Neuroprotective iron chelators and pharmaceutical compositions comprising them

Novel iron chelators exhibiting neuroprotective and good transport properties are useful in iron chelation therapy for treatment of a disease, disorder or condition associated with iron overload and oxidative stress, e.g., a neurodegenerative or cerebrovascular disease or disorder, a neoplastic disease, hemochromatosis, thalassemia, a cardiovascular disease, diabetes, an inflammatory disorder, anthracycline cardiotoxicity, a viral infection, a protozoal infection, a yeast infection, retarding aging, and prevention and/or treatment of skin aging and skin protection against sunlight and/or UV light. The iron chelator function is provided by a 8-hydroxyquinoline, a hydroxypyridinone or a hydroxamate moiety. The neuroprotective function is imparted to the compound, e.g., by a neuroprotective peptide. A combined antiapoptotic and neuroprotective function is provided by a propargyl group.

Novel exendin variant and conjugate thereof

The invention provides a novel Exendin variant and the Exendin variant conjugate conjugating polymer thereon, the pharmaceutical composition comprising them and use of them for treating diseases such as reducing blood glucose, treating diabetes, especially Type II diabetes. The invention also provides the use of Exendin conjugate for lowering body weight.

Radiolabeled compound directable in vivo to target tissue and use thereof

The present invention provides a clinically usable radiolabeled compound that is precisely directable in vivo to a target tissue. The compound of the present invention has a first polypeptide or an analogue thereof, and a second polypeptide bonded to an N-terminus of the first polypeptide or the analogue thereof. In the compound, the first polypeptide is a polypeptide that specifically binds with a protein expressed in a target tissue, the second polypeptide has an amino acid region that has a high affinity for a radioactive metal nuclide, and the radioactive metal nuclide that has a high affinity for the amino acid region is held in the amino acid region.

Site-directed peg-modified exendin-4 analogs and uses thereof

Disclosed are PEG-modified Exendin-4 analogs and uses thereof. In particular, disclosed are PEG-modified Exendin-4 analogs as shown in formula (I), i.e., PEG-M-X-(Ex-4), or pharmaceutically acceptable salts thereof, as well as Exendin-4 analogs as shown in formula (II), i.e., [Aa p ]Exendin-4, wherein the symbols are as defined in the specification. Further disclosed are methods for preparing PEG-modified Exendin-4 analogs, uses of PEG-modified Exendin-4 analogs, compositions comprising the same, as well as use of the Exendin-4 analogs in the preparation of the PEG-modified Exendin-4 analogs. In the PEG-modified Exendin-4 analogs, modification by polyethylene glycol occurs in a site-directed manner in the peptide chains of the Exendin-4 analogs. The PEG-modified Exendin-4 analogs can be used to prevent and/or treat diseases and/or symptoms related to decreased activity of GLP-1 receptors, such as type II diabetes.

Peptides Derivatized with A-B-C-D- and their Therapeutical Use

The invention relates to protracted peptide derivatives such as Glucagon-Like Peptide-1 (GLP-1), exendin-4, and analogues thereof, as well as therapeutic uses thereof. The peptide derivative of the invention comprises a peptide wherein at least one amino acid residue is derivatized with A-B—C—, or A-B—C-D-. These compounds are useful in the treatment or prevention of diabetes type 2 and related diseases. The compounds are potent, have a low ratio of binding affinity to the GLP-1 receptor in the presence of high/low albumin concentrations, have long half-lives, and have a high affinity of binding to albumin, all of which is of potential relevance for the overall aim of achieving long-acting, stable and active GLP-1 derivatives with a potential for once weekly administration.

Treatment of kidney disorders with vip fragments

The invention relates to compositions comprising vasoactive intestinal peptide (VIP) or fragments thereof, and the use of such compositions in the treatment of kidney disease, in particular kidney fibrosis, and other associated conditions.

Triple glucagon/glp-1/gip receptor agonist

The present invention relates to a triple agonist having activities to all of glucagon, GLP-1, and GIP receptors and uses thereof.

Pac1 antibodies and uses thereof

The present invention relates to neutralizing antibodies of the human pituitary adenylate cyclase activating polypeptide type I receptor (PAC1) and pharmaceutical compositions comprising such antibodies. Methods of treating or preventing headache conditions, such as migraine and cluster headache, using the neutralizing antibodies are also described.

Engineered polypeptides having enhanced duration of action

Compounds are provided having inter alia good duration of action, high potency and/or convenient dosing regimens including oral administration. The compounds are engineered polypeptides which incorporate an albumin binding domain in combination with one or more biologically active polypeptides. Also provided are pharmaceutical compositions and methods of treatment for diseases and disorders including obesity and overweight, diabetes, dyslipidemia, hyperlipidemia, Alzheimer's disease, fatty liver disease, short bowel syndrome, Parkinson's disease, cardiovascular disease, and other and disorders of the central nervous system.

METHOD OF PREPARING PEPTIDES COMPRISING A LIPOPHILICALLY MODIFIED LYSINE SIDE CHAIN

The present invention relates to a method of preparing a lysine side-chain modified peptide by solid phase peptide synthesis. 1. A method of preparing an isolated peptide comprising a lipophilically modified lysine side chain , comprising the steps of:(i) assembling the amino acid sequence of said peptide with protected reactive functional groups in the side chains in a step-wise manner using solid phase peptide synthesis (SPPS), wherein the side chain of lysine to be modified is protected by a trityl-based protecting group, particularly monomethoxytrityl (Mmt) or 4-methyltrityl (Mtt);(ii) drying the solid phase resin after the assembling of the amino acid sequence has been completed;(iii) treating the dried resin several times with a solution of trifluoroacetic acid (TFA) in dichloromethane (DCM) in order to deprotect the lysine side chain to be modified;(iv) neutralizing the resin;(v) coupling at least one activated 9-fluorenylmethyloxycarbonyl (Fmoc)-bound linker moiety to the deprotected lysine side chain;(vi) deprotecting the terminal functional group of the linker coupled to the lysine side chain in step (v);(vii) coupling an activated lipophilic moiety, particularly an activated fatty acid, to the deprotected terminal functional group of the linker of step (vi);(viii) drying the resin; and(ix) cleaving the peptide from the resin.2. The method of claim 1 , wherein the isolated peptide is an exendin-4 derivative having a length of between 30 and 44 claim 1 , particularly between 38 and 40 amino acids claim 1 , wherein(i) the sequence identity to wild-type exendin-4 in the region corresponding to amino acids 1-13 of wild-type exendin is at least 65%, and/or(ii) the sequence identity to wild-type exendin-4 in the region corresponding to amino acids 22-39 of wild-type exendin is at least 70%, and/or(iii) the lipophilically modified lysine side chain is at position 14 (Lys(14)) with respect to the amino acid positions of wild-type exendin-4.3. The method of or ...

ELEVATED INTRACRANIAL PRESSURE TREATMENT

Provided is an incretin, or analogue thereof, an incretin receptor agonist, an incretin enhancer, or any combination thereof, for use in a method of reducing elevated intracranial pressure (ICP) in a subject. Methods of reducing elevated ICP in a subject may comprise administering an incretin, or analogue thereof, an incretin receptor agonist, an incretin enhancer, or any combination thereof to the subject. The elevated ICP may be associated with idiopathic intracranial hypertension (IIH), secondary pseudotumour cerebri, hydrocephalus, normal pressure hydrocephalus, raised intracranial pressure secondary to a brain tumour, meningitis, brain trauma, brain injury, and venous sinus thrombosis. 1. An incretin , or analogue thereof , an incretin receptor agonist , an incretin enhancer , or any combination thereof , for use in a method of reducing elevated intracranial pressure (ICP) in a subject.215-. (canceled) The present invention relates to the treatment of undesirable increased intra-cranial pressure which may be due to irregularities in cerebral spinal fluid (CSF) secretion within/from the brain. Increased intracranial pressure is observed, for example, in subjects with idiopathic intracranial hypertension (IIH), secondary pseudotumour cerebri, hydrocephalus, normal pressure hydrocephalus, raised intracranial pressure secondary to a brain tumour, meningitis, brain trauma, brain injury, and venous sinus thrombosis.Elevated intracranial pressure (ICP) can be due to a rise in pressure of the cerebrospinal fluid (CSF), the fluid which surrounds the brain and spinal cord. An increase in ICP is a serious medical condition, as the increased pressure can lead to damage of the brain or spinal cord by pressing on important brain structures and by restricting blood flow into the brain. Thus, effective treatments to alleviate elevated ICP are required.One condition associated with elevated ICP is IIH, also known as benign intracranial hypertension or pseudotumour cerebri, ...

Ligands Modified by Circular Permutation as Agonists and Antagonists

The present invention provides fusion polypeptides comprising polypeptide ligands that are modified by circular permutation and fused to at least one polypeptide fusion partner wherein such fusion polypeptides have new, improved or enhanced biological functions or activities. Such improvements include, but are not limited to, increased binding affinity, increased activity, increased agonist activity (super agonist), antagonist activity, increased accessibility, increased flexibility of the active site, increased stability, broader and/or changed substrate specificity, and combinations thereof. 115-. (canceled)16. A fusion polypeptide comprising a first polypeptide fusion partner linked to a modified ligand corresponding to all or a portion of a native ligand of a target receptor , wherein the modified ligand has been circularly permuted to create a new N-terminus and a new C-terminus as compared to the native ligand , wherein the new C-terminus and the new N-terminus of the modified ligand do not disrupt any binding domain of the modified ligand for the target receptor , wherein the modified ligand is circularly permuted IL-2 , the fusion partner is IL-2Rα and the target receptor is IL-2Rβγ , wherein the fusion polypeptide is optionally further fused to the Fc region of an antibody.17. The fusion polypeptide of claim 16 , wherein the modified ligand is a circularly permuted IL-2 having a C145S mutation.18. A pharmaceutical composition comprising the fusion polypeptide of .19. A pharmaceutical composition comprising the fusion polypeptide of .20. A method of selectively agonizing IL-2Rβγ on a cell comprising contacting the cell with a fusion polypeptide of .21. The method of claim 20 , wherein the fusion polypeptide is contacted with the cell extracorporeally.22. A method of selectively agonizing IL-2Rβγ on a cell comprising contacting the cell with a fusion polypeptide of .23. The method of claim 22 , wherein the fusion polypeptide is contacted with the cell ...

PEPTIDES COMPRISING NON-NATURAL AMINO ACIDS AND METHODS OF MAKING AND USING THE SAME

This invention relates to novel compositions comprising analogs of naturally occurring polypeptides, wherein the analog comprises an α-amino acid and at least one β-amino acid. Administration of the compositions may be used for effecting treatment or prevention of a plurality of disease states caused by dysfunctional biochemical or biological pathways. The compositions and methods of this invention are particularly useful to identify novel therapeutic modulators of in-vivo receptor activity with extended half-lives and relevant bioactivity as compared to the naturally translated polypeptides upon which the analogs are derived. 1. A composition comprising at least one vasoactive intestinal peptide (VIP) analog comprising HSDAVFTDNYTRLRKQMAVKKYLNSILN wherein at least three amino acids of SEQ ID NO:1 are replaced with a cyclic beta-3 amino acids and wherein the analog comprises an amino acid sequence that selectively binds to VIP Receptor 1.25.-. (canceled)6. The composition of claim 1 , wherein the analog is derived from a human VIP amino acid sequence.713.-. (canceled)14. The composition of claim 1 , wherein the β-amino acids are spatially aligned along a longitudinal axis of the analog in order to constrain the conformation of the analog in an active state.15. The composition of claim 1 , wherein the ratio of total β-amino acids to amino acids in the analog is from 1 to 3 β-amino acids for every 7 amino acids of the analog.16. (canceled)17. The composition of claim 1 , wherein the analog does not comprise a repetitive pattern of sequential β-amino acids from the amino-terminus to the carboxy-terminus selected from the following: ααααααβ claim 1 , αααααβα claim 1 , ααααβαα claim 1 , αααβααα claim 1 , ααβαααα claim 1 , αβααααα claim 1 , βαααααα claim 1 , αααααββ claim 1 , ααααββα claim 1 , αααββαα claim 1 , ααββααα claim 1 , αββαααα claim 1 , ββααααα claim 1 , βαααααβ claim 1 , βααααβα claim 1 , βαααβαα claim 1 , βααβααα claim 1 , βαβαααα claim 1 , αβααααβ claim 1 , ...

MODIFIED THERAPEUTIC AGENTS AND COMPOSITIONS THEREOF

Methods and compositions are provided for extending the half-life of a therapeutic agent. A modified therapeutic agent (mTA) comprises a therapeutic agent, a staple, and a half-life extending molecule. The mTAs disclosed herein may be used to treat a disease or a condition in a subject in need thereof. 141-. (canceled)43. The mTA of claim 42 , wherein the TA comprises an amino acid sequence that is at least 97% homologous to an amino acid sequence selected from SEQ ID NOS: 7-30.44. The mTA of claim 42 , wherein the TA comprises any one of SEQ ID NOS: 7-30.45.45. The mTA of claim 42 , wherein each of the two amino acid residues is lysine.46. The mTA of claim 42 , further comprising a second staple and a second half-life extending molecule claim 42 , wherein the second half-life molecule is covalently attached to the second staple.47. The mTA of claim 42 , wherein the half-life of the mTA is longer than the half-life of the unmodified TA alone.48. The mTA of claim 42 , wherein the half-life of the mTA is at least 5-fold longer than the half-life of the unmodified TA alone.49. A pharmaceutical composition comprising the mTA of and a pharmaceutically acceptable excipient.50. A method for treating a disease or condition in a subject in need thereof claim 42 , the method comprising administering to the subject a composition comprising a therapeutically effective amount of the mTA of .51. The method of claim 50 , wherein the disease or condition is diabetes or obesity claim 50 , or a medical condition associated with diabetes claim 50 , obesity claim 50 , non-alcoholic fatty liver disease (NAFLD) claim 50 , nonalcoholic steatohepatitis (NASH) claim 50 , cardiovascular disease claim 50 , short bowel syndrome (SBS) claim 50 , inflammatory bowel disease (IBD) claim 50 , inflammatory bowel syndrome (IBS) claim 50 , psoriasis claim 50 , Crohn's disease claim 50 , ulcerative colitis claim 50 , Alzheimer's disease claim 50 , Parkinson's disease claim 50 , Huntington's disease.52. ...

Vip fragments and methods of use

The invention relates to composition comprising a pharmaceutically effective amount of one or more functional vasoactive intestinal peptide (VIP) fragments, and the use of those compositions in the treatment of fibrosis, hypertension and other disorder.

Formulations and Uses of Exendins and Exendin Agonist Analogs

Provided herein are formulations containing exendins, exendin agonists and/or exendin analogs and methods of using the exendins, exendin agonists and/or exendin analogs and formulations thereof to treat glucagonoma and necrolytic migratory erythema, or to suppress glucagon secretion.

Anti-pacap antibodies

The present invention is directed to antagonistic antibodies and antigen binding fragments thereof having binding specificity for PACAP. These antibodies inhibit, block or neutralize at least one biological effect associated with PACAP, e.g., vasodilation. In exemplary embodiments these antibodies and antigen binding fragments thereof may comprise specific VH, VL, and CDR polypeptides described herein. In some embodiments these antibodies and antigen binding fragments thereof bind to and/or compete for binding to specific epitope(s) on human PACAP. The invention is further directed to using these antagonistic anti-PACAP antibodies, and binding fragments thereof, for the diagnosis, assessment, and treatment of diseases and disorders associated with PACAP and conditions where antagonism of PACAP-related activities, such as vasodilation, mast cell degranulation, and/or neuronal activation, are therapeutically beneficial, e.g., headache and migraine indications.

