РАСШИРЕННАЯ АДОПТИВНАЯ КЛЕТОЧНАЯ ТЕРАПИЯ

Настоящее изобретение относится к биотехнологии. В частности, изобретение относится к терапии злокачественных опухолей человека. Более конкретно, настоящее изобретение относится к онколитическим аденовирусным векторам отдельно или вместе с терапевтическими композициями для терапевтического применения и к способам терапии злокачественных опухолей. В одном из аспектов настоящее изобретение относится к отдельному введению адоптивной клеточной терапевтической композиции и онколитических аденовирусных векторов. Кроме того, настоящее изобретение относится к фармацевтическому набору и фармацевтической композиции, в которых используют онколитические аденовирусные векторы. 3 н. и 2 з.п. ф-лы, 51 ил., 15 пр.

NEUES DERIVAT DES HUMANGAMMAINTERFERON-POLYPEPTIDS.

MODIFIZIERTE ZYTOKINE FÜR KREBS THERAPIE

HUMANE ANTIGAMMAINTERFERONANTIKÖRPER, WELCHE DETEKTIERT UND GEKLÄRT SIND MIT VERWENDUNG VON SYNTHETISCHEN PEPTIDEN.

Varianten des rekombinanten humanen Interferon- , Verfahren zu ihrer Herstellung und ihre Verwendung

HUMAN IMMUNE INTERFERON

Rekombinante gamma-Interferonen und diese enthaltende Pharmazeutische Zusammensetzungen

Fusion protein expression in plastids

A method of producing a protein of interest by expression of a polynucleotide encoding a fusion protein in a plastid. The protein of interest is linked to a fusion protein partner wherein the fusion protein has a greater half-life than the individually expressed protein of interest, is resistant to internal cleavage in vivo and comprises a cleavage site, preferably IEGR. Methods of protein purification, plastid transformation to create transplastomic plastids and plant propagation are also claimed. Also claimed is the use of a polynucleotide encoding a fusion partner to increase the stability of a recombinantly expressed protein of interest in a plastid.

PROCESS FOR PRODUCING HUMAN-SPECIFIC GAMMA-INTERFERON AND METHOD FOR ASSAYING THE GAMMA-INTERFERON PRODUCTIVITY OF BLOOD.

Use of lambda interferons in the treatment of obesity-related disorders and related diseases

The invention relates to the field of treatment or prevention of obesity-related disorders, atherosclerosis or a coagulation disorder. In particular, the present invention relates to the use of an activator of IFNλ receptor for the treatment or prevention of such disorders or conditions, and corresponding methods of treatment.

DEVICE FOR SURGICAL TREATMENT OF AMETROPIA

Human immunizing Interféron.

Recombinant gamma interferons having enhanced stability and methods therefor.

MULTI-FUNCTIONAL CYTOKINE

MODIFIED ZYTOKINE FOR CANCER THERAPY

HOMOGENEOUS, REKOMBINANTE IMMUNE INTERFERON FRAGMENTS

DERIVATIVES OF THE GROWTH HORMONE AND USED PROTEINS

MODIFIED PROTEINS, MODIFIED INTERFERONS ALPHA AND BETA PHOSPHORYLIERTE OF PROTEINS, DNA SEQUENCES AND SIMILAR ONE AND THEIR USE

(MET-1, DES-CYS1, DES-TYR2, DES-CYS3) HUMAN GAMMA INTERFERON AND BUT CODING DNSSEQUENZ.

PROCEDURE FOR THE PRODUCTION OF PEPTIDEN, IN ADDITION TO UTILIZATION OF REKOMBINANTES PLASMID AND WITH THIS PLASMID TRANSFORMED MYELOMZELLEN.

PEPTID AND ITS USE.

TO THE EFFECTIVE ONE GENE EXPRESSION CAPABLE VECTOR AND USE OF THE SAME.

PRODUCTION AND EXPRESSION LARGE STRUCTURAL GENES.

A GAMMA INTERFERON CODING SYNTHETIC GENE.

PROCEDURE FOR THE PRODUCTION HUMAN GAMMA INTERFERON OF A AEHNLICHEN POLYPEPTIDS.

VERFAHREN ZUR ERHOEHUNG DER AUSBEUTE VON CYTOKINEN

REKOMBINANTE CELLS THE MONOZYTEN MAKROPHAGEN CELL LINE TO THE GENE THERAPY

BACULOVIRUS TRANSFER VECTORS

SV40 PROMOTER AND VECTOR

Chinese hamster apoptosis-related genes

We provide an isolated polypeptide comprising a sequence capable of mediating apoptosis of a cell, the sequence being selected from a FAIM sequence shown as SEQ ID NO: 1; a FADD sequence shown as SEQ ID NO: 2; a PDCD6 sequence shown as SEQ ID NO: 3; and a Requiem sequence shown as SEQ ID NO: 4.

Macrophage activating factor for pharmaceutical compositions

The present invention relates to pharmaceutical compositions comprising macrophage activating factor (MAF) and method of producing same, particularly to MAF compositions essentially devoid of glycosidase enzymes. The compositions of the present invention and pharmaceutical compositions comprising same are particularly suitable for intravenous administration. Thus according to one aspect, the present invention provides a composition comprising,Gc protein-derived macrophage activating factor (GcMAF), wherein the composition is essentially devoid of glycosidase enzymes.

Novel multifunctional cytokines

NOVEL PEPTIDES AND THE APPLICATION THEREOF IN THERAPY

Remodeling and glycoconjugation of peptides

IMMUNOCONJUGATES FOR THE TREATMENT OF TUMOURS

Polypeptide constructs and uses thereof

The present invention provides a polypeptide construct comprising a peptide or polypeptide signaling ligand linked to an antibody or antigen binding portion thereof which binds to a cell surface-associated antigen, wherein the ligand comprises at least one amino acid substitution or deletion which reduces its potency on cells lacking expression of said antigen.

Allogeneic vaccine and method to synthesize same

Treatment of inflammatory bowel disease with IFN-gamma inhibitors

Recombinant virus immunotherapy

METHOD OF PRODUCING HUMAN GAMMA INTERFERON-LIKE POLYPEPTIDE

Antitumour cellular compositions expressing at least three transgenes

Interferon glycoprotein

Process for production of exogenous gene or its product in plant cells

E. COLI EXPRESSION PLASMID WITH LAC PROMOTER REPRESSOR GENE

AGENTS AND METHODS FOR PROMOTING BONE GROWTH

Agents for promoting bone deposition and growth in a mammalian subject. The agents are O-glycosylated and non-glycosylated peptides that are derived from vitamin D binding protein, collectively referred to hereinafter as "DBP" peptides. The DBP peptides are from 3 to 18, preferably from 4 to 14 amino acids in length and comprise a sequence which is at least 80 % identical, preferably at least 90 % identical to the amino acid sequence of a fragment contained within domain III of DBP. Methods for promoting bone deposition in a subject in need of the same are also provided. The methods comprise administering to the subject a therapeutically effective quantity of an agent selected from the group consisting of an activated form of vitamin D binding protein referred to hereinafter as "ADBP", one or more DBP peptides, and combinations thereof. The agents may be administered locally or systemically.

COMPOSITIONS AND METHODS FOR CANCER IMMUNOTHERAPY

Provided is a cancer therapeutic agent comprising a cancer targeting molecule linked to a liver-expressed chemokine (LEC). In one embodiment, the cancer targeting molecule is an antibody that targets cancer cells or tumors in vivo. The cancer targeting molecule is associated non-covalently or covalently with LEC. The cancer therapeutic agents of the invention are useful for the treatment of cancer in an individual by reducing the size of a tumor or inhibiting the growth of cancer cells in an individual and/or by inhibiting the development of metastasis. The effectiveness of the therapy using the LEC cancer therapeutic agents can be increased by reducing the activity of immunoregulatory T cells and/or by adoptively transferring immune T cells.

FULL-LENGTH INTERFERON GAMMA POLYPEPTIDE VARIANTS

The present invention relates to novel full-length interferon gamma (IFNG) polypeptide variants having interferon gamma activity. The full-length interferon gamma polypeptide variants of the invention are obtained by performing selected modifications in the C-terminal part of the molecule. The variant comprises at least one amino acid substitution in one of the positions S132 and S142, and at least one amino acid substitution in one of the positions R137, R139 and R140. Alternatively, the variant comprises at least amino acid substitutions in positions R137 and R140. The full-length interferon gamma polypeptide variants of the invention are useful in therapy, in particular for the treatment of interstitial pulmonary diseases, such as idiopathic pulmonary fibrosis.

MODIFIED CYTOKINES FOR USE IN CANCER THERAPY

Cytokine derivatives capable of homing the tumoral vessels and the antigen presenting cells and the use thereof as antitumoral agents.

PRIMARY CELL DERIVED BIOLOGIC MODIFIED MANUFACTURING PROCESS

A highly efficient method of making a primary cell derived biologic by purifying mononuclear cells (MNCs) in a automated cell processor to remove contaminating cells by loading leukocytes onto lymphocyte separation medium (LSM) and centrifuging the medium to obtain purified MNCs, storing the MNCs overnight in a closed sterile bag system, stimulating an induction mixture of the MNCs with phytohemagglutinin (PHA) or other mitogen and ciprofloxacin in a scalable cell culture device and producing a primary cell derived biologic from the MNCs, removing the mitogen from the induction mixture by filtering, incubating the induction mixture, clarifying the induction mixture by filtering to obtain a primary cell derived biologic supernatant, and clearing the primary cell derived biologic supernatant from adventitious agents by anion exchange chromatography, filtration. A closed system prevents contamination of the resulting primary cell derived biologic. An automated method of purifying cells. A ...

PURIFICATION OF BIOLOGICALLY ACTIVE HUMAN IMMUNE INTERFERON-(GAMMA)

There is provided a process for purification of human immune interferon (IFN- .gamma.) to homogeneity without appreciable loss of biological activity by the use of chromatography on controlled-pore glass, ultrafiltration and high performance cation exchange chromatography, resulting in essentially pure human interferon subtypes 21K and 26K, and there are provided said purified interferons and pharmaceutical compositions containing same.

CHEMICALLY MODIFIED LYMPHOKINE AND PRODUCTION THEREOF

The invention provides chemically modified lymphokines having R?-O-CH2CH2-?n wherein R is a protective group for the terminal oxygen and n is an optional positive integer, bonded directly to at least one primary amino group of the lymphokine moiety, and a method of producing the same. The chemically modified lymphokines according to the invention can be produced by reacting a lymphokine with an aldehyde of the formula R?-O-CH2CH2-?n-1O-CH2CHO wherein R and n are as defined above, in the presence of a reducing agent. The chemically modified lymphokines according to the invention are useful as drugs.

PROCESS FOR PRODUCING HUMAN-SPECIFIC GAMMA-INTERFERON AND METHOD FOR ASSAYING THE GAMMA-INTERFERON PRODUCTIVITY OF BLOOD

Production of HuIFN-gamma and assay of blood HuIFN-gamma productivity both using donated blood are disclosed. Human whole blood secrets a high titer of HuIFN-gamma when exposed to an IFN-gamma inducer (e.g. mitogen) in the presence of anticoagulant (e.g. heparin, ACD, and CPD). Blood HuIFN-gamma productivity is determined by titrating the secreted HuIFN-gamma with a suitable procedure (e. g. bioassay, radioimmunoassay, or enzyme-linked immunosorbent assay). The blood of cancer patient is lower in HuIFN-gamma productivity than that of healthy donor. The HuIFN-gamma per se is recovered and purified prior to its prophylactic and therapeutic uses.

HUMAN INTERFERON- ŸPOLYPEPTIDE DERIVATIVE

Disclosed is a novel derivative of human IFN-.gamma. polypeptide wherein certain amino acids of human IFN-.gamma. polypeptide are removed and certain amino acids other than said amino acids are replaced with other amino acids. The derivatives have high IFN-.gamma. activity and are expected to be useful as drugs such as anti-viral and anti-tumor agents.

COVALENTLY LINKED POLYPEPTIDE CELL MODULATORS

Described is a new class of polypeptide cell modulators characterized by being composed of two covalently linked cell modulators in a linear polypeptide sequence. Such dual function polypeptides have new and particularly useful activities when the component polypeptide cell modulators are interferons, lymphokines or cytotoxins which act through different and specific cell receptors to initiate complementary biological activities.

PHOSPHORYLATED FUSION PROTEINS AND USES RELATED THERETO

Modified proteins, modified interferons .alpha.'s and .beta.'s, phosphorylated modified proteins and DNA sequences encoding the above, applications and uses thereof. Modified phosphorylated Hu- IFN-.alpha.-like proteins are provided which carry an identifiable labe l such as a radio-label. Corresponding phosphorylatable Hu-IFN-.alpha.- like proteins which contain a putative phosphorylation site. DNA sequences which encode a Hu-IFN-.alpha.-like protein and contain a sequence encoding a putative phosphorylatable site. Appropriate expression vectors are used to transform compatible host cells of various microorganisms, such as E. coli. Numerous uses for the phosphorylated proteins are disclosed.

CELL LINES FOR USE IN THE PREPARATION OF HYBRIDOMA CELLS

METHOD FOR IMMUNOTHERAPY DRUG TREATMENT

The present invention provides a method that at least promotes, drives or directs a non-responsive neoplastic microenvironment towards a responsive phenotype. More particularly, the invention provides a method for enhancing the sensitivity of one or more neoplastic tumour to check point blockade agents. The present invention also provides a method for predicting the likelihood of responses to immune checkpoint blockade agents, bz measuring STATI activation and/or increase in NK cell number within the tumour microenvironement.

TYPE I AND TYPE III INTERFERON FUSION MOLECULES AND METHODS FOR USE THEREOF

Fusion molecules composed of a type I interferon protein or portion thereof and a type III interferon protein or portion thereof, pharmaceutical compositions containing the fusion molecules, and methods for their use in inhibiting infection, inhibiting or treating cancer, inducing signaling of transcription of IFN-stimulated genes through an IFN-aR2 chain in a subject suffering from an infection which degrades or downregulates an IFN-aRl chain, and treating various diseases or conditions are provided.

ONCOLYTIC VIRUS EXPRESSING INTERFERON AND APPLICATION THEREOF

Provided is an oncolytic virus expressing an interferon. Specifically provided is an oncolytic adenovirus expressing an interferon hybrid protein, said oncolytic virus being capable of effectively suppressing tumors in vitro and in vivo.

INTERFERON-GAMMA BIASED AGONISTS

Disclosed herein are compositions and methods for modulating IFN-?-mediated signaling by completely or partially agonizing the downstream signal transduction mediated through at least one of the IFN-? receptors. More particularly, the disclosure provides novel IFN-? polypeptide variants with reduced binding affinity to at least one of its receptors. The disclosure also provides compositions and methods useful for producing such molecules, as well as methods for the treatment of health diseases associated with the perturbation of signal transduction mediated by IFN-?.

VARIANT TYPE III INTERFERONS AND SYNTHEKINES

Compositions and methods are provided relating to Type III interferons.

METHOD OF PREPARING PORCINE CIRCOVIRUS TYPE 2 CAPSID PROTEIN AND PHARMACEUTICAL COMPOSITION COMPRISING SAME

The present invention provides a method of preparing a porcine circovirus type 2 capsid protein and a pharmaceutical composition comprising the same. The preparation method uses an arabinose-induced expression vector to express the porcine circovirus type 2 capsid protein.

MODULATING CYTOKINE OR HORMONE SIGNALLING IN AN ANIMAL COMPRISING UP-REGULATING THE EXPRESSION OF SOCS SEQUENCE IN THE ANIMAL

The present invention relates generally to a method for the treatment and/or prophylaxis of conditions arising from or otherwise associated with aberrations in hormone signalling. More particularly, the present invention contemplates a method for the treatment and/or prophylaxis of conditions, the amelioration of symptoms of which, are facilitated by an over-expression of a gene encoding a suppressor of cytokine signalling molecule. The present invention further contemplates agents useful for the prophylaxis and/or treatment of such conditions in mammals including humans.

MODIFIED CYTOKINES FOR USE IN CANCER THERAPY

... ²²²Cytokine derivatives capable of homing the tumoral vessels and the antigen ²presenting cells and the use thereof as antitumoral agents.² ...

ENHANCED ADOPTIVE CELL THERAPY

The present invention relates to the fields of life sciences and medicine. Specifically, the invention relates to cancer therapies of humans. More specifically, the present invention relates to oncolytic adenoviral vectors alone or together with therapeutic compositions for therapeutic uses and therapeutic methods for cancer. In one aspect the present invention relates to separate administration of adoptive cell therapeutic composition and oncolytic adenoviral vectors. Furthermore, the present invention relates to a pharmaceutical kit and a pharmaceutical composition, both utilizing oncolytic adenoviral vectors.

PROPROTEINS AND METHODS OF USE THEREOF

The present disclosure provides for proprotein and activatable proprotein compositions. A proprotein contains a functional protein (i.e. a full length protein or functional fragment thereof) which is coupled to a peptide mask that inhibits the binding of the functional protein to its target or binding partner. An activatable proprotein contains a functional protein coupled to a peptide mask, and further coupled to an activatable linker, wherein in an non-activated state, the peptide mask inhibits binding of the functional protein to its target or binding partner and in an activated state the peptide mask does not inhibit binding of the functional protein to its target or binding partner. Proproteins can provide for reduced toxicity and adverse side effects that could otherwise result from binding of a functional protein at non-treatment sites if it were not inhibited from binding its binding partner. Proproteins can further provide improved biodistribution characteristics. Proproteins containing ...

INTERLEUKIN-2-LEUKOTOXIN GENE FUSIONS AND USES THEREFOR

New chimeric proteins, DNA encoding the same, and the use of these proteins in stimulating immunity against re- spiratory diseases such as pneumonia; including shipping fever pneumonia, are disclosed. The chimeric proteins in- clude at least one epitope of leukotoxin fused to an active fragment of a cytokine. The chimeric proteins can be used in a vaccine composition. Also disclosed are methods of vacci- nation as well as methods of making the proteins employed in the vaccines.

PROCESS FOR THE EXTRACTION AND PURIFICATION OF HUMAN RECOMBINANT GAMMA INTERFERON

An extraction and purification process for human gamma interferon (HuIFN-gamma) from recombinant host cells producing the same in insoluble form is described, which comprises suspending the cells in a buffer solution having pH from 6.0 to 8.5, optionally complemented with an osmoprotector; disrupting the cells in conditions which do not activate the endocellular proteases; separating and solubilizing the pellet containing the insoluble HuIFN-gamma by extraction with phosphate buffer having pH comprised between 6.5 and 8.5 and finally purifying the solubilized HuIFNgamma by one or more chromatographic techniques. Such a process allows non-degraded HuIFN-gamma to be obtained, with a biological activity and chemical-physical properties unaffected vis-a-vis the native product and in high yield and purity.

EXPRESSION OF MALARIA POLYPEPTIDES

... 2095540 9208795 PCTABS00013 The present invention is directed to recombinant expression of malaria polypeptides. Nucleic acid constructs having a domain encoding a malaria polypeptide, preferably SERA or an epitope-containing fragment thereof, downstream from a domain encoding a ubiquitin polypeptide are presented. Additionally, constructs with a third domain encoding an immunomodulator polypeptide, preferably human .gamma.-interferon, and positioned between the first and second domains encoding, respectively, ubiquitin and a malaria polypeptide are also included. The malaria polypeptides of the present invention have utility as vaccine candidates and in immunodiagnostic applications.

HIGH EFFICIENCY EX VIVO TRANSDUCTION OF CELLS BY HIGH TITER RECOMBINANT RETROVIRAL PREPARATIONS

Compositions and methods for the efficient ex vivo introduction of nucleic acid into T cells, non-dividing cells, and cells resistant to standard transduction techniques mediated by high titer recombinant retroviral preparations is described. The recombinant vector constructs carried by the recombinant retrovirus particles code for the production of one or more desired gene products from one or more corresponding genes of interest, at least one of the gene products having a therapeutic application. Upon reintroduction into a patient, the transduced cells produce a desired gene product in an amount sufficient to treat a particular disease state.

DIAGNOSTIC AND THERAPEUTIC METHODS IN AUTOIMMUNE DISEASE

In one aspect, the invention provides a method of diagnosis. The diagnostic method may include steps of identifying a patient at risk of an arthritis, the patient having an interferon gamma gene. The patient may be tasted to characterize a polymorphism in a first intron of the interferon gamma gene. The polymorphism may comprise a variable length dinucleotide repeat region withi n the first intron, and the dinucleotide repeat region may be located at least partly between nucleotides 1349 and 1373 in the interferon, gamma gene. The method may be carried out so as to be capable of identifying alleles such as the 12 6 bp allele and the 122 bp allele, as further described herein. The polymorphisms may be distinguished based on a difference in the number of CA repeats in a portion of the first intron of the interferon gamma gene. The invention may also compri se testing a patient for a polymorphism is an HLA protein (or gene), such as th e HLA-DRB1 protein.

PROCESS FOR PREPARATION OF INTERFERON PREPARATION CONTAINING TYPE II AND TYPE II INTERFERON.

ESCHERICHIA COLI PLASMID VECTOR AND THE USE THEREOF.

