie 70 Ser- Of Arg Asp- Asn- -Ala 75 Lys- Of Thr Of Thr -Leu Tyr-80 -Leu Gin Met polypeptide Asn- Ser-85 -Leu Of Arg Of Pro Glu- Asp-90 Of Thr -Ala -Val Tyr- Tyr-95 Is Cys Of Thr lie -Gly -Gly 100 Ser- -Leu Ser- Of Arg Ser-105 Ser- Gin -Gly Of Thr Leu is 110 -Val Of Thr -Ala -Val Gin -Leu -Val Glu- Ser- -Gly -Gly -Gly -Leu -Val Gin Of Pro -Gly -Gly 1 5 10 15 Ser- -Leu Of Arg -Leu Ser- Is Cys -Ala -Ala Ser- -Gly Of Arg Of Thr Phe- Ser- Of Thr Tyr- 20 25 30 Of Thr -Val -Gly Teterapeptide Trp Phe- Of Arg Gin -Ala Of Pro -Gly Lys- Glu- Of Arg Glu- Phe- -Val 35 40 45 -Ala -Ala lie Of Arg Of Arg Of Arg -Gly Ser- Ser- Of Thr Tyr- Tyr- -Ala Asp- Ser- -Val 50 55 60 Lys- -Gly Of Arg Phe- Of Thr lie Ser- Of Arg Asp- Asn- Ser- Lys- Asn- Of Thr -Val Tyr- 65 70 75 80 -Leu Gin Met polypeptide Asn- Ser- -Leu Of Arg Of Pro Glu- Asp- Of Thr -Ala -Val Tyr- Tyr- Is Cys 85 90 95 -Ala -Ala Asp- Of Thr Of Arg Of Thr -Val -Ala -Leu -Leu Gin Tyr- Of Arg Tyr- Asp- Tyr- 100 105 110 Teterapeptide Trp -Gly Gin -Gly Of Thr -Leu -Val Of Thr -Val Ser- Ser- -Gly -Gly -Gly -Gly Ser- 115 120 125 -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- -Gly 130 135 140 -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- Glu- -Val 145 150 155 160 Gin -Leu -Val Glu- Ser- -Gly -Gly -Gly -Leu -Val Gin Of Pro -Gly Asn- Ser- -Leu 165 170 175 Of Arg -Leu Ser- Is Cys -Ala -Ala Ser- -Gly Phe- Of Thr Phe- Ser- Ser- Phe- -Gly Met polypeptide 180 185 190 Ser- Teterapeptide Trp -Val Of Arg Gin -Ala Of Pro -Gly Lys- -Gly -Leu Glu- Teterapeptide Trp -Val Ser- Ser- 195 200 205 lie Ser- -Gly Ser- -Gly Ser- Asp- Of Thr -Leu Tyr- -Ala Asp- Ser- -Val Lys- -Gly 210 215 220 Of Arg Phe- Of Thr lie Ser- Of Arg Asp- Asn- -Ala Lys- Of Thr Of Thr -Leu Tyr- -Leu Gin 225 230 235 240 Met polypeptide Asn- Ser- -Leu Of Arg Of Pro Glu- Asp- Of Thr -Ala -Val Tyr- Tyr- Is Cys Of Thr lie 245 250 255 -Gly -Gly Ser- -Leu Ser- Of Arg Ser- Ser- Gin -Gly Of Thr -Leu -Val Of Thr -Val Ser- 260 265 270 Ser- -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- 275 280 285 -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- -Gly 290 295 300 -Gly -Gly -Gly Ser- Glu- -Val Gin -Leu -Val Glu- Ser- -Gly -Gly -Gly -Leu -Val 305 310 315 320 Gin Of Pro -Gly -Gly Ser- -Leu Of Arg -Leu Ser- Is Cys -Ala -Ala Ser- -Gly Of Arg Of Thr 325 330 335 Phe- Ser- Ser- Tyr- -Ala Met polypeptide -Gly Teterapeptide Trp Phe- Of Arg Gin -Ala Of Pro -Gly Lys- Glu- 340 345 350 Of Arg Glu- Phe- -Val -Ala -Ala lie Ser- Teterapeptide Trp Ser- -Gly -Gly Ser- Of Thr Tyr- Tyr- 355 360 365 -Ala Asp- Ser- -Val Lys- -Gly Of Arg Phe- Of Thr lie Ser- Of Arg Asp- Asn- Ser- Lys- 370 375 380 Asn- Of Thr -Val Tyr- -Leu Gin Met polypeptide Asn- Ser- -Leu Of Arg Of Pro Glu- Asp- Of Thr -Ala 385 390 395 400 -Val Tyr- Tyr- Is Cys -Ala -Ala Ser- Of Pro lie Of Pro Tyr- -Gly Ser- -Leu -Leu Of Arg 405 410 415 Of Arg Of Arg Asn- Asn- Tyr- Asp- Tyr- Teterapeptide Trp -Gly Gin -Gly Of Thr -Leu -Val Of Thr -Val 420 425 430 Ser- Ser- -Ala 435 <210> 26 <211> 439 <212> Protein <213> Artificial sequence <22 0> <223> VHH-construct F013500571 <400> 26 -Ala -Val Gin -Leu -Val Glu- Ser- -Gly -Gly -Gly -Leu -Val Gin Of Pro -Gly -Gly 1 5 10 15 Ser- -Leu Of Arg -Leu Ser- Is Cys -Ala -Ala Ser- -Gly -Gly Of Thr Phe- Ser- Ser- Tyr- 20 25 30 -Ala Met polypeptide -Gly Teterapeptide Trp Phe- Of Arg Gin -Ala Of Pro -Gly Lys- Glu- Of Arg Glu- Phe- -Val 35 40 45 -Ala -Ala lie Of Arg Of Arg Ser- -Gly Of Arg Of Arg Of Thr Tyr- Tyr- -Ala Asp- Ser- -Val 50 55 60 Lys- -Gly Of Arg Phe- Of Thr lie Ser- Of Arg Asp- Asn- Ser- Lys- Asn- Of Thr -Val Tyr- 65 70 75 80 -Leu Gin Met polypeptide Asn- Ser- -Leu Of Arg Of Pro Glu- Asp- Of Thr -Ala -Val Tyr- Tyr- Is Cys 85 90 95 -Ala -Ala -Ala Of Arg Of Arg -Val Of Arg Ser- Ser- Of Thr Of Arg Tyr- Asn- Of Thr -Gly Of Thr 100 105 110 Teterapeptide Trp Teterapeptide Trp Teterapeptide Trp Glu- Tyr- Teterapeptide Trp -Gly Gin -Gly Of Thr -Leu -Val Of Thr -Val Ser- Ser- 115 120 125 -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- -Gly 130 135 140 -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- -Gly -Gly 145 150 155 160 -Gly -Gly Ser- Glu- -Val Gin -Leu -Val Glu- Ser- -Gly -Gly -Gly -Leu -Val Gin 165 170 175 Of Pro -Gly Asn- Ser- -Leu Of Arg -Leu Ser- Is Cys -Ala -Ala Ser- -Gly Phe- Of Thr Phe- 180 185 190 Ser- Ser- Phe- -Gly Met polypeptide Ser- Teterapeptide Trp -Val Of Arg Gin -Ala Of Pro -Gly Lys- -Gly -Leu 195 200 205 Glu- Teterapeptide Trp -Val Ser- Ser- lie Ser- -Gly Ser- -Gly Ser- Asp- Of Thr -Leu Tyr- -Ala 210 215 220 Asp- Ser- -Val Lys- -Gly Of Arg Phe- Of Thr lie Ser- Of Arg Asp- Asn- -Ala Lys- Of Thr 225 230 235 240 Of Thr -Leu Tyr- -Leu Gin Met polypeptide Asn- Ser- -Leu Of Arg Of Pro Glu- Asp- Of Thr -Ala -Val 245 250 255 Tyr- Tyr- Is Cys Of Thr lie -Gly -Gly Ser- -Leu Ser- Of Arg Ser- Ser- Gin -Gly Of Thr 260 265 270 -Leu -Val Of Thr -Val Ser- Ser- -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- 275 280 285 -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- -Gly 290 295 300 -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- Glu- -Val Gin -Leu -Val Glu- Ser- 305 310 315 320 -Gly -Gly -Gly -Leu -Val Gin Of Pro -Gly -Gly Ser- -Leu Of Arg -Leu Ser- Is Cys -Ala 325 330 335 -Ala Ser- -Gly -Gly Of Thr Phe- Ser- Ser- Tyr- -Ala Met polypeptide -Gly Teterapeptide Trp Phe- Of Arg Gin 340 345 350 -Ala Of Pro -Gly Lys- Glu- Of Arg Glu- Phe- -Val -Ala -Ala lie Ser- Teterapeptide Trp Of Arg Ser- 355 360 365 -Gly Ser- Of Thr Tyr- Tyr- -Ala Asp- Ser- -Val Lys- -Gly Of Arg Phe- Of Thr lie Ser- 370 375 380 Of Arg Asp- Asn- Ser- Lys- Asn- Of Thr -Val Tyr- -Leu Gin Met polypeptide Asn- Ser- -Leu Of Arg 385 390 395 400 Of Pro Glu- Asp- Of Thr -Ala -Val Tyr- Tyr- Is Cys -Ala -Ala Asp- Of Pro Of Arg -Gly Tyr- 405 410 415 -Gly -Val -Ala Tyr- -Val Ser- -Ala Tyr- Tyr- Glu- Tyr- Teterapeptide Trp -Gly Gin -Gly Of Thr 420 425 430 -Leu -Val Of Thr -Val Ser- Ser- -Ala 435 -Ala -Val Gin -Leu -Val Glu- Ser- -Gly -Gly -Gly -Leu -Val Gin Of Pro -Gly -Gly 1 5 10 15 Ser- -Leu Of Arg -Leu Ser- Is Cys -Ala -Ala