FUSION PROTEINS FOR TREATING A METABOLIC SYNDROME

The invention is directed to a fusion protein comprising at least one FGF-21 (fibroblast growth factor-21) compound and at least one GLP-1R (glucagon-like peptide-1 receptor) agonist as well as to pharmaceutical compositions, medical uses and methods of treatment involving the fusion protein, particularly in the field of diabetes, dyslipidemia, obesity and/or adipositas. 136-. (canceled)37. A fusion protein comprising a polypeptide with the structure A-B-C or C-B-A , whereinA is a GLP-1R (glucagon-like peptide-1 receptor) agonist andC is an FGF-21 (fibroblast growth factor 21) compound andB is a linker comprising 100 to 1000 amino acids,wherein the linker comprises an Fc portion of an immunoglobulin,wherein the FGF-21 compound is selected from the group consisting of native FGF-21, an FGF-21 mimetic being a protein having at least 96% amino acid sequence identity to the amino acid sequence shown in SEQ ID NO: 3 and having FGF-21 activity, an FGF-21 fragment with FGF-21 activity, and SEQ ID NO: 3, andwherein the GLP-1R agonist is selected from the group consisting of GLP-1(7-37), GLP-1(7-36)amide, exendin-4, liraglutide, CJC-1131, albugon, albiglutide, exenatide, exenatide-LAR, oxyntomodulin, lixisenatide, geniproside, and a short peptide with GLP-1R agonistic activity.38. The fusion protein according to claim 37 , wherein A is exenatide claim 37 , exendin-4 or lixisenatide.39. The fusion protein according to claim 38 , wherein A is exenatide.40. The fusion protein according to claim 37 , wherein C is an FGF-21 mutein comprising or consisting of SEQ ID NO: 102.41. The fusion protein according to claim 37 , wherein the immunoglobulin is IgG4.42. A pharmaceutical composition comprising the fusion protein of and a pharmaceutically acceptable excipient.43. Article of manufacture comprising{'claim-ref': {'@idref': 'CLM-00042', 'claim 42'}, 'a) a pharmaceutical composition according to and'}b) a container or packaging material.44. A method of treating a cardiovascular ...

Albumin fusion proteins

The present invention encompasses albumin fusion proteins. Nucleic acid molecules encoding the albumin fusion proteins of the invention are also encompassed by the invention, as are vectors containing these nucleic acids, host cells transformed with these nucleic acids vectors, and methods of making the albumin fusion proteins of the invention and using these nucleic acids, vectors, and/or host cells. Additionally the present invention encompasses pharmaceutical compositions comprising albumin fusion proteins and methods of treating, preventing, or ameliorating diseases, disorders or conditions using albumin fusion proteins of the invention.

Albumin fusion proteins

Provided herein are albumin fusion proteins. Nucleic acid molecules encoding the albumin fusion proteins and vectors containing these nucleic acids, host cells transformed with these nucleic acids vectors, and methods of making the albumin fusion proteins and using these nucleic acids, vectors, and/or host cells also are provided. Further described are pharmaceutical compositions comprising albumin fusion proteins and methods of treating, preventing, or ameliorating diseases, disorders or conditions using albumin fusion proteins of the invention.

ANALOGS OF PITUITARY ADENYLATE CYCLASE-ACTIVATING POLYPEPTIDE (PACAP) AND METHODS FOR THEIR USE

This invention relates to novel analogs of pituitary adenylate cyclase-activating polypeptide (PACAP), which are agonists for the PACAP/vasoactive intestinal peptide (VIP) receptors: PAC1, VPAC1 and VPAC2 receptors. These PACAP analogs can be used as prophylactic/therapeutic agents for a wide range of medical disorders, including (but not limited to) cancer and autoimmune disease. These PACAP analogs can be coupled to suitable radionuclides and used in the localization, diagnosis and treatment of disseminated cancers and metastatic tumors, or coupled to small molecule therapeutics and used as vectors for targeted drug delivery. This invention also provides pharmaceutical compositions of one or more PACAP-like compounds of the invention either alone or in combination with one or more other prophylactic/therapeutic agents. 1. An isolated compound having formula (I) , or a pharmaceutically acceptable salt thereof:{'br': None, 'sup': 1', '1', '2', '3', '4', '5', '6', '7', '8', '9', '10', '11', '12', '13', '14', '15-', '16', '17', '18', '19', '20', '21', '22', '23', '24', '25', '26', '27', '28', '30', '31', '32', '33', '34', '35', '36', '37', '38', '2, 'R-A-A-A-A-A-A-A-A-A-A-A-A-A-A-AA-A-A-A-A-A-A-A-A-A-A-A-A-A-A-A-A-A-A-A-A-A-R,'}wherein:{'sup': '1', 'smallcaps': D', 'D', 'D', 'D, 'Ais His, -His, Tyr, -Tyr, Trp, -Trp, Pal, or -Pal;'}{'sup': '2', 'smallcaps': D', 'D', 'D', 'D', 'D, 'Ais Ser, -Ser, hSer, N-Me-Ser, Thr, -Thr, Ala, -Ala, Ile, -Ile, Pro, -Pro, Abu, Aib, Acb, Ach, Acpe, or Acpr;'}{'sup': '3', 'Ais Pip;'}{'sup': '4', 'smallcaps': 'D', 'Ais Gly, Ala, -Ala, β-Ala, Gaba, Abu, Aib, Acb, Ach, Acpe, or Acpr;'}{'sup': '5', 'Ais Ile, Leu, Nle, Val, Nva, Aib, Acb, Ach, Acpe, or Acpr;'}{'sup': '6', 'Ais Phe, Tyr, Trp, Cha, Bip, or Nal;'}{'sup': '7', 'Ais Thr, Ser, hSer, or Val;'}{'sup': '8', 'Ais Asp, Asn, or Glu;'}{'sup': '9', 'Ais Ser, hSer, Thr, Asn, Asp, Ala, Abu, Aib, Acb, Ach, Acpe, or Acpr;'}{'sup': '10', 'Ais Tyr, Phe, Cha, Nal, or Trp;'}{'sup': '11', 'Ais Ser, ...

Use of modified vasoactive intestinal peptides in the treatment of hypertension

The present invention is based on the discovery that a VIP having a binding preference for VPAC2 can provide long-acting blood pressure control synergistically with concomitant anti-hypertensive therapies. Accordingly, methods and compositions useful for the treatment and/or amelioration of hypertension are provided.

Generating Targeted Sequence Diversity in Fusion Proteins

Methods of generating fusion protein variants are provided that comprise introducing sequence diversity at the junction region or regions in the fusion and allows for the generation of variants having a desired activity. Examples include immunoglobulins comprising a domain or polypeptide inserted into, or replacing, a CDR. Also provided are polynucleotides encoding a fusion protein and comprising two or more RSSs, and compositions and host cells comprising same, as well as fusion proteins variants produced by the described methods. 145-. (canceled)46. A method of generating a fusion protein which is an antibody , an antigen-binding domain of the antibody or a T-cell receptor (TCR) into which a heterologous polypeptide comprising a natural or synthetic polypeptide ligand has been grafted into a complementarity determining region (CDR) of the fusion protein , wherein the polypeptide ligand , when non-grafted , binds a target protein and wherein the fusion protein retains the target protein-binding functionality of the polypeptide ligand , the method comprising:(i) providing recombination-competent host cells that are capable of expressing RAG-1 and RAG-2 and which comprise at least one nucleic acid for expression of the fusion protein following in vitro recombination, the at least one nucleic acid comprising: a second nucleic acid sequence comprising a second RSS capable of functional recombination with the first RSS, a second coding sequence encoding the polypeptide comprising the ligand and further comprising a third RSS; and', 'a third nucleic acid sequence comprising a third coding sequence encoding a second portion of the antibody, the antigen-binding domain or the TCR, the third nucleic acid sequence further comprising a fourth RSS capable of functional recombination with the third RSS;', 'wherein the first nucleic acid sequence, the second nucleic acid sequence and the third nucleic acid sequence together comprise a tripartite recombination substrate capable of ...

SUPPRESSION OF CANCERS

The present invention relates to a method for suppressing or treating cancer, in particular to a method for suppressing or treating one or more of colorectal cancer, breast cancer, prostate cancer and/or lung cancer. The therapy employs use of a non-cytotoxic protease, which is targeted to a growth hormone-secreting cell such as to a pituitary cell. When so delivered, the protease is internalised and inhibits secretion/transmission of growth hormone from said cell. The present invention also relates to polypeptides and nucleic acids for use in said methods. 1. A polypeptide , for use in suppressing a cancer , said polypeptide comprising:a) a non-cytotoxic protease, which protease is capable of cleaving a protein of the exocytic fusion apparatus in a growth hormone-secreting cell;b) a Targeting Moiety (TM) that binds to a Binding Site on a growth hormone-secreting cell, which Binding Site is capable of undergoing endocytosis to be incorporated into an endosome within the growth hormone-secreting cell; andc) a translocation domain that translocates the protease from within the endosome, across the endosomal membrane and into the cytosol of said growth hormone-secreting cell.2. A polypeptide according to claim 1 , wherein the growth hormone-secreting cell is a pituitary cell.3. A polypeptide according to claim 1 , wherein the TM binds to a receptor selected from the group consisting of: a growth hormone-releasing hormone (GHRH) receptor claim 1 , a leptin (OB) receptor claim 1 , a ghrelin receptor claim 1 , a somatostatin (sst) receptor claim 1 , an insulin growth factor (IGF) receptor claim 1 , an ErbB receptor claim 1 , a VIP-glucagon-GRF-secretin superfamily receptor claim 1 , an orexin (OX) receptor claim 1 , an interleukin (IL) receptor claim 1 , a nerve growth factor (NTR) receptor claim 1 , a vascular endothelial growth factor (VEGF) receptor claim 1 , a bombesin receptor claim 1 , a urotensin receptor claim 1 , a melanin-concentrating hormone receptor 1 claim 1 ...

SATIATION PEPTIDES FOR WEIGHT LOSS AND ALTERED TASTE SENSITIVITY

The present application provides methods and compositions for AAV-mediated delivery of PYY and Glucagon-like Peptide 1 or an analog thereof (e.g., Exendin-4) to a subject (e.g., the saliva of a subject). In some embodiments, compositions and methods for topical delivery of Ex-4 and PYY peptides also are provided. Methods and compositions are useful to promote weight loss and/or altered lipid taste sensitivity, as well as for the treatment of diabetes. 124-. (canceled)25. A method of inducing satiation in a subject comprising administering to the subject PYY and GLP-1 or an analog thereof , wherein the PYY is formulated as an orally disintegrating tablet that is topically administered to a tongue of the subject.26. The method of claim 25 , wherein the PYY is PYYcomprising the sequence of SEQ ID NO: 2.27. The method of claim 25 , wherein the GLP-1 analog is Exendin-4 comprising the sequence of SEQ ID NO: 10.28. The method of claim 25 , wherein the PYY and the GLP-1 or analog thereof are administered separately.29. The method of claim 28 , wherein the PYY is administered first claim 28 , and the GLP-1 or analog thereof is administered second.30. The method of claim 28 , wherein the GLP-1 or analog thereof is administered first and the PYY is administered second.31. The method of claim 25 , wherein the PYY and GLP-1 or analog thereof are administered together.32. The method of claim 25 , wherein the GLP-1 or analog thereof is formulated as an orally disintegrating tablet.33. The method of claim 25 , wherein the GLP-1 or analog thereof is injected into the subject.34. The method of claim 25 , wherein the method does not substantially increase a plasma concentration of PYY or GLP-1 or analog thereof in the subject.35. The method of claim 31 , wherein the administering is performed between 30 and 120 minutes prior to eating. This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Patent Application No. 62/323,690, filed Apr. 16, 2016, entitled “ ...

Generating Targeted Sequence Diversity in Fusion Proteins

Methods of generating fusion protein variants are provided that comprise introducing sequence diversity at the junction region or regions in the fusion and allows for the generation of variants having a desired activity. Examples include immunoglobulins comprising a domain or polypeptide inserted into, or replacing, a CDR. Also provided are polynucleotides encoding a fusion protein and comprising two or more RSSs, and compositions and host cells comprising same, as well as fusion proteins variants produced by the described methods. 145-. (canceled)46. A fusion protein comprising an antibody antigen-binding domain that specifically binds GLP1R , the antigen-binding domain comprising a heterologous peptide grafted into heavy chain CDR3 of the antibody antigen-binding domain , the sequence of the heterologous peptide selected from the group consisting of SEQ ID NOs:72-80.47. The fusion protein of claim 46 , wherein the heterologous peptide is inserted into the heavy chain CDR3.48. The fusion protein of claim 46 , wherein the heterologous peptide replaces the D segment of the heavy chain CDR3.49. The fusion protein of claim 46 , wherein the heterologous peptide replaces the heavy chain CDR3.50. The fusion protein of claim 46 , wherein the antibody antigen-binding domain is comprised within a full length antibody selected from the group consisting of IgA claim 46 , IgA2 claim 46 , IgD claim 46 , IgE claim 46 , IgG and IgM.51. The fusion protein of claim 46 , wherein the antibody antigen-binding domain is comprised within a full length human IgG.52. The fusion protein of claim 46 , wherein the antibody antigen-binding domain is comprised within an antibody fragment or derivative selected from the group consisting of Fab claim 46 , Fab′ claim 46 , F(ab′)2 claim 46 , Fd claim 46 , Fv and single-chain Fv (scFv).53. The fusion protein of claim 46 , wherein the antibody antigen-binding domain is comprised within a camelid antibody claim 46 , a heavy chain antibody (hcAb) claim ...

METHODS OF MANAGING GRAFT VERSUS HOST DISEASE

This disclosure relates to the use of drugs to prevent graft versus host disease (GVHD) in a subject after, before, or during a hematopoietic stem cell transplant. In certain embodiments, the drugs are antagonist of vasoactive intestinal peptide signaling. In certain embodiments, the subject has a blood or bone marrow cancer or condition. 1. A method of treating or preventing host verses graft disease in a subject comprising administering an effective amount of an antagonist of vasoactive intestinal peptide signaling to a subject that is to receive or received transplanted allogeneic tissue or cells.2. The method of wherein the antagonist of vasoactive intestinal peptide signaling is a fragment of VIP claim 1 , or VIP fragment or analog containing one or more D-amino acids disclosed herein or variant thereof.3. The method of wherein the antagonist of vasoactive intestinal peptide signaling is a protein comprising SEQ ID NO: 12 (KPRRPYTDNYTRKQMAVKKYLNSILN) or greater than 80% claim 1 , 85% claim 1 , 90% claim 1 , or 95% identity or similarity thereto.4. The method of wherein the antagonist of vasoactive intestinal peptide signaling is an VIP antibody or antibody fragment with an epitope to VIP or a VIP receptor.5. The method of wherein the subject received transplanted allogeneic hematopoietic stem cells.6. The method of wherein the subject received transplanted allogeneic hematopoietic stem cells separated from peripheral blood.7. The method of wherein the subject received chemotherapy to radiation treatments prior to receiving transplanted allogeneic hematopoietic stem cells.8. The method of wherein the subject is a human.9. A method of treating cancers or conditions of the blood and bone marrow comprising the steps of claim 1 ,exposing the subject to radiation and/or administering a chemotherapy agent to the subject;transplanting allogeneic hematopoietic stem cells into the subject; andadministering an antagonist of vasoactive intestinal peptide signaling under ...