POLYPEPTIDE, WHICH THE AMINO ACID SEQUENCE AND THE BIOLOGICAL ACTIVITY OF RIPE IMMUNE INTERFERONINTERFERON IMMUNE INTERFERON EXHIBITING.

PROCEDURE FOR THE PRODUCTION OF HUMAN GAMMA INTERFERON.

Zellinie for the production of antibody forming Hybridomen, procedure for the production of a human Zellinie and antibody producing Hybridom.

VECTORS FOR GENETIC THERAPY AND TsITOZINDEZAMINAZY

FUSED PROTEIN AGAINST CANCER

ВЕКТОРЫ ДЛЯ ГЕННОЙ ТЕРАПИИ И ЦИТОЗИНДЕЗАМИНАЗЫ

Настоящее изобретение относится к модифицированным цитозиндезаминазам (CD). Настоящее изобретение дополнительно относится к клеткам и вектору, экспрессирующим или содержащим такие модифицированные CD, и способам использования таких модифицированных CD при лечении заболеваний или нарушений.

КОНЪЮГИРОВАННЫЕ ЦИТОКИНЫ, ИСПОЛЬЗУЕМЫЕ ДЛЯ ТЕРАПИИ ОПУХОЛЕЙ

В изобретении описаны конъюгированный продукт, обладающий противоопухолевой активностью, включающий цитокин, выбранный из TNF или IFNγ, и лиганд, содержащий NGR-мотив; кДНК, кодирующая этот конъюгированный продукт, предназначенный для генной терапии вектор, включающий указанную кДНК, а также фармацевтическая композиция, содержащая эффективное количество конъюгированного продукта в сочетании с фармацевтически приемлемыми носителями и эксципиентами. Кроме того в ней раскрыто применение конъюгированного продукта для приготовления противоопухолевых лекарственных средств или диагностических агентов и применение кДНК для приготовления лекарственных средств или диагностических агентов, предназначенных для применения в терапии опухоли.

RECOMBINANT PLASMID of pPHINS21, WHICH CODES HYBRID PROTEIN OF MAN, STRAIN OF THE BACTERIA OF ESCHERICHIA OF COLI JM109/PHINS21 - PRODUCER OF HYBRID PROTEIN OF MAN and THE METHOD OF OBTAINING OF THE MAN

VECTORS FOR GENETIC THERAPY AND TsITOZINDEZAMINAZY

RECOMBINANT REPLICATION COMPETENT RETROVIRUS HAVING CYTOSINE DEAMINASE ACTIVITY FOR GENE THERAPY OF CELL PROLIFERATIVE DISORDERS

METHODS OF TREATING CANCER

HUMAN IMMUNIZING INTERFERON

Novel IP-10 epitopes and antibodies binding to the same

interferons tipo iii variantes e sintecinas

AGENT FOR CONCURRENT INHIBITION OF ENDOGENOUS GAMMA INTERFERON

The invention relates to an agent for concurrent inhibition of the endogenous human IFN-gamma, in particular in autoimmune diseases. It represents inactive analogs of the human IFN-gamma with retained affinity to the gamma-interferon receptor.

HUMAN IMMUNE INTERFERON PROTEIN AND PROCESS FOR ITS PREPARATION

Substantially pure human immune interferon protein having a specific activity of 107 U/mg or more, and a process for preparing the same from a culture liquor of transformed cells containing DNA which has a human immune interferon-coding base sequence. The human immune interferon is obtained by destroying cells recovered from a culture liquor and purifying the resulting solution containing human immune interferon using anti-human immune interferon monoclonal antibody. The transformed cells are obtained by introducing recombinant DNA molecule into host cells. The human immune interferon protein can be used as antiviral agent and antitumor agent.

GELSOLIN ENRICHMENT OF BLOOD SAMPLES USING GOLD PARTICLES

The invention relates to a method for producing at least one therapeutically active protein or protein mixture in a container. In said method, the container is filled with a bodily fluid and gold particles and is incubated and the therapeutically active protein is formed in the bodily fluid.

NOVEL IFNGAMMA-LIKE POLYPEPTIDES

The present invention discloses novel open reading frames (ORFs) in human genome encoding for ORFs characterized for polypeptides having at least one activity of human Interferon gamma, and reagents related thereto including variants and fragments of said polypeptides, as well as the encoding nucleic acids and ligands directed against them. The invention provides methods for identifying and preparing these molecules, for manufacturing pharmaceutical compositions containing them, and for using them in the diagnosis, prevention and treatment of diseases.

THE MANUFACTURE AND EXPRESSION OF LARGE STRUCTURAL GENES

Rapid and highly efficient procedures for the total synthesis of linear, double stranded DNA sequences in excess of about 200 base pairs in length, which sequences may comprise entire structural genes. Novel sequences are prepared from two or more DNA subunits provided with terminal regions comprising restriction endonuclease cleavage sites facilitating insertion of subunits into a selected vector for purposes of amplification during the course of the total assembly process. The total, finally-assembled sequences include at least one, and preferably two or more, unique restriction endonuclease cleavage site(s) at intermediate positions along the sequence, allowing for easy excision and replacement of subunits and the correspondingly facile preparation of multiple structural analogs of polypeptides coded for by the sequences. Manufactured genes preferably include codons selected from among alternative codons specifying the same amino acid on the basis of preferential expression in a projected ...

ADENOVIRUS GENE EXPRESSION SYSTEM

The present invention provides a novel, highly efficient, recombinant adenovirus expression system for expression of a heterologous gene(s) and/or gene product(s) in a mammalian cell. The recombinant adenovirus was produced by cotransfecting a novel vector with the large fragment of the adenovirus-5 genome in 293 cells. Homologous recombination between these two DNA fragments resulted in the production of the recombinant adenovirus expression system. This vector, when converted to a recombinant virus has the unique capability of expressing one or more heterologous genes at very high levels. The novel vector, comprises, at least one cDNA insertion site for cloning a selected heterologous gene; a promoter sequence positioned upstream from the gene insertion site; the left end replication and packaging elements of the adenovirus-5 genome positioned upstream of the promoter; a highly efficient eukaryotic splice acceptor and splice donor site positioned immediately downstream of the promoter ...

PROCESS FOR THE PRODUCTION OF HUMAN GAMMA-INTERFERON

Process for the production of human gamma-interferon by separating the leukocyte fraction (buffy coat) of blood, removing the erythrocytes, suspending the leukocytes in a suitable nutrient medium, treating the same with a mitogenic agent and separating the liquid containing interferon from the cells which comprises pre-treating the leukocytes with 200-20000 IU/ml. of alpha- or beta-interferon prior to treatment with the mitogenic agent. The advantage of the process is that the gamma-interferon production is increased by 500-1000 %.

EXPRESSION OF MAMMALIAN PROTEINS IN PSEUDOMONAS FLUORESCENS

The invention is a process for improved production of a recombinant mammalian protein by expression in a Pseudomonad, particularly in a Pseudomonas fluorescens organism. The process improves production of mammalian proteins, particularly human or human-derived proteins, over known expression systems such as E. coli in comparable circumstances. Processes for improved production of isolated mammalian, particularly human, proteins are provided.

PROCESS FOR PURIFYING A PROTEIN

A process for purifying a protein and particularly the purification of a protein, such as gamma interferon, that forms highly insoluble aggregates during the growth of host cells transformed with DNA sequences coding for the protein.

Peptides for active anti-cytokine immunization

Peptide of a size comprised between 5 and 40 amino acids, originating from a cytokine, in which at least one of its amino acids comprises at least one of its atoms separated by a distance d of less than 5 angströms from an atom of the receptor corresponding to said cytokine, the spacing d being evaluated on the basis of structural data, derivatives, immunogenic compounds comprising them, use of a peptide or peptide derivative or immunogenic compound for the preparation of a curative or preventative medicament intended for the treatment or prevention of diseases linked to an excess or to the presence of cytokines or for the treatment of an auto-immune disease and pharmaceutical compositions which contain at least one abovementioned peptide or peptide derivative or immunogenic compound as active ingredient.

MULTIFUNCTIONAL CYTOKINES

The present invention relates to a novel fusion protein with the formula X-Y, or Y-X, wherein X represents a first immunoregulating polypeptide and Y represents a second immunoregulating polypeptide different from X. The present invention also relates to a nucleic acid molecule encoding such a fusion protein and a vector comprising such a nucleic acid molecule. The present invention also provides infectious viral particles and host cells comprising such a nucleic acid molecule or such a vector as well as a process for producing such infectious viral particles. The present invention also relates to a method for recombinantly producing such a fusion protein. Finally, the present invention also provides a pharmaceutical composition comprising such a fusion protein, a nucleic acid molecule, a vector, infectious viral particles and a host cell as well as the therapeutic use thereof.

Consensus human leukocyte interferon

Described are rapid and highly efficient procedures for the total synthesis of linear, double stranded DNA sequences in excess of about 200 base pairs in length, which sequences may comprise entire structural genes. Novel sequences are prepared from two or more DNA subunits provided with terminal regions comprising restriction endonuclease cleavage sites facilitating insertion of subunits into a selected vector for purposes of amplification during the course of the total assembly process. The total, finally-assembled assembled sequences include at least one, and preferably two or more, unique restriction endonuclease cleavage site(s) at intermediate positions along the sequence, allowing for easy excision and replacement of subunits and the correspondingly facile preparation of multiple structural analogs of polypeptides coded for by the sequences. Manufactured genes preferably include codons selected from among alternative codons specifying the same amino acid on the basis of preferential ...

Gastrin releasing peptide compounds

New and improved compounds for use in diagnostic imaging or therapy having the formula M-N—O—P-G, wherein M is a metal chelator having the structure: wherein R1-R5 and FG are as defined herein (in the form complexed with a metal radionuclide or not), N—O—P is the linker containing at least one non-alpha amino acid with a cyclic group, at least one substituted bile acid or at least one non-alpha amino acid, and G is the GRP receptor targeting peptide. In the preferred embodiment, M is an Aazta metal chelator or a derivative thereof. Methods for imaging a patient and/or providing radiotherapy or phototherapy to a patient using the compounds of the invention are also provided. Methods and kits for preparing a diagnostic imaging agent from the compound is further provided. Methods and kits for preparing a radiotherapeutic agent are further provided.

Mini-Hepcidin Peptides and Methods of Using thereof

Disclosed herein are peptides which exhibit hepcidin activity and methods of making and using thereof.

method for promoting bone growth using activin-actriia antagonists

In certain aspects, the present invention provides compositions and methods for promoting bone growth and increasing bone density.

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.

Glucose-dependent insulinotropic peptide analogs

The present invention provides compounds which are analogs of glucose-dependent insulinotropic polypeptide (GIP) and pharmaceutically acceptable salts of such compounds. These compounds have activity as agonists of GIP receptor.

Peptide and use thereof

The present invention aims to provide a peptide having a superior Y2 receptor agonist action and useful as an agent for the prophylaxis or treatment of obesity and the like. A peptide represented by the formula: P 1 -X 1 -A25-A26-A27-A28-A29-A30-A31-A32-A33-A34-A35-A36-NH 2 wherein each symbol is as described in the specification, or a salt thereof.

SOGA Polynucleotides and Polypeptides and Uses Thereof

The present invention relates to the identification of polynucleotides and polypeptides involved in insulin and adiponectin signaling and regulation of glucose production. The invention further relates to the use of the identified polynucleotides and polypeptides, and inhibitors of the polynucleotides and polypeptides, in the regulation of glucose production and the monitoring and treatment of metabolic disorders such as diabetes.

Modified Human Plasma Polypeptide or Fc Scaffolds and Their Uses

Modified human plasma polypeptides or Fc and uses thereof are provided.

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.

Drug fusions and conjugates with extended half life

The present invention relates to drug fusions and conjugates that have improved serum half lives. These fusions and conjugates comprise immunoglobulin (antibody) single variable domains and insulinotropic and/or incretin and/or gut peptide molecules. The invention further relates to uses, formulations, compositions and devices comprising such drug fusions and conjugates. The invention also relates to compositions which comprise more than one insulinotropic and/or incretin and/or gut peptide molecules present as part of a fusion or conjugate and to uses and formulations thereof.

Ifn-gamma inhibitors in the treatment of motoneuron diseases

The present invention is directed to new compositions uses thereof and related methods for the treatment of a motoneuron disease or disorder. In particular, the invention relates to the new use of IFNγ antagonists or viral vectors, uses, compositions thereof and related methods for the treatment of motoneuron disease or disorder such as ALS.

Peptides for active anti-cytokine immunization

Peptide of a size comprised between 5 and 40 amino acids, originating from a cytokine, in which at least one of its amino acids comprises at least one of its atoms separated by a distance d of less than 5 angströms from an atom of the receptor corresponding to said cytokine, the spacing d being evaluated on the basis of structural data, derivatives, immunogenic compounds comprising them, use of a peptide or peptide derivative or immunogenic compound for the preparation of a curative or preventative medicament intended for the treatment or prevention of diseases linked to an excess or to the presence of cytokines or for the treatment of an auto-immune disease and pharmaceutical compositions which contain at least one abovementioned peptide or peptide derivative or immunogenic compound as active ingredient.

Polypeptides

The invention relates to polypeptides comprising an amino acid sequence which is an analogue of pramlintide, pharmaceutical compositions comprising these polypeptides, and these polypeptides for use as medicaments.

Long-acting y2 receptor agonists

The present invention relates to PYY analogues or derivatives thereof comprising at least one alteration selected from the group consisting of substitutions, insertions, deletions and modifications and optionally a serum albumin binding side chain comprising an alkyl chain with at least 14 carbon atoms. Moreover, the invention relates to compositions hereof and methods of treatment of conditions responsive to Y2 receptor modulation.

Benzocyanine compounds

Compounds useful as labels with properties comparable to known fluorescent compounds. The compounds are conjugated to proteins and nucleic acids for biological imaging and analysis. Synthesis of the compounds, formation and use of the conjugated compounds, and specific non-limiting examples of each are provided.

Methods and compositions for treating prostate cancer

A polypeptide comprising an androgen binding region, the androgen binding region capable of binding to an androgen at a sufficient affinity or avidity such that upon administration of the polypeptide to a mammalian subject the level of biologically available androgen is decreased. Specifically disclosed is an AR IgG1 Fc fusion protein, comprising the androgen binding domain of human androgen receptor and the Fc region of IgG. This fusion protein is used in the treatment of prostate cancer and testosterone flare.

METHODS OF TREATING DIABETES AND COMPOSITIONS CAPABLE OF SAME

A composition of matter is disclosed which comprises isolated oligomers of human islet amyloid polypeptide (IAPP). Antibodies recognizing same are also disclosed. Use of the composition of matter and the antibodies are also disclosed. 1. A composition of matter comprising isolated oligomers of human islet amyloid polypeptide (IAPP).2. The composition of matter of claim 1 , wherein said oligomers comprise dimers and/or trimers.3. The composition of matter of claim 1 , wherein said oligomers have a molecular weight between 4 kDa and 90 kDa.4. The composition of matter of claim 1 , wherein the composition is devoid of fibrils of IAPP.5. The composition of matter of claim 1 , further comprising sodium dodecyl sulfate (SDS).6. The composition of matter of claim 1 , wherein said oligomers have an alpha helical conformation.7. The composition of matter of claim 1 , wherein said oligomers are crosslinked.8. The composition of matter of claim 1 , wherein said oligomers are non-crosslinked.9. The composition of matter of claim 8 , wherein said oligomers consist of dimers and/or trimers.10. The composition of matter of claim 1 , being stable for up to 7 days.11. A method of generating a composition of matter comprising isolated oligomers of human islet amyloid polypeptide (IAPP) claim 1 , the method comprising:(a) dissolving human IAPP in an agent that eliminates structured forms of IAPP;(b) removing said agent; and(c) redissolving said non-structured form of IAPP in a solvent and an anionic surfactant, thereby generating the composition of matter.12. The method of claim 11 , wherein said agent is selected from the group consisting of 1 claim 11 ,1 claim 11 ,1 claim 11 ,3 claim 11 ,3 claim 11 ,3 hexafluoro-2-propanol (HFIP) claim 11 , trifluoroethanol (TFE) claim 11 , and trifluoroacetic acid (TFA).13. The method of claim 11 , wherein said solvent is selected from the group consisting of sodium hydroxide claim 11 , potassium hydroxide claim 11 , ammonium hydroxide claim 11 , ...

Method for Preserving Polypeptides Using A Sugar and Polyethyleneimine

The invention relates to the preservation of an active agent, such as a polypeptide, by contacting the active agent with a preservation mixture including a sugar and polyethyleneimine. 1. A method for preserving a polypeptide comprising:(i) providing an aqueous solution of one or more sugars, a polyethyleneimine and said polypeptide; and(ii) drying the solution to form an amorphous solid matrix comprising said polypeptide.2. The method according to wherein the concentration of polyethyleneimine is 25 μM or less based on the number-average molar mass (M) of the polyethyleneimine and the sugar concentration or claim 1 , if more than one sugar is present claim 1 , total sugar concentration is greater than 0.1M claim 1 , and the method optionally further comprises providing the resulting dried amorphous solid matrix in the form of a powder in a sealed vial claim 1 , ampoule claim 1 , or syringe.3. The method according to in which{'sub': n', 'n, '(a) the Mof the polyethyleneimine is between 20 and 1000 kDa and the concentration of the polyethyleneimine is between 0.001 and 100 nM based on the M, and/or'}{'sub': n', 'n, '(b) the Mof the polyethyleneimine is between 1 and 10000 Da and the concentration of the polyethyleneimine is between 0.0001 and 1004 based on the M, and/or'}(c) the said concentration of polyethyleneimine is 20 μM or less or less than 500 nM, and/or(d) the said concentration of polyethyleneimine is 0.025 nM or more or 0.1 nM or more, and/or(e) the said concentration of polyethyleneimine is between 0.1 nM and 5 μM or between 0.1 nM and 200 nM.4. The method according to in which(a) the sugar concentration, or total sugar concentration, is between 0.5 and 2M; and/or(b) the sugar is sucrose, stachyose, raffinose or a sugar alcohol, or(c) two or more sugars are present in said aqueous solution, or{'sub': 'n', '(d) two or more sugars are present in said aqueous solution and wherein sucrose is present with another sugar; the concentration of sucrose relative to ...

THERAPEUTIC AGENTS COMPRISING ELASTIN-LIKE PEPTIDES

The present invention provides therapeutic agents and compositions comprising elastin-like peptides (ELPs) and therapeutic proteins. In some embodiments, the therapeutic protein is a GLP-1 receptor agonist, insulin, or Factor VII/VIIa, including functional analogs. The present invention further provides encoding polynucleotides, as well as methods of making and using the therapeutic agents. The therapeutic agents have improvements in relation to their use as therapeutics, including, inter alia, one or more of half-life, clearance and/or persistance in the body, solubility, and bioavailability. 1100.-. (canceled)101. A therapeutic agent comprising a fusion protein with an elastin-like-peptide (ELP) and an amino acid sequence of a glucagon-like peptide (GLP)-1 receptor agonist , the ELP comprising at least 60 units of VPGXG , where X is an independently selected amino acid.102. The therapeutic agent of claim 101 , wherein the GLP-1 receptor agonist is glucagon-like peptide (GLP)-1 claim 101 , or a functional analog thereof.103. The therapeutic agent of claim 102 , wherein the GLP-1 has from 1 to 3 amino acid modifications independently selected from an insertion claim 102 , a deletion claim 102 , a truncation claim 102 , and/or a substitution.104. The therapeutic agent of claim 103 , wherein the GLP-1 is GLP-1 (A-B) claim 103 , wherein A is an integer from 1 to 7 and B is an integer from 38 to 45.105. The therapeutic agent of claim 101 , wherein the GLP-1 receptor agonist is GLP-1 (7-37) claim 101 , or a functional analog thereof.106. The therapeutic agent of claim 105 , wherein the GLP-1 (7-37) has from 1 to 3 amino acid modifications independently selected from an insertion claim 105 , a deletion claim 105 , a truncation claim 105 , and/or a substitution.107. The therapeutic agent of claim 101 , wherein the GLP-1 receptor agonist is GLP-1 (7-36) claim 101 , or a functional analog thereof.108. The therapeutic agent of claim 107 , wherein the GLP-1 (7-36) has from 1 ...

LONG-ACTING Y2 RECEPTOR AGONISTS

The present invention relates to PYY derivatives comprising a serum albumin binding side chain, wherein said derivative has a half-life of at least 7 hours as determined by Assay (IV) described herein as well as compositions comprising said derivative and its use in therapy. 1. A PYY derivative comprising a serum albumin binding side chain , whereinsaid derivative has a half-life of at least 7 hours as determined by Assay (IV), and whereinsaid serum albumin binding side chain comprises an alkyl chain of at least 14 carbon atoms, and whereinsaid alkyl chain comprises a distal carboxylic acid group or a distal tetrazole group, and whereinsaid serum albumin binding side chain is attached to the N-terminal amino group or an amino acid in a position selected from the group consisting of position 1, 3, 6, 7, 9, 10, 11, 12, 14, 15, 17, 18, 19, 21, 22, 23 and 30, wherein said position is relative to hPYY(1-36).2. The PYY derivative according to claim 1 , wherein said derivative is notN-epsilon13-[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]-ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Lys13]hPYY3-36,N-epsilon13-[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Lys13]hPYY3-36,N-epsilon11-[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]-ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Lys11]hPYY3-36,N-epsilon11-[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]-ethoxy}ethoxy)acetyl][Lys11]hPYY3-36,N-epsilon13-[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]-ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Lys13]hPYY2-36,N-epsilon4-[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl] ...