Ser- -Gly -Leu Of Thr Phe- Ser- Of Arg Tyr- 20 25 30 Of Thr Met polypeptide -Gly Teterapeptide Trp Phe- Of Arg Gin -Ala Of Pro -Gly Lys- Glu- Of Arg Glu- Phe- -Val 35 40 45 -Ala -Ala lie -Val Of Arg Ser- -Gly -Gly Ser- Of Thr Tyr- Tyr- -Ala Asp- Ser- -Val 50 55 60 Lys- -Gly Of Arg Phe- Of Thr lie Ser- Of Arg Asp- Asn- Ser- Lys- Asn- Of Thr -Val Tyr- 65 70 75 80 -Leu Gin Met polypeptide Asn- Ser- -Leu Of Arg Of Pro Glu- Asp- Of Thr -Ala -Val Tyr- Tyr- Is Cys 85 90 95 -Ala -Ala Asp- Of Arg Of Arg -Gly Of Arg -Gly Glu- Asn- Tyr- lie -Leu -Leu Tyr- Ser- 100 105 110 Ser- -Gly Of Arg Tyr- Glu- Tyr- Teterapeptide Trp -Gly Gin -Gly Of Thr -Leu -Val Of Thr -Val Ser- 115 120 125 Ser- -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- 130 135 140 -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- -Gly 145 150 155 160 -Gly -Gly -Gly Ser- Glu- -Val Gin -Leu -Val Glu- Ser- -Gly -Gly -Gly -Leu -Val 165 170 175 Gin Of Pro -Gly Asn- Ser- -Leu Of Arg -Leu Ser- Is Cys -Ala -Ala Ser- -Gly Phe- Of Thr 180 185 190 Phe- Ser- Ser- Phe- -Gly Met polypeptide Ser- Teterapeptide Trp -Val Of Arg Gin -Ala Of Pro -Gly Lys- -Gly 195 200 205 -Leu Glu- Teterapeptide Trp -Val Ser- Ser- lie Ser- -Gly Ser- -Gly Ser- Asp- Of Thr -Leu Tyr- 210 215 220 -Ala Asp- Ser- -Val Lys- -Gly Of Arg Phe- Of Thr lie Ser- Of Arg Asp- Asn- -Ala Lys- 225 230 235 240 Of Thr Of Thr -Leu Tyr- -Leu Gin Met polypeptide Asn- Ser- -Leu Of Arg Of Pro Glu- Asp- Of Thr -Ala 245 250 255 -Val Tyr- Tyr- Is Cys Of Thr lie -Gly -Gly Ser- -Leu Ser- Of Arg Ser- Ser- Gin -Gly 260 265 270 Of Thr -Leu -Val Of Thr -Val Ser- Ser- -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly 275 280 285 Ser- -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- 290 295 300 -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- Glu- -Val Gin -Leu -Val Glu- 305 310 315 320 Ser- -Gly -Gly -Gly -Leu -Val Gin Of Pro -Gly -Gly Ser- -Leu Of Arg -Leu Ser- Is Cys 325 330 335 -Ala -Ala Ser- -Gly -Gly Of Thr Phe- Ser- Ser- Tyr- -Ala Met polypeptide -Gly Teterapeptide Trp Phe- Of Arg 340 345 350 Gin -Ala Of Pro -Gly Lys- Glu- Of Arg Glu- Phe- -Val -Ala -Ala lie Ser- Teterapeptide Trp Of Arg 355 360 365 Ser- -Gly Ser- Of Thr Tyr- Tyr- -Ala Asp- Ser- -Val Lys- -Gly Of Arg Phe- Of Thr lie 370 375 380 Ser- Of Arg Asp- Asn- Ser- Lys- Asn- Of Thr -Val Tyr- -Leu Gin Met polypeptide Asn- Ser- -Leu 385 390 395 400 Of Arg Of Pro Glu- Asp- Of Thr -Ala -Val Tyr- Tyr- Is Cys -Ala -Ala Asp- Of Pro Of Arg -Gly 405 410 415 Tyr- -Gly -Val -Ala Tyr- -Val Ser- -Ala Tyr- Tyr- Glu- Tyr- Teterapeptide Trp -Gly Gin -Gly 420 425 430 Of Thr -Leu -Val Of Thr -Val Ser- Ser- -Ala 435 440 Glu- -Val Gin -Leu -Val Glu- Ser- -Gly -Gly -Gly -Leu -Val Gin Of Pro -Gly -Gly 1 5 10 15 Ser- -Leu Of Arg -Leu Ser- Is Cys -Ala -Ala Ser- -Gly Of Arg Of Thr Phe- Ser- Ser- Tyr- 20 25 30 -Ala Met polypeptide -Gly Teterapeptide Trp Phe- Of Arg Gin -Ala Of Pro -Gly Lys- Glu- Of Arg Glu- Phe- -Val 35 40 45 -Ala -Ala lie Ser- Teterapeptide Trp Ser- -Gly -Gly Ser- Of Thr Tyr- Tyr- -Ala Asp- Ser- -Val 50 55 60 Lys- -Gly Of Arg Phe- Of Thr lie Ser- Of Arg Asp- Asn- Ser- Lys- Asn- Of Thr -Val Tyr- 65 70 75 80 -Leu Gin Met polypeptide Asn- Ser- -Leu Of Arg Of Pro Glu- Asp- Of Thr -Ala -Val Tyr- Tyr- Is Cys 85 90 95 -Ala -Ala Ser- Of Pro lie Of Pro Tyr- -Gly Ser- -Leu -Leu Of Arg Of Arg Of Arg Asn- Asn- 100 105 110 Tyr- Asp- Tyr- Teterapeptide Trp -Gly Gin -Gly Of Thr -Leu -Val Of Thr -Val Ser- Ser- -Ala -Ala 115 120 125 -Ala Glu- Gin Lys- -Leu lie Ser- Glu- Glu- Asp- -Leu Asn- -Gly -Ala -Ala His- 130 135 140 His- His- His- His- His- Glu- -Val Gin -Leu -Val Glu- Ser- -Gly -Gly -Gly -Leu -Val Gin Of Pro -Gly -Gly 1 5 10 15 Ser- -Leu Of Arg -Leu Ser- Is Cys -Ala -Ala Ser- -Gly -Gly Of Thr Phe- Ser- Ser- Tyr- 20 25 30 -Ala Met polypeptide -Gly Teterapeptide Trp Phe- Of Arg Gin -Ala Of Pro -Gly Lys- Glu- Of Arg Glu- Phe- -Val 35 40 45 -Ala -Ala lie Of Arg Of Arg Ser- -Gly Of Arg Of Arg Of Thr Tyr- Tyr- -Ala Asp- Ser- -Val 50 55 60 Lys- -Gly Of Arg Phe- Of Thr lie Ser- Of Arg Asp- Asn- Ser- Lys- Asn- Of Thr -Val Tyr- 65 70 75 80 -Leu Gin Met polypeptide Asn- Ser- -Leu Of Arg Of Pro Glu- Asp- Of Thr -Ala -Val Tyr- Tyr- Is Cys 85 90 95 -Ala -Ala -Ala Of Arg Of Arg -Val Of Arg Ser- Ser- Of Thr Of Arg Tyr- Asn- Of Thr -Gly Of Thr 100 105 110 Teterapeptide Trp Teterapeptide Trp Teterapeptide Trp Glu- Tyr- Teterapeptide Trp -Gly Gin -Gly Of Thr -Leu -Val Of Thr -Val Ser- Ser- 115 120 125 -Ala -Ala -Ala Glu- Gin Lys- -Leu lie Ser- Glu- Glu- Asp- -Leu Asn- -Gly -Ala 130 135 140 -Ala His- His- His- His- His- His- 145 150 <210> 30 <211> 148 <212> Protein <213> Artificial sequence <22 0> <223> VHH-and-domain F0129093A03 <400> 30 Glu- -Val Gin -Leu -Val Glu- Ser- -Gly -Gly -Gly -Leu -Val Gin Of Pro -Gly -Gly 1 5 10 15 Ser- -Leu Of Arg -Leu Ser- Is Cys -Ala -Ala Ser- -Gly Of Arg Of Thr Phe- Ser- Of Thr Tyr- 20 25 30 -Val Met polypeptide -Gly Teterapeptide Trp Phe- Of Arg Gin -Ala Of Pro -Gly Lys- Glu- Of Arg Glu- Phe- -Val 35 40 45 -Ala -Ala lie Asn- Teterapeptide Trp Ser- -Gly Ser- Of Arg Of Thr Tyr- Tyr- -Ala Asp- Ser- -Val 50 55 60 Lys- -Gly Of Arg Phe- Of Thr lie Ser- Of Arg Asp- Asn- Ser- Lys- Asn- Of Thr -Val Tyr- 65 70 75 80 -Leu Gin Met polypeptide Asn- Ser- -Leu Of Arg Of Pro Glu- Asp- Of Thr -Ala -Val Tyr- Tyr- Is Cys 85 90 95 -Ala -Ala Ser- Of Arg Ser- Ser- Tyr- -Ala -Gly Of Arg Of Thr Tyr- Tyr- Glu- -Leu Tyr- 100 105 110 Asp- Tyr- Teterapeptide Trp -Gly Gin -Gly Of Thr -Leu -Val Of Thr -Val Ser- Ser- -Ala -Ala -Ala 115 120 125 Glu- Gin Lys- -Leu lie Ser- Glu- Glu- Asp- -Leu Asn- -Gly -Ala -Ala His- His- 130 135 140 His- His- His- His- 145 <210> 31 <211> 146 <212> Protein Glu-Gin-Val -Leu -Val Glu- Ser- -Gly -Gly -Gly -Leu -Val Gin Of Pro -Gly -Gly 1 5 10 15 Of Ser-Leu Arg of -Leu Ser- Is Cys -Ala -Ala Ser- -Gly Of Arg Of Thr Phe- Ser- Of Thr Tyr- 20 25 30 Of Thr-Val-Gly Teterapeptide Trp Phe- Of Arg Gin -Ala Of Pro -Gly Lys- Glu- Of Arg Glu- Phe- -Val 35 40 45 -Ala-Ala lie Of Arg Of Arg Of Arg -Gly Ser- Ser- Of Thr Tyr- Tyr- Ser- Asp- Ser- -Val 