COMPOUNDS AS PEPTIDIC TRIGONAL GLP1/GLUCAGON/GIP RECEPTOR AGONISTS

The present invention relates to trigonal GLP-1/glucagon/GIP receptor agonists and their medical use, for example in the treatment of disorders of the metabolic syndrome, including diabetes and obesity, as well as for reduction of excess food intake. 1. A compound of the formula I:{'br': None, 'sub': '2', 'sup': '1', 'HN-His-Aib-His-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Leu-X14-Glu-Glu-Gln-Arg-Gln-X20-Glu-Phe-Ile-Glu-Trp-Leu-Lys-Ala-X29-Gly-X31-Pro-Ser-Aib-Lys-Pro-Pro-Pro-Lys-R'}wherein:{'sub': 2', '2, 'sup': 5', '5, 'X14 is an amino acid residue with a functionalized -NHside chain group, selected from the group consisting of Lys, Orn, Dab, and Dap, wherein the —NHside chain group is functionalized by —Z—C(O)—R, wherein Z is a linker in all stereoisomeric forms and Ris a moiety comprising up to 50 carbon atoms and heteroatoms selected from N and O,'}X20 is an amino acid residue selected from Aib and Lys,X29 is an amino acid residue selected from D-Ala and Gly,X31 is an amino acid residue selected from His and Pro,{'sup': '1', 'sub': '2', 'Ris NHor OH,'}or a salt or solvate thereof.2. The compound of claim 1 , wherein Ris NH claim 1 , or a salt or solvate thereof.3. The compound of claim 1 , or the salt or solvate thereof claim 1 , which has a relative activity of at least 5% compared to that of natural glucagon at the glucagon receptor.4. The compound of claim 1 , or the salt or solvate thereof claim 1 , which exhibits a relative activity of at least 7% compared to that of GLP-1(7-36)-amide at the GLP-1 receptor.5. The compound of claim 1 , or the salt or solvate thereof claim 1 , which exhibits a relative activity of at least 4% compared to that of GIP at the GIP receptor.6. The compound of claim 1 , wherein X14 is Lys claim 1 , wherein the —NHside chain group is functionalized with the group —Z—C(O)R claim 1 , wherein:Z is a group selected from gGlu, gGlu-gGlu, gGlu-AEEAc-gAAA-, gGlu-gGlu-AEEAc, AEEAc-AEEAc-gGlu and AEEAc-AEEAc-AEEAc; and{'sup': '5', 'Ris a group ...

COMPOUNDS AS PEPTIDIC GLP1/GLUCAGON/GIP RECEPTOR AGONISTS

The present invention relates to trigonal GLP-1/glucagon/GIP receptor agonists and their medical use, for example in the treatment of disorders of the metabolic syndrome, including diabetes and obesity, as well as for reduction of excess food intake. 2. The compound of claim 1 , wherein Ris NH claim 1 , or a salt or solvate thereof.3. The compound of claim 1 , or a salt or solvate thereof claim 1 , which has a relative activity of at least 1% compared to that of natural glucagon at the glucagon receptor.4. The compound of claim 1 , or a salt or solvate thereof claim 1 , which exhibits a relative activity of at least 10% compared to that of GLP-1(7-36)-amide at the GLP-1 receptor.5. The compound of claim 1 , or a salt or solvate thereof claim 1 , which exhibits a relative activity of at least 2% compared to that of GIP at the GIP receptor.6. The compound of claim 1 , wherein X14 is Lys claim 1 , wherein the —NHside chain group is functionalized with a group —Z—C(O)R claim 1 , wherein:Z is a group selected from gGlu, gGlu-gGlu, gGlu-AEEAc-gAAA-, gGlu-gGlu-AEEAc, AEEAc-AEEAc-gGlu and AEEAc-AEEAc-AEEAc, and{'sup': '5', 'Ris a group selected from pentadecanyl and heptadecanyl;'}or a salt or solvate thereof.7. The compound of claim 1 , wherein X14 is Lys claim 1 , wherein the —NHside chain group is functionalized with a group —Z—C(O)R claim 1 , wherein:Z is a group selected from gGlu, gGlu-gGlu, gGlu-AEEAc-gAAA- and gGlu-gGlu-AEEAc; and{'sup': '5', 'Ris a group selected from pentadecanyl and heptadecanyl;'}or a salt or solvate thereof.8. The compound of claim 1 , wherein:{'sub': '2', 'X14 is Lys, wherein the —NHside chain group is functionalized by a group selected from (S)-4-Carboxy-4-hexadecanoylamino-butyryl-, (S)-4-Carboxy-4-octadecanoylamino-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-, (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-hexadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl, (2-{2-[2-(2-{2-[(4S)-4- ...

Exendin-4 Peptide Analogues as Dual GLP-1/GIP Agonists

The present invention relates to exendin-4 derivatives and their medical use, for example in the treatment of disorders of the metabolic syndrome, including diabetes and obesity, as well as reduction of excess food intake

Long-acting conjugate of triple glucagon/glp-1/gip receptor agonist

A long-acting conjugate of a triple agonist which has activities to all of glucagon, GLP-1, and GIP receptors and uses thereof.

Glucose-regulating polypeptides and methods of making and using same

The present invention relates to compositions comprising glucose regulating peptides linked to extended recombinant polypeptide (XTEN), isolated nucleic acids encoding the compositions and vectors and host cells containing the same, and methods of making and using such compositions in treatment of glucose regulating peptide-related diseases, disorders, and conditions.

HIGHLY ACTIVE POLYPEPTIDES AND METHODS OF MAKING AND USING THE SAME

This invention relates to novel compositions comprising analogs of naturally occurring polypeptides, wherein the analog comprises an α-amino acid and at least one β-amino acid. Administration of the compositions may be used for effecting treatment or prevention of a plurality of disease states caused by dysfunctional biochemical or biological pathways. The compositions and methods of this invention are particularly useful to identify novel therapeutic modulators of in-vivo receptor activity with extended half-lives and relevant bioactivity as compared to the naturally translated polypeptides upon which the analogs are derived. 1. A composition comprising a vasoactive intestinal peptide (VIP) analog , wherein said analog comprises an α-amino acid and at least one β-amino acid.252.-. (canceled)53. A composition comprising a peptide or a pharmaceutical salt thereof comprising a repetitive pattern of α and β amino acids from the amino-terminus to the carboxy-terminus chosen from: ββαβαααβααβαααβαββ; βαββαααβααβαααβαββ; βααββααβααβαααβααβ; βααβαβαβααβαααβαββ; βααβααββααβαααβαββ; βααβαααββαβαααβαββ; βααβαααβαββαααβααβ; βααβαααβααββααβαββ; βααβαααβααβαβαβαββ; βααβαααβααβααββαββ; βααβαααβααβαααββαβ; and βααβαααβααβαααβαββ; wherein the peptide comprises between about 7% to about 50% β amino acids.54. The composition of claim 53 , wherein the peptide or pharmaceutical salt thereof comprises between about 10 and about 100 residues.55. The composition of claim 53 , wherein at least one β amino acid is a cyclic β amino acid.56. The composition of claim 55 , wherein the cyclic β amino acid is APC or ACPC.57. The composition of claim 53 , wherein the pattern of α and β amino acids repeats at least once.58. The composition of claim 53 , wherein the peptide or pharmaceutical salt thereof comprises an amino acid sequence from the group consisting of SEQ ID NO: 1 claim 53 , SEQ ID NO: 2 claim 53 , SEQ ID NO: 3 claim 53 , SEQ ID NO: 4 claim 53 , SEQ ID NO: 5 claim 53 , SEQ ID NO: 6 ...

Gip and glp-1 receptor dual-agonists for the treatment of diabetes

This disclosure provides GIP/GLP-1 dual agonist polypeptides for the treatment of hypoglycemic conditions, e.g., type-2 diabetes.

EXENDIN-4 ANALOGUE PEGYLATED WITH POLYETHYLENE GLYCOL OR DERIVATIVE THEREOF, PREPARATION METHOD THEREOF, AND PHARMACEUTICAL COMPOSITION FOR PREVENTING OR TREATING DIABETES, CONTAINING SAME AS ACTIVE INGREDIENT

The present disclosure relates to an exendin-4 analogue PEGylated with polyethylene glycol or a derivative thereof, a preparation method, and a pharmaceutical composition for prevention or treatment of diabetes containing the same as an active ingredient. According to the present invention, the yield of an exendin-4 analogue can be increased via the selective PEGylation by using exendin-4 in which a cysteine is introduced into #40 site of the C-terminal, and treatment effect of medications can be increased, so that the exendin-analogue can be usefully applied as a composition for prevention or treatment of diseases caused by insulin hypersecretion. 1. An exendin-4 analogue comprising SEQ ID NO:2 and a cysteine (Cys) introduced into the C-terminal end of SEQ ID NO:2 and PEGylated with polyethylene glycol (PEG) or a methoxy-activated derivative of PEG , wherein the PEG , or the methoxy-activated derivative of PEG is connected to the cysteine by a spacer comprising polyethylene glycol or a methoxy-activated derivative thereof.23-. (canceled)4. The exendin-4 analogue of claim 1 , having bound thereto one or two molecules of PEG or a methoxy-activated derivative of PEG and forming a dimeric or trimeric PEG or derivative thereof.5. The exendin-4 analogue of claim 1 , wherein the polyethylene glycol has a molecular weight of between 5 kDa and 60 kDa.6. The exendin-4 analogue of claim 5 , wherein the polyethylene glycol has a molecular weight of between 20 kDa and 50 kDa.7. The exendin-4 analogue of claim 1 , wherein the polyethylene glycol derivative is a branched derivative of methoxypolyethylene glycol succinimidylpropionate claim 1 , methoxypolyethylene glycol N-hydroxysuccinimide claim 1 , methoxypolyethylene glycol propionaldehyde claim 1 , and methoxypolyethylene glycol maleimide.8. (canceled)9. The exendin-4 analogue of claim 1 , wherein the methoxy-activated polyethylene glycol derivative is methoxypolyethylene glycol maleimide.10. A method of preparing the exendin ...

Anti-pacap antibodies

The present invention is directed to antagonistic antibodies and antigen binding fragments thereof having binding specificity for PACAP. These antibodies inhibit, block or neutralize at least one biological effect associated with PACAP, e.g., vasodilation. In exemplary embodiments these antibodies and antigen binding fragments thereof may comprise specific VH, VL, and CDR polypeptides described herein. In some embodiments these antibodies and antigen binding fragments thereof bind to and/or compete for binding to specific epitope(s) on human PACAP. The invention is further directed to using these antagonistic anti-PACAP antibodies, and binding fragments thereof, for the diagnosis, assessment, and treatment of diseases and disorders associated with PACAP and conditions where antagonism of PACAP-related activities, such as vasodilation, mast cell degranulation, and/or neuronal activation, are therapeutically beneficial, e.g., headache and migraine indications.

HIGHLY ACTIVE POLYPEPTIDES AND METHODS OF MAKING AND USING THE SAME

This invention relates to novel compositions comprising analogs of naturally occurring polypeptides, wherein the analog comprises an α-amino acid and at least one β-amino acid. Administration of the compositions may be used for effecting treatment or prevention of a plurality of disease states caused by dysfunctional biochemical or biological pathways. The compositions and methods of this invention are particularly useful to identify novel therapeutic modulators of in-vivo receptor activity with extended half-lives and relevant bioactivity as compared to the naturally translated polypeptides upon which the analogs are derived. 152.-. (canceled)53. A composition comprising a peptide or a pharmaceutical salt thereof comprising a repetitive pattern of α and β amino acids from the amino-terminus to the carboxy-terminus chosen from: ββαβαααβααβαααβααβ; βαββαααβααβαααβααβ; βααββααβααβαααβααβ; βααβαβαβααβαααβααβ; βααβααββααβαααβααβ; βααβαααββαβαααβααβ; βααβαααβαββαααβααβ; βααβαααβααββααβααβ; βααβαααβααβαβαβααβ; βααβαααβααβααββααβ; βααβαααβααβαααββαβ; and βααβαααβααβαααβαββ; wherein the peptide comprises between about 7% to about 50% β amino acids.54. The composition of claim 53 , wherein the peptide or pharmaceutical salt thereof comprises between about 10 and about 100 residues.55. The composition of claim 53 , wherein at least one β amino acid is a cyclic β amino acid.56. The composition of claim 55 , wherein the cyclic β amino acid is APC or ACPC.57. The composition of claim 53 , wherein the pattern of α and β amino acids repeats at least once.58. The composition of claim 53 , further comprising at least one other active agent.59. A method of manufacturing the composition of or a pharmaceutical salt derived therefrom comprising catalyzing a reaction between at least one α-amino acid with at least one β-amino acid.60. A kit comprising the composition of .61. The kit of claim 59 , wherein a first container comprises the composition and a second container comprise a ...

PEPTIDES COMPRISING NON-NATURAL AMINO ACIDS AND METHODS OF MAKING AND USING THE SAME

This invention relates to novel compositions comprising analogs of naturally occurring polypeptides, wherein the analog comprises an α-amino acid and at least one β-amino acid. Administration of the compositions may be used for effecting treatment or prevention of a plurality of disease states caused by dysfunctional biochemical or biological pathways. The compositions and methods of this invention are particularly useful to identify novel therapeutic modulators of in-vivo receptor activity with extended half-lives and relevant bioactivity as compared to the naturally translated polypeptides upon which the analogs are derived. 151.-. (canceled)52. A peptide comprising an amino acid sequence that is 95% homologous to SEQ ID NO: 17.53. The peptide of claim 52 , wherein the peptide comprises one amino acid modification from SEQ ID NO: 17 claim 52 , and wherein the modification comprises changing an alpha amino acid to a beta 3 amino acid or a cyclic beta amino acid.54. The peptide of claim 53 , wherein the modification is located between amino acid position numbers 10 and 19 of SEQ ID NO: 17.55. The peptide of claim 52 , wherein the peptide further comprises an acetyl group at the N-terminus and a primary amide at the C-terminus.56. A pharmaceutical composition claim 52 , comprising: (i) the peptide of claim 52 , or a pharmaceutical salt derived therefrom; and (ii) a pharmaceutically acceptable carrier.57. The pharmaceutical composition of claim 56 , wherein the composition further comprises one other active agent.58. A method of treating multiple sclerosis in a patient in need thereof claim 56 , comprising administrating the pharmaceutical composition of .59. A method of inhibiting secretion of TNF-α in a subject comprising administering the pharmaceutical composition of to a subject.60. A kit comprising a first container comprising the pharmaceutical composition of .610. The kit of claim further comprising a second container comprising a vehicle for administration of ...

Albumin fusion proteins

The present invention encompasses albumin fusion proteins. Nucleic acid molecules encoding the albumin fusion proteins of the invention are also encompassed by the invention, as are vectors containing these nucleic acids, host cells transformed with these nucleic acids vectors, and methods of making the albumin fusion proteins of the invention and using these nucleic acids, vectors, and/or host cells. Additionally the present invention encompasses pharmaceutical compositions comprising albumin fusion proteins and methods of treating, preventing, or ameliorating diseases, disorders or conditions using albumin fusion proteins of the invention.