Derivatisation of erythropoietin (epo)

The present invention relates to a compound which is a polysaccharide derivative of EPO, or of an EPO like protein, wherein the polysaccharide is anionic and comprises between 2 and 200 saccharide units. The present invention also relates to pharmaceutical compositions comprising the novel compounds, and methods for making the novel compounds.

HIGH AFFINITY LEPTINS AND LEPTIN ANTAGONISTS

Leptin muteins, in particular leptin antagonists, with increased binding affinity to leptin receptor are provided. These compounds as well as pharmaceutical composition comprising them are useful for the treatment of any disorder in which a non-desirable or deleterious activity of endogenous leptin or an altered innate immune response is implicated. 1. A synthetic leptin antagonist comprising of: (i) the LDFI hydrophobic binding site at the position corresponding to positions 39-42 of the wild-type human leptin is modified such that from two to four amino acid residues of said hydrophobic binding site are substituted with different amino acid residues such that the site becomes less hydrophobic, said modified mammalian leptin polypeptide being a leptin antagonist; and', '(ii) the aspartic acid at the position corresponding to position 23 of the wild-type human leptin (D23) is substituted with a different amino acid residue that is not negatively charged or the threonine at the position corresponding to position 12 of the wild-type human leptin (T12) is substituted with a different amino acid residue that is hydrophobic;, '(a) a modified mammalian leptin polypeptide in which(b) a fragment of said modified mammalian leptin polypeptide of (a), in which D23 is substituted with a different amino acid residue that is not negatively charged or T12 is substituted with a different amino acid residue that is hydrophobic, wherein said fragment is itself a leptin antagonist; or(c) a pharmaceutically acceptable salt of (a) or (b)2. The synthetic leptin antagonist of claim 1 , wherein D23 is substituted with a hydrophobic or positively charged amino acid residue.34-. (canceled)5. The synthetic leptin antagonist according to claim 2 , wherein further amino acid residues are substituted as follows:(d) the leucine at the position corresponding to position 68 of the wild-type human leptin (L68) is substituted with methionine, the serine at the position corresponding to position 97 of ...

FUSION PROTEIN OF EXENDIN-4 AND ITS ANALOG, PREPARATION METHOD AND USE THEREOF

Provided are a fusion protein of Exendin-4 and its analog, the preparation method and use thereof. The fusion protein is obtained by fusing of Exendin-4 or its analog to Fc region of human IgG2 via a linking peptide, which has the better stability and prolonged serum half-life, and can be used for treating diabetes and obesity. 1. A fusion protein , which is obtained by fusing peptide hormone to transport protein via linker , wherein , the said peptide hormone is Exendin-4 or analogue of Exendin-4 , and the said peptide hormone is capable of lowering the blood glucose; the said transport protein is the Fc fragment of the immunoglobulin IgG2; the said fusion protein is capable of lowering the blood glucose; {'br': None, 'sup': 2', '10', '12', '13', '14', '19', '20', '21', '24', '27', '28', '30', '31', '32', '33', '34', '35', '36', '37', '38', '39, 'His-Xaa-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Xaa-Ser-Xaa-Xaa-Xaa-Glu-Glu-Glu-Ala-Xaa-Xaa-Xaa-Phe-Ile-Xaa-Trp-Leu-Xaa-Xaa-Gly-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa\u2003\u2003Formula I'}, 'the said peptide hormone comprises the sequence shown by Formula IWherein:{'sup': '2', 'Xaais Gly, Thr, Ala, Ser, Leu, Ile or Lys;'}{'sup': '10', 'Xaais Leu, Ala, Ser, Leu, Ile, Glu or Lys;'}{'sup': '12', 'Xaais Lys, Leu, Thr, Ser, Leu, Ile or Cys;'}{'sup': '13', 'Xaais Gln, Thr, Ala, Val, Leu, Ile or Lys;'}{'sup': '14', 'Xaais Met, Tyr, Thr, Ala, Ser, Ile or Lys;'}{'sup': '19', 'Xaais Val, Cys, Ala, Ser, Leu, Ile or Lys;'}{'sup': '20', 'Xaais Arg, Thr, Tyr, Ser, Leu, Ile or Lys;'}{'sup': '21', 'Xaais Leu, Thr, Ala, Asp, Glu, His or Lys;'}{'sup': '24', 'Xaais Glu, Leu, Thr, Ala, Ser, Lys or Ile;'}{'sup': '27', 'Xaais Lys, Ala, Ser, Leu, Thr, Ile or Lys;'}{'sup': '28', 'Xaais Asp, Thr, Ala, Ser, Leu, Ile or Lys;'}{'sup': '30', 'Xaais Gly, Thr, Ala, Ser, Leu, Ile or Arg;'}{'sup': '31', 'Xaais Pro, Val, Ser, Ala, Leu, Ile or Lys;'}{'sup': '32', 'Xaais Ser, Thr, Glu, Ser, Asp, Lys or Ile;'}{'sup': '33', 'Xaais Thr, Ser, Ala, Met, Leu, Ile or Lys ...

Isoforms of brain natriuretic peptide

Methods and materials for diagnosing and treating heart conditions (e.g., heart failure) and kidney conditions (e.g., kidney failure) are described.

ORAL INSULIN THERAPY

This disclosure relates in part to synthesizing a cleavable proinsulin construct in transgenic plants by chloroplast expression. 1. A cleavable proinsulin construct comprising:a cholera toxin B (CTB) subunit fused to a proinsulin subunit; andat least one furin cleavage site on the cleavable proinsulin construct.2. The cleavable proinsulin construct of claim 1 , wherein the proinsulin subunit comprises a C peptide3. The cleavable proinsulin construct of claim 2 , wherein the proinsulin subunit further comprises an A chain and a B chain claim 2 , and wherein the C peptide is disposed between the A chain and the B chain.4. The cleavable proinsulin construct of claim 2 , wherein the at least one furin cleavage site comprises a pair of furin cleavage sites flanking each side of the C-peptide.5. The cleavable proinsulin construct of claim 1 , wherein the at least one furin cleavage site comprises a furin cleavage site located at a junction between the CTB subunit and the proinsulin subunit.6. The cleavable proinsulin construct of claim 5 , further comprising a GPGP (SEQ ID NO: 2) hinge sequence between the CTB sequence and the furin cleavage site.7. The cleavable proinsulin construct of claim 1 , wherein the at least one furin cleavage site comprises three furin cleavage sites.8. The cleavable proinsulin construct of claim 1 , wherein the proinsulin subunit comprises a C peptide claim 1 , an A chain claim 1 , and a B chain claim 1 , and wherein the C peptide is disposed between the A chain and the B chain claim 1 , wherein the at least one furin cleavage site comprises three furin cleavage sites claim 1 , wherein first and second furin cleavage sites flank opposed sides of the C-peptide claim 1 , and wherein a third furin cleavage site is located at a junction between the CTB subunit and the proinsulin subunit.9. The cleavable proinsulin construct of claim 1 , wherein the at least one furin cleavage site comprises an Arg Arg Lys Arg (SEQ ID NO: 3) furin cleavage sequence. ...

Targeting compounds

The present invention provides antibody targeting compounds in which the specificity of the antibody has been reprogrammed by covalently or noncovalently linking a targeting agent to the combining site of an antibody. By this approach, the covalently modified antibody takes on the binding specificity of the targeting agent. The compound may have biological activity provided by the targeting agent or by a separate biological agent. Various uses of the invention compounds are provided.

MODIFIED GHRELIN PEPTIDES

The present invention provides a novel peptide-type compound which induces secretion of growth hormone and which has the activity of increasing the intracellular calcium ion concentration, wherein at least one amino acid is replaced by a modified amino acid and/or a non-amino acid compound, or a pharmaceutically acceptable salt thereof. 1. A peptide-type compound , wherein in a peptide having the activity of increasing the intracellular calcium ion concentration , at least one amino acid is replaced by a modified amino acid and/or a non-amino acid compound , or a pharmaceutically acceptable salt thereof.236-. (canceled)37. A method for treatment of diseases attributable to a defect or decrease in growth hormone claim 1 , which comprises administering a pharmaceutical composition comprising the peptide-type compound or a pharmaceutically acceptable salt thereof as an active ingredient.38. A method for treatment of diseases not attributable to a defect or decrease in growth hormone claim 1 , which comprises administering an agent for treating diseases not attributable to a defect or decrease in growth hormone and the peptide-type compound of or a pharmaceutically acceptable salt thereof.39. The treatment method according to claim 37 , which is applied to animals other than human beings.40. A DNA coding for an amino acid sequence of the peptide-type compound of claim 1 , which comprises a nucleotide sequence coding for a peptide containing an amino acid sequence recognizing at least one modifiable amino acid in the amino acid sequence encoded by said DNA.41. The DNA according to claim 40 , wherein the nucleotide sequence is one nucleotide sequence selected from the group consisting of nucleotide sequences set forth in SEQ ID NOS: 6 claim 40 , 7 claim 40 , 14 claim 40 , 15 claim 40 , 20 claim 40 , 21 claim 40 , 24 claim 40 , 36 claim 40 , 37 claim 40 , 38 and 39.42. The DNA according to claim 40 , wherein the nucleotide sequence is an amino acid-coding nucleotide ...

Methods for Preparing Conjugates

The present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable excipient and a conjugate having a degradable linkage. The conjugates include at least one of each the following: an aromatic moiety comprising an ionizable hydrogen atom, a spacer moiety, and a water-soluble polymer. Methods for delivering such compositions are also provided. 2. The method of claim 1 , wherein said contacting step is conducted using a molar excess of polymeric reagent.3. The method of claim 1 , wherein said contacting step is conducted using a molar ratio of polymeric reagent:amino-group containing active agent of 2:1.4. The method of claim 1 , wherein said contacting step is conducted using a molar ratio of polymeric reagent:amino-group containing active agent of 3:1.5. The method of claim 1 , wherein said contacting step is conducted using a molar ratio of polymeric reagent:amino-group containing active agent of 4:1.6. The method of claim 1 , wherein said contacting step is conducted using a molar ratio of polymeric reagent:amino-group containing active agent of 5:1.7. The method of claim 1 , wherein said contacting step is conducted using a molar ratio of polymeric reagent:amino-group containing active agent of 6:1.8. The method of claim 1 , wherein said contacting step is conducted using a molar ratio of polymeric reagent:amino-group containing active agent of 8:1.9. The method of claim 1 , wherein said contacting step is conducted using a molar ratio of polymeric reagent:amino-group containing active agent of 10:1.10. The method of claim 1 , wherein each of POLYand POLYis a poly(ethylene glycol).11. The method of claim 10 , wherein each poly(ethylene glycol) has a weight-average molecular weight in the range of from about 120 Daltons to about 6 claim 10 ,000 Daltons.12. The method of claim 10 , wherein each poly(ethylene glycol) has a weight-average molecular weight in the range of from about 6 claim 10 ,000 Daltons to about 100 claim 10 ,000 ...

BETA THYMOSIN FRAGMENTS

Peptide fragments having amino acid sequences corresponding to portions of a thymosin beta 4, a thymosin beta 10 and/or a thymosin beta 15 amino acid sequence are provided, as well as methods of treatment utilizing same. 1. A peptide having an amino acid sequence selected from Ac-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-Ile-Glu-Lys-Phe-Asp-Lys-Ser-OH (SEQ ID NO: 3) , Ac-Leu-Lys-Lys-Thr-Glu-Thr-Gln-OH (SEQ ID NO: 4) , a variant of said Ac-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-Ile-Glu-Lys-Phe-Asp-Lys-Ser-OH which has an amino acid substituent substituted for said methionine residue , an isolated R-enantiomer of Ac-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-Ile-Glu-Lys-Phe-Asp-Lys-Ser-OH (SEQ ID NO: 3) or Ac-Leu-Lys-Lys-Thr-Glu-Thr-Gln-OH (SEQ ID NO: 4) , an isolated S-enantiomer of Ac-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-Ile-Glu-Lys-Phe-Asp-Lys-Ser-OH (SEQ ID NO: 3) or Ac-Leu-Lys-Lys-Thr-Glu-Thr-Gln-OH (SEQ ID NO: 4) , or a methionine-containing variant thereof in which any methionine is oxidized or superoxidized.2. The peptide of claim 1 , having amino acid sequence Ac-Ser-Asp-Lys-Pro-Asp-Met-Ala-Glu-Ile-Glu-Lys-Phe-Asp-Lys-Ser-OH (SEQ ID NO: 3).3. The peptide of claim 1 , having amino acid sequence Ac-Leu-Lys-Lys-Thr-Glu-Thr-Gln-OH (SEQ ID NO: 4).4. The peptide of claim 1 , wherein said peptide has an amino acid substituent substituted for a methionine residue claim 1 , said substituent being a leucine claim 1 , valine claim 1 , isoleucine claim 1 , alanine claim 1 , phenylalanine or proline substituted for said methionine.5. A method of at least one of suppressing inflammation in tissue of a subject in need thereof claim 1 , stimulating cell migration in tissue of a subject in need thereof claim 1 , protecting tissue from cytotoxicity in tissue of a subject in need thereof claim 1 , inhibiting apoptosis in tissue of a subject in need thereof claim 1 , stimulating collagen in tissue of a subject in need thereof claim 1 , inhibiting collagen in tissue of a subject in need thereof claim 1 , ...

GIP ANALOG AND HYBRID POLYPEPTIDES WITH SELECTABLE PROPERTIES

The present invention relates generally to novel GIP analogs and GIP hybrid polypeptides with selectable properties, useful as agents for the treatment and prevention of metabolic diseases and disorders, for example those which can be alleviated by control plasma glucose levels, insulin levels, and/or insulin secretion, positive inotropic effects, reduction of catabolic effects, slowing of gastric emptying. Such conditions and disorders include, but are not limited to, hypertension, dyslipidemia, cardiovascular disease, eating disorders, critical care, insulin-resistance, obesity, and diabetes mellitus of any kind, including type 1, type 2, and gestational diabetes. 1. A method to treat a patient undergoing critical care , comprising administering to the patient in need thereof a therapeutically effective amount of a gastric inhibitory peptide (GIP) hybrid polypeptide exhibiting at least two hormonal activities , said GIP hybrid polypeptide comprising a first bio-active peptide hormone covalently linked to at least one additional bio-active peptide hormone; the first bio-active peptide hormone is a GIP, a bio-active fragment of the GIP of at least 21 amino acids that exhibits at least one hormonal activity of the GIP, a bio-active analog of the GIP that exhibits at least one hormonal activity of the GIP or a bio-active derivative with a water soluble polymer thereof that exhibits at least one hormonal activity of the GIP, GIP analog or GIP fragment;', 'the at least one additional bio-active peptide is an amylin, a bio-active fragment of the amylin that exhibits at least one hormonal activity of the amylin, a bio-active analog of the amylin that exhibits at least one hormonal activity of the amylin or a bio-active derivative with a water soluble polymer thereof that exhibits at least one hormonal activity of the amylin, amylin analog or amylin fragment; and', 'each of the bio-active peptide hormones exhibits at least one hormonal activity of its parent peptide ...

HIGHLY SOLUBLE LEPTINS

The disclosure provides chimeric polypeptides and nucleic acid molecules encoding chimeric polypeptides. Also provided are pharmaceutical compositions and methods of treatment for diseases and disorders including lipodystrophy, dyslipidemia, hyperlipidemia, overweight, obesity, hypothalamic amenorrhea, Alzheimer's disease, leptin deficiency, fatty liver disease or diabetes (including type I and type II). Additional diseases and disorders which can be treated by the compounds and methods described herein include nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver disease (NAFLD), metabolic syndrome X and Huntington's Disease. 1. A chimeric polypeptide comprising a wild type seal leptin polypeptide wherein at least one contiguous region of 1-30 amino acids of a wild type seal leptin sequence has been replaced with a contiguous region of 1-30 amino acids of a mature human leptin sequence.2. The chimeric polypeptide of claim 1 , wherein two or more contiguous regions of 1-30 amino acids of a wild type seal leptin sequence have been replaced at each region with a contiguous region of 1-30 amino acids of a mature human leptin sequence.3. The chimeric polypeptide of claim 1 , wherein a wild type seal leptin sequence comprises the amino acid sequence of SEQ ID NO:28 or SEQ ID NO:31.4. The chimeric polypeptide of claim 1 , wherein a mature human leptin sequence comprises an amino acid sequence selected from the group consisting of: SEQ ID NO:12 claim 1 , SEQ ID NO:13 claim 1 , SEQ ID NO:20 claim 1 , SEQ ID NO:21 claim 1 , SEQ ID NO:22 claim 1 , SEQ ID NO:23 claim 1 , SEQ ID NO:24 claim 1 , SEQ ID NO:25 claim 1 , SEQ ID NO:26 claim 1 , SEQ ID NO:27 claim 1 , SEQ ID NO:34 claim 1 , SEQ ID NO:35 claim 1 , SEQ ID NO:36 claim 1 , SEQ ID NO:37 claim 1 , SEQ ID NO:38 claim 1 , SEQ ID NO:39 claim 1 , SEQ ID NO:40 claim 1 , SEQ ID NO:41 claim 1 , SEQ ID NO:42 claim 1 , SEQ ID NO:43 claim 1 , SEQ ID NO:44 claim 1 , SEQ ID NO:45 claim 1 , SEQ ID NO:46 claim 1 , SEQ ID NO: ...

SITE-SPECIFIC CHEMICAL MODIFICATION OF PROTEINS AT THEIR N-TERMINI, ENABLING THE FORMATION OF HOMOGENEOUS ADDUCTS

Site-specific modifications of proteins at their N-termini are provided. In particular, a chemical modification of proteins at their N-termini via a transamination reaction to form homogeneous adducts such as, the corresponding oxime derivatives is provided. Methods of making and using the adducts in radio-labelling, molecular imaging applications, and treatment of disorders such as cancer, Crohn's disease, arthritis, atherothrombosis and plaque rupture are also provided. 3. The compound of wherein Ris hydrogen claim 1 , or methyl.4. The compound of wherein Ris CH.5. The compound of wherein X is O.6. The compound of wherein R is hydrogen claim 1 , or C-Calkyl.7. The compound of wherein R3 is hydrogen or methyl.8. The compound of wherein Z is optionally substituted aryl.9. The compound of wherein n is 3-14.10. The compound of wherein n is 6.1115-. (canceled)16. The compound of further substituted with a reduced oxime linkage claim 1 , wherein at least one oxime linkage is reduced to a corresponding aminoxy group.1922.-. (canceled)23. The compound of further substituted with a therapeutic agent claim 1 , a diagnostic agent claim 1 , a solid support claim 1 , or any combination thereof.24. The compound of claim 23 , wherein the therapeutic agent or diagnostic agent is a radionucleotide claim 23 , small molecule therapeutic agent claim 23 , antibody claim 23 , optical label claim 23 , fluorescent label claim 23 , biosynthetic label claim 23 , or oligonucleotide.25. The compound of claim 23 , wherein the diagnostic agent is a NOTA or DOTA chelate of gallium or technetium claim 23 , Cu-64 claim 23 , Ga-67 claim 23 , Ga-68 claim 23 , Zr-89 claim 23 , Ru-97 claim 23 , Tc-99m claim 23 , Rh-105 claim 23 , Pd-109 claim 23 , In-111 claim 23 , I-123 claim 23 , I-125 claim 23 , I-131 claim 23 , Re-186 claim 23 , Re-188 claim 23 , Au-198 claim 23 , Au-199 claim 23 , Pb-203 claim 23 , At-211 claim 23 , Pb-212 claim 23 , Bi-212 claim 23 , fluorochrome claim 23 , fluorescein claim 23 ...