50 55 60 Lys-of Arg-Gly Phe- Of Thr lie Ser- Of Arg Asp- Asn- Ser- Lys- Asn- Of Thr -Val Tyr- 65 70 75 80 -Leu Gin met polypeptide Asn- Ser- -Leu Of Arg Of Pro Glu- Asp- Of Thr -Ala -Val Tyr- Tyr- Is Cys 85 90 95 -Ala-Ala-Asp Of Thr Of Arg Of Thr -Val -Ala -Leu -Leu Gin Tyr- Of Arg Tyr- Asp- Tyr- 100 105 110 Teterapeptide Trp-Gly Gin -Gly Of Thr -Leu -Val Of Thr -Val Ser- Ser- -Ala -Ala -Ala Glu- Gin 115 120 125 Lys-Leu is lie Ser- Glu- Glu- Asp- -Leu Asn- -Gly -Ala -Ala His- His- His- His- 130 135 140 His-His-145 <210> 32 <211> 152 <212> Protein <213> Artificial sequence <22 0> <223> VHH-and-domain F0130332D03 <400> 32 Glu-Gin-Val -Leu -Val Glu- Ser- -Gly -Gly -Gly -Leu -Val Gin Of Pro -Gly -Gly 1 5 10 15 Of Ser-Leu Arg of -Leu Ser- Is Cys -Ala -Ala Ser- -Gly -Leu Of Thr Phe- Ser- Of Arg Tyr- 20 25 30 Of Thr met polypeptide-Gly Teterapeptide Trp Phe- Of Arg Gin -Ala Of Pro -Gly Lys- Glu- Of Arg Glu- Phe- -Val 35 40 45 -Ala-Ala lie Asn- Of Arg Ser- -Gly -Gly Ser- Of Thr Tyr- Tyr- Ser- Asp- Ser- -Val 50 55 60 Lys-of Arg-Gly Phe- Of Thr lie Ser- Of Arg Asp- Asn- Ser- Lys- Asn- Of Thr -Val Tyr- 65 70 75 80 -Leu Gin met polypeptide Asn- Ser- -Leu Of Arg Of Pro Glu- Asp- Of Thr -Ala -Val Tyr- Tyr- Is Cys 85 90 95 -Ala-Ala-Asp Of Arg Of Arg -Gly Of Arg -Gly Glu- Asn- Tyr- Ser- -Leu -Leu Tyr- Ser- 100 105 110 Ser-Asn-Arg of Tyr- Glu- Tyr- Teterapeptide Trp -Gly Gin -Gly Of Thr -Leu -Val Of Thr -Val Ser- 115 120 125 Of Ser-Ala-Ala -Ala Glu- Gin Lys- -Leu lie Ser- Glu- Glu- Asp- -Leu Asn- -Gly 130 135 140 -Ala-Ala-His His- His- His- His- His- 145 150 <210> 33 <211> 148 <212> Protein <213> Artificial sequence <22 0> <223> VHH-and-domain F0130367B10 <400> 33 Glu-Gin-Val -Leu -Val Glu- Ser- -Gly -Gly -Gly -Leu -Val Gin Of Pro -Gly -Gly 1 5 10 15 Ser- -Leu Of Arg -Leu Ser- Is Cys -Ala -Ala Ser- -Gly -Gly Of Thr Phe- Ser- Ser- Tyr- 20 25 30 -Ala Met polypeptide -Gly Teterapeptide Trp Phe- Of Arg Gin -Ala Of Pro -Gly Lys- Glu- Of Arg Glu- Phe- -Val 35 40 45 -Ala -Ala lie Ser- Teterapeptide Trp Of Arg Ser- -Gly Ser- Of Thr Tyr- Tyr- -Ala Asp- Ser- -Val 50 55 60 Lys- -Gly Of Arg Phe- Of Thr lie Ser- Of Arg Asp- Asn- Ser- Lys- Asn- Of Thr -Val Tyr- 65 70 75 80 -Leu Gin Met polypeptide Asn- Ser- -Leu Of Arg Of Pro Glu- -Gly Of Thr -Ala -Val Tyr- Tyr- Is Cys 85 90 95 -Ala -Ala Asp- Of Pro Of Arg -Gly Tyr- -Gly -Val -Ala Tyr- -Val Ser- -Ala Tyr- Tyr- 100 105 110 Glu- Tyr- Teterapeptide Trp -Gly Gin -Gly Of Thr -Leu -Val Of Thr -Val Ser- Ser- -Gly -Ala -Ala 115 120 125 Glu- Gin Lys- -Leu lie Ser- Glu- Glu- Asp- -Leu Asn- -Gly -Ala -Ala His- His- 130 135 140 His- His- His- His- Glu- -Val Gin -Leu -Val Glu- Ser- -Gly -Gly -Gly -Leu -Val Gin Of Pro -Gly -Gly 1 5 10 15 Ser- -Leu Of Arg -Leu Ser- Is Cys -Val -Ala Ser- -Gly Of Arg Of Thr Phe- Ser- Ser- Tyr- 20 25 30 -Ala Met polypeptide -Gly Teterapeptide Trp Phe- Of Arg Gin -Ala Of Pro -Gly Lys- Glu- Of Arg Glu- Phe- -Val 35 40 45 -Ala -Ala lie Ser- Of Arg Ser- -Gly -Gly Of Arg Of Thr Tyr- Tyr- -Ala Asp- Ser- -Val 50 55 60 Lys- -Gly Of Arg Phe- Of Thr lie Ser- Of Arg Asp- Asn- Ser- Lys- Asn- Of Thr -Val Tyr- 65 70 75 80 -Leu Gin Met polypeptide Asn- Ser- -Leu Of Arg Of Pro Glu- Asp- Of Thr -Ala -Val Tyr- Tyr- Is Cys 85 90 95 -Ala -Ala Asp- Of Arg Of Arg -Val Tyr- Ser- Of Thr -Leu Of Pro Of Pro Of Thr Of Thr Ser- Of Arg 100 105 110 Tyr- Asn- Tyr- Teterapeptide Trp -Gly Gin -Gly Of Thr -Leu -Val Of Thr -Val Ser- Ser- -Ala -Ala 115 120 125 -Ala Glu- Gin Lys- -Leu lie Ser- Glu- Glu- Asp- -Leu Asn- -Gly -Ala -Ala His- 130 135 140 His- His- His- His- His- -Ala -Ala lie Of Thr Of Arg Of Thr -Gly Of Arg Of Arg Of Thr Tyr- Tyr- -Ala Asp- Ser- -Val 50 55 60 Lys- -Gly Of Arg Phe- Of Thr lie Ser- Of Arg Asp- Asn- Ser- Lys- Asn- Of Thr -Val Tyr- 65 70 75 80 -Leu Gin Met polypeptide Asn- Ser- -Leu Of Arg Of Pro Glu- Asp- Of Thr -Ala -Val Tyr- Tyr- Is Cys 85 90 95 -Ala -Ala Asp- Of Arg Of Arg -Gly Tyr- Tyr- Tyr- Tyr- Asp- Ser- Ser- Phe- Tyr- Asp- 100 105 110 Tyr- Teterapeptide Trp -Gly Gin -Gly Of Thr -Leu -Val Of Thr -Val Ser- Ser- -Ala -Ala -Ala Glu- 115 120 125 Gin Lys- -Leu lie Ser- Glu- Glu- Asp- -Leu Asn- -Gly -Ala -Ala His- His- His- 130 135 140 His- His- His- Glu- -Val Gin -Leu -Val Glu- Ser- -Gly -Gly -Gly -Leu -Val Gin Of Pro -Gly -Gly 1 5 10 15 Ser- -Leu Of Arg -Leu Ser- Is Cys -Ala -Ala Ser- -Gly Of Arg Of Thr Phe- Ser- Asp- Tyr- 20 25 30 -Gly Met polypeptide -Gly Teterapeptide Trp Phe- Of Arg Gin -Ala Of Pro -Gly Lys- Glu- Of Arg Glu- Phe- -Val 35 40 45 -Ala -Ala lie Ser- Teterapeptide Trp Ser- -Gly -Gly Of Arg Of Thr Tyr- Tyr- -Ala Asp- Ser- -Val 50 55 60 Lys- -Gly Of Arg Phe- Of Thr lie Ser- Of Arg Asp- Asn- Ser- Lys- Asn- Of Thr -Val Tyr- 65 70 75 80 -Leu Gin Met polypeptide Asn- Ser- -Leu Of Arg Of Pro Glu- Asp- Of Thr -Ala -Val Tyr- Tyr- Is Cys 85 90 95 -Ala -Ala Lys- Of Arg Of Arg -Gly Of Arg -Gly Ser- -Val Ser- Of Pro Asn- Ser- Ser- Ser- 100 105 110 Of Arg Tyr- Asn- Tyr- Teterapeptide Trp -Gly Gin -Gly Of Thr -Leu -Val Of Thr -Val Ser- Ser- -Ala 115 120 125 -Ala -Ala Glu- Gin Lys- -Leu lie Ser- Glu- Glu- Asp- -Leu Asn- -Gly -Ala -Ala 130 135 140 His- His- His- His- His- His- 145 150 Glu-1 -Val Gin -Leu -Val 5 Glu- Ser- -Gly -Gly -Gly 10 -Leu -Val Gin Of Pro -Gly 15 -Gly Ser- -Leu Of Arg Leu is 20 Ser- Is Cys -Ala -Ala Ser-25 -Gly -Leu Of Thr Phe- Ser-30 Of Arg Tyr- Of Thr Met polypeptide -Gly 35 Teterapeptide Trp Phe- Of Arg Gin -Ala 40 Of Pro -Gly Lys- Glu- Arg of 45 Glu- Phe- -Val -Ala -Ala 50 lie Asn- Of Arg Ser- -Gly 55 -Gly Ser- Of Thr Tyr- Tyr-60 Ser- Asp- Ser- -Val Lys-65 -Gly Of Arg Phe- Of Thr lie 70 Ser- Of Arg Asp- Asn- Ser-75 Lys- Asn- Of Thr -Val Tyr-80 -Leu Gin Met polypeptide Asn- Ser- -Leu Of Arg Of Pro Glu- Asp- Of Thr -Ala -Val Tyr- Tyr- Is Cys 85 90 95 -Ala -Ala Asp- Of Arg Of Arg -Gly Of Arg -Gly Glu- Asn- Tyr- Ser- -Leu -Leu Tyr- Ser- 100 105 110 Ser- Asn- Of Arg Tyr- Glu- Tyr- Teterapeptide Trp -Gly Gin -Gly Of Thr -Leu -Val Of Thr -Val Ser- 115 120 125 Ser- -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- 130 135 140 -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- -Gly 145 150 155 160 -Gly -Gly -Gly Ser- Glu- -Val Gin -Leu -Val Glu- Ser- -Gly -Gly -Gly -Leu -Val 165 170 175 Gin Of Pro -Gly Asn- Ser- -Leu Of Arg -Leu Ser- Is Cys -Ala -Ala Ser- -Gly Phe- Of Thr 180 185 190 Phe- Ser- Ser- Phe- -Gly Met polypeptide Ser- Teterapeptide Trp -Val Of Arg Gin -Ala Of Pro -Gly Lys- -Gly 195 200 205 -Leu Glu- Teterapeptide Trp -Val Ser- Ser- lie Ser- -Gly Ser- -Gly Ser- Asp- Of Thr -Leu Tyr- 210 215 220 -Ala Asp- Ser- -Val Lys- -Gly Of Arg Phe- Of Thr lie Ser- Of Arg Asp- Asn- -Ala Lys- 225 230 235 240 Of Thr Of Thr -Leu Tyr- -Leu Gin Met polypeptide Asn- Ser- -Leu Of Arg Of Pro Glu- Asp- Of Thr -Ala 245 250 255 -Val Tyr- Tyr- Is Cys Of Thr lie -Gly -Gly Ser- -Leu Ser- Of Arg Ser- Ser- Gin -Gly 260 265 270 Of Thr -Leu -Val Of Thr -Val Ser- Ser- -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly 275 280 285 Ser- -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- 290 295 300 -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- Glu- -Val Gin -Leu -Val Glu- 305 310 315 320 Ser- -Gly -Gly -Gly -Leu -Val Gin Of Pro -Gly -Gly Ser- -Leu Of Arg -Leu Ser- Is Cys 325 330 335 -Ala -Ala Ser- -Gly -Gly Of Thr Phe- Ser- Ser- Tyr- -Ala Met polypeptide -Gly Teterapeptide Trp Phe- Of Arg 340 345 350 Gin -Ala Of Pro -Gly Lys- Glu- Of Arg Glu- Phe- -Val -Ala -Ala lie Ser- Teterapeptide Trp Of Arg 355 360 365 Ser- -Gly Ser- Of Thr Tyr- Tyr- -Ala Asp- Ser- -Val Lys- -Gly Of Arg Phe- Of Thr lie 370 375 380 Ser- Of Arg Asp- Asn- Ser- Lys- Asn- Of Thr -Val Tyr- -Leu Gin Met polypeptide Asn- Ser- -Leu 385 390 395 400 Of Arg Of Pro Glu- -Gly Of Thr -Ala -Val Tyr- Tyr- Is Cys -Ala -Ala Asp- Of Pro Of Arg -Gly 405 410 415 Tyr- -Gly -Val -Ala Tyr- -Val Ser- -Ala Tyr- Tyr- Glu- Tyr- Teterapeptide Trp -Gly Gin -Gly 420 425 430 Of Thr -Leu -Val Of Thr -Val Ser- Ser- -Gly -Ala -Ala Glu- Gin Lys- -Leu lie Ser- 435 440 445 Glu- Glu- Asp- -Leu Asn- -Gly -Ala -Ala His- His- His- His- His- His- 450 455 460 -Ala -Ala 50 lie Asn- Lys-65 -Gly Of Arg Phe- -Leu Gin Met polypeptide Asn- -Ala -Ala Asp- Arg of 100 Ser- Asn- Arg of 115 Tyr- Ser- -Gly 130 -Gly -Gly -Gly 145 -Gly -Gly -Gly -Gly -Gly -Gly Ser- Gin Of Pro -Gly Asn-180 Phe- Ser- Ser-195 Phe- -Leu Glu-210 Teterapeptide Trp -Val -Ala 225 Asp- Ser- -Val Of Thr Of Thr -Leu Tyr- -Val Tyr- Tyr- Is Cys 260 Of Thr -Leu -Val 275 Of Thr Ser- -Gly 290 -Gly -Gly -Gly 305 -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Val -Ala Ser- -Gly 340 Gin -Ala Of Pro 355 -Gly -Gly -Gly 370 Of Arg Of Thr Ser-385 Of Arg Asp- Asn- Of Arg Of Pro Glu- Asp- Tyr- Ser- Of Thr Leu is 420 -Gly Of Thr Leu is 435 -Val Ser- Glu-450 Glu- Asp- Of Arg Ser- -Gly 55 -Gly Of Thr lie 70 Ser- Of Arg Ser-85 -Leu Of Arg Of Pro Of Arg -Gly Of Arg -Gly Glu- Tyr- Teterapeptide Trp -Gly 120 -Gly Ser- -Gly 135 -Gly Ser- -Gly 150 -Gly -Gly Glu-165 -Val Gin -Leu Ser- -Leu Of Arg -Leu -Gly Met polypeptide Ser- Teterapeptide Trp 200 Ser- Ser- lie 215 Ser- Lys- -Gly 230 Of Arg Phe- Leu is 245 Gin Met polypeptide Asn- Of Thr lie -Gly -Gly -Val Ser- Ser- -Gly 280 -Gly Ser- -Gly 295 -Gly Ser- -Gly 310 -Gly -Gly Leu is 325 -Val Gin Of Pro Of Arg Of Thr Phe- Ser- Lys- Glu- Of Arg Glu-360 Tyr- Tyr- -Ala 375 Asp- Ser- Lys-390 Asn- Of Thr Of Thr 405 -Ala -Val Tyr- Of Pro Of Pro Of Thr Of Thr Of Thr -Val Ser- Ser-440 -Leu Asn- -Gly 455 -Ala Ser- Of Thr Tyr- Tyr-60 Asp- Asn- Ser-75 Lys- Glu- Asp-90 Of Thr -Ala Glu-105 Asn- Tyr- Ser- Gin -Gly Of Thr -Leu -Gly -Gly Ser- -Gly 140 -Gly Ser- -Gly 155 -Gly -Val Glu-170 Ser- -Gly Ser-185 Is Cys -Ala -Ala -Val Of Arg Gin -Ala -Gly Ser- -Gly Ser-220 Of Thr lie Ser-235 Of Arg Ser- Leu is 250 Of Arg Of Pro Ser-265 -Leu Ser- Of Arg -Gly -Gly -Gly Ser- -Gly -Gly Ser- -Gly 300 -Gly Ser- Glu-315 -Val -Gly -Gly 330 Ser- -Leu Ser-345 Tyr- -Ala Met polypeptide Phe- -Val -Ala -Ala Ser- -Val Lys- -Gly 380 -Val Tyr- Leu is 395 Gin Tyr- Is Cys 410 -Ala -Ala Ser-425 Of Arg Tyr- Asn- -Gly -Ala -Ala Glu- -Ala His- His- His-460 Ser- Asp- Ser- -Val Asn- Of Thr -Val Tyr-80 -Val Tyr- Tyr-95 Is Cys -Leu Leu is 110 Tyr- Ser- -Val 125 Of Thr -Val Ser- -Gly -Gly -Gly Ser- -Gly -Gly Ser- -Gly 160 -Gly -Gly -Leu 175 -Val Ser- -Gly 190 Phe- Of Thr Of Pro 205 -Gly Lys- -Gly Asp- Of Thr -Leu Tyr- Asp- Asn- -Ala Lys-240 Glu- Asp- Of Thr 255 -Ala Ser- Ser-270 Gin -Gly -Gly 285 -Gly -Gly -Gly -Gly -Gly -Gly Ser- Gin -Leu -Val Glu-320 Of Arg -Leu Ser-335 Is Cys -Gly Teterapeptide Trp 350 Phe- Of Arg lie 365 Ser- Of Arg Ser- Of Arg Phe- Of Thr lie Met polypeptide Asn- Ser- Leu is 400 Asp- Of Arg Arg of 415 -Val Tyr- Teterapeptide Trp 430 -Gly Gin Gin 445 Lys- -Leu lie His- His- His- Ser- -Leu Of Arg -Leu Ser- Is Cys -Ala -Ala Ser- -Gly -Gly Of Thr Phe- Ser- Ser- Tyr- 20 25 30 -Ala Met polypeptide -Gly Teterapeptide Trp Phe- Of Arg Gin -Ala Of Pro -Gly Lys- Glu- Of Arg Glu- Phe- -Val 35 40 45 -Ala -Ala lie Of Arg Of Arg Ser- -Gly Of Arg Of Arg Of Thr Tyr- Tyr- -Ala Asp- Ser- -Val 50 55 60 Lys- -Gly Of Arg Phe- Of Thr lie Ser- Of Arg Asp- Asn- Ser- Lys- Asn- Of Thr -Val Tyr- 65 70 75 80 -Leu Gin Met polypeptide Asn- Ser- -Leu Of Arg Of Pro Glu- Asp- Of Thr -Ala -Val Tyr- Tyr- Is Cys 85 90 95 -Ala -Ala -Ala Of Arg Of Arg -Val Of Arg Ser- Ser- Of Thr Of Arg Tyr- Asn- Of Thr -Gly Of Thr 100 105 110 Teterapeptide Trp Teterapeptide Trp Teterapeptide Trp Glu- Tyr- Teterapeptide Trp -Gly Gin -Gly Of Thr -Leu -Val Of Thr -Val Ser- Ser- 115 120 125 -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- -Gly 130 135 140 -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- -Gly -Gly 145 150 155 160 -Gly -Gly Ser- Glu- -Val Gin -Leu -Val Glu- Ser- -Gly -Gly -Gly -Leu -Val Gin 165 170 175 Of Pro -Gly Asn- Ser- -Leu Of Arg -Leu Ser- Is Cys -Ala -Ala Ser- -Gly Phe- Of Thr Phe- 180 185 190 Ser- Ser- Phe- -Gly Met polypeptide Ser- Teterapeptide Trp -Val Of Arg Gin -Ala Of Pro -Gly Lys- -Gly -Leu 195 200 205 Glu- Teterapeptide Trp -Val Ser- Ser- lie Ser- -Gly Ser- -Gly Ser- Asp- Of Thr -Leu Tyr- -Ala 210 215 220 Asp- Ser- -Val Lys- -Gly Of Arg Phe- Of Thr lie Ser- Of Arg Asp- Asn- -Ala