VIP FRAGMENTS AND METHODS OF USE

The invention relates to composition comprising a pharmaceutically effective amount of one or more functional vasoactive intestinal peptide (VIP) fragments, and the use of those compositions in the treatment of fibrosis, hypertension and other disorders. 1. A composition comprising one or more VIP fragments selected from the group consisting of: VIP(10-28) (SEQ ID NO: 92) , VIP(16-28) (SEQ ID NO: 88) , and conservative substitutions thereof that do not alter the biological activity of the fragment.2. The composition of further comprising a pharmaceutically acceptable carrier.3. The composition of in combination with one or more other active agents useful in the treatment of cardiovascular conditions.4. The composition of formulated for administration by oral claim 1 , intravenous claim 1 , intramuscular or subcuticular routes.5. A method of therapeutic or prophylactic treatment of myocardial fibrosis claim 1 , or an associated condition claim 1 , in a subject claim 1 , wherein the method comprises administering to the subject a composition comprising one or more VIP fragments selected from the group consisting of: VIP(10-28) (SEQ ID NO: 92) claim 1 , VIP(16-28) (SEQ ID NO: 88) claim 1 , and conservative substitutions thereof that do not alter the biological activity of the fragment.6. The method of claim 5 , wherein the method slows the progression of myocardial fibrosis.7. The method of claim 5 , wherein the method reduces the degree of myocardial fibrosis.8. The method of claim 5 , wherein the method treats myocardial fibrosis by inhibiting or reducing the production of fibrotic mediators claim 5 , reducing collagen formation claim 5 , enhancing collagen degradation claim 5 , or lowering blood pressure.9. The method of claim 5 , wherein the associated condition is selected from the group consisting of: hypertension claim 5 , diabetes claim 5 , myocarditis claim 5 , ischaemic heart disease claim 5 , left ventricular hypertrophy claim 5 , diastolic dysfunction claim ...

Use of pituitary adenylate cyclase-activating polypeptide (pacap) and pacap analogs for treating contrast-induced nephropathy

Featured are methods and compositions for treating, managing, preventing, or reducing injury to the kidney of a mammal (e.g., a human) caused by one or more iodinated radiocontrast media. The methods include administering an effective amount of one or more pituitary adenylate cyclase-activating polypeptide (PACAP)-like compounds, which includes native human PACAP38, native human PACAP27, native human vasoactive intestinal peptide (VIP), their agonists, analogs, fragments, and derivatives, with activities toward one or more of the PACAP/VIP receptors, including all of their various isoforms. Also provided are pharmaceutical compositions of one or more PACAP-like compounds, either alone or in combination with one or more other prophylactic/therapeutic agents useful for treating, managing, or preventing injury to the kidney of a mammal (e.g., a human) undergoing treatment with one or more iodinated radiocontrast media. Also featured is an in vivo mouse model for testing the efficacy of cytoprotective agents against contrast-induced nephropathy.

Elevated intracranial pressure treatment

Provided is an incretin, or analogue thereof, an incretin receptor agonist, an incretin enhancer, or any combination thereof, for use in a method of reducing elevated intracranial pressure (ICP) in a subject. Methods of reducing elevated ICP in a subject may comprise administering an incretin, or analogue thereof, an incretin receptor agonist, an incretin enhancer, or any combination thereof to the subject. The elevated ICP may be associated with idiopathic intracranial hypertension (IIH), secondary pseudotumour cerebri, hydrocephalus, normal pressure hydrocephalus, raised intracranial pressure secondary to a brain tumour, meningitis, brain trauma, brain injury, and venous sinus thrombosis.

PEPTIDE THERAPEUTIC CONJUGATES AND USES THEREOF

The present invention features a compound having the formula A-X-B, where A is peptide vector capable of enhancing transport of the compound across the blood-brain barrier or into particular cell types, X is a linker, and B is a peptide therapeutic. The compounds of the invention can be used to treat any disease for which the peptide therapeutic is useful. 1. A compound having the formula{'br': None, 'A-X-B'}whereinA is a peptide vector comprising an amino acid sequence at least 70% identical to a sequence selected from the group consisting of SEQ ID NO:1-105 and 107-114, or a fragment thereof;X is a linker; andB is a peptide therapeutic.2. The compound of claim 1 , where said peptide therapeutic is selected from the group consisting of antimicrobial or antibiotic peptides claim 1 , gastrointestinal peptides claim 1 , pancreatic peptides claim 1 , peptide hormones claim 1 , hypothalamic hormones claim 1 , pituitary hormones claim 1 , and neuropeptides.3. The compound of claim 1 , wherein A is a polypeptide has an amino acid sequence at least 70% identical to a sequence selected from the group consisting of Angiopep-1 (SEQ ID NO:67) claim 1 , Angiopep-2 (SEQ ID NO:97) claim 1 , cys-Angiopep-2 (SEQ ID NO:113) claim 1 , and Angiopep-2-cys (SEQ ID NO:114).4. The compound of claim 3 , wherein said polypeptide comprises or consists of an amino acid sequence selected from the group consisting of Angiopep-1 (SEQ ID NO:67) claim 3 , Angiopep-2 (SEQ ID NO:97) claim 3 , cys-Angiopep-2 (SEQ ID NO:113) claim 3 , and Angiopep-2-cys (SEQ ID NO:114).6. The compound of claim 5 , wherein n is 3 claim 5 , 6 claim 5 , or 11.7. The compound of claim 1 , wherein X is peptide bond.8. The compound of claim 1 , wherein X is at least one amino acid; and A and B are each covalently bonded to X by a peptide bond.9. A nucleic acid molecule encoding the compound of .10. A method of treating cancer claim 1 , a neurological disease claim 1 , or a lysosomal storage disorder in a subject claim 1 , ...

Stabilized insulinotropic peptides and methods of use

The present invention provides stably crosslinked insulinotropic polypeptides having superior and unexpected benefits in the treatment of conditions involving abnormal glucose homeostasis, e.g., type 2 diabetes and conditions relating to type 2 diabetes. Such benefits include, but are not limited to, extended polypeptide half-life, enhanced alpha-helicity, improved thermal stability and protease resistance, increased functional activity and pharmacologic properties, improved bioavailability when administered by any route, and improved bioavailability and gastrointestinal absorption when delivered orally, as compared to the corresponding unmodified polypeptides. The invention also provides compositions for administering the polypeptides of the invention, as well as methods for preparing and evaluating the polypeptides of the invention.

MIRAC PROTEINS

This disclosure relates to a method of generating conditionally active biologic proteins from wild type proteins, in particular therapeutic proteins, which are reversibly or irreversibly inactivated at the wild type normal physiological conditions. For example, evolved proteins are virtually inactive at body temperature, but are active at lower temperatures. 118-. (canceled)19. A method of preparing a conditionally active biologic protein , the method comprising:i. selecting a wild-type biologic protein;ii. evolving a DNA which encodes the wild-type biologic protein using one or more evolutionary techniques to create mutant DNAs;iii. expressing the mutant DNAs to obtain mutant protein;iv. subjecting the mutant proteins and the wild-type protein to an assay under a normal physiological condition and to an assay under an aberrant condition;v. selecting a mutant protein exhibits both (a) a decrease in activity in the assay at the normal physiological condition compared to the wild-type protein, and (b) an increase in activity in the assay under the aberrant condition compared to the wild-type protein; andvi. producing the conditionally active biologic protein from the mutant protein selected in step (v) by a technique selected from a protein chemical synthesis technique and a recombinant technique.2019. The method of , wherein the conditionally active biologic protein comprises at least one non-natural amino acid.21. The method of claim 19 , wherein the biologic protein is an antibody.22. The method of claim 19 , wherein the conditionally active biologic protein is a synthetic protein of the mutant protein selected in step (v) produced by the protein synthesis technique and at least one non-natural amino acid is introduced into the synthetic protein by the protein synthesis technique.23. The method of claim 19 , where the conditionally active biologic protein is a recombinant protein of the mutant protein selected in step (v) produced by the recombinant technique and ...

Selective glucagon receptor agonists comprising a chelating moiety for imaging purposes

The present invention relates to exendin-4 peptide analogues which selectively bind and activate the glucagon receptor and comprise a chelating moiety capable of binding a metal ion and their use, for example in PET imaging.

COILED COIL IMMUNOGLOBULIN FUSION PROTEINS AND COMPOSITIONS THEREOF

Disclosed herein are immunoglobulin fusion proteins comprising a first antibody region, a first therapeutic agent, and a first connecting peptide; wherein the first therapeutic agent is attached to the first antibody region by the connecting peptide; and wherein the connecting peptide does not comprise a region having beta strand secondary structure. The connecting peptide may comprise an extender peptide. The extender peptide may have an alpha helical secondary structure. The connecting peptide may comprise a linker peptide. The linker peptide may not comprise any secondary structure. Also disclosed herein are compositions comprising the immunoglobulin fusion proteins and methods for using the immunoglobulin fusion proteins for the treatment or prevention of a disease or condition in a subject. 1101-. (canceled)102. An immunoglobulin fusion protein comprising a human or humanized antibody domain and a first extender fusion region positioned within the antibody domain , wherein the extender fusion region comprises a therapeutic agent positioned between a first extender peptide and a second extender peptide , the first extender peptide comprising (AKLAALK)n (SEQ ID NO: 148) where n is from 1 to 5 , and the second extender peptide comprising (ELAALEA)m (SEQ ID NO: 158) where m is from 1 to 5.103. The immunoglobulin fusion protein of claim 102 , wherein n is from 1 to 3.104. The immunoglobulin fusion protein of claim 102 , wherein n is 2.105. The immunoglobulin fusion protein of claim 102 , wherein m is from 1 to 3.106. The immunoglobulin fusion protein of claim 102 , wherein m is 2.107. The immunoglobulin fusion protein of claim 102 , wherein the antibody domain comprises a heavy chain and a light chain claim 102 , and the antibody domain comprises an antibody variable domain claim 102 , and the first extender fusion region is positioned within the antibody variable domain.108. The immunoglobulin fusion protein of claim 107 , wherein the first extender fusion region ...

Use of fibroblast growth factor 1 (fgf1)-vagus nerve targeting chimeric proteins to treat hyperglycemia

The present disclosure provides FGF1 mutant proteins, which include an N-terminal deletion, point mutation(s), or combinations thereof, as well as FGF1-vagus targeting chimeric proteins which include an FGF1 portion (e.g., native FGF1 or mutant FGF1) and a portion that targets the chimera to the vagus nerve (e.g., GLP or exendin-4). Also provided are nucleic acid molecules that encode such proteins, and vectors and cells that include such nucleic acids. The disclosed FGF1 mutants and FGF1-vagus targeting chimeric proteins can reduce blood glucose in a mammal, and in some examples are used to treat a metabolic disorder.

METHOD FOR PREPARING LIXISENATIDE

A method for preparing Lixisenatide. According to a peptide sequence structure of Lixisenatide peptide, specially protected serine dipeptide is used as a raw material and coupled into a peptide sequence. Because of a ring-shaped structure similar to that of proline is formed, the rotation of a peptide bond can be effectively prevented, the contraction of a peptide chain curling agent is suppressed, so that active functional groups are fully exposed, thereby facilitating the coupling of the amino acid, and reducing the occurrence of defects and other side effects. 1. A method for preparing lixisenatide , comprising:step 1: synthesizing Fmoc-Lys-resin by solid-phase synthesis;step 2: coupling an amino acid or a dipeptide to the Fmoc-Lys-resin according to the peptide sequence of lixisenatide to obtain lixisenatide peptide resin; wherein the dipeptide is selected from the group consisting of -Gly-Thr, -Phe-Thr, -Thr-Ser, -Leu-Ser, -Ser-Ser and -Pro-Ser; andstep 3: cleaving the lixisenatide peptide resin to obtain lixisenatide.2. The method according to claim 1 , whereincoupling -Gly-Thr is performed by using Fmoc-Gly-Thr(PSI ME, ME Pro)-OH;coupling -Phe-Thr is performed by using Fmoc-Phe-Thr(PSI ME, ME Pro)-OH;coupling -Thr-Ser is performed by using Fmoc-Thr(tBu)-Ser(PSI ME, ME Pro)-OH;coupling -Leu-Ser is performed by using Fmoc-Leu-Ser(PSI ME, ME Pro)-OH;coupling -Ser-Ser is performed by using Fmoc-Ser(tBu)-Ser(PSI ME, ME Pro)-OH; andcoupling -Pro-Ser is performed by using Fmoc-Pro-Ser(PSI ME, ME Pro)-OH,3. The method according to claim 1 , wherein coupling agent for the coupling is a mixture of HOBt and DIC; and wherein the molar ratio of HOBt to DIC is 1:1.4. The method according to claim 1 , wherein cleaving agent for the cleaving comprises TFA and component B; and wherein the component B is selected from the group consisting of PhSMe claim 1 , PhOMe claim 1 , EDT claim 1 , HO claim 1 , TIS and PhOH.5. The method according to claim 1 , after the step 3 claim 1 , ...

COMPOSITION FOR LONG-ACTING PEPTIDE ANALOGS

The invention describes compositions of peptide analogs that are active in blood or cleavable in blood to release an active peptide. The peptide analogs have a general formula: A-(Cm)-Peptide (SEQ ID NO: 76), wherein A is hydrophobic moiety or a metal binding moiety, e.g., a chemical group or moiety containing 1) an alkyl group having 6 to 36 carbon units, 2) a nitrilotriacetic acid group, 3) an imidiodacetic acid group, or 4) a moiety of formula (ZHis)(SEQ ID NO: 50), wherein Z is any amino acid residue other than histidine, His is histidine, y is an integer from 0-6; w is an integer from 1-6; and p is an integer from 1-6; wherein if A has alkyl group with 6 to 36 carbon units x is greater than 0; and Cm is a cleavable moiety consisting of glycine or alanine or lysine or arginine or N-Arginine or N-lysine, wherein x is an integer between 0-6 and N may be any amino acid or none. The peptide analogs are complexed with polymeric carrier to provide enhanced half-life. 1. A peptide analog having a general formula: A-(Cm)x-peptide , wherein: (i) Gly,', '(ii) Ala,', '(iii) Arg,', '(iv) Lys,', {'sub': 'q', '(v) (N)-Lys, wherein N is any amino acid, q is 0 or 1, and'}, {'sub': 'q', '(vi) (N)-Arg, wherein N is any amino acid, q is 0 or 1;'}], 'a. Cm is independently selected from'}b. x is an integer from 2-6;c. A is an alkyl group with 6 to 36 carbon units with a linker group selected from carbonyl and amino; andd. the peptide comprises glucagon-like peptide (GLP), leptin fragment, gastric inhibitory polypeptide (GIP), epidermal growth factor (EGF) receptor ligand, EGF, transforming growth factor alpha (TGF-alpha), gastrin/cholecystokinin receptor ligand, gastrin, cholecystokinin, auristatin, nisin, insulin, insulin-like growth factor, parathyroid hormone (PTH), atrial natriuretic factor, somatostatin, gonadotropin-releasing hormone, luteinizing-hormone-releasing-hormone, or vasoactive intestinal peptide (VIP).2. The composition of claim 1 , further comprising a polymeric ...