SOYBEAN DERIVED HUMAN THYROGLOBULIN, METHODS OF PRODUCING AND APPLICATIONS THEREOF

The present invention includes novel soybean derived human thyroglobulin, methods of producing human thyroglobulin in plants such as soybean, and novel diagnostic applications for the detection and stratification of endocrine malignancies including thyroid cancer and thyroiditis. The invention also includes the use of soybean-derived human thyroglobulin in affinity matrices to remove autoreactive anti-thyroglobulin antibodies from patient's sera prior to analyses. Moreover, the invention also includes methods and compositons of treating, preventing and or/ameliorating symptoms associated with thyroiditis. 1. A transgenic plant transformed with an exogenous nucleotide sequence that expresses a protein or a domain thereof wherein said protein or domain thereof is human thyroglobulin or a domain thereof and wherein said exogenous nucleotide sequence comprises one or more sequences selected from the group consisting of SEQ ID NO: 1 , SEQ ID NO: 3 , SEQ ID NO: 4 , SEQ ID NO: 5 , SEQ ID NO: 6 , SEQ ID NO: 7 , SEQ ID NO: 8 , SEQ ID NO: 9 , SEQ ID NO: 10. SEQ ID NO: 11 , SEQ ID NO: 12 , SEQ ID NO: 13 , SEQ ID NO: 14 , SEQ ID NO: 15. SEQ ID NO: 16 , SEQ ID NO: 17 , SEQ ID NO: 18 , SEQ ID NO: 19 , SEQ ID NO: 20 , SEQ ID NO: 21 , SEQ ID NO: 22 , SEQ ID NO: 23 , SEQ ID NO: 24 , SEQ ID NO: 25 , SEQ ID NO: 26 , SEQ ID NO: 27 , SEQ ID NO: 28 , SEQ ID NO: 29 , SEQ ID NO: 30 , SEQ ID NO: 31 , and SEQ ID NO: 32.2. The transgenic plant according to claim 1 , wherein the plant is a soybean plant claim 1 , and the soybean optionally comprises exogenous nucleotide sequence SEQ ID NO: 1.3. The transgenic soybean according to claim 2 , wherein said exogenous nucleotide sequence comprises one or more sequences selected from the group consisting of SEQ ID NO: 3. SEQ ID NO: 4 claim 2 , SEQ ID NO: 5 claim 2 , SEQ ID NO: 6 claim 2 , SEQ ID NO: 7 claim 2 , SEQ ID NO: 8 claim 2 , SEQ ID NO: 9 claim 2 , SEQ ID NO: 10 claim 2 , SEQ ID NO: 11 claim 2 , SEQ ID NO: 12 claim 2 , SEQ ID NO: 13 claim 2 , ...

Methods and compositions related to improving properties of pharmacological agents targeting nervous system

Disclosed are compositions and methods related to improving pharmacological properties of bioactive compounds targeting nervous system.

Methods for treatment of nephrotic syndrome and related conditions

The present disclosure provides a method for treating and/or preventing nephrotic syndrome, such as but not limited to MCD and MN, and conditions related to nephrotic syndrome, such as but not limited to, proteinuria and edema, as well as diabetic nephropathy, diabetes mellitus, lupus nephritis or primary glomerular disease. The present disclosure further provides methods for reducing proteinuria and other disease states as discussed herein. Such methods comprise the therapeutic delivery of an Angptl4 polypeptide or Angptl4 polypeptide derivative to a subject.

DIAGNOSIS AND RISK STRATIFICATION BY MEANS OF THE NOVEL MARKER CT-PROADM

The invention relates to a novel diagnostic marker CT-proADM (C-terminal fragment of preproADM, SEQ ID No. 1) for diagnosing and/or stratifying the risk of diseases. Also disclosed is a method for diagnosing and/or stratifying the risk of diseases, particularly cardiovascular diseases, cardiac insufficiency, and infections and/or inflammations of the lungs and respiratory tract. In said method, the CT-proADM (SEQ ID No. 1) marker, or a partial peptide of fragment thereof, or said marker contained in a marker combination (panel, cluster) is determined in a patient who is to be examined. The invention further relates to a diagnostic apparatus as well as a kit for carrying out said method. 1. Diagnostic marker consisting of CT-proADM (SEQ ID No. 1) , or partial peptides or fragments thereof.2. A method for diagnosing and/or stratifying the risk of diseases , comprising determining CT-proADM (SEQ ID No , 1) , or a partial peptide of fragment thereof , in a patient.3. The method of claim 2 , wherein the method is an in-vitro diagnosis.4. The method of claim 2 , wherein the diagnosis or risk stratification of diseases is an in vitro diagnosis or risk stratification of cardiovascular diseases claim 2 , cardiac insufficiency claim 2 , infections and/or inflammations of the lungs and respiratory.5. The method of claim 4 , wherein the cardiac diseases comprise a disease selected from the group consisting of high blood pressure claim 4 , coronary heart diseases claim 4 , especially acute coronary syndrome claim 4 , (acute) myocardial infarct claim 4 , and angina pectoris.6. The method of claim 4 , wherein the cardiac insufficiency comprises a chronic cardiac insufficiency claim 4 , hypertensive heart disease with (congestive) cardiac insufficiency claim 4 , hypertensive heart and kidney disease with (congestive) cardiac insufficiency claim 4 , primary right-ventricular heart failure claim 4 , secondary right-ventricular heart failure claim 4 , left-ventricular heart failure ...

Screening Method for Candidate Agonist Compounds for Adiponectin Receptor I

A method of screening for candidate compounds for adiponectin receptor 1 agonist including a step of bringing test compounds into contact with cells to determine whether they cause intracellular influx of extracellular calcium ions and selecting, from the test compounds, compounds causing the intracellular influx of extracellular calcium ions as the candidate compounds for adiponectin receptor 1 agonist.

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 once weekly 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 lipodystrophy, dyslipidemia, hyperlipidemia, overweight, obesity, hypothalamic amenorrhea, Alzheimer's disease, leptin deficiency, fatty liver disease or diabetes (including type I and type II). Additional diseases and disorders which can be treated by the compounds and methods described herein include nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver disease (NAFLD), metabolic syndrome X and Huntington's Disease. 1. An engineered polypeptide comprising: an albumin binding domain polypeptide (ABD) and a first peptide hormone domain (HD1) selected from a leptin , a leptin analog or an active fragment thereof.2. The engineered polypeptide according to claim 1 , further comprising a first linker (L1) covalently linked to said HD1.3. The engineered polypeptide according to claim 1 , wherein said engineered polypeptide comprises said ABD as an N-terminal moiety and said HD1 as a C-terminal moiety.4. The engineered polypeptide according to claim 1 , wherein said engineered polypeptide comprises said ABD as a C-terminal moiety and said HD1 as an N-terminal moiety.5. The engineered polypeptide according to claim 1 , wherein said HD1 has at least 50% identity with an amino acid sequence selected from the group consisting of: SEQ ID NO:1 claim 1 , SEQ ID NO:2 claim 1 , SEQ ID NO:3 claim 1 , SEQ ID NO:4 claim 1 , SEQ ID NO:5 claim 1 , SEQ ID NO:6 claim 1 , SEQ ID NO:7 claim 1 , SEQ ID NO:8 claim 1 , SEQ ID NO:9 claim 1 , SEQ ID NO:10 claim 1 , SEQ ID NO:11 claim 1 , and SEQ ID NO:12. SEQ ID NO:13 claim 1 , SEQ ID NO:14 claim 1 , SEQ ID NO:15 claim 1 , SEQ ID ...

Pharmaceutical for Pseudo-Exercise Therapy

A pharmaceutical for pseudo-exercise therapy containing an adiponectin receptor 1 agonist compound as an active ingredient and changing the physiological state of muscle to a post-exercise one without applying an exercise stress to the muscle. 1. A pharmaceutical for pseudo-exercise therapy , comprising an adiponectin receptor 1 agonist compound as an active ingredient.2. A pharmaceutical comprising an adiponectin receptor 1 agonist compound as an active ingredient and changing the physiological state of muscle to a post-exercise physiological state without applying exercise stress.3. The pharmaceutical according to or , which is used for a drug therapy substituted for an exercise therapy in the prevention and/or treatment of diabetes.4. A type I muscle fiber enhancer comprising an adiponectin receptor 1 agonist compound as an active ingredient. The present invention relates to a pharmaceutical for pseudo-exercise therapy.One of the goals of diabetes treatment is to prevent or inhibit progression of various chronic complications in diabetes, for example, microvascular disorders such as diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy and macrovascular disorders such as cerebrovascular disorders, ischemic heart disease, and diabetic gangrene. Diet therapy and exercise therapy are fundamental in the diabetes treatment. In addition to these therapies, drug therapy using insulin preparations, sulfonyl urea drugs and incretin-related drugs stimulating pancreatic insulin secretion, biguanide drugs having mainly extra-pancreatic action, thiazolidine-based drugs, and carbohydrate absorption inhibitors (α-glucosidase inhibitors) is used to control blood sugar levels.The exercise therapy, when used for the treatment of diabetes, accelerates utilization of glucose and fatty acids and thereby decreases blood sugar levels, as an acute effect of exercise and at the same time, ameliorates insulin resistance as a chronic effect. In addition, an effect on weight ...

POLYPEPTIDES

The invention relates to polypeptides comprising an amino acid sequence which is an analogue of human amylin, pharmaceutical compositions comprising these polypeptides, and these polypeptides for use as medicaments. 1. A polypeptide comprising an amino acid sequence which is an analogue of SEQ ID No: 1 , wherein: said analogue comprises an aspartic acid residue at position 14 , an arginine residue at position 17 , a proline residue at position 21 , a proline residue at position 27 and an arginine residue at position 35; wherein the amino acid sequence numbering of the analogue corresponds to the amino acid numbering sequence of SEQ ID No: 1.2. The polypeptide of claim 1 , wherein at least one substituent is attached to at least one amino acid residue of said polypeptide.3. The polypeptide of claim 2 , wherein the substituent is selected from the group consisting of C20diacid claim 2 , C20diacid-γGlu claim 2 , C20diacid-γGlu-γGlu claim 2 , C20diacid-γGlu-γGlu-γGlu claim 2 , C20diacid-OEG claim 2 , C20diacid-γGlu-OEG claim 2 , C20diacid-γGlu-OEG-OEG claim 2 , C16diacid-γGlu claim 2 , and C14diacid-γGlu.4. The polypeptide of claim 2 , wherein the substituent is attached to the α-amino group of the N-terminal amino acid residue or to a Lys residue.5. The polypeptide of claim 2 , wherein the substituent is only attached to a Lys residue at position 1.6. The polypeptide of claim 2 , wherein the substituent is attached to a lysine residue via the ε-amino group.7. The polypeptide according to claim 1 , wherein the polypeptide is N-[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]butanoyl]-[Asp14 claim 1 ,Arg17 claim 1 ,Pro21 claim 1 ,Pro27 claim 1 ,Arg35]-h-amylin.8. A pharmaceutical composition comprising the polypeptide of and a pharmaceutical acceptable excipient.9. A process for preparing a pharmaceutical composition comprising mixing the polypeptide of with a pharmaceutically acceptable excipient.10. A method of treating type 2 diabetes ...

PNEUMONIA BIOMARKERS

Ghrelin signal peptide fragment assays and kits useful in the diagnosis, prognosis, risk stratification, assessing, staging, monitoring, categorizing and determination of further diagnoses and treatment regimens in subjects with various disorders, diseases and conditions including, pneumonia, heart failure, or pneumonia and heart failure or suspected pneumonia, heart failure, or pneumonia and heart failure, and methods for monitoring treatment.

AQUARETIC AND NATRIURETIC POLYPEPTIDES LACKING VASODILATORY ACTIVITY

This document provides aquaretic and natriuretic polypeptides. For example, this document provides polypeptides having aquaretic and/or natriuretic activities. In some cases, a polypeptide provided herein can have aquaretic and natriuretic activities, while lacking the ability to lower blood pressure. This document also provides methods and materials for inducing aquaretic and/or natriuretic activities within a mammal. 115-. (canceled)16. A natriuretic polypeptide less than 45 amino acid residues in length , wherein said polypeptide comprises , in an order from amino terminus to carboxy terminus:(a) the sequence set forth in SEQ ID NO:2 or the sequence set forth in SEQ ID NO:2 with no more than two mismatches, and(b) the sequence set forth in SEQ ID NO:3 or the sequence set forth in SEQ ID NO:3 with no more than one mismatch.17. The polypeptide of claim 16 , wherein said polypeptide has natriuretic activity.18. The polypeptide of claim 16 , wherein said polypeptide lacks vasodilatory activity.19. The polypeptide of claim 16 , wherein said polypeptide lacks the sequence set forth in SEQ ID NO:1.20. The polypeptide of claim 16 , wherein said polypeptide comprises the sequence set forth in SEQ ID NO:2.21. The polypeptide of claim 16 , wherein said polypeptide comprises the sequence set forth in SEQ ID NO:3.22. The polypeptide of claim 16 , wherein said polypeptide comprises the sequence set forth in SEQ ID NO:2 and the sequence set forth in SEQ ID NO:3.23. The polypeptide of claim 16 , wherein said polypeptide comprises the sequence set forth in SEQ ID NO:8.24. The polypeptide of claim 16 , wherein said polypeptide consists of the sequence set forth in SEQ ID NO:8.25. An isolated nucleic acid encoding a natriuretic polypeptide less than 45 amino acid residues in length claim 16 , wherein said polypeptide comprises claim 16 , in an order from amino terminus to carboxy terminus:(a) the sequence set forth in SEQ ID NO:2 or the sequence set forth in SEQ ID NO:2 with no ...

PANCREATIC POLYPEPTIDE FAMILY MOTIFS, POLYPEPTIDES AND METHODS COMPRISING THE SAME

The present invention provides novel Pancreatic Polypeptide Family (“PPF”) polypeptides and methods for their use. 1. A method for treating diabetes , obesity , a gastrointestinal disorder , an eating disorder , insulin-resistance syndrome , a cardiovascular disease , nonalcoholic steatohepatitis , or lipodystrophy in a mammal in need thereof comprising administering to the mammal a therapeutically effective amount of a PPF polypeptide to treat the obesity , diabetes , gastrointestinal disorder , eating disorder , insulin-resistance syndrome , cardiovascular disease , nonalcoholic steatohepatitis , or lipodystrophy.2. The method of for treating diabetes in the mammal in need thereof.3. The method of claim 2 , wherein the diabetes is Type 1 diabetes.4. The method of claim 2 , wherein the diabetes is Type 2 diabetes.5. The method of for treating obesity in the mammal in need thereof.7. The method of claim 1 , wherein the PPF polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 266 claim 1 , 437 claim 1 , 438 claim 1 , 439 claim 1 , 442 claim 1 , 462 claim 1 , 469 claim 1 , 470 claim 1 , 471 claim 1 , and 472.8. The method of claim 1 , wherein the PPF polypeptide further comprises an N-terminal cap.9. The method of claim 1 , wherein the PPF polypeptide is linked to one or more water-soluble polymers.10. The method of claim 9 , wherein the one or more water-soluble polymers are selected from at least one of the group consisting of polyethylene glycol and a fatty acid molecule claim 9 , wherein the polymer is linked to the N- or C-terminus of the polypeptide claim 9 , or the side chain of a lysine or serine amino acid residue within the sequence of the polypeptide.11. A method for reducing food intake claim 9 , reducing nutrient availability claim 9 , causing weight loss claim 9 , affecting body composition claim 9 , altering body energy content or energy expenditure claim 9 , or improving lipid profile in a mammal in need ...

NOVEL COMPOUNDS AND THEIR EFFECTS ON FEEDING BEHAVIOUR

Peptide analogues of PYY, compositions comprising said analogues, and methods of using said analogues for the treatment and prevention of metabolic disorders, for example disorders of energy metabolism such as diabetes and obesity, and for reduction in appetite, reduction in food intake or reduction of calorie intake in a subject, are provided herein. 2. An analogue of PYY as claimed in which is not a variant.3. An analogue of PYY as claimed in claim 1 , wherein Xaais Pro [SEQ ID NO 18].4. An analogue of PYY as claimed in claim 1 , wherein Xaais Leu [SEQ ID NO 21].5. An analogue of PYY as claimed in claim 1 , wherein{'sup': '2', 'Xaais Pro'}{'sup': '18', 'Xaais Leu;'}{'sup': '21', 'Xaais Tyr;'}{'sup': '22', 'Xaais Ile or Leu;'}{'sup': '23', 'Xaais Ala;'}{'sup': '25', 'Xaais selected from the group consisting of Arg or His; and'}{'sup': '30', 'Xaais selected from the group consisting of Leu and His [SEQ ID NO 47].'}6. An analogue of PYY as claimed in claim 1 , wherein Xaais Arg [SEQ ID NO 28].7. An analogue of PYY as claimed in claim 1 , wherein Xaais Ile [SEQ ID NO 26].8. An analogue of PYY as claimed in claim 1 , wherein Xaais Leu [SEQ ID NO 25].9. An analogue of PYY as claimed in claim 1 , wherein Xaais Leu [SEQ ID NO 31].10. An analogue of PYY as claimed in which is a derivative that has been modified by one or more processes selected from amidation claim 1 , glycosylation claim 1 , carbamoylation claim 1 , acylation claim 1 , sulfation claim 1 , phosphylation claim 1 , cyclization claim 1 , lipidization and pegylation.11. An analogue of PYY as claimed in which is a derivative that is a fusion protein.12. An analogue of PYY as claimed in that is produced by a recombinant method.13. An analogue of PYY as claimed in that is produced by a synthetic method.14. An analogue of PYY as claimed in for use as a medicament.15. A pharmaceutical composition comprising an analogue of PYY as claimed in together with a pharmaceutically acceptable carrier and optionally other ...

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.

GELSOLIN ENRICHMENT OF BLOOD SAMPLES USING GOLD PARTICLES

In the method for producing at least one therapeutically effective protein or a protein mixture in a container, the container is filled with a body fluid and gold particles and incubated, and in this process the therapeutically effective protein is formed in the body fluid. 131-. (canceled)32. A medicament composition for creating blood serum comprising:autologous or homologous blood;gold particles; andgelsolin in an amount which is at least twice the corresponding value for standard blood gelsolin.33. The medicament composition for creating blood serum of wherein:the gold particles are of about 1 μm in size.34. The medicament composition for creating blood serum of wherein:the gold particles are about 0.3 mg per 1 ml of blood.35. The medicament composition for creating blood serum of further comprising:cytokines above the relevant standard blood level for cytokines.36. A method for producing autologous proteins comprising:providing a mixture of body fluid and gold particles in a container;incubating the body fluid and gold particles to produce protein-enriched body fluid serum;removing the gold particles from the protein enriched body fluid serum.37. The method for producing autologous proteins of wherein the body fluid is autologous or homologous blood.38. The method for producing autologous proteins of wherein incubating the body fluid and gold particles produces gelsolin enriched blood serum.39. The method for producing autologous proteins of wherein incubating the body fluid and gold particles produces gelsolin enriched blood serum in an amount which is at least twice the corresponding value for standard blood gelsolin.40. The method for producing autologous proteins of wherein incubating the body fluid and gold particles produces gelsolin enriched and cytokine enriched blood serum.41. The method for producing autologous proteins of further comprising:removing the somatic cells and insoluble aggregates from the blood serum.42. A method of treating a patient ...

Neuropeptide analogs, compositions, and methods for treating pain

Neuropeptide analogs and compositions including neuropeptide analogs are described herein. Also provided are methods of producing and using the neuropeptide analogs and compositions including one or more neuropeptide analogs.

FGF-9 VARIANTS AND METHODS OF USE THEREOF

A method of treating an individual (i) having abnormal bone; or (ii) afflicted with a disease or disorder related to normal or abnormal FGF receptors or a skeletal disorder; or (iii) having dysplasic bone. The method includes administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of a fibroblast growth factor 9 (FGF-9) variant comprising at least one amino acid substitution in the beta 8-beta 9 loop, wherein said FGF-9 variant incorporates one of the amino acid sequences set forth in SEQ ID NO: 11, 13, 14, 15, 16 or 17. 1. A method of treating an individual that (i) has abnormal bone; or (ii) is afflicted with a disease or disorder related to normal or abnormal FGF receptors or a skeletal disorder; or (iii) has dysplasic bone , which method comprises administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of a fibroblast growth factor 9 (FGF-9) variant comprising at least one amino acid substitution in the beta 8-beta 9 loop , wherein the FGF-9 variant is an antagonist; wherein the FGF-9 variant reduces proliferation of target cells having at least one FGF receptor subtype compared to the corresponding wild type FGF-9; wherein the FGF-9 variant has enhanced receptor specificity for the at least one receptor subtype compared to the corresponding wild type FGF-9 by decreasing the biological activity mediated by at least one receptor subtype while retaining the activity mediated through another receptor subtype; wherein the FGF-9 variant further comprises a truncation at the N-terminus , or at the C-terminus , or at both termini; and wherein the FGF-9 variant comprises an amino acid sequence selected from one of the sequences forth in SEQ ID NO: 11 , 13 , 14 , 15 , 16 and 17.2. The method according to claim 1 , for treating an individual having an abnormal bone or a dysplasic bone.3. The method according to claim 1 , for treating an individual having an abnormal bone ...

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.

Prognosis and risk assessment in stroke patients by determining the level of marker peptides

The present invention relates to a method for prognosis of an outcome or assessing the risk of a patient having suffered a stroke or a transient ischemic attack, comprising the determination of the level of at least one marker peptide in said sample said marker peptide selected from the group comprising ANP, AVP, ADM, ET-1, troponin, CRP, calcitonin and hGH or fragments thereof or its precursor or fragments thereof and attributing the level of said at least one marker peptides its precursor or fragments thereof with the prognosis of an outcome or assessing the risk for said patient.