Lys- Of Thr 225 230 235 240 Of Thr -Leu Tyr- -Leu Gin Met polypeptide Asn- Ser- -Leu Of Arg Of Pro Glu- Asp- Of Thr -Ala -Val 245 250 255 Tyr- Tyr- Is Cys Of Thr lie -Gly -Gly Ser- -Leu Ser- Of Arg Ser- Ser- Gin -Gly Of Thr 260 265 270 -Leu -Val Of Thr -Val Ser- Ser- -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- 275 280 285 -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- -Gly 290 295 300 -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- Glu- -Val Gin -Leu -Val Glu- Ser- 305 310 315 320 -Gly -Gly -Gly -Leu -Val Gin Of Pro -Gly -Gly Ser- -Leu Of Arg -Leu Ser- Is Cys -Ala 325 330 335 -Ala Ser- -Gly -Gly Of Thr Phe- Ser- Ser- Tyr- -Ala Met polypeptide -Gly Teterapeptide Trp Phe- Of Arg Gin 340 345 350 -Ala Of Pro -Gly Lys- Glu- Of Arg Glu- Phe- -Val -Ala -Ala lie Ser- Teterapeptide Trp Of Arg Ser- 355 360 365 -Gly Ser- Of Thr Tyr- Tyr- -Ala Asp- Ser- -Val Lys- -Gly Of Arg Phe- Of Thr lie Ser- 370 375 380 Of Arg Asp- Asn- Ser- Lys- Asn- Of Thr -Val Tyr- -Leu Gin Met polypeptide Asn- Ser- -Leu Of Arg 385 390 395 400 Of Pro Glu- -Gly Of Thr -Ala -Val Tyr- Tyr- Is Cys -Ala -Ala Asp- Of Pro Of Arg -Gly Tyr- 405 410 415 -Gly -Val -Ala Tyr- -Val Ser- -Ala Tyr- Tyr- Glu- Tyr- Teterapeptide Trp -Gly Gin -Gly Of Thr 420 425 430 -Leu -Val Of Thr -Val Ser- Ser- -Gly -Ala -Ala Glu- Gin Lys- -Leu lie Ser- Glu- 435 440 445 Glu- Asp- -Leu Asn- -Gly -Ala -Ala His- His- His- His- His- His- 450 455 460 Glu-1 -Val Gin -Leu -Val 5 Glu- Ser- -Gly Ser- -Leu Of Arg Leu is 20 Ser- Is Cys -Ala -Ala Of Thr -Val -Gly 35 Teterapeptide Trp Phe- Of Arg Gin -Ala 40 -Ala -Ala 50 lie Of Arg Of Arg Of Arg -Gly 55 Ser- Lys-65 -Gly Of Arg Phe- Of Thr lie 70 Ser- Of Arg -Leu Gin Met polypeptide Asn- Ser-85 -Leu Of Arg Of Pro -Ala -Ala Asp- Of Thr 100 Of Arg Of Thr -Val -Ala Teterapeptide Trp -Gly Gin 115 -Gly Of Thr -Leu -Val Of Thr 120 -Gly -Gly 130 -Gly -Gly Ser- -Gly -Gly 135 -Gly -Gly 145 -Gly -Gly Ser- -Gly -Gly 150 -Gly -Gly Gin -Leu -Val Glu- Ser-165 -Gly -Gly -Gly Of Arg -Leu Ser- Is Cys 180 -Ala -Ala Ser- -Gly Ser- Teterapeptide Trp -Val 195 Of Arg Gin -Ala Of Pro -Gly 200 lie Ser-210 -Gly Ser- -Gly Ser- -Asp 215 Of Thr Arg of 225 Phe- Of Thr lie Ser- Arg of 230 Asp- Asn- Met polypeptide Asn- Ser- -Leu Arg of 245 Of Pro Glu- Asp- -Gly -Gly Ser- Leu is 260 Ser- Of Arg Ser- Ser- Ser- -Gly -Gly 275 -Gly -Gly Ser- -Gly -Gly 280 -Gly -Gly 290 -Gly -Gly Ser- -Gly -Gly 295 -Gly -Gly 305 -Gly -Gly Ser- Glu- -Val 310 Gin -Leu Gin Of Pro -Gly -Gly Ser-325 -Leu Of Arg -Leu Phe- Ser- Ser- Tyr-340 -Ala Met polypeptide -Gly Teterapeptide Trp Of Arg Glu- Phe-355 -Val -Ala -Ala lie Ser-360 -Ala Asp-370 Ser- -Val Lys- -Gly Arg of 375 Phe- Asn-385 Of Thr -Val Tyr- -Leu Gin 390 Met polypeptide Asn- -Val Tyr- Tyr- Is Cys -Ala 405 -Ala Asp- Of Pro Ser- -Ala Tyr- Tyr-420 Glu- Tyr- Teterapeptide Trp -Gly Ser- -Gly -Ala 435 -Ala Glu- Gin Lys- Leu is 440 -Ala -Ala 450 His- His- His- His- His-455 His- -Gly -Gly 10 -Leu -Val Gin Of Pro -Gly 15 -Gly Ser-25 -Gly Of Arg Of Thr Phe- Ser-30 Of Thr Tyr- Of Pro -Gly Lys- Glu- Arg of 45 Glu- Phe- -Val Ser- Of Thr Tyr- Tyr-60 Ser- Asp- Ser- -Val Asp- Asn- Ser-75 Lys- Asn- Of Thr -Val Tyr-80 Glu- Asp-90 Of Thr -Ala -Val Tyr- Tyr-95 Is Cys Leu is 105 -Leu Gin Tyr- Of Arg Tyr-110 Asp- Tyr- -Val Ser- Ser- -Gly -Gly 125 -Gly -Gly Ser- -Gly Ser- -Gly -Gly 140 -Gly -Gly Ser- -Gly Ser- -Gly -Gly 155 -Gly -Gly Ser- Glu- -Val 160 -Leu -Val 170 Gin Of Pro -Gly Asn- Ser-175 -Leu Phe-185 Of Thr Phe- Ser- Ser- Phe-190 -Gly Met polypeptide Lys- -Gly -Leu Glu- Teterapeptide Trp 205 -Val Ser- Ser- -Leu Tyr- -Ala Asp-220 Ser- -Val Lys- -Gly -Ala Lys- Of Thr 235 Of Thr -Leu Tyr- -Leu Gin 240 Of Thr -Ala 250 -Val Tyr- Tyr- Is Cys Of Thr 255 lie Gin 265 -Gly Of Thr -Leu -Val Of Thr 270 -Val Ser- -Gly -Gly Ser- -Gly -Gly 285 -Gly -Gly Ser- -Gly Ser- -Gly -Gly 300 -Gly -Gly Ser- -Gly -Val Glu- Ser-315 -Gly -Gly -Gly -Leu -Val 320 Ser- Is Cys 330 -Ala -Ala Ser- -Gly -Gly 335 Of Thr Phe-345 Of Arg Gin -Ala Of Pro -Gly 350 Lys- Glu- Teterapeptide Trp Of Arg Ser- -Gly Ser-365 Of Thr Tyr- Tyr- Of Thr lie Ser- Arg of 380 Asp- Asn- Ser- Lys- Ser- -Leu Arg of 395 Of Pro Glu- -Gly Of Thr -Ala 400 Of Arg -Gly 410 Tyr- -Gly -Val -Ala Tyr-415 -Val Gin 425 -Gly Of Thr -Leu -Val Of Thr 430 -Val Ser- lie Ser- Glu- Glu- Asp-445 -Leu Asn- -Gly Glu-1 -Val Gin -Leu -Val 5 Glu- Ser- -Gly Ser- -Leu Of Arg Leu is 20 Ser- Is Cys -Val -Ala -Ala Met polypeptide -Gly 35 Teterapeptide Trp Phe- Of Arg Gin -Ala 40 -Ala -Ala 50 lie Ser- Of Arg Ser- -Gly 55 -Gly Lys-65 -Gly Of Arg Phe- Of Thr lie 70 Ser- Of Arg -Leu Gin Met polypeptide Asn- Ser-85 -Leu Of Arg Of Pro -Ala -Ala Asp- Arg of 100 Of Arg -Val Tyr- Ser- Tyr- Asn- Tyr-115 Teterapeptide Trp -Gly Gin -Gly Of Thr 120 -Gly -Gly 130 Ser- -Gly -Gly -Gly -Gly 135 Ser- -Gly 145 Ser- -Gly -Gly -Gly -Gly 150 Ser- -Gly Ser- Glu- -Val Gin Leu is 165 -Val Glu- Ser- Asn- Ser- -Leu Arg of 180 -Leu Ser- Is Cys -Ala Phe- -Gly Met polypeptide 195 Ser- Teterapeptide Trp -Val Of Arg Gin 200 -Val Ser-210 Ser- lie Ser- -Gly Ser-215 -Gly -Val 225 Lys- -Gly Of Arg Phe- Of Thr 230 lie Ser- Tyr- -Leu Gin Met polypeptide Asn-245 Ser- -Leu Of Arg Is Cys Of Thr lie -Gly 260 -Gly Ser- -Leu Ser- Of Thr -Val Ser-275 Ser- -Gly -Gly -Gly -Gly 280 -Gly -Gly 290 Ser- -Gly -Gly -Gly -Gly 295 Ser- -Gly 305 Ser- -Gly -Gly -Gly -Gly 310 Ser- Glu- -Gly -Leu -Val Gin Of Pro 325 -Gly -Gly Ser- -Gly Of Arg Of Thr Phe-340 Ser- Asp- Tyr- -Gly -Gly Lys- Glu-355 Of Arg Glu- Phe- -Val -Ala 360 Of Thr Tyr-370 Tyr- -Ala Asp- Ser- -Val 375 Lys- Asn-385 Ser- Lys- Asn- Of Thr -Val 390 Tyr- -Leu Asp- Of Thr -Ala -Val Tyr-405 Tyr- Is Cys -Ala -Val Ser- Of Pro Asn-420 Ser- Ser- Ser- Of Arg -Leu -Val Of Thr 435 -Val Ser- Ser- -Gly -Ala 440 Glu- Asp-450 -Leu Asn- -Gly -Ala -Ala 455 His- -Gly -Gly 10 -Leu -Val Gin Of Pro -Gly 15 -Gly Ser-25 -Gly Of Arg Of Thr Phe- Ser-30 Ser- Tyr- Of Pro -Gly Lys- Glu- Arg of 45 Glu- Phe- -Val Of Arg Of Thr Tyr- Tyr-60 -Ala Asp- Ser- -Val Asp- Asn- Ser-75 Lys- Asn- Of Thr -Val Tyr-80 Glu- Asp-90 Of Thr -Ala -Val