ANTI-SERUM ALBUMIN BINDING VARIANTS

The invention relates to improved variants of the anti-serum albumin immunoglobulin single variable domain DOM7h-11, as well as ligands and drug conjugates comprising such variants, compositions, nucleic acids, vectors and hosts. 1. An anti-serum albumin (SA) immunoglobulin single variable domain variant of DOM7h-11 (DOM7h-11 as shown in ) , wherein the variant comprises at least one mutation in the FW2/CDR2 junction (positions 49 to 51 , numbering according to Kabat) compared to DOM7h-11 , and wherein the variant has from 2 to 8 changes compared to the amino acid sequence of DOM7h-11.2. The variant of claim 1 , wherein position 49 (according to Kabat) is Leu.3. The variant of or claim 1 , wherein position 50 (according to Kabat) is Ala or Trp.4. The variant of claim 1 , or claim 1 , wherein position 51 (according to Kabat) is Phe or Asn.5. The variant of claim 1 , wherein the variant comprises an amino acid sequence that is identical to the amino acid sequence of a single variable domain selected from DOM7h-11-3 (SEQ ID NO: 5) claim 1 , DOM7h-11-15 (SEQ ID NO: 2) claim 1 , DOM7h-11-12 (SEQ ID NO: 1) and DOM7h-11-19 (SEQ ID NO: 4) or has up to 4 changes compared to the selected amino acid sequence claim 1 , provided that the amino acid sequence of the variant has at least one mutation in the FW2/CDR2 junction as defined in any one of to .6. The variant of claim 1 , wherein the variant comprises an amino acid sequence that is identical to the amino acid sequence of DOM7h-11-15(SEQ ID NO: 414) or has up to 4 changes compared to the amino acid sequence of DOM7h-11-15 claim 1 , provided that the amino acid sequence of the variant has at least one mutation in the FW2/CDR2 junction as defined in any one of to .7. An anti-serum albumin (SA) immunoglobulin single variable domain variant of DOM7h-11 claim 1 , wherein the variant comprises a Met at position 32 (numbering according to Kabat) compared to DOM7h-11 (as shown in ) claim 1 , and wherein the variant has from 0 to 4 ...

ANTI-SERUM ALBUMIN BINDING VARIANTS

The invention relates to improved variants of the anti-serum albumin immunoglobulin single variable domain DOM7h-11, as well as ligands and drug conjugates comprising such variants, compositions, nucleic acids, vectors and hosts. 1. An anti-serum albumin (SA) immunoglobulin single variable domain variant of DOM7h-11 (DOM7h-11 as shown in ) , wherein the variant comprises at least one mutation in the FW2/CDR2 junction (positions 49 to 51 , numbering according to Kabat) compared to DOM7h-11 , and wherein the variant has from 2 to 8 changes compared to the amino acid sequence of DOM7h-11.2. The variant of claim 1 , wherein position 49 (according to Kabat) is Leu.3. The variant of claim 1 , wherein position 50 (according to Kabat) is Ala or Trp.4. The variant of claim 1 , wherein position 51 (according to Kabat) is Phe or Asn.5. The variant of claim 1 , wherein the variant comprises an amino acid sequence that is identical to the amino acid sequence of a single variable domain selected from DOM7h-11-3 (SEQ ID NO: 5) claim 1 , DOM7h-11-15 (SEQ ID NO: 2) claim 1 , DOM7h-11-12 (SEQ ID NO: 1) and DOM7h-11-19 (SEQ ID NO: 4) or has up to 4 changes compared to the selected amino acid sequence claim 1 , provided that the amino acid sequence of the variant has at least one mutation in the FW2/CDR2 junction.6. The variant of claim 1 , wherein the variant comprises an amino acid sequence that is identical to the amino acid sequence of DOM7h-11-15(SEQ ID NO: 414) or has up to 4 changes compared to the amino acid sequence of DOM7h-11-15 claim 1 , provided that the amino acid sequence of the variant has at least one mutation in the FW2/CDR2 junction.7. An anti-serum albumin (SA) immunoglobulin single variable domain variant of DOM7h-11 claim 1 , wherein the variant comprises a Met at position 32 (numbering according to Kabat) compared to DOM7h-11 (as shown in ) claim 1 , and wherein the variant has from 0 to 4 further changes compared to the amino acid sequence of DOM7h-11.8. The ...

EXENDIN-4 DERIVATIVES AS PEPTIDIC DUAL GLP-1/GLUCAGON RECEPTOR AGONISTS

The present invention relates to dual GLP-1/glucagon receptor agonists and their medical use, for example in the treatment of disorders of the metabolic syndrome, including diabetes and obesity, as well as for reduction of excess food intake. 1. A peptidic compound having the formula (I):{'br': None, 'sub': '2', 'sup': '1', 'HN-His-Aib-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Leu-S er-Lys-Gln-X14-Asp-Glu-Gln-Arg-Ala-Lys-Leu-Phe-Ile-Glu-Trp-Leu-Aib-X28-X29-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-R\u2003\u2003(I)'}{'sub': 2', '2, 'sup': '5', 'X14 is an amino acid residue with a functionalized —NHside chain group selected from the group consisting of Lys, Orn, Dab, and Dap, wherein the —NHside chain group is functionalized by —Z—C(O)—R, wherein'}Z is a linker in all stereoisomeric forms,{'sup': '5', 'Ris a moiety comprising up to 50 carbon atoms and heteroatoms selected from the group consisting of N and O,'}X28 is an amino acid residue selected from the group consisting of Ala, Lys, and Ser,X29 is an amino acid residue selected from the group consisting of D-Ala and Gly, and{'sup': '1', 'sub': '2', 'Ris NHor OH,'}or a salt or solvate thereof.2. The compound of claim 1 ,{'sup': '1', 'sub': '2', 'wherein Ris NH,'}or a salt or solvate thereof.3. The compound or salt or solvate thereof according to claim 1 ,wherein the peptidic compound has a relative activity of at least 0.09% compared to that of natural glucagon at the glucagon receptor.4. The compound or salt or solvate thereof according to claim 1 , wherein the peptidic compound exhibits a relative activity of at least 0.1% compared to that of GLP-1(7-36)-amide at the GLP-1 receptor.5. The compound or salt or solvate thereof of claim 1 , wherein{'sub': '2', 'sup': '5', 'X14 is Lys wherein the —NHside chain group is functionalized with a group —Z—C(O)R, wherein'}Z is a group selected from the group consisting of γE, γE-γE, AEEAc-AEEAc-γE, and AEEAc-AEEAc-AEEAc, and{'sup': '5', 'Ris a group selected from the group consisting of ...

Nanoparticles Conjugated with Vasoactive Intestinal Peptide Antagonists

This disclosure relates to compositions comprising an antagonist of vasoactive intestinal polypeptide signaling coupled to a nanoparticle and methods of use related thereto. In certain embodiments, the nanoparticle is a poloxamer-stabilized polypropylene sulfide nanoparticle. 1. A composition comprising a nanoparticle comprising an antagonist of vasoactive intestinal polypeptide signaling.2. The composition of claim 1 , wherein the nanoparticle is comprised of poloxamer-stabilized polypropylene sulfide.3. The composition of claim 2 , wherein the nanoparticle has a diameter of between 10 and 100 nm.4. The composition of claim 2 , wherein the nanoparticle has a diameter between 20 and 50 nm or about 30 nm.7. The composition of claim 1 , wherein the molar ratio of antagonist peptide to the nanoparticles is about 60.8. The composition of claim 1 , wherein the chemical linkage between the VIP antagonistic peptide and the nanoparticles is a disulfide bond.9. A method of augmenting T-cell activation and ex vivo expansion by co-incubation of human T cells with a nanoparticle containing a small molecule antagonist of VIP signaling.10. The method of claim 9 , wherein the human T cells are activated with anti-CD3 antibody bound to a plate.11. The method of claim 9 , wherein human T cells are activated in a mixed lymphocyte reaction.12. The method of claim 9 , wherein the human T cells are activated in vitro by co-incubation with tumor associated antigens.13. The method of claim 12 , wherein the tumor associate antigens are presented on tumor microvesicles.14. The method of claim 12 , wherein the activated human T cells are infused into a human patient with cancer.15. The method of claim 9 , wherein the human T cells are activated in vitro by co-incubation with viral antigens.16. The method of claim 15 , wherein the viral antigens are presented on microvesicles.17. The method of claim 15 , wherein the viral antigens are presented on dendritic cells.18. The method of claim 12 , ...

AAV Mediated Exendin-4 Gene Transfer to Salivary Glands to Protect Subjects from Diabetes or Obesity

The invention relates to a gene transfer-based method to protect a subject from diabetes or obesity. The method comprises administering to a salivary gland of the subject an AAV virion comprising an AAV vector that encodes an exendin-4 protein. Also provided are exendin-4 proteins and nucleic acid molecules that encode such exendin-4 proteins. Also provided are AAV vectors and AAV virions that encode an exendin-4 protein. One embodiment is an exendin-4 protein that is a fusion protein comprising an NGF secretory segment joined to the amino terminus of an exendin-4 protein domain.

ENTEROKINASE CLEAVABLE POLYPEPTIDES

The present invention relates to Enterokinase-cleavable polypeptides comprising an Enterokinase cleavage site connected to a polypeptide and their use for making the target polypeptide by expression. The invention also relates to DNA sequences, vectors and host cells for use in expressing the Enterokinase-cleavable polypeptides. 1. A method for making a target polypeptide , said method comprising the steps: [{'br': None, 'sub': 2', '6', '5', '4', '1, 'Z-X-X-X-G-D-R-Z\u2003\u2003(I) SEQ ID NO: 1'}, 'wherein', {'sub': '1', 'Zis a polypeptide comprising at least 2 amino acid residues;'}, {'sub': '4', 'Xis an amino acid selected from the group consisting of E, Q, L, D, G, A, S, F, H, Y, W, T or M;'}, {'sub': '5', 'Xis an amino acid selected from the group consisting of genetically encoded amino acids other than S and I;'}, {'sub': '6', 'Xis absent or an amino acid selected from the group consisting of genetically encoded amino acids;'}, {'sub': '2', 'Zis optionally a polypeptide or an amino acid residue;'}, {'sub': '1', 'wherein said target polypeptide is Zin formula (I);'}], 'a) expressing an Enterokinase-cleavable fusion polypeptide comprising a polypeptide of formula Ib) contacting said Enterokinase-cleavable fusion polypeptide with an Enterokinase under conditions facilitating cleavage of said fusion polypeptide; andc) optionally isolating said target polypeptide from said cleavage reaction in b).2. The method according to claim 1 , wherein Xis E claim 1 , Q claim 1 , L claim 1 , D claim 1 , G or A.3. The method according to claim 2 , wherein X-Xis selected from the group consisting of DD claim 2 , DE claim 2 , DL claim 2 , DQ claim 2 , EE claim 2 , and EQ.4. The method according to claim 3 , wherein X-Xis DD or DE.5. The method according to claim 1 , wherein Zis a polypeptide facilitating the expression of said Enterokinase-cleavable fusion polypeptide in a host cell.6. The method according to claim 1 , wherein Zis a polypeptide having from 2 to 50 amino acid ...

Albumin fusion proteins

The present invention encompasses albumin fusion proteins. Nucleic acid molecules encoding the albumin fusion proteins of the invention are also encompassed by the invention, as are vectors containing these nucleic acids, host cells transformed with these nucleic acids vectors, and methods of making the albumin fusion proteins of the invention and using these nucleic acids, vectors, and/or host cells. Additionally the present invention encompasses pharmaceutical compositions comprising albumin fusion proteins and methods of treating, preventing, or ameliorating diseases, disorders or conditions using albumin fusion proteins of the invention.

HIGH-ACTIVITY LONG-ACTING HYPOGLYCEMIC FUSION PROTEIN AS WELL AS PREPARATION METHOD AND MEDICAL APPLICATION THEREOF

The disclosure provides a high-activity long-acting hypoglycemic fusion protein, which is formed by connecting, via a linker peptide or directly, a high-activity Exendin-4 mutant with an optimally mutated Fc fragment of a human immunoglobulin IgG1. The optimally mutated Fc fragment of the human immunoglobulin IgG1 comprises an optimally mutated human IgG1 hinge region and human IgG1 constant regions CH2 and CH3. 1. A high-activity long-acting hypoglycemic fusion protein , wherein the hypoglycemic fusion protein is formed by connecting , via a linker peptide or directly , a high-activity Exendin-4 mutant with an optimally mutated Fc fragment of a human immunoglobulin IgG1.2. The hypoglycemic fusion protein according to claim 1 , wherein claim 1 , the optimally mutated Fc fragment of the human immunoglobulin IgG1 comprises an optimally mutated human IgG1 hinge region and human IgG1 constant regions CH2 and CH3 claim 1 , and the amino acid sequence of the optimally mutated human IgG1 hinge region is as shown in SEQ ID NO: 6.3. The hypoglycemic fusion protein according to claim 2 , wherein claim 2 , the amino acid sequences of the human IgG1 constant regions CH2 and CH3 are as shown in SEQ ID NO: 7.4. The hypoglycemic fusion protein according to claim 1 , wherein claim 1 , the linker peptide is a flexible peptide rich in Gly and/or Ala and/or Ser claim 1 , having 1˜50 amino acid residues in length.5. The hypoglycemic fusion protein according to claim 4 , wherein claim 4 , the amino acid sequence of the linker peptide is as shown in SEQ ID NO: 8.6. The hypoglycemic fusion protein according to claim 1 , wherein claim 1 , the amino acid sequence of the high-activity Exendin-4 mutant is as shown in SEQ ID NO:2 claim 1 , SEQ ID NO: 3 claim 1 , or SEQ ID NO: 4.7. The fusion protein according to claim 1 , wherein claim 1 , the amino acid sequence of the fusion protein is as shown in SEQ ID NO: 11 claim 1 , SEQ ID NO: 15 or SEQ ID NO: 16.8E. coli. A method for preparing the ...

PAC1 RECEPTOR AGONISTS (MAXCAPS) AND USES THEREOF

In certain embodiments novel PAC1 receptor agonists are provided wherein the agonists comprise a targeting sequence that binds to the PAC1 receptor and said targeting sequence is attached to an amino acid sequence comprising a fragment of the maxadilan amino acid sequence, wherein the targeting sequence comprises a full-length 38 amino acid PACAP peptide or an N-terminus fragment thereof containing the amino acid sequence HSDGIF, wherein said targeting sequence optionally comprises an amino acid insertion between residues 11 and 12 of said PACAP peptide or fragment thereof; and the fragment of the maxadilan amino acid sequence comprises a fragment of the maxadilan sequence effective to activate PAC1 signaling. 1. A PAC1 receptor agonist , said agonist comprising: said targeting sequence comprises a maxadilan peptide or fragment thereof effective to bind a PAC1 receptor; and', {'sub': 1-38', '1-38, 'said peptide that activates PAC1 signaling comprises PACAPor a fragment thereof, effective to activate PAC1 signaling, wherein said PACAPor fragment thereof optionally comprises an amino acid deletion, insertion, or substitution.'}], 'a targeting sequence that binds to the PAC1 receptor attached to a peptide that activates PAC1 signaling, wherein2. The PAC1 receptor agonist of claim 1 , wherein said PACAPcomprises an amino acid insertion between residues 11 and 12 of said PACAP.3. The PAC1 receptor agonist according to any one of - claim 1 , wherein said PAC1 receptor agonist does not substantially activate the VPAC2 receptor or the PAC2 receptor.4. The PAC1 receptor agonist according to any one of - claim 1 , wherein said PAC1 receptor agonist does not activate the VPAC2 receptor or the PAC2 receptor.5. The PAC1 receptor agonist according to any one of - claim 1 , wherein said peptide that activates PAC1 signaling comprises an amino acid insertion between residues 11 and 12 of said PACPpeptide.6. The PAC1 receptor agonist of claim 5 , wherein said insertion is a serine ...