AMYLIN ANALOGUES AND PHARMACEUTICAL COMPOSITIONS THEREOF

The invention relates to polypeptides comprising an amino acid sequence which is an analogue of pramlintide, pharmaceutical compositions comprising these polypeptides, and these polypeptides for use as medicaments. 1. A polypeptide comprising an amino acid sequence which is an analogue of SEQ ID No: 2 wherein:said analogue comprises a proline residue at position 37;wherein the amino acid sequence numbering of the analogue corresponds to the amino acid numbering sequence of SEQ ID No: 2.2. The polypeptide according to wherein said analogue comprises a residue at position 14 which is selected from the group consisting of glutamic acid and asparagine.3. The polypeptide according to wherein said analogue comprises a residue at position 17 which is selected from the group consisting of histidine claim 1 , arginine claim 1 , lysine and valine.4. The polypeptide according to wherein said analogue comprises a residue at position 35 which is selected from the group consisting of histidine claim 1 , arginine claim 1 , lysine claim 1 , aspartic acid claim 1 , glutamic acid claim 1 , asparagine and glutamine.5. The polypeptide according to wherein the analogue comprises an amino acid residue at position 14 which is glutamic acid claim 1 , a residue at position 17 which is arginine and a residue at position 37 which is proline.7. The polypeptide according to wherein at least one substituent is attached to at least one amino acid residue of said polypeptide.8. The polypeptide according to wherein the substituent group is selected from the group consisting of C20diacid claim 7 , C20diacid-γGlu claim 7 , C20diacid-γGlu-γGlu claim 7 , C20diacid-γGlu-γGlu-γGlu claim 7 , C20diacid-OEG claim 7 , C20diacid-γGlu-OEG claim 7 , C20diacid-γGlu-OEG-OEG claim 7 , C18diacid-γGlu claim 7 , C16diacid-γGlu claim 7 , and C14diacid-γGlu.9. The polypeptide according to wherein a substituent is attached to the α-amino group of the N-terminal amino acid residue or to a Lys residue.10. The polypeptide ...

LEPTIN DERIVATIVES

The invention relates to Leptin derivatives, compositions and therapeutic use there-of. 2. A compound according to claim 1 , wherein the Z—Y—X-moiety is connected to an amino group present in the N terminal alpha-amino group of the Leptin compound.5. The compound according to claim 1 , wherein the Z—Y—X-moiety is attached to the Leptin compound by alkylation chemistry.6. The compound according to claim 1 , wherein the Leptin compound is an analogue of Leptin.7. The compound according to claim 1 , wherein Z comprises a fatty acid or fatty diacid.8. The compound according to claim 1 , wherein Z comprises an alpha and omega carboxy group.9. The compound according to claim 7 , wherein Z comprises a fatty acid or fatty diacid with 12-22 carbon atoms.10. The compound according to claim 7 , wherein Z comprises a fatty acid or fatty diacid with 16-20 carbon atoms.13. (canceled)14. (canceled)15. A composition comprising a compound as defined in and a pharmaceutically acceptable excipients.16. The compound according to claim 6 , wherein the analogue of Leptin-is an analogue of rat Leptin.17. The compound according to claim 6 , wherein the analogue of Leptin-is an analogue of human Leptin.18. The composition of further comprising an anti-obesity agent or anti-diabetic agent.19. The composition of claim 18 , wherein the anti-diabetic agent comprises pramlintide.20. A method of treating obesity comprising administering the compound of to a patient in need thereof. The present invention relates to novel Leptin derivatives and aspects related thereto, such as compositions thereof and therapeutic use thereof.Leptin is a 16 kDa protein hormone that plays a key role in regulating energy intake and energy expenditure, including appetite and metabolism. Leptin is secreted predominantly by white adipose tissue. Studies in mice have demonstrated homozygous mutations of the Leptin gene cause massive obesity and lead to hyperglycaemic conditions in the ob/ob mice. Leptin administration ...

COMPOSITIONS, METHODS AND KITS RELATING TO RESISTIN

The invention relates to novel nucleic acids encoding a mammalian resistin gene, and proteins encoded thereby, whose expression is suppressed by the antidiabetic compounds thiazolidinediones. The invention further relates to methods of treating and detecting type 2 diabetes and Syndrome X comprising modulating or detecting resistin expression and/or production and activity of resistin polypeptide. 1. An isolated mammalian resistin polypeptide comprising the amino acid sequence of SEQ ID NO: 2 or SEQ ID NO: 4 or a sequence sharing at least 80% sequence identity with SEQ ID NO: 2 or SEQ ID NO: 4.2. (canceled)3. The isolated polypeptide of claim 1 , wherein said resistin is encoded by a nucleic acid sequence having at least about 80% sequence identity with a nucleic acid having the sequence of SEQ ID NO:1 or SEQ ID NO: 3.4. (canceled)5. An isolated nucleic acid sequence encoding the polypeptide of .67-. (canceled)8. The nucleic acid of claim 5 , said nucleic acid further comprising a nucleic acid encoding a tag polypeptide covalently linked thereto.9. The nucleic acid of claim 8 , wherein said tag polypeptide is selected from the group consisting of a myc tag polypeptide claim 8 , a glutathione-S-transferase tag polypeptide claim 8 , a green fluorescent protein tag polypeptide claim 8 , a myc-pyruvate kinase tag polypeptide claim 8 , a His6 tag polypeptide claim 8 , an influenza virus hemagglutinin tag polypeptide claim 8 , a flag tag polypeptide claim 8 , and a maltose binding protein tag polypeptide.10. The nucleic acid of claim 5 , said nucleic acid further comprising a nucleic acid encoding a promoter or regulatory sequence operably linked thereto.11. A vector comprising the nucleic acid of .12. The vector of claim 11 , said vector further comprising a nucleic acid encoding a promoter or regulatory sequence operably linked thereto.13. A recombinant cell comprising the isolated nucleic acid of .14. A recombinant cell comprising the vector of .15. An antibody that ...

Expression System With Sar Element From IFNalpha2

A short human genomic nucleotide sequence from the SAR3 region of the human interferon α2 gene permits enhances expression stability in the absence of drug selection and permits generation of stable clones or stable pools of cells for producing recombinant proteins. Although stable clones may be generated, the ability to generate stable pools reduces the burden of generating stable clones. 1. An isolated polynucleotide comprising no more than 755 nucleotides and comprising at least 500 contiguous nucleotides from the nucleotide sequence as set forth in SEQ ID NO: 1.2. The isolated polynucleotide according to claim 1 , comprising at least 600 contiguous nucleotides from the nucleotide sequence as set forth in SEQ ID NO: 1.3. The isolated polynucleotide according to claim 1 , comprising at least 700 contiguous nucleotides from the nucleotide sequence as set forth in SEQ ID NO: 1.4. The isolated polynucleotide according to claim 1 , comprising at least 750 contiguous nucleotides from the nucleotide sequence as set forth in SEQ ID NO: 1.5. An expression system for producing recombinant protein in a host cell comprising: a gene for encoding a protein of interest; nucleotide sequences for operation of the expression system; and claim 1 , an expression enhancer incorporated in cis in the expression system for enhancing expression of the gene claim 1 , the expression enhancer comprising a polynucleotide as defined in .6. The expression system according to comprising a plasmid vector containing the gene and the expression enhancer.7. The expression system according to comprising an episomal vector containing the gene and the expression enhancer.8. The expression system according to claim 5 , wherein the gene encodes a monoclonal antibody claim 5 , an erythropoietin claim 5 , an interferon claim 5 , a vascular endothelial growth factor claim 5 , a stem cell growth factor claim 5 , a growth hormone or an insulin-like growth factor binding protein.9. The expression system ...

Single Chain Relaxin Polypeptides

The present invention relates to biologically active single chain relaxin polypeptides comprising a relaxin B chain derived from relaxin-3, the polypeptides being truncated by one or more amino acids at the C-terminus of the relaxin-3 B chain. Typically the single chain relaxin polypeptides are antagonists of the RXFP3 receptor, and in some embodiments are selective antagonists of the RXFP3 receptor. 1. A biologically active single chain relaxin polypeptide comprising a relaxin B chain derived from relaxin-3 , the polypeptide being truncated by one or more amino acids at the C-terminus of the relaxin-3 B chain.2. The polypeptide of wherein the polypeptide is truncated by up to about 5 amino acids at the C-terminus compared to the native relaxin-3 B chain sequence and a basic amino acid is incorporated at the C-terminus of the relaxin-3 derived B chain.3. The polypeptide of wherein the basic amino acid residue is arginine.4. (canceled)5. The polypeptide of wherein the C-terminus is truncated by 5 amino acids from the native sequence of the relaxin-3 B chain claim 1 , and these residues are replaced by a terminal arginine residue.6. The polypeptide of wherein the B chain sequence is derived from human relaxin-3 and the C-terminal sequence GGSRW is replaced by R.7. The polypeptide of wherein the single chain polypeptide is further modified such that one or more cysteine residues in the native relaxin-3 B chain sequence are replaced by neutral amino acids.8. The polypeptide of wherein the neutral amino acids are serine or alanine residues.9. (canceled)10. The polypeptide of wherein the B chain sequence is derived from human relaxin-3 and the cysteine residues at positions 10 and 22 of the native human relaxin-3 sequence are replaced by serine residues.11. The polypeptide of comprising a C-terminal amide group.12. The polypeptide of further comprising a truncation of one or more amino acids from the N-terminus of the relaxin-3 B chain when compared to the native relaxin- ...

POLYMERIC CONJUGATES AND METHODS OF PREPARING THE SAME

Methods of preparing polymer target conjugates which are substantially free of polymer attachment on the N-terminal of the targets are provided. Also provided are compositions comprising a plurality of polymer-polypeptide conjugates, said polymer-polypeptide conjugate comprising a polypeptide covalently attached to at least one polymer through an epsilon amino group of a Lysine or a Histidine found on the polypeptide and said conjugates containing less than 5% of the polymer-polypeptide conjugates having a polymer attached to the N-terminal of the polypeptide; and polymer target conjugates comprising a target moiety selected from the group consisting of polypeptides, proteins and the like having at least one polymer attached thereto at a site which is not the N-terminal of the target. 1. A method of preparing a polymer target conjugate which is substantially free of polymer attachment on the N-terminal of said target , said target being selected from the group consisting of proteins , peptides , and the like , comprising:(a) reacting a target with a capping reagent under conditions to selectively cap the N-terminal of the target;(b) reacting the N-terminal-capped target with an activated polymer under conditions to allow polymer attachment to at least one site on the N-terminal-capped target to form a polymer-target conjugate which is substantially free of polymer attachment on the N-terminal of said target.2. The method of further comprising isolating the polymer-target conjugate which is substantially free of polymer attachment on the N-terminal of said target resulting from step (b).3. The method of further comprising deprotecting the N-terminal of the polymer-target conjugate.4. The method of claim 1 , wherein said conditions to selectively cap the N-terminal of the target include reacting the target with the capping reagent at pH of from about 4.0 to about 7.0.6. The method of claim 4 , wherein said conditions further comprise reducing the bond attaching the ...

Antibodies to TTR and Methods of Use

The disclosure pertains to antibodies and binding fragments thereof that specifically binds all or part of EHAEVVFTA. Also provided are isolated peptides, isolated nucleic acids, immunogens, compositions, immunoassays and kits and method of using said reagents to detect misfolded TTR. 1. An antibody or binding fragment thereof that specifically binds all or part of EHAEVVFTA , wherein the part comprises at least 4 or at least 5 or more contiguous amino acids of EHAEVVFTA.2. The antibody or binding fragment thereof of claim 1 , wherein the antibody or binding fragment specifically binds misfolded and/or monomeric TTR claim 1 , optionally TTR fibrils.3. The antibody or binding fragment thereof of claim 1 , wherein the antibody or binding fragment thereof is capable of disrupting or reducing TTR fibril formation when monomeric TTR or misfolded TTR intermediates in solution is/are contacted with the antibody or binding fragment.4. The antibody or binding fragment thereof of claim 1 , wherein the antibody is a monoclonal or polyclonal antibody and/or a chimeric and/or a humanized antibody or binding fragment thereof.5. The antibody binging fragment of claim 1 , wherein the antibody fragment is a Fab claim 1 , Fab′ claim 1 , F(ab′) claim 1 , scFv claim 1 , dsFv claim 1 , ds-scFv claim 1 , dimer claim 1 , minibody claim 1 , diabody claim 1 , or multimer thereof or a bispecific antibody fragment.6. The antibody of claim 1 , wherein the antibody is affinity purified.7. An isolated peptide comprising all or part of EHAEVVFTA claim 1 , the part comprising at least 4 or at least 5 or more contiguous amino acids.8. The isolated peptide of claim 7 , further comprising one or more amino acid linkers conjugated to one or more of the peptide N and/or C termini claim 7 , optionally wherein the amino acid linkers include one or more G or K or S residues and for example the amino acid linker or linkers each independently comprise GG or GGKG or glycine serine linkers.9. The isolated ...

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.

Ghrelin Mimetic Polypeptide Hapten Immunoconjugates Having Improved Solubility and Immunogenicity and Methods of Use Thereof

Immunoconjugates for impeding weight gain and treating obesity in a subject are disclosed. The immunoconjugates comprise a ghrelin mimetic polypeptide hapten, a spacer moiety comprising one of more polyethylene glycol (PEG) units, and a protein carrier moiety. Immunoconjugates optionally include a conjugation moiety for conjugating the polypeptide hapten with a linker moiety or the protein carrier moiety and a linker moiety for conjugating the conjugation moiety with the protein carrier moiety. 2. The immunoconjugate of claim 1 , wherein R comprises CHCHCHor CHCHCHCHCHCHCH.3. The immunoconjugate of claim 1 , wherein B comprises 0 residues of SEQ ID NO: 1.4. The immunoconjugate of claim 1 , wherein the PEG units are linear claim 1 , branched claim 1 , or multiply branched.5. The immunoconjugate of claim 1 , wherein y is between 1 to about 30 inclusive.6. The immunoconjugate of claim 1 , wherein y comprises between 1 to about 8 inclusive.7. The immunoconjugate of claim 1 , wherein C comprises one PEG amino acid spacer containing four PEG units claim 1 , wherein x=1 claim 1 , y=4 claim 1 , z=1 and p=1.8. The immunoconjugate of claim 1 , wherein D comprises a Lys claim 1 , Cys claim 1 , His claim 1 , Arg claim 1 , Asp claim 1 , Glut claim 1 , Ser claim 1 , Thr claim 1 , or Tyr residue.9. The immunoconjugate of claim 8 , wherein D is a Cys residue.10. The immunoconjugate of claim 1 , wherein E comprises a N-maelimidoalkylcarboxyl moiety.11. The immunoconjugate of claim 10 , where E comprises a N-γ-maleimidobutyryl (GMB) linker.12. The immunoconjugate of claim 1 , wherein the protein carrier moiety F comprises serum albumin claim 1 , keyhole limpet hemocyanin (KLH) claim 1 , thyroglobulin claim 1 , ovalbumin claim 1 , bovine serum albumin (BSA) claim 1 , tetanus toxoid (TT) claim 1 , or diphtheria toxoid (CRM).13. The immunoconjugate of claim 1 , wherein{'sub': 2', '2', '3, 'R comprises CHCHCH;'}B comprises 0 residues of SEQ ID NO: 1;C comprises one PEG amino acid spacer ...

PRODUCTION OF GLYCOPROTEINS USING MANGANESE

Culture media comprising manganese and methods of culturing cells to improve sialylation and glycosylation of glycoproteins are provided. 1. A product made by a process for producing an erythropoietic composition comprising sialylated erythropoiesis-stimulating molecules , wherein said erythropoiesis-stimulating molecules comprise analogs of erythropoietin (SEQ ID NO:3) or darbepoetin (SEQ ID NO:2) with 75% homology to SEQ ID NO:3 or SEQ ID NO:2 , respectively , and still retaining erythropoietic activity , said process comprising the steps of: growing a manganese-responsive host cell transfected with DNA encoding said analog in a culture medium containing an amount of manganese effective to increase the percentage of sialylated molecules or degree of sialylation of said erythropoietic composition , wherein the concentration of manganese in said culture medium ranges from about 0.01 to about 40 μM; and recovering said erythropoietic composition , wherein less than about 5% of the erythropoiesis-stimulating molecules are lower sialylated.2. The process of in which the amount of manganese is effective to increase the percentage of highly sialylated erythropoiesis-stimulating molecules.3. The process of wherein the amount of manganese is effective to increase the percentage of erythropoiesis-stimulating molecules which are glycosylated at potential O-linked glycosylation sites.4. The process of wherein the amount of manganese is effective to increase the percentage of galactose among the sugars attached to erythropoiesis-stimulating molecules.54. The process of any one of and - wherein the culture medium is essentially serum-free.64. The process of any one of and - wherein the erythropoiesis-stimulating molecules comprise the amino acid sequence of SEQ ID NO: 3 (erythropoietin) or erythropoietic fragments thereof.74. The process of any one of and - wherein the erythropoiesis-stimulating molecules comprise the amino acid sequence of SEQ ID NO: 2 (darbepoetin) or ...

PEPTIDE MODULATORS OF ANGIOGENESIS AND USE THEREOF

The invention generally features compositions and methods that are useful for modulating blood vessel formation, as well as methods that provide for the systematic and efficient identification of angiogenesis modulators. As described in more detail below, a systematic computational methodology based on bioinformatics was used to identify novel peptide modulators of angiogenesis that have been characterized in vitro and/or in vivo. 2. The isolated peptide of claim 1 , wherein the peptide comprises an amino acid sequence shown in Table 1-6 claim 1 , 8 and 9.3. An isolated peptide or analog thereof having at least 85% identity to an amino acid sequence shown in Table 1-10.4. The isolated peptide of claim 3 , wherein the peptide comprises an amino acid sequence shown in Table 1-10.5. The isolated peptide of claim 3 , wherein the peptide consists essentially of an amino acid sequence shown in Table 1-10.98. The isolated peptide of any one of - claims 1 , wherein the peptide comprises an alteration in one amino acid relative to a reference sequence shown in Tables 1-10.109. The isolated peptide of any one of - claims 1 , wherein the peptide comprises at least one modification.11. The isolated peptide of claim 10 , wherein the modification is a sequence alteration or post-translational modification that increases protease resistance claim 10 , biodistribution claim 10 , or therapeutic efficacy.1210. The isolated peptide of any one of - claims 1 , wherein the peptide is cyclized.1310. The isolated peptide of any one of - claims 1 , wherein the peptide is pegylated.1410. The isolated peptide of any one of - claims 1 , wherein the sequence alteration replaces a cysteine with aminobutyric acid (Abu) claims 1 , serine or alanine claims 1 , replaces methionine with isoleucine claims 1 , or replaces lysine with arginine.1510. The isolated peptide of any one of - claims 1 , wherein the peptide comprises at least 10 or 20 amino acids of a peptide shown in Table 1-10.16. A ...

Modified Cell Expressing Therapeutic Agent and Uses thereof

Compositions and methods for enhancing T cell response which increases the efficacy of CAR T cell therapy for treating cancer are described. Embodiments include a modified cell comprising an isolated nucleic acid comprising a first nucleic acid and a second nucleic acid, the first nucleic acid encoding a chimeric antigen receptor (CAR), the second nucleic acid encoding a therapeutic agent comprising at least one of IFN-, IL-2, IL-6, IL-7, IL-15, IL-17, and IL-23. The modified cell expresses and secretes the therapeutic agent. 119-. (canceled)20. A pharmaceutical composition comprising modified T cells , wherein the modified T cells comprise chimeric antigen receptor (CAR) and an exogenous polynucleotide encoding one or more proteins , the one or more proteins comprising IFNγ.21. The pharmaceutical composition of claim 20 , wherein the exogenous polynucleotide comprises SEQ ID NO: 469 and a polynucleotide encoding SEQ ID NO: 328.22. The pharmaceutical composition of claim 20 , wherein the modified T cells express and secrete the one or more proteins in response to activation of the modified T cells claim 20 , hypoxia claim 20 , or a combination thereof.23. The pharmaceutical composition of claim 20 , wherein the exogenous polynucleotide is present in the modified T cell in a recombinant DNA construct claim 20 , in an mRNA claim 20 , or in a viral vector.24. The pharmaceutical composition of claim 20 , wherein the one or more proteins further comprise IL-6.25. The pharmaceutical composition of claim 24 , wherein the exogenous polynucleotide comprises a polynucleotide encoding SEQ ID NOS: 287 and a polynucleotide encoding SEQ ID NO: 328.26. The pharmaceutical composition of claim 20 , wherein the exogenous polynucleotide comprises a promoter comprising a binding site for a transcription modulator that modulates the expression and/or secretion of the one or more proteins in the modified T cells.27. The pharmaceutical composition of claim 26 , wherein the transcription ...

Dual function proteins comprising fgf21 mutant protein and pharmaceutical composition comprising same

A dual function protein is disclosed. The dual function protein may be prepared by linking a biologically active protein and an FGF mutant protein to an Fc region of an immunoglobulin. The dual function protein has improved pharmacological efficacy, in vivo duration and protein stability. The dual function protein exhibits improved pharmacological efficacy, in vivo duration and protein stability. A pharmaceutical composition containing the dual function protein as an active ingredient may be effectively used as a therapeutic agent for diabetes, obesity, dyslipidemia, metabolic syndrome, non-alcoholic fatty liver diseases, non-alcoholic steatohepatitis or cardiovascular diseases.