Tyr- Tyr-95 Is Cys Of Thr 105 -Leu Of Pro Of Pro Of Thr Of Thr 110 Ser- Of Arg -Leu -Val Of Thr -Val Ser-125 Ser- -Gly -Gly -Gly -Gly -Gly -Gly 140 Ser- -Gly -Gly -Gly -Gly -Gly -Gly 155 Ser- -Gly -Gly -Gly -Gly 160 -Gly -Gly 170 -Gly -Leu -Val Gin Of Pro 175 -Gly -Ala 185 Ser- -Gly Phe- Of Thr Phe-190 Ser- Ser- -Ala Of Pro -Gly Lys- -Gly 205 -Leu Glu- Teterapeptide Trp Ser- Asp- Of Thr Leu is 220 Tyr- -Ala Asp- Ser- Of Arg Asp- Asn-235 -Ala Lys- Of Thr Of Thr Leu is 240 Of Pro Glu-250 Asp- Of Thr -Ala -Val Tyr-255 Tyr- Arg of 265 Ser- Ser- Gin -Gly Of Thr 270 -Leu -Val Ser- -Gly -Gly -Gly -Gly 285 Ser- -Gly -Gly -Gly -Gly -Gly -Gly 300 Ser- -Gly -Gly -Gly -Val Gin Leu is 315 -Val Glu- Ser- -Gly -Gly 320 -Leu Arg of 330 -Leu Ser- Is Cys -Ala -Ala 335 Ser- Met polypeptide 345 -Gly Teterapeptide Trp Phe- Of Arg Gin 350 -Ala Of Pro -Ala lie Ser- Teterapeptide Trp Ser-365 -Gly -Gly Of Arg -Gly Of Arg Phe- Of Thr 380 lie Ser- Of Arg Asp- Gin Met polypeptide Asn-395 Ser- -Leu Of Arg Of Pro Glu-400 -Ala Lys-410 Of Arg Of Arg -Gly Of Arg -Gly 415 Ser- Tyr-425 Asn- Tyr- Teterapeptide Trp -Gly Gin 430 -Gly Of Thr -Ala-His -Glu-His Gin-His Lys-His-460 445-His-Leu lie Ser- Glu- Glu-1 -Val Gin -Leu -Val 5 Glu- Ser- -Gly Ser- -Leu Of Arg Leu is 20 Ser- Is Cys -Ala -Ala -Ala Met polypeptide -Gly 35 Teterapeptide Trp Phe- Of Arg Gin -Ala 40 -Ala -Ala 50 lie Of Thr Of Arg Of Thr -Gly 55 Of Arg Lys-65 -Gly Of Arg Phe- Of Thr lie 70 Ser- Of Arg -Leu Gin Met polypeptide Asn- Ser-85 -Leu Of Arg Of Pro -Ala -Ala Asp- Arg of 100 Of Arg -Gly Tyr- Tyr- Tyr- Teterapeptide Trp -Gly 115 Gin -Gly Of Thr -Leu -Val 120 Ser- -Gly 130 -Gly -Gly -Gly Ser- -Gly 135 -Gly -Gly 145 -Gly -Gly -Gly Ser- -Gly 150 -Gly -Gly -Val Gin -Leu -Val Glu-165 Ser- -Gly -Gly -Leu Of Arg -Leu Ser-180 Is Cys -Ala -Ala Ser- Met polypeptide Ser- Teterapeptide Trp 195 -Val Of Arg Gin -Ala Of Pro 200 Ser- lie 210 Ser- -Gly Ser- -Gly Ser-215 Asp- -Gly 225 Of Arg Phe- Of Thr lie Ser-230 Of Arg Asp- Gin Met polypeptide Asn- Ser- Leu is 245 Of Arg Of Pro Glu- lie -Gly -Gly Ser-260 -Leu Ser- Of Arg Ser- Ser- Ser- -Gly 275 -Gly -Gly -Gly Ser- -Gly 280 Ser- -Gly 290 -Gly -Gly -Gly Ser- -Gly 295 -Gly -Gly 305 -Gly -Gly -Gly Ser- Glu-310 -Val Gin -Val Gin Of Pro -Gly -Gly 325 Ser- -Leu Of Arg Of Thr Phe- Ser- Ser-340 Tyr- -Ala Met polypeptide -Gly Glu- Of Arg Glu-355 Phe- -Val -Ala -Ala lie 360 Tyr- -Ala 370 Asp- Ser- -Val Lys- -Gly 375 Of Arg Lys-385 Asn- Of Thr -Val Tyr- -Leu 390 Gin Met polypeptide -Ala -Val Tyr- Tyr- Is Cys 405 -Ala -Ala -Ala Tyr- Asn- Of Thr -Gly 420 Of Thr Teterapeptide Trp Teterapeptide Trp Teterapeptide Trp -Gly -Gly 10 -Leu -Val Gin Of Pro -Gly 15 -Gly Ser-25 -Gly Of Arg Of Thr Phe- Ser-30 Ser- Tyr- Of Pro -Gly Lys- Glu- Arg of 45 Glu- Phe- -Val Of Arg Of Thr Tyr- Tyr-60 -Ala Asp- Ser- -Val Asp- Asn- Ser-75 Lys- Asn- Of Thr -Val Tyr-80 Glu- Asp-90 Of Thr -Ala -Val Tyr- Tyr-95 Is Cys Tyr-105 Tyr- Asp- Ser- Ser- Phe-110 Tyr- Asp- Of Thr -Val Ser- Ser- -Gly 125 -Gly -Gly -Gly -Gly -Gly Ser- -Gly 140 -Gly -Gly -Gly Ser- -Gly Ser- -Gly 155 -Gly -Gly -Gly Ser- Glu-160 -Gly Leu is 170 -Val Gin Of Pro -Gly Asn-175 Ser- -Gly 185 Phe- Of Thr Phe- Ser- Ser-190 Phe- -Gly -Gly Lys- -Gly -Leu Glu-205 Teterapeptide Trp -Val Ser- Of Thr -Leu Tyr- -Ala 220 Asp- Ser- -Val Lys- Asn- -Ala Lys-235 Of Thr Of Thr -Leu Tyr- Leu is 240 Asp- Of Thr 250 -Ala -Val Tyr- Tyr- Is Cys 255 Of Thr Ser-265 Gin -Gly Of Thr -Leu -Val 270 Of Thr -Val -Gly -Gly -Gly Ser- -Gly 285 -Gly -Gly -Gly -Gly -Gly Ser- -Gly 300 -Gly -Gly -Gly Ser- -Leu -Val Glu-315 Ser- -Gly -Gly -Gly Leu is 320 -Leu Ser-330 Is Cys -Ala -Ala Ser- -Gly 335 -Gly Teterapeptide Trp 345 Phe- Of Arg Gin -Ala Of Pro 350 -Gly Lys- Of Arg Of Arg Ser- -Gly Arg of 365 Of Arg Of Thr Tyr- Phe- Of Thr lie Ser-380 Of Arg Asp- Asn- Ser- Asn- Ser- Leu is 395 Of Arg Of Pro Glu- Asp- Of Thr 400 Of Arg Arg of 410 -Val Of Arg Ser- Ser- Of Thr 415 Of Arg Glu-425 Tyr- Teterapeptide Trp -Gly Gin -Gly 430 Of Thr -Leu Glu-1 -Val Gin -Leu -Val 5 Glu- Ser- -Gly Ser- -Leu Of Arg Leu is 20 Ser- Is Cys -Val -Ala -Ala Met polypeptide -Gly 35 Teterapeptide Trp Phe- Of Arg Gin -Ala 40 -Ala -Ala 50 lie Ser- Of Arg Ser- -Gly 55 -Gly Lys-65 -Gly Of Arg Phe- Of Thr lie 70 Ser- Of Arg -Leu Gin Met polypeptide Asn- Ser-85 -Leu Of Arg Of Pro -Ala -Ala Asp- Arg of 100 Of Arg -Val Tyr- Ser- Tyr- Asn- Tyr-115 Teterapeptide Trp -Gly Gin -Gly Of Thr 120 -Gly -Gly 130 Ser- -Gly -Gly -Gly -Gly 135 Ser- -Gly 145 Ser- -Gly -Gly -Gly -Gly 150 Ser- -Gly Ser- Glu- -Val Gin Leu is 165 -Val Glu- Ser- Asn- Ser- -Leu Arg of 180 -Leu Ser- Is Cys -Ala Phe- -Gly Met polypeptide 195 Ser- Teterapeptide Trp -Val Of Arg Gin 200 -Val Ser-210 Ser- lie Ser- -Gly Ser-215 -Gly -Val 225 Lys- -Gly Of Arg Phe- Of Thr 230 lie Ser- Tyr- -Leu Gin Met polypeptide Asn-245 Ser- -Leu Of Arg Is Cys Of Thr lie -Gly 260 -Gly Ser- -Leu Ser- Of Thr -Val Ser-275 Ser- -Gly -Gly -Gly -Gly 280 -Gly -Gly 290 Ser- -Gly -Gly -Gly -Gly 295 Ser- -Gly 305 Ser- -Gly -Gly -Gly -Gly 310 Ser- Glu- -Gly -Leu -Val Gin Of Pro 325 -Gly -Gly Ser- -Gly -Gly Of Thr Phe-340 Ser- Ser- Tyr- -Ala -Gly Lys- Glu-355 Of Arg Glu- Phe- -Val -Ala 360 Of Thr Tyr-370 Tyr- -Ala Asp- Ser- -Val 375 Lys- Asn-385 Ser- Lys- Asn- Of Thr -Val 390 Tyr- -Leu -Gly -Gly 10 -Leu -Val Gin Of Pro -Gly 15 -Gly Ser-25 -Gly Of Arg Of Thr Phe- Ser-30 Ser- Tyr- Of Pro -Gly Lys- Glu- Arg of 45 Glu- Phe- -Val Of Arg Of Thr Tyr- Tyr-60 -Ala Asp- Ser- -Val Asp- Asn- Ser-75 Lys- Asn- Of Thr -Val Tyr-80 Glu- Asp-90 Of Thr -Ala -Val Tyr- Tyr-95 Is Cys Of Thr 105 -Leu Of Pro Of Pro Of Thr Of Thr 110 Ser- Of Arg -Leu -Val Of Thr -Val Ser-125 Ser- -Gly -Gly -Gly -Gly -Gly -Gly 140 Ser- -Gly -Gly -Gly -Gly -Gly -Gly 155 Ser- -Gly -Gly -Gly -Gly 160 -Gly -Gly 170 -Gly -Leu -Val Gin Of Pro 175 -Gly -Ala 185 Ser- -Gly Phe- Of Thr Phe-190 Ser- Ser- -Ala Of Pro -Gly Lys- -Gly 205 -Leu Glu- Teterapeptide Trp Ser- Asp- Of Thr Leu is 220 Tyr- -Ala Asp- Ser- Of Arg Asp- Asn-235 -Ala Lys- Of Thr Of Thr Leu is 240 Of Pro Glu-250 Asp- Of Thr -Ala -Val Tyr-255 