Use of anti-pacap antibodies and antigen binding fragments thereof for treatment, prevention, or inhibition of photophobia

This invention relates to methods of screening for anti-PACAP antibodies, or anti-PACAP receptor antibodies, and antigen binding fragments thereof, for potential use in treating or preventing PACAP-associated photophobia or light aversion, and therapeutic compositions containing and methods of using anti-PACAP antibodies, or anti-PACAP receptor antibodies, and antigen binding fragments thereof.

TRIBLOCK PEPTIDE AMPHIPHILES, MICELLES AND METHODS OF USE

One aspect of the present invention is directed to triblock peptides comprising a lipid moiety, a peptide block and a zwittenon-like block. Another aspect of the invention is directed to pharmaceutical compositions comprising the triblock peptides of the present in invention arranged in micelles in a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical compositions of the present invention are vaccine compositions, which may further comprise an adjuvant. Another aspect of the invention is directed to methods of using the triblock peptides and compositions of the invention to treat a disease or condition. 1. A triblock peptide of the formula:{'br': None, 'A-B-C'}whereinA is a lipid moiety; andB and C are independently a peptide block or a zwitterion-like block, wherein one of B andC is a peptide block and the other of B and C is a zwitterion-like block.2. The triblock peptide of claim 1 , wherein the lipid moiety comprises a plurality of lipid molecules.3. The triblock peptide of claim 1 , wherein the lipid moiety comprises a lipid molecule selected from the group consisting of a C-Csaturated fatty acid claim 1 , a C-Cunsaturated fatty acid claim 1 , a bioactive lipid moiety and combinations thereof.4. The triblock peptide of claim 3 , wherein the bioactive lipid moiety comprises from 1 to 8 saturated fatty acids claim 3 , unsaturated fatty acids or combinations thereof claim 3 , linked together.5. The triblock peptide of claim 3 , wherein the saturated and unsaturated fatty acids of the bioactive lipid comprise C-Cfatty acids.6. The triblock peptide of claim 1 , wherein the lipid moiety comprises a lipid molecule selected from the group consisting ofacetic acid claim 1 , propionic acid claim 1 , butyric acid claim 1 , valeric acid claim 1 , caproic acid claim 1 , enanthic acid claim 1 , caprylic acid claim 1 , pelargonic acid claim 1 , capric acid claim 1 , undecylic acid claim 1 , lauric acid claim 1 , tridecylic acid claim 1 , myristic ...

Peptide agonists of glp-1 activity

Novel peptide agonists of GLP-1 activity useful for lowering blood glucose levels. The novel peptides comprise variants of the GLP-1 or the exendin-4 polypeptide sequence and are pharmacologically active and stable. These peptides are useful in the treatment of diseases that benefit from regulation of excess levels of blood glucose and/or regulation of gastric emptying, such as diabetes and eating disorders.

MIRAC PROTEINS

This disclosure relates to a method of generating conditionally active biologic proteins from wild type proteins, in particular therapeutic proteins, which are reversibly or irreversibly inactivated at the wild type normal physiological conditions. For example, evolved proteins are virtually inactive at body temperature, but are active at lower temperatures. 118-. (canceled)19. A method of preparing a conditionally active antibody , the method comprising steps of:i. evolving a DNA which encodes a parent antibody to an antigen using one or more evolutionary techniques to create mutant DNAs;ii. expressing the mutant DNAs to obtain at least one mutant antibody which exhibits an increased binding activity to the antigen in an assay at an aberrant condition that deviates from a normal range of a physiological condition at a site of administration of the mutant antibody, or at a tissue or organ at a site of action of the mutant antibody, when compared to the binding activity to the antigen by the same mutant antibody in an assay at a normal physiological condition that is within the normal range of the physiological condition at the site of administration of the mutant antibody, or at the tissue or organ at the site of action of the mutant antibody; andiii. selecting the conditionally active antibody from the at least one mutant antibody which exhibits an increased binding activity to the antigen in the assay at the aberrant condition that deviates from the normal range of the physiological condition at the site of administration of the conditionally active antibody, or at the tissue or organ at the site of action of the conditionally active antibody, compared to the binding activity by the same conditionally active antibody in the assay under the normal physiological condition that is within the normal range of the physiological condition at the site of administration of the conditionally active antibody, or at the tissue or organ at the site of action of the ...

PEPTIDES COMPRISING NON-NATURAL AMINO ACIDS AND METHODS OF MAKING AND USING THE SAME

This invention relates to novel compositions comprising analogs of naturally occurring polypeptides, wherein the analog comprises an α-amino acid and at least one β-amino acid. Administration of the compositions may be used for effecting treatment or prevention of a plurality of disease states caused by dysfunctional biochemical or biological pathways. The compositions and methods of this invention are particularly useful to identify novel therapeutic modulators of in-vivo receptor activity with extended half-lives and relevant bioactivity as compared to the naturally translated polypeptides upon which the analogs are derived. 1. A composition comprising a vasoactive intestinal peptide (VIP) analog disclosed herein , wherein said analog is optionally modified by one or more active agents.2. The composition of claim 1 , wherein the total number of β-amino acids in the analog is from about 14 percent to about 50 percent of the total number of amino acids of the analog.322.-. (canceled)23. A method of inhibiting secretion of TNF-α in a subject comprising administering a composition comprising a VIP analog to a subject claim 1 , wherein said analog comprises an α-amino acid and at least one β-amino acid.24. A method of identifying a modulator of human VIP receptor activity comprising:a) contacting a human VIP receptor with a VIP analog, wherein said analog comprises an α-amino acid and at least one β-amino acidb) measuring the association of the VIP analog to the human VIP receptor in the presence and absence of an unknown compound andc) comparing the rate of association of the VIP analog to the human VIP receptor in the presence of an unknown compound to the rate of association of the VIP analog to the human VIP receptor in the absence of an unknown compound.2551.-. (canceled)52. The composition of claim 1 , wherein the VIP analog comprises an amino acid sequence selected from the group consisting of: SEQ ID NO: 1 claim 1 , SEQ ID NO: 7 claim 1 , SEQ ID NO: 8 claim 1 , ...

Chemically modified metabolites of regulatory peptides and methods of producing and using same

The present invention relates to a peptide of Formula (I), or a pharmaceutically acceptable salt thereof: X-P Formula (I) wherein: P is a DPPIV peptide metabolite of regulatory peptides obtained by cleavage of the two N-terminal amino acids; and X is defined by Formula (II): wherein: A is selected from the group consisting of C1-C10 alkylene, C2-C10 alkenylene, C2-C10 alkynylene, C1-C10 heteroalkylene, C2-C10 heteroalkenylene, C2-C10 heteroalkynylene and phenyl; and B is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl and C3-C7 cycloalkyl.

Albumin fusion proteins

The present invention encompasses albumin fusion proteins. Nucleic acid molecules encoding the albumin fusion proteins of the invention are also encompassed by the invention, as are vectors containing these nucleic acids, host cells transformed with these nucleic acids vectors, and methods of making the albumin fusion proteins of the invention and using these nucleic acids, vectors, and/or host cells. Additionally the present invention encompasses pharmaceutical compositions comprising albumin fusion proteins and methods of treating, preventing, or ameliorating diseases, disordrs or conditions using albumin fusion proteins of the invention.

葡萄糖调节多肽及其制备和使用方法

本发明涉及包含与延伸的重组多肽(XTEN)连接的葡萄糖调节肽的组合物、编码所述组合物的分离的核酸和含有所述分离的核酸的载体和宿主细胞，以及制备所述组合物的方法和使用所述组合物治疗葡萄糖调节肽相关疾病、疾患和病症的方法。

Exendin-4类似物的定位聚乙二醇化修饰物及其用途

本发明涉及Exendin-4类似物的定位聚乙二醇化修饰物及其用途。特别地，本发明涉及式(I)所示的Exendin-4类似物的聚乙二醇修饰物：或其可药用盐，其中各符号如说明书所述。本发明还涉及式(II)所示的Exendin-4类似物：其中各符号如说明书所述。本发明进一步涉及所述聚乙二醇修饰物的制备方法、其用途、包含其的组合物、以及所述Exendin-4类似物用于制备所述聚乙二醇修饰物的用途。通过本发明可以使聚乙二醇专一性地定位修饰于Exendin-4类似物的肽链中并且修饰物具有有益的生物学活性。PEG-M-X-(Ex-4) (I)[Aa p ]Exendin-4 (II)。

Method for amidating polypeptides with basic aminoacid C-terminals by means of specific endoproteases

본 발명은 트립신의 생물학적 활성을 갖는 효소의 존재 하에서 2개의 펩티드를 반응시키는 단계 및, 필요한 경우, 수득가능한 화학식 I의 화합물을 단백질 화학적 정제로 처리하는 단계로 이루어지는, C-말단 아미드화된 2염기성 또는 다염기성 펩티드를 제조하는 방법에 관한 것이다. The present invention consists of reacting two peptides in the presence of an enzyme having the biological activity of trypsin and, if necessary, treating the obtainable compound of formula (I) by protein chemical purification, C-terminal amidated dibasic Or to a method for preparing a polybasic peptide. C-말단 아미드화, GLP-1, 트립신, 엔테로키나제 C-terminal Amidation, GLP-1, Trypsin, Enterokinase

Mirac proteins

본 발명은, 정상 생리학적 조건에서 가역적으로 또는 비가역적으로 비활성화되는 야생형 항체, 특히 치료용 단백질로부터 조건 활성 항체를 생성하는 방법에 관한 것이다. 예를 들어, 진화된 단백질은 사실상 체온에서는 비활성이지만, 더 낮은 온도에서는 활성이다. The present invention relates to a method of producing a conditionally active antibody from a wild-type antibody, particularly a therapeutic protein, that is reversibly or irreversibly inactivated under normal physiological conditions. For example, an evolved protein is inactive at body temperature, but is active at lower temperatures.

口服降糖肽、其脂肪酸衍生物及用途

本发明涉及口服降糖肽、其脂肪酸衍生物及用途。该多肽的序列如SEQ ID NO.1所示。该多肽或脂肪酸衍生物其可用于制备预防或治疗糖尿病的药物或药物组合物，或用于制备降血糖的药物或药物组合物。与现有技术相比，本发明的多肽具有针对种蛋白酶的酶解抗性，能很好地避免在胃肠道中被酶解失效，更加适宜作为口服降血糖药物。

抗pacap抗体及其用途

本发明涉及对PACAP具有结合特异性的拮抗性抗体及其抗原结合片段。这些抗体抑制、阻断或中和与PACAP相关联的至少一种生物学效应，例如血管舒张。在示例性实施方案中，这些抗体及其抗原结合片段可包含本文所述的特定的VH、VL和CDR多肽。在一些实施方案中，这些抗体及其抗原结合片段结合和/或竞争结合至人PACAP上的特异性表位。本发明还涉及使用这些拮抗性抗PA‑CAP抗体及其结合片段用于诊断、评估和治疗与PACAP相关联的疾病和病症以及其中PACAP相关活性(诸如血管舒张、肥大细胞脱颗粒和/或神经元激活)的拮抗作用是治疗有益的病状，例如头痛和偏头痛适应症。

Method of purifying cyclic or acyclic peptide

FIELD: chemistry. SUBSTANCE: invention relates to a method of purifying a cyclic or an acyclic peptide selected from a group comprising eptifibatide, exenatide, atosiban and nesiritide or combination thereof, from a mixture containing at least one impurity, involving contacting said mixture with a reverse phase HPLC matrix and an ion-exchange chromatography matrix and obtaining a purified peptide product with purity of at least 96% and, preferably, at least about 99%. EFFECT: obtaining a purified peptide product. 11 cl, 4 tbl, 18 ex РОССИЙСКАЯ ФЕДЕРАЦИЯ (19) RU (11) 2 461 564 (13) C2 (51) МПК C07K C07K C07K C07K B01D B01D ФЕДЕРАЛЬНАЯ СЛУЖБА A61K ПО ИНТЕЛЛЕКТУАЛЬНОЙ СОБСТВЕННОСТИ A61K (12) ОПИСАНИЕ 1/18 1/20 14/605 7/06 15/32 15/36 38/26 38/08 (2006.01) (2006.01) (2006.01) (2006.01) (2006.01) (2006.01) (2006.01) (2006.01) ИЗОБРЕТЕНИЯ К ПАТЕНТУ (21)(22) Заявка: 2010137008/04, 26.03.2008 (24) Дата начала отсчета срока действия патента: 26.03.2008 (73) Патентообладатель(и): Байокон Лимитид (IN) (43) Дата публикации заявки: 20.03.2012 Бюл. № 8 C 2 2 4 6 1 5 6 4 R U C 2 (56) Список документов, цитированных в отчете о поиске: SU 688124 А, 30.09.1979. WO 2005019262 А1, 03.03.2005. WO 2007071767 А1, 28.06.2007. US 6492327 В2, 10.12.2003. US 2006/0148699 А1, 06.07.2006. WO 2005100388 A1, 27.10.2005. JP 6256399 A, 13.09.1994. TERANISHI H et al: "Isolation and characterization of four VIP-related peptides from red-bellied newt, Cynops pyrrhogaster", REGULATORY PEPTIDES, 2004, vol. 123, no. 13, pages 173-179. (см. прод.) (85) Дата начала рассмотрения заявки PCT на национальной фазе: 06.09.2010 (86) Заявка PCT: IN 2008/000191 (26.03.2008) (87) Публикация заявки РСТ: WO 2009/098707 (13.08.2009) Адрес для переписки: 127055, Москва, а/я 11, Н.К.Попеленскому (54) СПОСОБ ОЧИСТКИ ЦИКЛИЧЕСКОГО ИЛИ НЕЦИКЛИЧЕСКОГО ПЕПТИДА (57) Реферат: Изобретение относится к способу очистки циклического или нециклического пептида, выбранного из группы пептидов, включающей эптифибатид, эксенатид, атозибан ...

anti-PACAP antibodies and uses thereof

本发明涉及对PACAP具有结合特异性的拮抗性抗体及其抗原结合片段。这些抗体抑制、阻断或中和与PACAP相关联的至少一种生物学效应，例如血管舒张。在示例性实施方案中，这些抗体及其抗原结合片段可包含本文所述的特定的VH、VL和CDR多肽。在一些实施方案中，这些抗体及其抗原结合片段结合和/或竞争结合至人PACAP上的特异性表位。本发明还涉及使用这些拮抗性抗PA‑CAP抗体及其结合片段用于诊断、评估和治疗与PACAP相关联的疾病和病症以及其中PACAP相关活性(诸如血管舒张、肥大细胞脱颗粒和/或神经元激活)的拮抗作用对治疗有益的病状，例如头痛和偏头痛适应症。

新規化合物，その製法及びそれを含む医薬組成物

(57)【要約】本公報は電子出願前の出願データであるた め要約のデータは記録されません。

Peptide compositions with effects on blood glucose

The present invention provides compositions and methods for ameliorating neurological or memory disorders and improving learning and cognition through the increase of cyclic AMP. Gilatides, peptides comprising the nine amino acid sequence (SEQ ID NO:1), and functional analogs thereof are disclosed to modulate neurological activity when administered to a subject. The methods of the invention can be used to prevent or treat neurological disorders as well as improve memory retention and acquisition. In addition, the invention can be used to modulate insulin levels and blood glucose. The invention includes pharmaceutical compositions comprising a therapeutically or prophylactically effective amount of a Gilatide peptide or a functional analog thereof.