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. 1. A modified therapeutic agent (mTA) comprising a therapeutic agent , a first half-life extending molecule , and a first staple , wherein the therapeutic agent is a modified or unmodified therapeutic peptide that is covalently attached to the first staple via two amino acid residues on the modified or unmodified therapeutic peptide; each of the two amino acid residues has an amine-containing sidechain for attachment to the first staple through the formation of an amide; the first half-life extending molecule is covalently attached to the first staple; and the half-life of the mTA is longer than the half-life of the unmodified therapeutic peptide alone.2. The mTA of claim 1 , wherein the first half-life extending molecule comprises a lipid claim 1 , a polyglycol region claim 1 , or a combination thereof.3. The mTA of claim 2 , wherein the first half-life extending molecule comprises a lipid.4. The mTA of claim 2 , wherein the first half-life extending molecule comprises a lipid and a polyglycol region.5. The mTA of claim 2 , wherein the first half-life extending molecule comprises a polyglycol region.6. The mTA of any one of - claim 2 , wherein the lipid is selected from a group consisting of sterols claim 2 , sterol derivatives claim 2 , bile acids claim 2 , vitamin E derivatives claim 2 , fatty di-acids claim 2 , fatty acids claim 2 , fatty amides claim 2 , fatty amines claim 2 , and fatty alcohols claim 2 , and derivatives thereof.7. The mTA of any one of claim 2 , claim 2 , and claim 2 , wherein the polyglycol region comprises one or more polyethylene glycol units claim 2 , polypropylene glycol units claim 2 , or polybutylene glycol units claim 2 , or a ...

PROTEIN AND PROTEIN CONJUGATE FOR DIABETES TREATMENT, AND APPLICATIONS THEREOF

The present invention relates to the field of biopharmaceuticals, and in particular to a protein, a protein conjugate, a pharmaceutical composition and its use for treating diabetes. The fusion protein of the present invention is obtained by linking two polypeptides, wherein one polypeptide is an interleukin-1 receptor antagonistic protein or an analogue thereof, and another polypeptide is GLP-1 receptor binding polypeptide or an analogue thereof, or an insulin receptor binding polypeptide or an analogue thereof, or a GIP receptor binding polypeptide or an analogue thereof. The fusion proteins of the present invention and conjugates thereof have a significant efficacy in treating diabetes, and can be used in a lower dose, resulting in marked reduction in side effects. 6. The protein of claim 5 , wherein the sequence of insulin receptor binding polypeptide or an analogue thereof is{'sub': L', 'IN107', '[1]', '[2]', 'IN110', 'IN111', 'IN112', 'IN113', 'IN114', 'IN115', 'L', '[3]', '[4]', '[6]', 'IN128', 'IN129', 'L, 'claim-ref': {'@idref': 'CLM-00002', 'claim 2'}, 'U-XHLCGSHLVEALYLVCGERGFXXXXXX-C-G IVEQCCTSICSLYQLENYCXX(SEQ ID NO:415), Uis defined as in .'}9. The protein of claim 8 , wherein Cis GAGSSSAAAPQT (SEQ ID NO:385) claim 8 , GSGSSSAAAPQT(SEQ ID NO:386) claim 8 , GSGSSSAAPQT(SEQ ID NO:387) claim 8 , GSGSSSAPQT(SEQ ID NO:388) claim 8 , or GSGSSAPQT (SEQ ID NO389).10. The protein of claim 1 , wherein the sequence of said protein is{'sub': L', 'IN107', '[1]', 'IN108', '[2]', 'IN109', 'IN110', 'IN111', 'IN112', 'IN113', 'IN114', 'IN115', 'L', '[3]', '[4]', 'IN127', '[5]', '[6]', 'IN128', 'IN129', 'j', 'IL0', 'IL66', 'IL69', 'IL84', 'IL116', 'IL122', '[1]', '[4]', '[2]', '[6]', '[3]', '[5]', 'L, 'claim-ref': {'@idref': 'CLM-00002', 'claim 2'}, 'U-XHLCGSXLVEALYLVCGEXGFNXXXXX-C-GIVEQCCXSICSLYQLENYCXX-L-XRPSGRKSSKMQAFR IWDVNQKTFYLRNNQLVAGYLQGPNVNLEEKIDVVPIEPHALFLGIHGGKMXLSXVKSGDETRLQLEAVXITDLSENRKQDKRFAFIRSDSGPTTSFESAAXPGWFL XTAMEADQPVSLTNMPDEGVMVTKFYFQEDE(SEQ ID NO: ...

ANALOGUES OF HEPCIDIN MIMETICS WITH IMPROVED IN VIVO HALF LIVES

The present invention provides hepcidin analogues with improved in vivo half-lives, and related pharmaceutical compositions and methods of use thereof. 2. The hepcidin analogue of claim 1 , comprising one of more of the following:X1 is Asp;X4 is Phe or Dpa;X7 is Ile, Leu, Val, nLeu, or Lys;X7 is Ile or Lys;X8 is Lys or Arg;Y1 is Pro or hPro;Y1 is Pro;Y2 is Arg or Lys;Y2 is Arg;Y3 is Ser;Y4 is Lys, Arg or His;Y4 is Lys; orY5 is Gly or Sar.3. The hepcidin analogue of claim 1 , wherein:X1 is Asp;X4 is Phe or Dpa;X7 is Ile, Leu, Val, nLeu, or Lys;X8 is Lys or Arg;Y1 is Pro or hPro;Y2 is Arg or Lys;Y3 is Ser;Y4 is Lys, Arg or His; andY5 is Gly or Sar.4. The hepcidin analogue of claim 3 , wherein:X7 is Ile or Lys;Y1 is Pro;Y2 is Arg; andY4 is Lys.5. The hepcidin analogue of any one of - claim 3 , comprising a structure of Formula II:{'br': None, 'sup': 1', '2, 'R—X-L-Y—R\u2003\u2003(II)'}or a pharmaceutically acceptable salt or solvate thereof, wherein:{'sup': '1', 'Ris hydrogen, a C1-C6 alkyl, a C6-C12 aryl, a C6-C12 aryl C1-C6 alkyl, or a C1-C20 alkanoyl, and including PEGylated versions alone or as spacers of any of the foregoing;'}{'sup': '2', 'sub': '2', 'Ris OH or NH;'}X is a peptide sequence having the formula Xa;L is absent, a bond, or a linker moiety; andY is absent or present;provided that if Y is present, Y is a peptide having the formula Ya.6. The hepcidin analogue of any one of - claim 3 , wherein X or Y further comprise one to three additional amino acids at the N-terminus or C-terminus.7. The hepcidin analogue of any one of - claim 3 , wherein Y is present.8. The hepcidin analogue of claim 7 , comprising a disulfide bond between X6 and Y6.9. The hepcidin analogue of or claim 7 , wherein L is a bond.10. The hepcidin analogue of any one of - claim 7 , comprising a half-life extension moiety conjugated to a Lys at X8 or X10.12. The hepcidin analogue of any one of - claim 7 , wherein Y is absent.13. The hepcidin analogue of claim 12 , wherein X10 is absent.14. ...

NEUROPEPTIDE Y-DERIVED PEPTIDES

The present invention discloses peptide fragments derived from neuropeptide Y (NPY), which are capable of selective binding to the neural cell adhesion molecule (NCAM) and inducing neuroplastic and neuroprotective effects, and the use of said peptide fragments as neuritogenic agents for treatment of pathological conditions in which neuroprotection and neuroplastic changes are desired, such as brain and retina disorders. 118.-. (canceled)19. A nucleic acid construct encoding a peptide derived from neuropeptide Y (NPY) (SEQ ID NO:22) , wherein said peptide is selected from the group consisting of:a peptide consisting of 33 contiguous amino acid residues having the sequence SKPDNPGEDAPAEDMARYYSALRHYINLITRQR (NPY3-35, SEQ ID NO: 1),a peptide consisting of 32 contiguous amino acid residues having the sequence KPDNPGEDAPAEDMARYYSALRHYINLITRQR (NPY4-35, SEQ ID NO: 2),a peptide consisting of 31 contiguous amino acid residues having the sequence PDNPGEDAPAEDMARYYSALRHYINLITRQR (NPY5-35, SEQ ID NO: 3),a peptide consisting of 30 contiguous amino acid residues having the sequence DNPGEDAPAEDMARYYSALRHYINLITRQR (NPY6-35, SEQ ID NO: 4),a peptide consisting of 29 contiguous amino acid residues having the sequence NPGEDAPAEDMARYYSALRHYINLITRQR (NPY7-35, SEQ ID NO: 5),a peptide consisting of 28 contiguous amino acid residues having the sequence PGEDAPAEDMARYYSALRHYINLITRQR (NPY8-35, SEQ ID NO: 6),a peptide consisting of 27 contiguous amino acid residues having the sequence GEDAPAEDMARYYSALRHYINLITRQR (NPY9-35, SEQ ID NO: 7),a peptide consisting of 26 contiguous amino acid residues having the sequence EDAPAEDMARYYSALRHYINLITRQR (NPY10-35, SEQ ID NO: 8),a peptide consisting of 25 contiguous amino acid residues having the sequence DAPAEDMARYYSALRHYINLITRQR (NPY11-35, SEQ ID NO: 9),a peptide consisting of 24 contiguous amino acid residues having the sequence APAEDMARYYSALRHYINLITRQR (NPY12-35, SEQ ID NO: 10),a peptide consisting of 23 contiguous amino acid residues having the sequence ...

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.

COMPOSITIONS OF ACTIVE WNT PROTEIN

Compositions of purified biologically active Wnt proteins are provided. Wnt proteins are found to be hydrophobic and post-translationally modified by addition of a lipid moiety at a conserved cysteine residue. Methods for isolation of Wnt utilize detergents that maintain the solubility of the modified protein. 112-. (canceled)13. An article of manufacture , comprising:a container;a label on the container; anda composition comprising a Wnt protein comprising a lipid moiety within the container.14. The article of manufacture of claim 13 , wherein the composition further comprises a liposome.15. The article of manufacture of claim 13 , wherein the Wnt protein is a biologically active Wnt protein.16. The article of manufacture of claim 13 , wherein the Wnt protein is a human Wnt protein.17. The article of manufacture of claim 16 , wherein the human Wnt protein is human Wnt3A protein.18. The article of manufacture of claim 13 , wherein specific activity of the Wnt protein is at least 5% of the specific activity of Wnt protein in a lysate or culture medium.19. The article of manufacture of claim 13 , wherein the Wnt protein is at a concentration of at least about 10 μg/mL.20. The article of manufacture of claim 13 , wherein the Wnt protein is formulated for intravenous claim 13 , intramuscular claim 13 , intraperitoneal claim 13 , intracerobrospinal claim 13 , subcutaneous claim 13 , intra-articular claim 13 , intrasynovial claim 13 , intrathecal claim 13 , oral claim 13 , topical claim 13 , or inhalation administration.21. The article of manufacture of claim 13 , wherein the composition further comprises isolated cells.22. The article of manufacture of claim 21 , wherein the isolated cells are stem cells.23. The article of manufacture of claim 22 , wherein the stem cells are hematopoietic stem cells.24. The article of manufacture of claim 13 , wherein the container is glass.25. The article of manufacture of claim 13 , wherein the container is plastic.26. The article of ...

IMMUNOMODULATORY POLYNUCLEOTIDES AND USES THEREOF

Provided are immunomodulatory polynucleotides with sequences of SEQ ID NOs:1-12 which are TLR9 agonists. Therapeutic combinations comprising the immunomodulatory polynucleotides are provided too. 1. An immunomodulatory polynucleotide , comprising a sequence selected from the group consisting of: SEQ ID NO.: 1 , SEQ ID NO.: 2 , SEQ ID NO.: 3 , SEQ ID NO.: 4 , SEQ ID NO.: 5 , SEQ ID NO.: 6 , SEQ ID NO.: 7 , SEQ ID NO.: 8 , SEQ ID NO.: 9 , SEQ ID NO.: 10 , SEQ ID NO.: 11 , and SEQ ID NO.: 12.2. The immunomodulatory polynucleotide of claim 1 , wherein said polynucleotide comprises a chemical modification.3. The immunomodulatory polynucleotide of claim 1 , wherein said polynucleotide comprises a modification of one or more phosphate groups.4. The immunomodulatory polynucleotide of claim 3 , wherein said modification of one or more phosphate groups is a phosphorothioate linkage.5. The immunomodulatory polynucleotide of claim 3 , wherein phosphate backbone of said polynucleotide is completely phosphorothioate-modified.6. The immunomodulatory polynucleotide of claim 2 , wherein the modification of one or more phosphate group is a linkage.7. A method of modulating an immune response in a subject claim 1 , comprising: administering to a subject an immunomodulatory polynucleotide according to claim 1 , in an amount sufficient to modulate an immune response in said individual.8. A method of increasing interferon-gamma (IFN-α) in a subject claim 1 , comprising: administering an immunomodulatory polynucleotide according to to a subject in an amount sufficient to increase IFN-α in said subject.9. A method of increasing interferon-gamma (IFN-γ) in a subject claim 1 , comprising: administering an immunomodulatory polynucleotide according to to a subject in an amount sufficient to increase IFN-γ in said subject.10. A method of ameliorating a symptom of an infectious disease in a subject claim 1 , comprising: administering an effective amount of an immunomodulatory polynucleotide ...

LONG-ACTING ADRENOMEDULLIN DERIVATIVE

The invention provides a novel adrenomedullin derivative sustainable for a long period which is capable of substantially suppressing unwanted side effects while maintaining pharmacological effects of adrenomedullin. In an exemplary embodiment, the invention relates to a compound represented by formula (I): A-CH-B (I) [wherein A is a modifying group comprising one or more polyethylene glycol groups, and B is a peptide moiety derived from adrenomedullin or a modified form thereof with adrenomedullin activity, wherein the peptide moiety B is linked to the other moieties through a covalent bond of the nitrogen atom of the N-terminal α-amino group of the peptide moiety B to the carbon atom of the methylene group] or a salt thereof, or a hydrate thereof. 4. The compound according to claim 1 , wherein the polyethylene glycol group represented by formula (III) has a weight-average molecular weight ranging from 1 to 100 kDa in total.5. The compound according to claim 1 , wherein the adrenomedullin or the modified form thereof with adrenomedullin activity is a peptide selected from the group consisting of:(i) a peptide consisting of an amino acid sequence of adrenomedullin,(ii) a peptide that consists of an amino acid sequence of adrenomedullin and has a disulfide bond formed by two cysteine residues in the amino acid sequence,(iii) the peptide of (ii) wherein the disulfide bond of the peptide is substituted with an ethylene group and the peptide has adrenomedullin activity,(iv) any peptide of (i) to (iii) wherein the peptide has the amino acid sequence comprising deletion, substitution, or addition of one to fifteen amino acid residues and has adrenomedullin activity,(v) any peptide of (i) to (iv) wherein the peptide is amidated at the C-terminus thereof, and(vi) any peptide of (i) to (iv) wherein the peptide has a glycine residue added to the C-terminus thereof.6. The compound according to claim 5 , wherein the adrenomedullin or the modified form thereof is a peptide ...

PROTEIN TYROSINE-TYROSINE ANALOGS AND METHODS OF USING THE SAME

PYY analogs are disclosed that include modifications that increase half-life when compared to native, human PYY, as well as additional modifications that increase potency and selectivity to the NPY2 receptor. Pharmaceutical compositions also are disclosed that include one or more of the PYY analogs described herein in a pharmaceutically acceptable carrier. Methods of making and using the PYY analogs also are disclosed, especially for treating obesity and obesity-related diseases and disorders such as type II diabetes mellitus. 128-. (canceled)30. The method of claim 29 , wherein the PYY analog or pharmaceutically acceptable salt thereof is subcutaneously (SQ) administered to the individual.31. The method of claim 29 , where the PYY analog or pharmaceutically acceptable salt thereof is orally administered to the individual.32. The method of claim 29 , wherein the PYY analog or pharmaceutically acceptable salt thereof is administered daily claim 29 , every other day claim 29 , three times a week claim 29 , two times a week claim 29 , one time a week claim 29 , or biweekly.33. The method of claim 29 , wherein the PYY analog or pharmaceutically acceptable salt thereof is administered SQ one time a week (QW).34. The method of claim 29 , wherein the PYY analog or pharmaceutically acceptable salt thereof is administered orally one time a week.35. The method of further comprising administering an additional therapeutic agent.36. The method of claim 35 , wherein the additional therapeutic agent is an incretin selected from the group consisting of glucagon (GCG) claim 35 , a GCG analog claim 35 , glucagon-like peptide-1 (GLP-1) claim 35 , GLP-1 claim 35 , a GLP-1 analog claim 35 , gastric inhibitory peptide (GIP) claim 35 , a GIP analog claim 35 , oxyntomodulin (OXM) claim 35 , an OXM analog claim 35 , a GIP/GLP-1 claim 35 , a GLP-1/GCG claim 35 , or an incretin analog having triple receptor activity.37. The method of claim 35 , wherein the additional therapeutic agent is a ...

Fusion Protein Comprising Leptin and Methods for Producing and Using the Same

The present invention provides fusion proteins comprising leptin and a second protein. The presence of the second protein provides increased biological activity and/or increased half-life in vivo. The present invention also provides human, canine and feline leptin molecules fused to peptides, antibodies or antibody fragments which enhances the abilities of the leptin molecules to transport through the blood-brain-barrier (BBB). The present invention also provides fusion proteins further comprising a peptide agonist that is capable of binding to and stimulate one, two or all three of the following receptors: GLP-1 receptor, Glucagon receptor, and GIP receptor. Also disclosed is a method of production such fusion proteins through recombinant technologies. The invention further discloses a pharmaceutical composition comprising one of the fusion proteins as an active intergradient as well as a method for using such a pharmaceutical composition to treat diseases in dogs, cats and humans. 1. A fusion protein comprising a first protein that is linked to a second protein , wherein said first protein comprises:(a) a canine immunoglobulin Fc (“Ig Fc”) region;(b) a canine albumin having amino acid sequence of at least 75% sequence identity to SEQ ID NO:25;(c) a feline Ig Fc region; or(d) a feline albumin having amino acid sequence of at least 75% sequence identity to SEQ ID NO:26; andwhen said first protein is said canine Ig Fc region or said canine albumin, then said second protein is a canine leptin protein having at least 87% amino acid sequence identity with a canine leptin of SEQ ID NO:4 or SEQ ID NO:5; andwhen said first protein is said feline Ig Fc region or said feline albumin, then said second protein is a feline leptin having amino acid sequence of at least 87% sequence identity to SEQ ID NO:6 or SEQ ID NO:7.2. The fusion protein of claim 1 , wherein said first protein is linked to said second protein through a protein linker.3. The fusion protein of claim 1 , ...

THERAPEUTIC TARGETING OF SET1B/COMPASS PATHWAY FOR TREATING CANCERS

Disclosed are methods for treating Set1/COMPASS-associated cancers characterized by expression of Set1B/COMPASS. The methods typically include administering a therapeutic amount of an inhibitor of the Set1B/COMPASS pathway and/or an agonist for a target that is negatively regulated by the Set1B/COMPASS pathway. 1. A method for treating a cancer characterized by expression of Set1B/COMPASS in a subject in need thereof , the method comprising administering to the subject a therapeutic amount of an inhibitor of Set1B/COMPASS and/or administering an agonist of a target that is negatively regulated by Set1B/COMPASS.2. The method of claim 1 , wherein the cancer is breast cancer.3. The method of claim 1 , wherein the cancer is ER-negative breast cancer.4. The method of claim 1 , wherein the cancer is HERB2-negative breast cancer.5. The method of claim 1 , wherein the cancer is PR-negative breast cancer.6. The method of claim 1 , wherein the cancer is triple negative breast cancer (TNBC).7. The method of comprising administering to the subject an agonist of the of adiponectin receptor 1.9. The method of comprising administering to the subject a therapeutic agents selected from the group consisting of a peptide mimetic of adiponectin claim 1 , matairesinol claim 1 , arctiin claim 1 , (−)-arctigenin claim 1 , gramine claim 1 , and 6-C-beta-D-glcypyranosyl-(2S claim 1 ,3S)-(+)-5 claim 1 ,7 claim 1 ,3′ claim 1 ,4′-tetrahydroxydihydroflavonol (GTDF).10. The method of comprising administering to the subject RNA interference (RNAi) therapy and inhibiting expression of Set1B/COMPASS.11. A method comprising identifying a cancer subject that has one or more mutations in a gene of the Set1/COMPASS pathway and/or identifying a cancer subject that is overexpressing Set1/COMPASS claim 1 , and administering to the subject a therapeutic amount of an inhibitor of Set1B/COMPASS and/or administering an agonist of a target that is negatively regulated by Set1B/COMPASS.12. The method of claim ...