Tyr- Arg of 265 Ser- Ser- Gin -Gly Of Thr 270 -Leu -Val Ser- -Gly -Gly -Gly -Gly 285 Ser- -Gly -Gly -Gly -Gly -Gly -Gly 300 Ser- -Gly -Gly -Gly -Val Gin Leu is 315 -Val Glu- Ser- -Gly -Gly 320 -Leu Arg of 330 -Leu Ser- Is Cys -Ala -Ala 335 Ser- Met polypeptide 345 -Gly Teterapeptide Trp Phe- Of Arg Gin 350 -Ala Of Pro -Ala lie Of Arg Of Arg Ser-365 -Gly Of Arg Of Arg -Gly Of Arg Phe- Of Thr 380 lie Ser- Of Arg Asp- Gin Met polypeptide Asn-395 Ser- -Leu Of Arg Of Pro Glu-400 Glu- -Val Gin -Leu -Val Glu- Ser- -Gly -Gly -Gly -Leu -Val Gin Of Pro -Gly -Gly 1 5 10 15 Ser- -Leu Of Arg -Leu Ser- Is Cys -Ala -Ala Ser- -Gly Of Arg Of Thr Phe- Ser- Of Thr Tyr- 20 25 30 -Val Met polypeptide -Gly Teterapeptide Trp Phe- Of Arg Gin -Ala Of Pro -Gly Lys- Glu- Of Arg Glu- Phe- -Val 35 40 45 -Ala -Ala lie Asn- Teterapeptide Trp Ser- -Gly Ser- Of Arg Of Thr Tyr- Tyr- -Ala Asp- Ser- -Val 50 55 60 Lys- -Gly Of Arg Phe- Of Thr lie Ser- Of Arg Asp- Asn- Ser- Lys- Asn- Of Thr -Val Tyr- 65 70 75 80 -Leu Gin Met polypeptide Asn- Ser- -Leu Of Arg Of Pro Glu- Asp- Of Thr -Ala -Val Tyr- Tyr- Is Cys 85 90 95 -Ala -Ala Ser- Of Arg Ser- Ser- Tyr- -Ala -Gly Of Arg Of Thr Tyr- Tyr- Glu- -Leu Tyr- 100 105 110 Asp- Tyr- Teterapeptide Trp -Gly Gin -Gly Of Thr -Leu -Val Of Thr -Val Ser- Ser- -Gly -Gly -Gly 115 120 125 -Gly Ser- -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly 130 135 140 Ser- -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- 145 150 155 160 Glu- -Val Gin -Leu -Val Glu- Ser- -Gly -Gly -Gly -Leu -Val Gin Of Pro -Gly Asn- 165 170 175 Ser- -Leu Of Arg -Leu Ser- Is Cys -Ala -Ala Ser- -Gly Phe- Of Thr Phe- Ser- Ser- Phe- 180 185 190 -Gly Met polypeptide Ser- Teterapeptide Trp -Val Of Arg Gin -Ala Of Pro -Gly Lys- -Gly -Leu Glu- Teterapeptide Trp -Val 195 200 205 Ser- Ser- lie Ser- -Gly Ser- -Gly Ser- Asp- Of Thr -Leu Tyr- -Ala Asp- Ser- -Val 210 215 220 Lys- -Gly Of Arg Phe- Of Thr lie Ser- Of Arg Asp- Asn- -Ala Lys- Of Thr Of Thr -Leu Tyr- 225 230 235 240 -Leu Gin Met polypeptide Asn- Ser- -Leu Of Arg Of Pro Glu- Asp- Of Thr -Ala -Val Tyr- Tyr- Is Cys 245 250 255 Of Thr lie -Gly -Gly Ser- -Leu Ser- Of Arg Ser- Ser- Gin -Gly Of Thr -Leu -Val Of Thr 260 265 270 -Val Ser- Ser- -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly 275 280 285 -Gly Ser- -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly 290 295 300 Ser- -Gly -Gly -Gly -Gly Ser- Glu- -Val Gin -Leu -Val Glu- Ser- -Gly -Gly -Gly 305 310 315 320 -Leu -Val Gin Of Pro -Gly -Gly Ser- -Leu Of Arg -Leu Ser- Is Cys -Ala -Ala Ser- -Gly 325 330 335 Of Arg Of Thr Phe- Ser- Of Thr Tyr- Of Thr -Val -Gly Teterapeptide Trp Phe- Of Arg Gin -Ala Of Pro -Gly 340 345 350 Lys- Glu- Of Arg Glu- Phe- -Val -Ala -Ala lie Of Arg Of Arg Of Arg -Gly Ser- Ser- Of Thr 355 360 365 Tyr- Tyr- Ser- Asp- Ser- -Val Lys- -Gly Of Arg Phe- Of Thr lie Ser- Of Arg Asp- Asn- 370 375 380 Ser- Lys- Asn- Of Thr -Val Tyr- -Leu Gin Met polypeptide Asn- Ser- -Leu Of Arg Of Pro Glu- Asp- 385 390 395 400 Of Thr -Ala -Val Tyr- Tyr- Is Cys -Ala -Ala Asp- Of Thr Of Arg Of Thr -Val -Ala -Leu -Leu 405 410 415 Gin Tyr- Of Arg Tyr- Asp- Tyr- Teterapeptide Trp -Gly Gin -Gly Of Thr -Leu -Val Of Thr -Val Ser- 420 425 430 Ser- -Gly -Ala -Ala Glu- Gin Lys- -Leu lie Ser- Glu- Glu- Asp- -Leu Asn- -Gly 435 440 445 -Ala -Ala His- His- His- His- His- His- 450 455 Glu-1 -Val Gin -Leu -Val 5 Glu- Ser- -Gly Ser- -Leu Of Arg Leu is 20 Ser- Is Cys -Ala -Ala Of Thr Met polypeptide -Gly 35 Teterapeptide Trp Phe- Of Arg Gin -Ala 40 -Ala -Ala 50 lie Asn- Of Arg Ser- -Gly 55 -Gly Lys-65 -Gly Of Arg Phe- Of Thr lie 70 Ser- Of Arg -Leu Gin Met polypeptide Asn- Ser-85 -Leu Of Arg Of Pro -Ala -Ala Asp- Arg of 100 Of Arg -Gly Of Arg -Gly Ser- Asn- Arg of 115 Tyr- Glu- Tyr- Teterapeptide Trp -Gly 120 Ser- -Gly 130 -Gly -Gly -Gly Ser- -Gly 135 -Gly -Gly 145 -Gly -Gly -Gly Ser- -Gly 150 -Gly -Gly -Gly -Gly -Gly Ser- Glu-165 -Val Gin -Leu Gin Of Pro -Gly Asn-180 Ser- -Leu Of Arg -Leu Phe- Ser- Ser-195 Phe- -Gly Met polypeptide Ser- Teterapeptide Trp 200 -Leu Glu-210 Teterapeptide Trp -Val Ser- Ser- lie 215 Ser- -Ala 225 Asp- Ser- -Val Lys- -Gly 230 Of Arg Phe- Of Thr Of Thr -Leu Tyr- Leu is 245 Gin Met polypeptide Asn- -Val Tyr- Tyr- Is Cys 260 Of Thr lie -Gly -Gly Of Thr -Leu -Val 275 Of Thr -Val Ser- Ser- -Gly 280 Ser- -Gly 290 -Gly -Gly -Gly Ser- -Gly 295 -Gly -Gly 305 -Gly -Gly -Gly Ser- -Gly 310 -Gly -Gly Ser- -Gly -Gly -Gly Leu is 325 -Val Gin Of Pro -Gly -Gly 10 -Leu -Val Gin Of Pro -Gly 15 -Gly Ser-25 -Gly -Leu Of Thr Phe- Ser-30 Of Arg Tyr- Of Pro -Gly Lys- Glu- Arg of 45 Glu- Phe- -Val Ser- Of Thr Tyr- Tyr-60 Ser- Asp- Ser- -Val Asp- Asn- Ser-75 Lys- Asn- Of Thr -Val Tyr-80 Glu- Asp-90 Of Thr -Ala -Val Tyr- Tyr-95 Is Cys Glu-105 Asn- Tyr- Ser- -Leu Leu is 110 Tyr- Ser- Gin -Gly Of Thr -Leu -Val 125 Of Thr -Val Ser- -Gly -Gly Ser- -Gly 140 -Gly -Gly -Gly Ser- -Gly Ser- -Gly 155 -Gly -Gly -Gly Ser- -Gly 160 -Val Glu-170 Ser- -Gly -Gly -Gly -Leu 175 -Val Ser-185 Is Cys -Ala -Ala Ser- -Gly 190 Phe- Of Thr -Val Of Arg Gin -Ala Of Pro 205 -Gly Lys- -Gly -Gly Ser- -Gly Ser-220 Asp- Of Thr -Leu Tyr- Of Thr lie Ser-235 Of Arg Asp- Asn- -Ala Lys-240 Ser- Leu is 250 Of Arg Of Pro Glu- Asp- Of Thr 255 -Ala Ser-265 -Leu Ser- Of Arg Ser- Ser-270 Gin -Gly -Gly -Gly -Gly Ser- -Gly 285 -Gly -Gly -Gly -Gly -Gly Ser- -Gly 300 -Gly -Gly -Gly Ser- -Gly Ser- Glu-315 -Val Gin -Leu -Val Glu-320 -Gly -Gly 330 Ser- -Leu Of Arg -Leu Ser-335 Is Cys -Ala -Ala Ser- -Gly Of Arg Of Thr Phe- Ser- Ser- Tyr- -Ala Met polypeptide -Gly Teterapeptide Trp Phe- Of Arg 340 345 350 Gin -Ala Of Pro -Gly Lys- Glu- Of Arg Glu- Phe- -Val -Ala -Ala lie Ser- Teterapeptide Trp Ser- 355 360 365 -Gly -Gly Ser- Of Thr Tyr- Tyr- -Ala Asp- Ser- -Val Lys- -Gly Of Arg Phe- Of Thr lie 370 375 380 Ser- Of Arg Asp- Asn- Ser- Lys- Asn- Of Thr -Val Tyr- -Leu Gin Met polypeptide Asn- Ser- -Leu 385 390 395 400 Of Arg Of Pro Glu- Asp- Of Thr -Ala -Val Tyr- Tyr- Is Cys -Ala -Ala Ser- Of Pro lie Of Pro 405 410 415 Tyr- -Gly Ser- -Leu -Leu Of Arg Of Arg Of Arg Asn- Asn- Tyr- Asp- Tyr- Teterapeptide