GCSF-Albumin fusion proteins

Peptide conjugates of glp-1 receptor agonists and gastrin and their use

The present invention relates, inter alia, to certain peptide conjugates, and to the use of the conjugates in the treatment of a variety of diseases or disorders, including diabetes (type 1 and/or type 2) and diabetes-related diseases or disorders.

Exendin 4 polypeptide segment

本发明涉及一种Exendin 4多肽片段，该多肽具有降低血糖的作用，可用于治疗II型糖尿病。所述多肽为HGEGTX 1 TSDLSKQX 2 EEEAVX 3 LFIEWLKNGX 4 PX 5 ，其中，X 1 表示Phe或Tyr，X 2 表示Met、Ile或Leu，X 3 表示Lys，X 4 表示Gly或缺失，X 5 表示Arg或缺失。本发明还涉及Exendin4多肽片段的制备方法。

Stabilised compounds of exendin-4

FIELD: medicine. SUBSTANCE: invention proposes compositions, which contain stabilised exendin-4(1-39) and allied compounds. Invention describes stabilised agonists of exendin-4, which contain at least one modified amino-acid remainder, in particular in position Asn28 of exendin-4(1-39) molecule. EFFECT: increased efficiency of application in treatment of diseases. 15 cl, 9 dwg, 2 tbl, 6 ex РОССИЙСКАЯ ФЕДЕРАЦИЯ (19) RU (11) 2 376 314 (13) C2 (51) МПК C07K 14/575 (2006.01) A61K 38/22 (2006.01) A61P 3/10 (2006.01) ФЕДЕРАЛЬНАЯ СЛУЖБА ПО ИНТЕЛЛЕКТУАЛЬНОЙ СОБСТВЕННОСТИ, ПАТЕНТАМ И ТОВАРНЫМ ЗНАКАМ (12) ОПИСАНИЕ ИЗОБРЕТЕНИЯ К ПАТЕНТУ (21), (22) Заявка: 2005113291/04, 02.10.2003 (24) Дата начала отсчета срока действия патента: 02.10.2003 (73) Патентообладатель(и): ЗИЛЭНД ФАРМА А/С (DK) (43) Дата публикации заявки: 20.01.2006 2 3 7 6 3 1 4 (45) Опубликовано: 20.12.2009 Бюл. № 35 (56) Список документов, цитированных в отчете о поиске: RU 2126264 С1, 20.02.1999. WO 0104156 А, 18.01.2001. DE 19637230 А, 19.03.1998. WO 0066629 А, 09.11.2000. WO 9943708 A, 02.09.1999. 2 3 7 6 3 1 4 R U (86) Заявка PCT: DK 03/00651 (02.10.2003) C 2 C 2 (85) Дата перевода заявки PCT на национальную фазу: 03.05.2005 (87) Публикация PCT: WO 2004/035623 (29.04.2004) Адрес для переписки: 129090, Москва, ул. Б.Спасская, 25, стр.3, ООО "Юридическая фирма Городисский и Партнеры", пат.пов. Е.Е.Назиной (54) СТАБИЛИЗИРОВАННЫЕ СОЕДИНЕНИЯ ЭКСЕНДИНА-4 (57) Реферат: В данном изобретении предлагаются композиции, содержащие стабилизированный эксендин-4(1-39) и родственные соединения. В изобретении описаны стабилизированные агонисты эксендина-4, которые содержат, по меньшей мере, один модифицированный аминокислотный остаток, в частности в положении Asn28 молекулы эксендина-4(1-39). Изобретение также относится к способам получения и применения стабилизированных соединений эксендина, таким как для лечения диабета. 3 н. и 12 з.п. ф-лы, 9 ил., 2 табл. Ñòð.: 1 ru R U (30) Конвенционный приоритет: 02.10.2002 US 60/415,626 ...

Peptide for medical treatment of pancreatic diabetes of 2nd type and its complications

FIELD: bioengineering. SUBSTANCE: analogue of exenatide with formula H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Gly-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-Gly-OH is suggested. EFFECT: invention ensures medical treatment and preventive treatment of the pancreatic diabetes, as well as medical treatment and preventive treatment of complications of the pancreatic diabetes of 2nd type, such as diabetic neuropathy, muscular dystrophy and endotheliopathy. 3 dwg, 7 tbl, 13 ex РОССИЙСКАЯ ФЕДЕРАЦИЯ (19) RU (11) (51) МПК C07K 14/00 (13) 2 573 933 C1 (2006.01) ФЕДЕРАЛЬНАЯ СЛУЖБА ПО ИНТЕЛЛЕКТУАЛЬНОЙ СОБСТВЕННОСТИ (12) ОПИСАНИЕ (21)(22) Заявка: ИЗОБРЕТЕНИЯ К ПАТЕНТУ 2014134341/10, 21.08.2014 (24) Дата начала отсчета срока действия патента: 21.08.2014 (45) Опубликовано: 27.01.2016 Бюл. № 3 (73) Патентообладатель(и): Дафот Энтерпрайсис Лимитед (CY) R U 2 5 7 3 9 3 3 (54) ПЕПТИД ДЛЯ ЛЕЧЕНИЯ САХАРНОГО ДИАБЕТА 2-ГО ТИПА И ЕГО ОСЛОЖНЕНИЙ (57) Реферат: Изобретение относится к биотехнологии. Arg-D-Arg-Gly-OH. Изобретение позволяет лечить Представлен аналог эксенатида формулы H-Hisи проводить профилактику сахарного диабета, а Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Glnтакже лечить и проводить профилактику Gly-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trpосложнений сахарного диабета 2-го типа, таких Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Proкак диабетическая нейропатия, мышечная Pro-Ser-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-Dдистрофия и эндотелиопатия. 3 ил., 7 табл., 13 пр. Стр.: 1 C 1 C 1 Адрес для переписки: 123100, Москва, Шмитовский пр., 2, стр. 2, Агентство "Ермакова, Столярова и партнеры" 2 5 7 3 9 3 3 (56) Список документов, цитированных в отчете о поиске: US 5,424,286 C1, 11.01.2011. RU 2498814 C2, 20.11.2013. R U Приоритет(ы): (22) Дата подачи заявки: 21.08.2014 (72) Автор(ы): Кашкин Владимир Александрович (RU), Макаров Валерий Геннадьевич (RU), Макарова ...

Method of enhancing neural stem cell proliferation, differentiation, and survival using pituitary adenylate cyclase activating polypeptide (PACAP)

The present invention relates to a method of increasing the number and/or differentiation of neural stem cells and/or neural stem cell progeny using pituitary adenylate cyclase-activating polypetide (PACAP). In a preferred embodiment, additional growth factors are also utilized. The present invention can be practiced in vivo and in vitro, rendering it useful for the treatment of neurodegenerative disease and other neural trauma.

Fusion proteins for use in the treatemnt of cancer

The present invention relates to a method for suppressing or treating cancer, in particular to a method for suppressing or treating one or more of colorectal cancer, breast cancer, prostate cancer and/ or lung cancer. The therapy employs use of a non-cytotoxic protease, which is targeted to a growth hormone-secreting cell such as to a pituitary cell. When so delivered, the protease is internalised and inhibits secretion/ transmission of growth hormone from said cell. The present invention also relates to polypeptides and nucleic acids for use in said methods.

Composition for long-acting peptide analogs

The invention describes compositions of peptide analogs exemplified by peptides derived from vasopressin, terlipressin, and GLP1 and others that are active in blood or cleavable in blood to release an active peptide. The peptide analogs have a general formula: A-(Cm) x -Peptide, wherein A is a hydrophobic moiety or a metal binding moiety, and Cm is a cleavable moiety consisting of glycine or alanine or lysine or arginine or N-Arginine or N-lysine, wherein x is an integer between 0-6 and N may be any amino acid or none. A may be linked to Cm by a linker group. The peptide analogs are complexed with polymeric carrier to provide enhanced half-life.

Method of enhancing neural stem cell proliferation, differentiation, and survival using pituitary adenylate cyclase activating polypeptide (PACAP)

The present invention relates to a method of increasing the number and/or differentiation of neural stem cells and/or neural stem cell progeny using pituitary adenylate cyclase-activating polypetide (PACAP). In a preferred embodiment, additional growth factors are also utilized. The present invention can be practiced in vivo and in vitro, rendering it useful for the treatment of neurodegenerative disease and other neural trauma.

Method of Enhancing Neural Stem Cell Proliferation, Differentiation, and Survival Using Pituitary Adenylate Cyclase Activating Polypeptide (PACAP)

The present invention relates to a method of increasing the number and/or differentiation of neural stem cells and/or neural stem cell progeny using pituitary adenylate cyclase-activating polypeptide (PACAP). In a preferred embodiment, additional growth factors are also utilized. The present invention can be practiced in vivo and in vitro, rendering it useful for the treatment of neurodegenerative disease and other neural trauma.

Long-acting hypoglycemic weight-loss peptide, preparation method thereof and application thereof as medicine

本发明涉及一类长效化降糖减重的胃泌酸调节素(OXM)杂合肽及其应用及其合成方法。通过对OXM肽序进行改变，并与Exenatide的肽序杂合，得到具有更长药理作用时间和更好的减肥效果的OXM杂合肽。目标多肽的合成是是通过正交保护策略固相合成方法快速实现，粗品经纯化，冻干得到目标化合物。

Exendin-4 derivatives as selective glucagon receptor agonists

本发明涉及胰高血糖素受体激动剂和它们的医药用途，例如用于治疗严重低血糖。提供了毒蜥外泌肽‑4类似物，其强力且选择性地活化胰高血糖素受体，并显示与天然胰高血糖素相比在接近中性pH的较高溶解度和在溶液中增强的化学稳定性。所述类似物在位置1具有人工的氨基酸4‑噻唑丙氨酸。这导致当对于仅在位置1不同的相同化合物(在位置1为Tza而非His)彼此进行比较时对胰高血糖素受体相较于GLP1受体更高的选择性。本发明提供高选择性的胰高血糖素受体激动剂。

PEGylated Exendin-4 analogues or its derivatives, preparation method thereof and pharmaceutical composition containing the same for preventing and treating a diabetes

본 발명은 폴리에틸렌글라이콜 또는 이의 유도체로 페길화된 엑센딘-4 유사체, 이의 제조방법 및 이를 유효성분으로 함유하는 당뇨병 예방 또는 치료용 약학적 조성물에 관한 것이다. 본 발명에 의하면 C-말단 40번 위치에 시스테인(Cys)이 도입된 엑센딘-4를 사용하여 상기 시스테인 선택적 페길화(PEGylation)을 통하여 페길화(PEGylation)된 엑센딘-4 유사체의 수율을 증가시킬 수 있고, 약물의 치료효과를 증가시킬 수 있어, 인슐린 과다분비에 의해 유발되는 질환의 예방 또는 치료용 조성물로 유용하게 사용할 수 있다. The present invention relates to an exendin-4 analogue pegylated with polyethylene glycol or a derivative thereof, a preparation method thereof, and a pharmaceutical composition for preventing or treating diabetes containing the same as an active ingredient. According to the present invention, the yield of PEGylated exendin-4 analogue is increased through the cysteine selective PEGylation (PEGylation) using exendin-4 having cysteine (Cys) introduced at position C-terminal 40. It can increase the therapeutic effect of the drug, it can be usefully used as a composition for the prevention or treatment of diseases caused by insulin hypersecretion.

Patent RU2017101377A3

7 ВУ” 2017101377” АЗ Дата публикации: 06.02.2019 Форма № 18 ИЗПМ-2011 Федеральная служба по интеллектуальной собственности Федеральное государственное бюджетное учреждение 5 «Федеральный институт промышленной собственности» (ФИПС) ОТЧЕТ О ПОИСКЕ 1. . ИДЕНТИФИКАЦИЯ ЗАЯВКИ Регистрационный номер Дата подачи 2017101377/10(002280) 17.06.2015 РСТ/ЕР2015/063607 17.06.2015 Приоритет установлен по дате: [ ] подачи заявки [ ] поступления дополнительных материалов от к ранее поданной заявке № [ ] приоритета по первоначальной заявке № из которой данная заявка выделена [ ] подачи первоначальной заявки № из которой данная заявка выделена [ ] подачи ранее поданной заявки № [Х] подачи первой(ых) заявки(ок) в государстве-участнике Парижской конвенции (31) Номер первой(ых) заявки(ок) (32) Дата подачи первой(ых) заявки(ок) (33) Код страны 1. 14305935.0 18.06.2014 ЕР Название изобретения (полезной модели): [Х] - как заявлено; [ ] - уточненное (см. Примечания) Производные эксендина-4 в качестве селективных агонистов рецепторов глюкагона Заявитель: САНОФИ, ЕК 2. ЕДИНСТВО ИЗОБРЕТЕНИЯ [Х] соблюдено [ ] не соблюдено. Пояснения: см. Примечания 3. ФОРМУЛА ИЗОБРЕТЕНИЯ: [Х] приняты во внимание все пункты (см. П см. Примечания [ ] приняты во внимание следующие пункты: [ ] принята во внимание измененная формула изобретения (см. Примечания) 4. КЛАССИФИКАЦИЯ ОБЪЕКТА ИЗОБРЕТЕНИЯ (ПОЛЕЗНОЙ МОДЕЛИ) (Указываются индексы МПК и индикатор текущей версии) С07К 14/605 (2006.01) Аб1К 38/26 (2006.01) Аб1Р 3/10 (2006.01) 5. ОБЛАСТЬ ПОИСКА 5.1 Проверенный минимум документации РСТ (указывается индексами МПК) С07К 14/605; Аб1К 38/26; Аб1Р 3/10 5.2 Другая проверенная документация в той мере, в какой она включена в поисковые подборки: 5.3 Электронные базы данных, использованные при поиске (название базы, и если, возможно, поисковые термины): Е-Габгагу, Езрасепес, Рабеагсв, РАТЕМТЬСОРЕ, КУРТО, МСВ1Т, ЕМВГ-ЕВ1, боозе, СооЗе эсвБо][аг, РиИБМеа, ОЗРТО, Заепсе/ ес 6. ДОКУМЕНТЫ, ОТНОСЯЩИЕСЯ К ПРЕДМЕТУ ПОИСКА Кате- ...