MULTIFUNCTIONAL MOLECULES AND USES THEREOF

Multispecific molecules that include a first tumor-targeting moiety; a second tumor-targeting moiety; and one, two or all of: an immune cell engager (e.g., chosen from an NK cell engager, a T cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager); a cytokine molecule or a modulator of a cytokine molecule; and/or a stromal modifying moiety are disclosed. Additionally disclosed are nucleic acids encoding the same, methods of producing the aforesaid molecules, and methods of treating a cancer using the aforesaid molecules. 1. A multifunctional molecule , comprising:(i) a first tumor-targeting moiety that binds to a first tumor antigen;(ii) a second tumor-targeting moiety that binds to a second tumor antigen; andone, two, or all of:(iii) an immune cell engager chosen from a T cell engager, an NK cell engager, a B cell engager, a dendritic cell engager, or a macrophage cell engager;(iv) a cytokine molecule or a modulator of a cytokine molecule; and(v) a stromal modifying moiety, wherein:the first and second tumor antigens are each independently chosen from: CD34, CD41, G6B, P-selectin, Clec2, cKIT, FLT3, MPL, ITGB3, ITGB2, GP5, GP6, GP9, GP1BA, DSC2, FCGR2A, TNFRSF10A, TNFRSF10B, or TM4SF1, optionally wherein:the first tumor antigen is different from the second tumor antigen.2. The multifunctional molecule of claim 1 , further comprising:(vi) a third tumor-targeting moiety that binds to a third tumor antigen.3. The multifunctional molecule of claim 2 , wherein:the third tumor antigen is chosen from: CD34, CD41, G6B, P-selectin, Clec2, cKIT, FLT3, MPL, ITGB3, ITGB2, GP5, GP6, GP9, GP1BA, DSC2, FCGR2A, TNFRSF10A, TNFRSF10B, or TM4SF1, optionally wherein:the third tumor antigen is different from the first or second tumor antigen.4. The multifunctional molecule of any one of - claim 2 , wherein:the first and second tumor antigens are present on the same tumor cell,the first and third tumor antigens are present on the same tumor cell,the ...

NUCLEIC ACIDS ENCODING REPETITIVE AMINO ACID SEQUENCES RICH IN PROLINE AND ALANINE RESIDUES THAT HAVE LOW REPETITIVE NUCLEOTIDE SEQUENCES

The present invention relates to a nucleic acid molecule comprising a low repetitive nucleotide sequence encoding a proline/alanine-rich amino acid repeat sequence. The encoded polypeptide comprises a repetitive amino acid sequence that forms a random coil. The nucleic acid molecule comprising said low repetitive nucleotide sequences can further comprise a nucleotide sequence encoding a biologically or pharmacologically active protein. Further, the present invention provides for selection means and methods to identify said nucleic acid molecule comprising said low repetitive nucleotide sequence. The present invention also relates to a method for preparing said nucleic acid molecules. Also provided herein are methods for preparing the encoded polypeptide or drug conjugates with the encoded polypeptide using the herein provided nucleic acid molecules. The drug conjugate may comprise a biologically or pharmacologically active protein or a small molecule drug. Also provided herein are vectors and hosts comprising such nucleic acid molecules. 2. The nucleic acid molecule of claim 1 , wherein said encoded polypeptide consists of proline and alanine.3. The nucleic acid molecule of claim 2 , wherein said proline residues constitute more than about 10% and less than about 75% of said encoded polypeptide.4. The nucleic acid molecule of claim 1 , wherein said encoded polypeptide consists of proline claim 1 , alanine and serine.5. The nucleic acid molecule of claim 4 , wherein said proline residues constitute more than 4% and less than 40% of said encoded polypeptide.6. The nucleic acid molecule of any one of to claim 4 , wherein said Nucleotide Repeat Score (NRS) is lower than 100.7. The nucleic acid molecule of any one of to claim 4 , wherein said Nucleotide Repeat Score (NRS) is lower than 50.8. The nucleic acid molecule of any one of to claim 4 , wherein said Nucleotide Repeat Score (NRS) is lower than 35.9. The nucleic acid molecule of any one of to claim 4 , wherein the ...

FUSOKINES INVOLVING CYTOKINES WITH STRONGLY REDUCED RECEPTOR BINDING AFFINITIES

The present invention relates to a fusion protein comprising at least two cytokines, of which at least one is a modified cytokine with a strongly reduced binding affinity to its receptor, or to one of its receptors. Preferably, both cytokines are connected by a linker, preferably a GGS linker. The invention relates further to said fusion protein for use in treatment of diseases. 18.-. (canceled)9. A composition comprising a fusion protein comprising at least two cytokines ,wherein the cytokines are human chemokine (C motif) ligand (XCL1) and human interferon alpha 2 (IFNα2), andwherein at least one cytokine comprises a mutation that reduces binding activity to its receptor as compared to wild type cytokine and at least one cytokine is a wild-type cytokine which provides cell-specific targeting that restores activity of the mutant cytokine on the targeted cells.10. The composition of claim 9 , further comprising a linker.11. The composition of claim 10 , wherein the linker is one or more GSS repeats.12. The composition of claim 9 , wherein the human IFNα2 comprises the mutation.13. The composition of claim 12 , wherein the wild-type cytokine is the human XCL1.14. A method of stimulating an immune response in a cell claim 12 , comprising contacting the cell with a composition comprising a composition comprising at least two cytokines claim 12 ,wherein the cytokines are human XCL1 and human IFNα2, andwherein at least one of the cytokines has a mutation which provides reduced affinity for its receptor as compared to wild type cytokine and at least one cytokine is a wild-type cytokine that provides cell-specific targeting that restores activity of the mutant cytokine on the targeted cells.15. The method of claim 14 , wherein the composition further comprises a linker.16. The method of claim 15 , wherein the linker is one or more GSS repeats.17. The method of claim 14 , wherein the human IFNα2 comprises the mutation.18. The method of claim 17 , wherein the wild-type ...

Polypeptide for Inhibition of Tumor

The present invention provides peptides for inhibiting tumor, which are fragments of the N terminus of endostatin, having 45 or less amino acid residues, and which at least contain amino acid residues 1-20 of the N terminus, wherein amino acid residues at positions 2 to 18 of the N terminus of endostatin are shown in the disclosure, and the peptides optionally contain mutations at positions 17 and 20-22 as disclosed in the disclosure. The present invention also relates to the coding sequences of the peptides, expression vectors containing the coding sequence, pharmaceutical compositions comprising the peptide, and use of the peptide and pharmaceutical composition in the inhibition, prevention or treatment of tumor. 2. The polypeptide of , wherein the polypeptide contains at least amino acid residues 1-22 of SEQ ID NO: 38 , and the amino acid residues at positions 2 and 18 are defined as in .3. The polypeptide of claim 1 , wherein:{'claim-ref': {'@idref': 'CLM-00001', 'claim 1'}, 'the polypeptide contains at least amino acid residues 1-22 of SEQ ID NO: 38, or at least amino acid residues 1-25 of SEQ ID NO: 38, and the amino acid residue at position 2 is T, the amino acid residue at position 18 is N, G, K, M, F, S or T, and the amino acid residues at positions 17, 20, 21 and 22 are defined as in ; or'}{'claim-ref': {'@idref': 'CLM-00001', 'claim 1'}, 'the polypeptide contains at least amino acid residues 1-22 of SEQ ID NO: 38, or at least amino acid residues 1-25 of SEQ ID NO: 38, and the amino acid residue at position 18 is N, the amino acid residue at position 2 is T, and the amino acid residues at positions 17, 20, 21 and 22 are defined as in ; or'}{'claim-ref': {'@idref': 'CLM-00001', 'claim 1'}, 'the polypeptide contains at least amino acid residues 1-22 of SEQ ID NO: 38, or at least amino acid residues 1-25 of SEQ ID NO: 38, and the amino acid residue at position 18 is S, the amino acid residue at position 2 is E, H, L, T, W or V, and the amino acid residues at ...

APELIN PEPTIDES AND USES THEREOF

The disclosure relates to modified apelin polypeptides having increased stability against kallikrein, NEP and ACE2 degradation and/or potency relative to the native apelin-13 and apelin-17 polypeptides. Embodiments also disclose methods of using the polypeptides for treating cardiovascular disorders. 1. A peptidomimetic of Formula (I):Z1-pGlu-aa2-aa3-aa4-aa5-aa6-aa7-aa8-aa9-aa10-aa11-aa12-aa13; or pharmaceutically acceptable salts thereof,wherein Z1 is H or a long chain moiety;wherein each of aa2, aa3, aa4, aa5, aa6, aa7, aa8, aa9, aa10, aa11, aa12, and aa13 is independently an amino acid, aa2 comprises Arg or a conservative variant thereof;', 'aa3 comprises Pro or a conservative variant thereof;', 'aa4 comprises an amino acid or a conservative variant thereof selected from the group consisting of Arg, Arg-D, αMeArg and azaArg;', 'aa5 comprises an amino acid or a conservative variant thereof selected from the group consisting of Leu, NMeLeu, αMeLeu and azaLeu;', 'aa6 comprises Ser or a conservative variant thereof;', 'aa7 comprises His or a conservative variant thereof;', 'aa8 comprises Lys or a conservative variant thereof;', 'aa9 comprises Gly or a conservative variant thereof;', 'aa10 comprises Pro or a conservative variant thereof;', 'aa11 is comprises Nle or a conservative variant thereof, wherein Nle is norleucine;', 'aa12 is comprises Aib or a conservative variant thereof, wherein Aib is α-aminoisobutryic acid; and', 'aa13 is comprises paraBrPhe or a conservative variant thereof., 'wherein2. The peptidomimetic of claim 1 , wherein aa2-aa3-aa4-aa5-aa6-aa7-aa8-aa9-aa10-aa11-aa12-aa13 is Arg-Pro-Arg-D-Leu-Ser-His-Lys-Gly-Pro-Nle-Aib-paraBrPhe.3. The peptidomimetic of claim 1 , wherein aa2-aa3-aa4-aa5-aa6-aa7-aa8-aa9-aa10-aa11-aa12-aa13 is Arg-Pro-Arg-NMeLeu-Ser-His-Lys-Gly-Pro-Nle-Aib-paraBrPhe.4. The peptidomimetic of claim 1 , wherein aa2-aa3-aa4-aa5-aa6-aa7-aa8-aa9-aa10-aa11-aa12-aa13 is Arg-Pro-αMeArg-Leu-Ser-His-Lys-Gly-Pro-Nle-Aib-paraBrPhe.5. The ...

PEPTIDE ANALOGS

Analogs for CLR/RAMP receptor ligands are provided that have agonist, superagonist, antagonist or superantagonist activity. The analogs can be selective for one or more CLR/RAMP receptors, or can be pan-specific. 1. A CLR/RAMP receptor agonist peptide , comprising a structure of Formula I:{'br': None, 'sup': a', 'a', 'a, 'B—C-D\u2003\u2003(I)'}wherein:{'sup': 'a', 'Bis a modified N-terminal fragment of adrenomedullin peptide family member comprising from twenty to twenty eight amino acid residues, wherein two amino acid residues of the fragment are cysteine (Cys), wherein the C-terminal residue of the fragment is threonine (Thr);'}{'sup': 'a', 'Cis a central core consist of 3-12 amino acids; and'}{'sup': 'a', 'Dis a modified C-terminal fragment of intermedin (IMD) comprising from 3-6 amino acid residues with a C-terminal amide, where at least one amino acid of the C-terminal fragment is histidine (His), proline (P), serine (Ser), tyrosine (Tyr).'}2. The agonist of claim 1 , wherein Cis a core of 3-12 residues.3. The agonist of or wherein the N-terminal fragment Bcomprises: B—B—B—B—B—B-G-B—C—B—B—B—B—B—B—B—B—B—B—B—B—B(SEQ ID NO: 1) where: Bis absent or present claim 1 , or an amino string of KTKKTLRT; Bis selected from the group consisting of an empty residue claim 1 , histidine (His) claim 1 , acylated histidine (acy-His) claim 1 , double acylated histidine (acy-His(acy)) claim 1 , ace-histidine(acy) (ace-His(acy)) claim 1 , mini-PEG-acylated-histidine (mini-PEG-His(acy)) claim 1 , arginine (Arg) claim 1 , acylated arginine (acy-Arg) claim 1 , double acylated arginine (acy-Arg(acy)) claim 1 , ace-arginine(acy) (ace-Arg(acy)) claim 1 , mini-PEG-acylated-arginine (mini-PEG-Arg(acy)) claim 1 , lysine (Lys) claim 1 , acylated lysine (acy-Lys) claim 1 , double acylated lysine (acy-Lys(acy)) claim 1 , ace-lysine(acy) (ace-Lys(acy)) claim 1 , and mini-PEG-acylated-lysine (mini-PEG-Lys(acy)); Bis selected from the group consisting of glycine (Gly) and an empty residue; Bis ...

Chimera of Bone Morphogenic Protein 2 and the Mullerian-Inhibiting Substance Type II Receptor Binding Region of Mullerian-Inhibiting Substance

Recombinant proteins that comprise a bone morphogenic protein 2 backbone onto which was grafted a Müllerian-inhibiting substance type II receptor binding region of the Müllerian-inhibiting substance protein are provided. These proteins bind to this receptor on the surface of epithelial cancer cells, and induce apoptosis of such cells. These proteins are useful, for example, in the treatment of cancers such as ovarian, uterine, endometrial, fallopian tube, breast, prostate, and lung cancers. 1. A protein comprising a chimera of bone morphogenic protein 2 (BMP2) and the Müllerian-inhibiting substance type II receptor (MISIIR)-binding region of the Müllerian-inhibiting substance (MIS) protein comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 3 , SEQ ID NO: 4 , SEQ ID NO: 5 , and SEQ ID NO: 6.25-. (canceled)6. The protein of claim 1 , wherein the chimera comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 7 claim 1 , SEQ ID NO:8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, and SEQ ID NO: 17.723-. (canceled)24. A method for inducing apoptosis in a cell claim 1 , comprising contacting the cell with the protein of in an amount effective to stimulate the Müllerian-inhibiting substance type II receptor (MISIIR) claim 1 , thereby inducing apoptosis in the cell.25. The method of claim 24 , wherein the cell is a cancer cell claim 24 , optionally selected from the group consisting of an ovarian cancer cell claim 24 , a breast cancer cell claim 24 , a uterine cancer cell claim 24 , an endometrial cancer cell claim 24 , a fallopian tube cancer cell claim 24 , a mixed Müllerian tumor cell claim 24 , a prostate cancer cell claim 24 , and a lung cancer cell.26. (canceled)27. The method of claim 24 , wherein the protein is comprised in a composition comprising the protein and a carrier.28. (canceled)29. A method for inducing apoptosis in a tumor ...

LONG ACTING PROTEINS AND PEPTIDES AND METHODS OF MAKING AND USING THE SAME

Disclosed is a method for refolding a protein or peptide that does not contain essential disulfides and that contains at least one free cysteine residue. Also disclosed are polymer IFN-γ conjugates that have been created by the chemical coupling of polymers such as polyethylene glycol moieties to IFN-γ, particularly via a free cysteine in the protein. Also disclosed are analogs of bioactive peptides that may be used to create longer acting versions of the peptides, including analogs of glucagon, glucagon-like peptide-1 (GLP-1), GLP-2, Gastric inhibitory peptide (GIP), PYY, exendin, ghrelin, gastrin, amylin, and oxyntomodulin. 1125.-. (canceled)126. A method for refolding an insoluble or aggregated protein or peptide that lacks essential disulfides and that comprises one free cysteine residue , comprising the following steps:a) denaturing and reducing the protein or peptide in a solution comprising both a denaturing agent and a reducing agent, wherein said reducing agent does not form a mixed disulfide with the free cysteine in the protein or peptide, and wherein said reducing agent does not inactivate a thiol-reactive polyethylene glycol (PEG) or does not interfere with modification of the protein by a thiol-reactive PEG reagent;b) refolding the protein by reducing the concentrations of the denaturing agent and reducing agents in the solution of (a) to levels sufficient to allow the protein or peptide to renature into a soluble, biologically active form;c) wherein steps (a) and (b) occur in the absence of a cysteine blocking agent.127. The method of claim 126 , wherein said denaturing agent is selected from the group consisting of: urea claim 126 , guanidine and N-lauroyl sarcosine.128. The method of claim 126 , wherein the reducing agent in step (a) is a reducing agent that does not contain a thiol moiety.129. The method of claim 126 , wherein the reducing agent in step (a) is a phosphine reductant.130. The method of claim 126 , wherein the reducing agent in step ( ...

Novel Fatty Acid Modified Urocortin-2 Analogs for the Treatment of Diabetes and Chronic Kidney Disease

The present invention provides a compound or a pharmaceutically acceptable salt of the Formula: 1. A compound of the Formula:{'br': None, 'sub': 1', '2', '3', '4', '2, 'XIVXSLDVPIGLLQILXEQEKQEKEKQQAK*TNAXILAQV-NH'}{'sub': '1', 'wherein Xdenotes that the I residue is modified by either acetylation or methylation at the N-terminus;'}{'sub': '2', 'wherein Xis L or T;'}{'sub': '3', 'wherein Xis L or I;'}{'sub': '4', 'wherein Xis Q or E; and'}{'sub': 5', '6, 'wherein a modified K residue (“K*”) at position 29 is modified through conjugation to the epsilon-amino group of the K-side chain with a group of the formula —X—X, wherein'}{'sub': '5', 'claim-text': one to four more amino acids;', 'one to four ([2-(2-Amino-ethoxy)-ethoxy]-acetyl) moieties; and', 'combinations of one to four amino acids and one to four ([2-(2-Amino-ethoxy)-ethoxy]-acetyl) moieties;, 'Xis selected from the group consisting of{'sub': 6', '14', '24, 'Xis a C-Cfatty acid (SEQ ID NO:16);'}or a pharmaceutically acceptable salt thereof.2. The compound or salt of claim 1 , wherein Xis selected from the group consisting of:one to four E or γE amino acids;one to four ([2-(2-Amino-ethoxy)-ethoxy]-acetyl) moieties; andcombinations of one to four E or γE amino acids and one to four ([2-(2-Amino-ethoxy)-ethoxy]-acetyl) moieties.3. The compound or salt of claim 2 , wherein Xis a combination of one to four E or γE amino acids and one to four ([2-(2-Amino-ethoxy)-ethoxy]-acetyl) moieties.4. The compound or salt of claim 3 , wherein Xis a combination of two to four γE amino acids and one to four ([2-(2-Amino-ethoxy)-ethoxy]-acetyl) moieties.5. The compound or salt of claim 3 , wherein Xis a combination of two γE amino acids and two ([2-(2-Amino-ethoxy)-ethoxy]-acetyl) moieties.6. The compound or salt of claim 1 , wherein Xis a straight chain fatty acid of the formula CO—(CH)—COH claim 1 , wherein x is 16 claim 1 , 18 claim 1 , or 20.7. The compound or salt of claim 1 , wherein group of the formula{'sub': 5', '6', '2 ...

Method for immunotherapy drug treatment

The present invention provides a method that at least promotes, drives or directs a non-responsive neoplastic microenvironment towards a responsive phenotype. More particularly, the invention provides a method for enhancing the sensitivity of one or more neoplastic tumour to check point blockade agents. The present invention also provides a method for predicting response to immune checkpoint blockade.

ANGIOPOIETIN-LIKE PROTEIN 8 POLYPEPTIDE FRAGMENTS AND COMPOSITIONS THEREOF

Methods and compositions for reducing one or more of triglyceride levels, total cholesterol levels and LDL cholesterol levels in a subject are provided. The methods include administering a fragment of ANGPTL8 to a subject having or at risk of developing elevated triglyceride levels, elevated total cholesterol levels and/or elevated LDL cholesterol levels. 141.-. (canceled)42. A polypeptide comprising a fragment of full-length ANGPTL8 (SEQ ID NO:1) , wherein the polypeptide comprises the two coiled coil domains of full-length ANGPTL8 and wherein the polypeptide lacks the amino acids 21-70 of full-length ANGPTL8 , wherein the polypeptide can decrease triglyceride levels in a human subject.43. The polypeptide of claim 42 , wherein the polypeptide comprises a contiguous amino acid sequence having at least 95% sequence identity to amino acids 80-198 of full-length ANGPTL8.44. The polypeptide of claim 42 , wherein the polypeptide consists of amino acids 80-198 of SEQ ID NO:1.45. The polypeptide of claim 42 , wherein the polypeptide lacks the amino acids 21-80 of full-length ANGPTL8.46. The polypeptide of claim 42 , wherein a heterologous polypeptide is conjugated to the N-terminus or C-terminus of the polypeptide.47. The polypeptide of claim 46 , wherein the heterologous polypeptide is albumin claim 46 , human serum albumin claim 46 , or an immunoglobulin Fc.48. The polypeptide of claim 46 , wherein the heterologous polypeptide is conjugated to the polypeptide via a linker sequence.49. The polypeptide of claim 48 , wherein the linker sequence is a cleavable linker sequence or a non-cleavable linker sequence.50. A pharmaceutical composition comprising the polypeptide of and a pharmaceutically acceptable carrier.51. A polynucleotide that encodes the polypeptide of .52. A method of reducing triglyceride levels in a human subject having or at risk of developing elevated triglyceride levels claim 42 , the method comprising administering to the human subject the polypeptide of ...