Trp -Gly Gin 420 425 430 -Gly Of Thr -Leu -Val Of Thr -Val Ser- Ser- -Gly -Ala -Ala Glu- Gin Lys- -Leu lie 435 440 445 Ser- Glu- Glu- Asp- -Leu Asn- -Gly -Ala -Ala His- His- His- His- His- His- 450 455 460 Glu- -Val Gin -Leu -Val Glu- Ser- -Gly -Gly -Gly -Leu -Val Gin Of Pro -Gly -Gly 1 5 10 15 Ser- -Leu Of Arg -Leu Ser- Is Cys -Ala -Ala Ser- -Gly Of Arg Of Thr Phe- Ser- Of Thr Tyr- 20 25 30 Of Thr -Val -Gly Teterapeptide Trp Phe- Of Arg Gin -Ala Of Pro -Gly Lys- Glu- Of Arg Glu- Phe- -Val 35 40 45 -Ala -Ala lie Of Arg Of Arg Of Arg -Gly Ser- Ser- Of Thr Tyr- Tyr- Ser- Asp- Ser- -Val 50 55 60 Lys- -Gly Of Arg Phe- Of Thr lie Ser- Of Arg Asp- Asn- Ser- Lys- Asn- Of Thr -Val Tyr- 65 70 75 80 -Leu Gin Met polypeptide Asn- Ser- -Leu Of Arg Of Pro Glu- Asp- Of Thr -Ala -Val Tyr- Tyr- Is Cys 85 90 95 -Ala -Ala Asp- Of Thr Of Arg Of Thr -Val -Ala -Leu -Leu Gin Tyr- Of Arg Tyr- Asp- Tyr- 100 105 110 Teterapeptide Trp -Gly Gin -Gly Of Thr -Leu -Val Of Thr -Val Ser- Ser- -Gly -Gly -Gly -Gly Ser- 115 120 125 -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- -Gly 130 135 140 -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- Glu- -Val 145 150 155 160 Gin -Leu -Val Glu- Ser- -Gly -Gly -Gly -Leu -Val Gin Of Pro -Gly Asn- Ser- -Leu 165 170 175 Of Arg -Leu Ser- Is Cys -Ala -Ala Ser- -Gly Phe- Of Thr Phe- Ser- Ser- Phe- -Gly Met polypeptide 180 185 190 Ser- Teterapeptide Trp -Val Of Arg Gin -Ala Of Pro -Gly Lys- -Gly -Leu Glu- Teterapeptide Trp -Val Ser- Ser- 195 200 205 lie Ser- -Gly Ser- -Gly Ser- Asp- Of Thr -Leu Tyr- -Ala Asp- Ser- -Val Lys- -Gly 210 215 220 Of Arg Phe- Of Thr lie Ser- Of Arg Asp- Asn- -Ala Lys- Of Thr Of Thr -Leu Tyr- -Leu Gin 225 230 235 240 Met polypeptide Asn- Ser- -Leu Of Arg Of Pro Glu- Asp- Of Thr -Ala -Val Tyr- Tyr- Is Cys Of Thr lie 245 250 255 -Gly -Gly Ser- -Leu Ser- Of Arg Ser- Ser- Gin -Gly Of Thr -Leu -Val Of Thr -Val Ser- 260 265 270 Ser- -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- 275 280 285 -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- -Gly -Gly -Gly -Gly Ser- -Gly 290 295 300 -Gly -Gly -Gly Ser- Glu- -Val Gin -Leu -Val Glu- Ser- -Gly -Gly -Gly -Leu -Val 305 310 315 320 Gin Of Pro -Gly -Gly Ser- -Leu Of Arg -Leu Ser- Is Cys -Ala -Ala Ser- -Gly Of Arg Of Thr 325 330 335 Phe- Ser- Ser- Tyr- -Ala Met polypeptide -Gly Teterapeptide Trp Phe- Of Arg Gin -Ala Of Pro -Gly Lys- Glu- 340 345 350 Of Arg Glu- Phe- -Val -Ala -Ala lie Ser- Teterapeptide Trp Ser- -Gly -Gly Ser- Of Thr Tyr- Tyr- 355 360 365 -Ala Asp- Ser- -Val Lys- -Gly Of Arg Phe- Of Thr lie Ser- Of Arg Asp- Asn- Ser- Lys- 370 375 380 Asn- Of Thr -Val Tyr- -Leu Gin Met polypeptide Asn- Ser- -Leu Of Arg Of Pro Glu- Asp- Of Thr -Ala 385 390 395 400 -Val Tyr- Tyr- Is Cys -Ala -Ala Ser- Of Pro lie Of Pro Tyr- -Gly Ser- -Leu -Leu Of Arg 405 410 415 Of Arg Of Arg Asn- Asn- Tyr- Asp- Tyr- Teterapeptide Trp -Gly Gin -Gly Of Thr -Leu -Val Of Thr -Val 420 425 430 Ser- Ser- -Gly -Ala -Ala Glu- Gin Lys- -Leu lie Ser- Glu- Glu- Asp- -Leu Asn- 435 440 445 -Gly -Ala -Ala His- His- His- His- His- His- 450 455 Glu-1 -Val Gin -Leu -Val 5 Glu- Ser- -Gly Ser- -Leu Of Arg Leu is 20 Ser- Is Cys -Ala -Ala -Ala Met polypeptide -Gly 35 Teterapeptide Trp Phe- Of Arg Gin -Ala 40 -Ala -Ala 50 lie Ser- Teterapeptide Trp Ser- -Gly 55 -Gly Lys-65 -Gly Of Arg Phe- Of Thr lie 70 Ser- Of Arg -Leu Gin Met polypeptide Asn- Ser-85 -Leu Of Arg Of Pro -Ala -Ala Ser- Of Pro 100 lie Of Pro Tyr- -Gly Tyr- Asp- Tyr-115 Teterapeptide Trp -Gly Gin -Gly Of Thr 120 -Gly -Gly 130 Ser- -Gly -Gly -Gly -Gly 135 Ser- -Gly 145 Ser- -Gly -Gly -Gly -Gly 150 Ser- -Gly Ser- Glu- -Val Gin Leu is 165 -Val Glu- Ser- Asn- Ser- -Leu Arg of 180 -Leu Ser- Is Cys -Ala Phe- -Gly Met polypeptide 195 Ser- Teterapeptide Trp -Val Of Arg Gin 200 -Val Ser-210 Ser- lie Ser- -Gly Ser-215 -Gly -Val 225 Lys- -Gly Of Arg Phe- Of Thr 230 lie Ser- Tyr- -Leu Gin Met polypeptide Asn-245 Ser- -Leu Of Arg Is Cys Of Thr lie -Gly 260 -Gly Ser- -Leu Ser- -Gly -Gly 10 -Leu -Val Gin Of Pro -Gly 15 -Gly Ser-25 -Gly Of Arg Of Thr Phe- Ser-30 Ser- Tyr- Of Pro -Gly Lys- Glu- Arg of 45 Glu- Phe- -Val Ser- Of Thr Tyr- Tyr-60 -Ala Asp- Ser- -Val Asp- Asn- Ser-75 Lys- Asn- Of Thr -Val Tyr-80 Glu- Asp-90 Of Thr -Ala -Val Tyr- Tyr-95 Is Cys Ser-105 -Leu -Leu Of Arg Of Arg Arg of 110 Asn- Asn- -Leu -Val Of Thr -Val Ser-125 Ser- -Gly -Gly -Gly -Gly -Gly -Gly 140 Ser- -Gly -Gly -Gly -Gly -Gly -Gly 155 Ser- -Gly -Gly -Gly -Gly 160 -Gly -Gly 170 -Gly -Leu -Val Gin Of Pro 175 -Gly -Ala 185 Ser- -Gly Phe- Of Thr Phe-190 Ser- Ser- -Ala Of Pro -Gly Lys- -Gly 205 -Leu Glu- Teterapeptide Trp Ser- Asp- Of Thr Leu is 220 Tyr- -Ala Asp- Ser- Of Arg Asp- Asn-235 -Ala Lys- Of Thr Of Thr Leu is 240 Of Pro Glu-250 Asp- Of Thr -Ala -Val Tyr-255 Tyr- Arg of 265 Ser- Ser- Gin -Gly Of Thr 270 -Leu -Val Of Thr -Val Ser-275 Ser- -Gly -Gly -Gly -Gly 280 -Gly -Gly 290 Ser- -Gly -Gly -Gly -Gly 295 Ser- -Gly 305 Ser- -Gly -Gly -Gly -Gly 310 Ser- Glu- -Gly -Leu -Val Gin Of Pro 325 -Gly -Gly Ser- -Gly -Gly Of Thr Phe-340 Ser- Ser- Tyr- -Ala -Gly Lys- Glu-355 Of Arg Glu- Phe- -Val -Ala 360 Of Thr Tyr-370 Tyr- -Ala Asp- Ser- -Val 375 Lys- Asn-385 Ser- Lys- Asn- Of Thr -Val 390 Tyr- -Leu Asp- Of Thr -Ala -Val Tyr-405 Tyr- Is Cys -Ala Of Thr Of Arg Tyr- Asn-420 Of Thr -Gly Of Thr Teterapeptide Trp Of Thr -Leu -Val 435 Of Thr -Val Ser- Ser- -Gly 440 Glu- Glu-450 Asp- -Leu Asn- -Gly -Ala 455 -Ala Ser- -Gly -Gly -Gly -Gly 285 Ser- -Gly -Gly -Gly -Gly -Gly -Gly 300 Ser- -Gly -Gly -Gly -Val Gin Leu is 315 -Val Glu- Ser- -Gly -Gly 320 -Leu Arg of 330 -Leu Ser- Is Cys -Ala -Ala 335 Ser- Met polypeptide 345 -Gly Teterapeptide Trp Phe- Of Arg Gin 350 -Ala Of Pro -Ala lie Of Arg Of Arg Ser-365 -Gly Of Arg Of Arg -Gly Of Arg Phe- Of Thr 380 lie Ser- Of Arg Asp- Gin Met polypeptide Asn-395 Ser- -Leu Of Arg Of Pro Glu-400 -Ala -Ala 410 Of Arg Of Arg -Val Of Arg Ser-415 Ser- Teterapeptide Trp 425 Teterapeptide Trp Glu- Tyr- Teterapeptide Trp -Gly 430 Gin -Gly -Ala-His -Ala-His -Glu-His Gin-His 460 Lys-445-His -Leu-His lie Ser-