Derivatives of structurally modified vip and pharmaceutical compositions containing them

本发明提供了治疗男性阳萎的新化合物，该化合物属于血管活性肠肽(VIP)和VIP 7-28 VIP 16-28 片，(其中天然氨基酸序列通过用其它天然或非天然氨基酸取代任何5、17和19位氨基酸残基被改性)，它们带有至少一个末端亲脂基团。 改性的VIP序列和片段通过常规的肽链装配方法制备。 该新化合物和含有它们的组合物适于透皮施用。

Patent RU2016141925A3

`7ВУ’” 2016141925`” АЗ Дата публикации: 19.11.2018 Форма № 18 ИЗПМ-2011 Федеральная служба по интеллектуальной собственности Федеральное государственное бюджетное учреждение 5 «Федеральный институт промышленной собственности» (ФИПС) ОТЧЕТ О ПОИСКЕ 1. . ИДЕНТИФИКАЦИЯ ЗАЯВКИ Регистрационный номер Дата подачи 2016141925/10(067177) 02.04.2015 РСТ/ЕР2015/057418 02.04.2015 Приоритет установлен по дате: [ ] подачи заявки [ ] поступления дополнительных материалов от к ранее поданной заявке № [ ] приоритета по первоначальной заявке № из которой данная заявка выделена [ ] подачи первоначальной заявки № из которой данная заявка выделена [ ] подачи ранее поданной заявки № [Х] подачи первой(ых) заявки(ок) в государстве-участнике Парижской конвенции (31) Номер первой(ых) заявки(ок) (32) Дата подачи первой(ых) заявки(ок) (33) Код страны 1. 14305503.6 07.04.2014 ЕР* Название изобретения (полезной модели): [Х] - как заявлено; [ ] - уточненное (см. Примечания) ДВОИНЫЕ ПЕПТИДНЫЕ АГОНИСТЫ РЕЦЕПТОРОВ ОГР-1/ГЛЮКАГОНА, ЯВЛЯЮЩИЕСЯ ПРОИЗВОДНЫМИ ЭКСЕНДИНА-4 Заявитель: САНОФИ, ЕК 2. ЕДИНСТВО ИЗОБРЕТЕНИЯ [Х] соблюдено [ ] не соблюдено. Пояснения: см. Примечания 3. ФОРМУЛА ИЗОБРЕТЕНИЯ: [Х] приняты во внимание все пункты (см. Примечания) [ ] приняты во внимание следующие пункты: [ ] принята во внимание измененная формула изобретения (см. Примечания) 4. КЛАССИФИКАЦИЯ ОБЪЕКТА ИЗОБРЕТЕНИЯ (ПОЛЕЗНОЙ МОДЕЛИ) (Указываются индексы МПК и индикатор текущей версии) С07К 14/435 (2006.01) С07К 14/605 (2006.01) Аб1К 38/26 (2006.01) А6б1К 45/06 (2006.01) 5. ОБЛАСТЬ ПОИСКА 5.1 Проверенный минимум документации РСТ (указывается индексами МПК) СО7К 14/435, СО7К 14/605, Аб1К 38/26, Аб1К 45/06 5.2 Другая проверенная документация в той мере, в какой она включена в поисковые подборки: 5.3 Электронные базы данных, использованные при поиске (название базы, и если, возможно, поисковые термины): Е-Габгагу, Езрасепев, Раеагсв, РАТЕМТСОРЕ, КУРТО, МСВТ1, ЕМВГ-ЕВ1, Соозе, Соозе эспо[аг, РиБМеа, ОЗРТО, ЗслепсеПгесе 6. ...

Peptide exendin-4 derivatives

Изобретение относится к биотехнологии. Описаны пептидные производные эксендина-4, модифицированные у С-конца амином и которые N-концом связываются с GLP-1-рецепторами и частично или полностью содержат аминокислотную последовательность пептида эксендина-4. Раскрыто применение пептидных производных эксендина-4 для получения средства для диагностики и терапии заболеваний, при которых играет роль экспрессия рецепторов GLP-1, для определения плотности инсулинпродуцирующих клеток в ткани, для определения экспрессии GLP-1-рецепторов или их плотности. Изобретение может быть использовано для получения средства для диагностики и терапии доброкачественных и злокачественных заболеваний, в которых играет роль экспрессия рецепторов GLP-1. 13 н. и 12 з.п. ф-лы, 3 табл. РОССИЙСКАЯ ФЕДЕРАЦИЯ (19) RU (11) 2 420 536 (13) C2 (51) МПК C07K 14/575 (2006.01) C07K 14/605 (2006.01) A61K 38/16 (2006.01) ФЕДЕРАЛЬНАЯ СЛУЖБА ПО ИНТЕЛЛЕКТУАЛЬНОЙ СОБСТВЕННОСТИ, ПАТЕНТАМ И ТОВАРНЫМ ЗНАКАМ (12) ОПИСАНИЕ ИЗОБРЕТЕНИЯ К ПАТЕНТУ (21)(22) Заявка: 2007112115/10, 26.08.2005 (24) Дата начала отсчета срока действия патента: 26.08.2005 C 2 (56) Список документов, цитированных в отчете о поиске: NISHIZAWA M. et al: "The hepatic vagal reception ofintraportal GLP-1 is via receptor different from the pancreatic GLP-1 receptor" J Auton Nerv Syst. 2000 Apr 12; 80(1-2), реферат. RITZEL U. et al: "A synthetic glucagon-like peptide-1 analog with improved plasma stability" J Endocrinol 1998 Oct; 159(1):93-102, реферат. RU 2214418 C2, 27.06.2003. (85) Дата начала рассмотрения заявки PCT на национальной фазе: 03.04.2007 (86) Заявка PCT: DE 2005/001503 (26.08.2005) (87) Публикация заявки РСТ: WO 2006/024275 (09.03.2006) Адрес для переписки: 129090, Москва, ул. Б.Спасская, 25, стр.3, ООО "Юридическая фирма Городисский и Партнеры", пат.пов. Е.Е.Назиной (54) ПЕПТИДНЫЕ ПРОИЗВОДНЫЕ ЭКСЕНДИНА-4 (57) Реферат: Изобретение относится к биотехнологии. Описаны пептидные производные эксендина-4, модифицированные у С-конца амином и ...

New version of exendin or its conjugate

Изобретение относится к области биотехнологии, конкретно к конъюгату варианта эксендина с молекулой ПЭГ, и может быть использовано в медицине. Указанный конъюгат включает эксендин с аминокислотной последовательностью SEQ ID NO: 4 и одну молекулу ПЭГ с молекулярным весом от 21 кДа до 29 кДа, конъюгированную с остатком цистеина в эксендине. Изобретение относится также к способу получения конъюгата эксендина, фармацевтической композиции и набору для снижения уровня глюкозы в крови, предусматривающим использование конъюгата эксендина. Изобретение позволяет получить конъюгат эксендина с ПЭГ с активностью агониста рецептора GLP-1 и с сохранением максимального эффекта в отношении стимуляции продукции цАМФ (E max ) при ПЭГилировании. 4 н. и 3 з.п. ф-лы, 44 ил., 5 табл., 26 пр. РОССИЙСКАЯ ФЕДЕРАЦИЯ (19) RU (11) (51) МПК C07K 14/575 C07K 17/08 A61K 38/22 A61K 47/48 A61P 3/10 A61P 3/04 (13) 2 528 734 C2 (2006.01) (2006.01) (2006.01) (2006.01) (2006.01) (2006.01) ФЕДЕРАЛЬНАЯ СЛУЖБА ПО ИНТЕЛЛЕКТУАЛЬНОЙ СОБСТВЕННОСТИ (12) ОПИСАНИЕ (21)(22) Заявка: ИЗОБРЕТЕНИЯ К ПАТЕНТУ 2011147083/10, 23.04.2010 (24) Дата начала отсчета срока действия патента: 23.04.2010 Приоритет(ы): (30) Конвенционный приоритет: (43) Дата публикации заявки: 27.05.2013 Бюл. № 15 (73) Патентообладатель(и): ПЕГБИО КО., ЛТД. (CN) (45) Опубликовано: 20.09.2014 Бюл. № 26 C 2 C 2 EA009366 B1, 28.12.2007. . WO2008058461 А1, 22.05.2008. . FRANCESCO M. VERONESSE, Peptide and protein PEGylation: a review of problems and solutions, Biomaterials, 2001, v. 22, p. 405-417. JOSE A. RODRIGUEZMARTINEZ et al, Enzymatic activity and thermal stability of PEG-α-chymotrypsin conjugates, Biotechnol Lett, (см. прод.) (85) Дата начала рассмотрения заявки PCT на национальной фазе: 23.11.2011 (86) Заявка PCT: 2 5 2 8 7 3 4 2 5 2 8 7 3 4 (56) Список документов, цитированных в отчете о поиске: WO2006074600 A1, 20.07.2006. R U R U 23.04.2009 CN 200910135363.5 (72) Автор(ы): СЮЙ Майкл М. (CN), ВАН Юнсян (CN), ЧЖАН Инхой (CN), ЛО Сяосу (CN), ...

Long-actingization Exenatide derivative and its salt and preparation method and purposes

本发明是一种长效化艾塞那肽衍生物，属多肽化合物技术领域。该艾塞那肽衍生物是对艾塞那肽序列进行结构优化，使其同时具备降糖及减重效果，并将两倍量的艾塞那肽与单倍量的脂肪酸链缀合，利用脂肪酸链发挥与血清白蛋白的结合作用，得到具有更长药理作用时间的艾塞那肽衍生物。本发明还公开了艾塞那肽衍生物的制备方法、其药学上可接受的艾塞那肽衍生物盐、艾塞那肽衍生物药剂、药物组合物和用途，该用途为艾塞那肽衍生物在制备治疗和/或预防糖尿病、肥胖症、高血脂症、非酒精性脂肪肝的药物中的应用。长效化艾塞那肽衍生物可以在保留降糖活性的基础上，具有减重作用，且生物半衰期较艾塞那肽原型显著延长，部分达到了36小时以上，极大的延长了降糖减重作用时间。

Improved anti-serum albumin binding variants

본 발명은 항-혈청 알부민 이뮤노글로불린 단일 가변 도메인 DOM7h-11의 개선된 변이체 뿐만 아니라, 이러한 변이체를 포함하는 리간드 및 약물 접합체, 조성물, 핵산, 벡터 및 숙주에 관한 것이다.

Coiled coil immunoglobulin fusion proteins and compositions thereof

본원은, 제1 항체 영역, 제1 치료제, 및 제1 연결 펩티드를 포함하는 면역글로불린 융합 단백질로서, 상기 제1 치료제는 제1 항체 영역에 연결 펩티드에 의해 부착되고, 상기 연결 펩티드는 베타 가닥의 이차 구조를 가진 영역을 포함하지 않는 것인 면역글로불린 융합 단백질을 개시한다. 연결 펩티드는 익스텐더(extender) 펩티드를 포함할 수 있다. 익스텐더 펩티드는 알파 나선의 이차 구조를 가질 수 있다. 연결 펩티드는 링커 펩티드를 포함할 수 있다. 링커 펩티드는 어떤 이차 구조도 포함하지 않을 수 있다. 또한, 본원에서 면역글로불린 융합 단백질을 포함하는 조성물 및 피험체에서 질환 또는 병태를 치료 또는 예방하기 위한 면역글로불린 융합 단배질의 이용 방법을 개시한다. Disclosed herein is an immunoglobulin fusion protein comprising a first antibody region, a first therapeutic agent, and a first linking peptide, wherein the first therapeutic agent is attached to the first antibody region by a linking peptide, and wherein the linking peptide is of the beta strand. An immunoglobulin fusion protein comprising no region having a secondary structure is disclosed. The connecting peptide may comprise an extender peptide. The extender peptide may have a secondary structure of an alpha helix. The linking peptide may comprise a linker peptide. The linker peptide may not include any secondary structure. Also disclosed herein are compositions comprising an immunoglobulin fusion protein and methods of using the immunoglobulin fusion protein to treat or prevent a disease or condition in a subject.

Derivative of insulinotropic peptide that contains modified n-ended aminoacid

FIELD: bioengineering. SUBSTANCE: invention refers to the field of bioengineering, notably to production of exendin-4 and to a pharmaceutical composition for diabetes treatment. The derivative of exendin-4 is obtained by substituting the N-ended residual of exendin-4 histidine with the fragment chosen from the group consisting of N-dimethylhistidyl, beta-hydroxy-imidazopropionyl, 4-imidazoacetyl and beta-carboxyimidazopropionyl. EFFECT: increased stability in blood and improved activity if compared with exendin-4. 7 cl, 3 dwg, 3 tbl, 4 ex РОССИЙСКАЯ ФЕДЕРАЦИЯ (19) RU (11) 2 442 792 (13) C2 (51) МПК C07K 14/435 (2006.01) C07K 14/65 (2006.01) ФЕДЕРАЛЬНАЯ СЛУЖБА ПО ИНТЕЛЛЕКТУАЛЬНОЙ СОБСТВЕННОСТИ (12) ОПИСАНИЕ ИЗОБРЕТЕНИЯ К ПАТЕНТУ (21)(22) Заявка: 2010101232/10, 16.07.2008 (24) Дата начала отсчета срока действия патента: 16.07.2008 (56) Список документов, цитированных в отчете о поиске: WO 2006097538 А1, 21.09.2006. WO 2007024700 А2, 01.03.2007. US 7,220,721, 22.05.2007. RU 2005113291 A, 20.01.2006. 2 4 4 2 7 9 2 R U (86) Заявка PCT: KR 2008/004170 (16.07.2008) C 2 C 2 (85) Дата начала рассмотрения заявки PCT на национальной фазе: 15.01.2010 (87) Публикация заявки РСТ: WO 2009/011544 (22.01.2009) Адрес для переписки: 129090, Москва, ул. Б.Спасская, 25, стр.3, ООО "Юридическая фирма Городисский и Партнеры", пат.пов. Е.Е.Назиной (54) ПРОИЗВОДНОЕ ИНСУЛИНОТРОПНОГО ПЕПТИДА, СОДЕРЖАЩЕЕ МОДИФИЦИРОВАННУЮ N-КОНЦЕВУЮ АМИНОКИСЛОТУ (57) Реферат: Изобретение относится к области биотехнологии, а именно к производному эксендина-4 и фармацевтической композиции для лечения диабета. Производное эксендина-4 получают с помощью замены N-концевого остатка гистидина эксендина-4 фрагментом, выбранным из группы, состоящей из N- диметилгистидила, бета-гидроксиимидазопропионила, 4-имидазоацетила и бетакарбоксиимидазопропионила. Предложенное изобретение проявляет увеличенную стабильность в крови и улучшенную активность по сравнению с эксендином-4. 2 н. и 5 з.п. ф-лы, 3 ил., 3 табл. Ñòð.: 1 ru 2 4 ...

Positioning pegylation modified compound of Exendin-4 analog and application thereof

本发明涉及Exendin-4类似物的定位聚乙二醇化修饰物及其用途。特别地，本发明涉及式(I)所示的Exendin-4类似物的聚乙二醇修饰物：或其可药用盐，其中各符号如说明书所述。本发明还涉及式(II)所示的Exendin-4类似物：其中各符号如说明书所述。本发明进一步涉及所述聚乙二醇修饰物的制备方法、其用途、包含其的组合物、以及所述Exendin-4类似物用于制备所述聚乙二醇修饰物的用途。通过本发明可以使聚乙二醇专一性地定位修饰于Exendin-4类似物的肽链中并且修饰物具有有益的生物学活性。PEG-M-X-(Ex-4) (I)[Aa p ]Exendin-4 (II)。

Drug fusions and conjugates

The present invention relates to drug fusions that have improved serum half lives. These fusions and conjugates comprise polypeptides, immunoglobulin (antibody) single variable domains and GLP and/or exendin molecules. The invention further relates to uses, formulations, compositions and devices comprising such drug fusions and conjugates.