MOLECULAR AND CELLULAR IMAGING USING ENGINEERED HEMODYNAMIC RESPONSES

According to some aspects, the invention relates to methods and compositions for evaluation of hemodynamic responses (e.g., using molecular imaging) with high sensitivity. 1. A method for evaluating a tissue in a subject , the method comprising:producing a hemodynamic response in a tissue of a subject by providing an effective amount of a vasoactive agent to the tissue;obtaining an image representation of the tissue; andevaluating the tissue based on a hemodynamic response detected in the image representation.2. The method of claim 1 , wherein the hemodynamic response is produced by providing to the tissue an exogenous vasoactive agent in a submicromolar concentration that is effective for inducing a hemodynamic response in the tissue3. The method of claim 1 , wherein the vasoactive agent is provided to the tissue by administering the vasoactive agent to the subject.421-. (canceled)22. The method of claim 1 , wherein the hemodynamic response comprises a change in blood volume in the tissue.23. The method of claim 1 , wherein the hemodynamic response comprises an increase in blood flow in the tissue.24. The method of claim 1 , wherein the hemodynamic response comprises a decrease in blood flow in the tissue.25. The method of claim 1 , wherein the hemodynamic response comprises changes in oxy/deoxyhemoglobin balance in the tissue.26. The method of claim 1 , wherein the tissue is neuronal tissue and wherein the hemodynamic response is associated with changes in neural activity.27. The method of further comprising determining that the hemodynamic response is associated with excitatory neural activity in the tissue.28. The method of further comprising determining that the hemodynamic response is associated with inhibitory activity in the tissue.29. The method of claim 1 , wherein the vasoactive agent is a molecule having the formula X-L-X-L-X claim 1 , in which Xis a blocking domain and/or ligand binding domain claim 1 , Land Lare independently linkers or absent claim 1 ...

METHODS OF PRODUCING AND PURIFYING MATRIX-BINDING FUSION PROTEINS BY ION-EXCHANGE CHROMATOGRAPHY

The invention provides methods of producing and purifying fusion proteins containing a domain capable of binding one or more extracellular matrix components, such as heparin and chondroitin sulfate, by cation-exchange chromatography. 1. A method of purifying a fusion protein comprising a matrix-binding domain , said method comprising contacting a mixture of polypeptides comprising the fusion protein with a substance comprising one or more negatively-charged agents so that the matrix-binding domain of the fusion protein specifically binds said one or more negatively-charged agents from said mixture , thereby producing a mixture that is enriched with said fusion protein.2. The method of claim 1 , wherein said substance comprising one or more negatively-charged agents is contained within a column claim 1 , optionally wherein said column is in fluid connection with one or more pumps.3. (canceled)4. The method of claim 1 , wherein said matrix-binding domain is capable of specifically binding a glycosaminoglycan selected from the group consisting of heparin claim 1 , heparan sulfate claim 1 , chondroitin sulfate claim 1 , dermatan sulfate claim 1 , and hyaluronic acid.5. The method of claim 1 , wherein said matrix-binding domain has at least 85% sequence identity to claim 1 , or the amino acid sequence of claim 1 , any one of SEQ ID NOs: 1-27.6. The method of claim 1 , wherein said fusion protein comprises a therapeutic polypeptide claim 1 , optionally wherein said therapeutic polypeptide:(a) is selected from the group consisting of growth and differentiation factor 11 (GDF11), stromal cell-derived factor 1 (SDF-1), growth and differentiation factor 8 (GDF8), insulin-like growth factor 1 (IGF-1), parathyroid hormone (PTH), parathyroid hormone related peptide (PTHrP), interleukin 1 receptor antagonist (IL-1RA), fibroblast growth factor 9 (FGF-9), fibroblast growth factor 18 (FGF-18), high-mobility group protein 2 (HMG-2), hepatocyte growth factor, transforming growth ...

Tissue protective peptides and uses thereof

The present invention is directed to novel tissue protective peptides. The tissue protective peptides of the invention may bind to a tissue protective receptor complex. In particular, the present invention is drawn to tissue protective peptides derived from or sharing consensus sequences with portions of cytokine receptor ligands, including Erythropoietin (EPO), that are not involved in the binding of the ligand to the receptor complex, e.g., to the EPO receptor homodimer. Accordingly, the tissue protective peptides of the invention are derived from the amino acid sequences of regions of cytokine receptor ligands that are generally located on or within the region of the ligand protein that is opposite of the receptor complex, i.e., are generally derived from amino acid sequences of regions of the ligand protein that face away from the receptor complex while the ligand is bound to the receptor. The invention is further directed to the consensus sequences for use in engineering a synthetic tissue protective peptide. These tissue protective peptides also include fragments, chimeras, as well as peptides designed to mimic the spatial localization of key amino acid residues within the tissue protective receptor ligands, e.g., EPO. The invention further encompasses methods for treating or preventing a disease or disorder using tissue protective peptides of the current invention. The invention also encompasses methods for enhancing excitable tissue function using tissue protective peptides of the current invention.

ENDOTHELIN-1 RECEPTOR BASED ENDOTHELIN-1 SPONGE

Fusion polypeptides capable of binding endothelin-1 to form a non-functional complex are provided, including amino acid sequences of the fusion polypeptides. The fusion polypeptides will be linked to the Fe portion of human IgG I to form dimers that will function as endothelin-1 antagonists (endothelin-1 sponge). 1. A fusion polypeptide comprising the amino acid sequence of the endothelin A receptor ligand binding domains of SEQ ID NO: 1 or the amino acid sequence of the endothelin A receptor ligand binding domains of SEQ ID NO: 2.2. The fusion polypeptide of claim 1 , fused to the Fc portion of human IgG1.3. The fusion polypeptide of claim 1 , in the form of a monomer.4. The fusion polypeptide of in the form of a multimer.5. The multimer of claim 4 , which is a dimer.6. A composition comprising a fusion polypeptide of .7. A method of treating an endothelin-1 related disease or disorder claim 1 , said method comprising administering a fusion polypeptide of to an individual in need thereof.8. The method of claim 7 , wherein the disease or disorder is preeclampsia.9. The method of claim 7 , wherein the disease or disorder is diabetes.10. The method of claim 7 , wherein the disease or disorder is a cardiovascular disease.11. The method of claim 7 , wherein the disease or disorder is neurodegenerative disorder.12. The method of claim 7 , wherein the fusion polypeptide is in the form of a multimer.13. The method of claim 7 , wherein the fusion polypeptide is in the form of a monomer.14. A recombinant nucleic acid molecule encoding a fusion polypeptide of .15. A vector comprising the nucleic acid molecule of .16. An expression vector comprising the nucleic acid molecule of claim 14 , operatively linked to an expression control sequence. The present application is a continuation-in-part of international application no. PCT/IB2016/050337, filed Jan. 22, 2016, insofar as it designates the United States. The entire contents of this international application are hereby ...

HEPCIDIN AND MINI-HEPCIDIN ANALOGUES AND USES THEROF

The present invention provides novel hepcidin analogues, and related methods of using these hepcidin analogues to treat or prevent a variety of diseases and disorders, including iron overload diseases such as hereditary hemochromatosis, iron-loading anemias, and other conditions and disorders described herein. 3. The hepcidin analogue of claim 1 , wherein the hepcidin analogue comprises an amino acid sequence or a structure shown in Table 2.5. The hepcidin analogue of claim 4 , wherein the hepcidin analogue comprises an amino acid sequence or a structure shown in Table 3.6. A dimer comprising two hepcidin analogues claim 4 , each hepcidin analogue having the structure of Formula I claim 4 , the structure of Formula II claim 4 , the structure of Formula III claim 4 , the structure of Formula IV claim 4 , the structure of Formula V claim 4 , the structure of Formula VI claim 4 , or a sequence or structure shown in any one of Tables 2-4 and 6-8 claim 4 , or 10-12 claim 4 , provided that when the dimer comprises a hepcidin analogue having the structure of Formula III claim 4 , Formula IV claim 4 , Formula V claim 4 , or Formula VI claim 4 , the two hepcidin analogues are linked via a lysine linker.7. The dimer of claim 6 , wherein one or both hepcidin analogue has the structure of Formula I.8. The dimer of claim 6 , wherein one or both hepcidin analogue has the structure of Formula II.13. The dimer of claim 6 , wherein one or both hepcidin analogue has a sequence or structure shown in Table 4.14. The dimer of claim 6 , having a sequence or structure shown in any one of Tables 6 claim 6 , 7 claim 6 , 8 claim 6 , and any one of compounds 1-361 in Table 12.1518.-. (canceled)19. The hepcidin analogue of claim 1 , wherein two cysteine residues of one or more hepcidin analogue are linked by an intramolecular disulfide bridge.2022.-. (canceled)23. A pharmaceutical composition comprising the hepcidin analogue of claim 1 , and a pharmaceutically acceptable carrier claim 1 , ...

NPRA AGONISTS, COMPOSITIONS, AND USES THEREOF

This disclosure provides a natriuretic peptide derivative of Formula (I), and to compositions including a natriuretic peptide derivative of Formula (I), 1. A composition comprising a natriuretic peptide derivative of Formula (I) ,{'br': None, 'i': z', 'x', 'y, '(fatty acyl)-(B)-(G)-NP\u2003\u2003 (I),'}wherein:z is 1, x is an integer from 2 to 4 and y is 3; orz is 0, x is an integer from 0 to 4 and y is an integer from 1 to 3;fatty acyl comprises from 12 to 24 (e.g., 12 to 18) carbons atoms;B is lysine or arginine;G is glycine;NP is a natriuretic peptide;if present, (fatty acyl)z- is covalently linked to the N-terminus of (B)x;(fatty acyl)z-(B)x- is covalently linked to the N-terminus of (G)y; and(fatty acyl)z-(B)x-(G)y- is covalently linked to the N-terminus of NP,wherein the natriuretic peptide derivative increases the level of blood cGMP when parenterally administered to a mammal to a level higher than the natriuretic peptide NP when parenterally administered to a mammal at an equivalent dose (e.g., mole/Kg dose, mg/Kg dose, or both mole/Kg and mg/Kg dose); andwherein NP is selected from human BNP (Sequence ID 41) and human CNP (Sequence ID 57).27-. (canceled)8. The composition according to claim 1 , wherein B is lysine.9. The composition according to claim 1 , wherein the natriuretic peptide derivative is of Formula (II){'br': None, 'sub': x', '3, 'fatty acyl-(B)(G)-NP\u2003\u2003 (II),'}wherein:the fatty acyl comprises from 12 to 24 (e.g., 12 to 18) carbons atoms;B is lysine or arginine;x is an integer from 2 to 4;G is glycine;NP is a natriuretic peptide selected from human BNP (Sequence ID 41) and human CNP (Sequence ID 57);{'sub': 'x', 'fatty acyl- is covalently linked to the N-terminus of (B);'}{'sub': x', '3, 'fatty acyl-(B)- is covalently linked to the N-terminus of (G); and'}{'sub': x', '3, 'fatty acyl-(B)-(G)- is covalently linked to the N-terminus of NP.'}1012-. (canceled)13. The composition according to claim 9 , wherein fatty acyl comprises 18 carbon ...

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.

COMPOSITION FOR INCREASING EXPRESSION LEVEL OF INTERFERON IN ANIMAL CELLS USING PLANT-DERIVED DNA DEMETHYLASE, ANTIVIRAL COMPOSITION, AND METHOD USING SAME

Provided are a composition or a kit for increasing the expression level of interferon in animal cells, an antiviral composition, and a method for increasing the expression level of interferon in animal cells using the same. Accordingly, by inducing the expression of DME in animal cells, the expression of IFNβ is increased without cell division, and thus it is possible to induce an antiviral reaction within a short time. 1. A composition for increasing an expression level of interferon in animal cells , the composition comprising a polypeptide of a plant-derived DNA demethylase having catalytic activity in DNA demethylation , or comprising a polynucleotide encoding the polypeptide.2Arabidopsis thaliana. The composition of claim 1 , wherein the plant-derived polypeptide is -derived DNA demethylase.3. The composition of claim 1 , wherein the polypeptide is DEMETER (DME) or a variant thereof.4. The composition of claim 3 , wherein the DEMETER variant has a deletion of an amino acid sequence at positions 1 to 677 from the N-terminus of an amino acid sequence of DME of SEQ ID NO: 1.5. The composition of claim 3 , wherein the DEMETER variant consists of an amino acid sequence of SEQ ID NO: 2.6. The composition of claim 1 , wherein the polypeptide is a demethylase that excises methylated cytosine from DNA.7. The composition of claim 1 , wherein the animal cell is a cell derived from a human claim 1 , a cow claim 1 , a horse claim 1 , a pig claim 1 , a dog claim 1 , a sheep claim 1 , a goat claim 1 , a cat claim 1 , or a mouse.8. The composition of claim 1 , wherein the interferon is selected from the group consisting of interferon-alpha (IFNα) claim 1 , interferon-beta (IFNβ) claim 1 , interferon-gamma (IFNγ) claim 1 , interferon kappa (IFN-κ) claim 1 , interferon-delta (IFN-δ) claim 1 , interferon epsilon (IFN-ε) claim 1 , interferon tau (IFN-τ) claim 1 , interferon omega (IFN-ω) claim 1 , and interferon zeta (IFN-ζ).9. The composition of claim 1 , wherein the composition ...

Stabilized bioactive peptides and methods of identification, synthesis, and use

An intracellular selection system allows screening for peptide bioactivity and stability. Randomized recombinant peptides are screened for bioactivity in a tightly regulated expression system, preferably derived from the wild-type lac operon. Bioactive peptides thus identified are inherently protease- and peptidase-resistant. Also provided are bioactive peptides stabilized by a stabilizing group at the N-terminus, the C-terminus, or both. The stabilizing group can be a small stable protein, such as the Rop protein, glutathione sulfotransferase, thioredoxin, maltose binding protein, or glutathione reductase, an α-helical moiety, or one or more proline residues.

METHODS FOR PRODUCTION AND PURIFICATION OF POLYPEPTIDES

The present invention relates to a method for production and purification of polypeptides. In particular, the present invention relates to a fusion protein comprising a solubility-enhancing peptide tag moiety, a self-aggregating peptide moiety and a moiety of target peptide and to a method for production and purification of target peptides through expressing said fusion protein. 1. A fusion protein comprising a solubility-enhancing peptide tag moiety , a self-aggregating peptide moiety and a target polypeptide moiety , wherein said target polypeptide moiety is located between said solubility-enhancing peptide tag moiety and said self-aggregating peptide moiety , and said target polypeptide moiety is attached to said self-aggregating peptide moiety through a first linker comprising a first cleavage site , wherein said fusion proteins , upon expression in a host cell , are capable of forming active aggregates through said self-aggregating peptide moiety.2. The fusion protein according to claim 1 , wherein said self-aggregating claim 1 , peptide comprises an amphipathic self-assembling short peptide.3. The fusion protein according to claim 2 , wherein said amphipathic self-assembling short peptide is selected from the group consisting of amphipathic β-sheet short peptides claim 2 , amphipathic α-helix short peptides and surfactant-like short peptides.4. The fusion protein according to claim 3 , wherein said self-aggregating peptide moiety comprises one said amphipathic β-sheet short peptide.5. The fusion protein according to claim 3 , wherein said self-aggregating peptide moiety comprises a tandem repeat of two or more of said amphipathic β-sheet short peptides.6. The fusion protein according to claim 4 , wherein said amphipathic β-sheet short peptide is 4-30 amino acid residues in length.7. The fusion protein according to claim 4 , wherein 40%-80% of the amino acid residues in said amphipathic β-sheet short peptide are hydrophobic amino acids.8. The fusion protein ...

LONG ACTING PROTEINS AND PEPTIDES AND METHODS OF MAKING AND USING THE SAME

Disclosed is a method for refolding a protein or peptide that does not contain essential disulfides and that contains at least one free cysteine residue. Also disclosed are polymer IFN-γ conjugates that have been created by the chemical coupling of polymers such as polyethylene glycol moieties to IFN-γ, particularly via a free cysteine in the protein. Also disclosed are analogs of bioactive peptides that may be used to create longer acting versions of the peptides, including analogs of glucagon, glucagon-like peptide-1 (GLP-1), GLP-2, Gastric inhibitory peptide (GIP), PYY, exendin, ghrelin, gastrin, amylin, and oxyntomodulin. 1125-. (canceled)126. An isolated cysteine variant of human interferon-gamma (IFN-γ) (SEQ ID NO:1) , wherein a cysteine residue is substituted for at least one amino acid located in at least one region of IFN-gamma selected from the group consisting of: the A-B loop , the B-C loop , the C-D loop , the D-E loop , the E-F loop , the region preceding Helix A and the region following helix F; and wherein Q1 is deleted or substituted by a non-glutamine amino acid.127. The cysteine variant of claim 126 , wherein a cysteine residue is substituted for at least one amino acid located in the A-B loop.128. The cysteine variant of claim 126 , wherein a cysteine residue is substituted for at least one amino acid located in the B-C loop.129. The cysteine variant of claim 126 , wherein a cysteine residue is substituted for at least one amino acid located in the C-D loop.130. The cysteine variant of claim 126 , wherein a cysteine residue is substituted for at least one amino acid located in the D-E loop.131. The cysteine variant of claim 126 , wherein a cysteine residue is substituted for at least one amino acid located in the E-F loop.132. The cysteine variant of claim 126 , wherein a cysteine residue is substituted for at least one amino acid located in the region preceding Helix A.133. The cysteine variant of claim 126 , wherein a cysteine residue is ...

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.

NOVEL BIOMOLECULE CONJUGATES AND USES THEREFOR

Provided herein are biomolecule conjugates, and methods of use thereof, wherein the conjugate comprises a cytokine, typically an immunopotentiating cytokine, and a peptide comprising or consisting of the sequence CSGRRSSKC (SEQ ID NO:1). Biomolecule conjugates of the invention find application, inter alia, in the treatment of turnouts, atherosclerosis and fibrosis, and the degradation of ECM associated therewith. Also provided herein are uses of a peptide comprising or consisting of the sequence of SEQ ID NO:1, optionally linked to a delectable agent and/or a carrier, in the detection and/or localisation of tumour, atherosclerotic and fibrotic tissue. 1. A biomolecule conjugate comprising a cytokine and a peptide comprising or consisting of the sequence set forth in SEQ ID NO:1 or a conservative variant thereof.2. A biomolecule conjugate according to claim 1 , wherein the cytokine is an immunopotentiating cytokine.3. A biomolecule conjugate according to wherein the immunopotentiating cytokine is a cytokine that mediates a cellular immune response.4. A biomolecule conjugate according to or claim 21 , wherein the immunopotentiating cytokine is TNFα or IFNγ.5. A biomolecule conjugate according to any one of to claim 21 , wherein the peptide comprising or consisting of the sequence set forth claim 21 , in SEQ ID NQ:1 claim 21 , or conservative variant thereof claim 21 , is conjugated to the C-terminal end of the cytokine.6. A biomolecule conjugate according to claim 5 , wherein the peptide is conjugated to the cytokine via a linker sequence.7. A biomolecule conjugate according to claim 6 , wherein the linker comprises one or more claim 6 , optionally two or more claim 6 , or three or more claim 6 , glycine (G) residues.8. A polynucleotide encoding a biomolecule conjugate according to any one of to .9. A pharmaceutical composition comprising a biomolecule conjugate according to any one of to claim 6 , or a polynucleotide encoding the same claim 6 , wherein the ...

Stresscopins and their Uses

The invention provides novel nucleic acids and polypeptides, referred to herein as stresscopin 1 and stresscopin 2, which preferentially activate the CRH-R2 receptor over the R1 receptor. Stresscopins, analogs and mimetics, and related CRH-R2 agonists suppress food intake and heat-induced edema; but do not induce substantial release of ACTH. Stresscopin also finds use in the recovery phase of stress responses, as an anti-inflammatory agent, as a hypotensive agent, as a cardioprotective agent, and in the treatment of psychiatric and anxiolytic disorders. Stresscopin nucleic acid compositions find use in identifying homologous or related proteins and the DNA sequences encoding such proteins; in producing compositions that modulate the expression or function of the protein; and in studying associated physiological pathways. 122-. (canceled)23. An isolated nucleic acid molecule encoding the polypeptide as set forth in SEQ ID NO:3 or sequences having at least 75% identity to SEQ ID NO:3.24. An isolated nucleic acid molecule encoding the polypeptide as set forth in SEQ ID NO:2 or sequences having at least 75% identity to SEQ ID NO:2.25. An isolated nucleic acid molecule as set forth in SEQ ID NO:1 or sequences having at least 75% identity to SEQ ID NO:1.26. A recombinant vector comprising an operative promoter and the nucleic acid molecule of .27. The vector of claim 26 , wherein the vector is a plasmid.28. The vector of claim 26 , wherein the vector is a retroviral vector.29. The vector of claim 26 , wherein the vector is an adenoviral vector.30. The nucleic acid molecule of any of claim 26 , or claim 26 , wherein the nucleic acid molecule has at least about 90% identity.31. The nucleic acid molecule of any of claim 26 , or claim 26 , wherein the nucleic acid molecule has at least about 95% identity.32. An isolated host cell comprising the vector of .33. A method of treating a metabolic disease comprising administering to a subject in need thereof claim 26 , a vector of ...