Bayer Corporation

Bayer Pharmaceuticals Corporation

Other

Roche Diagnostics Operations, Inc.

Roche Diagnostics Gmbh

Aerovance, Inc.

Armen B Shanafelt

Jeffrey M Greve

Robert Gundel

Clark Qun Pan

Gary J Jesmok

Manami Tsutsumi

Gayle D Wetzel

Christopher C Lawrence

Steven Roczniak

Kenneth Lembach

Malinda Longphre

Wei W Yuan

David C Boisvert

Sydney Morgan Zaremba

This invention provides novel peptides that function in vivo to stimulate insulin release from pancreatic beta cells in a glucose-dependent fashion. These insulin secretagogue peptides are shown to stimulate insulin release in rat islet cells in vitro, and in vivo. The peptides of the present invention provide a new therapy for patients with decreased endogenous insulin secretion, in particular type 2 diabetics. In particular, the invention is a polypeptide selected from a specific group of VIP/PACAP-related polypeptides, or functional equivalents thereof. The invention is also directed to a method of treating a metabolic disease in a mammal comprising administering a therapeutically effective amount of the insulin secretagogue peptides to said mammal. Also disclosed are methods of making the peptides, both recombinant and synthetic.

Pituitary adenylate cyclase activating peptide (PACAP) receptor 3 (R3) agonists and their pharmacological methods of use

This invention relates to IL-9 muteins that inhibit the activity of wild-type IL-9, multimers and Fc-fusion constructs of IL-9 proteins, and an efficient method to purify IL-9 proteins produced by eukaryotic cells. Related formulations, dosages and methods of administration thereof for therapeutic purposes are also provided. More particularly, these IL-9 muteins, compositions, and methods provide a treatment option for individuals afflicted with conditions where inhibiting IL-9 mediated immune responses would be beneficial, such as allergy, asthma, chronic obstructive pulmonary disease (emphysema and chronic bronchitis), pulmonary and gastro-intestinal mucus hyperplasia, inflammation, immunological disorders, leukemia, and lymphoma.

Interleukin-9 antagonist muteins and their pharmacological methods of use

The invention is directed to a polypeptide comprising a human IL-2 mutein numbered in accordance with wild-type IL-2 wherein said human IL-2 is substituted at at least one of positions 20, 88 or 126, whereby said mutein preferentially activates T cells over NK cells. D20H and I, N88G, I, and R, in particular have a relative T cell-differential activity much greater than native IL-2, with predicted associated reduced in vivo toxicity. The invention also includes polynucleotides coding for the muteins of the invention, vectors containing the polynucleotides, transformed host cells, pharmaceutical compositions comprising the muteins, and therapeutic methods of treatment.

IL-2 selective agonists and antagonists

Pituitary adenylate cyclase activating peptide (PACAP)receptor 3 (R3) agonists and their pharmacological methods of use

A method of treating particles to be used in immunoassays reduces interference in particle agglutination assays. For particles having covalently bound antibodies and residual NHS-ester or sNHS-ester groups on the surface, the reactive esters are treated with an aqueous mixture containing an amine compound of formula (I):HN&#x2014;R&#x2014;X&#x2003;&#x2003;(I).The moiety &#x2014;X is &#x2014;NH, &#x2014;OH, or &#x2014;COCHCH; and R is an alkyl group or an alkyl ether group. When &#x2014;X is &#x2014;NHor &#x2014;COCHCH, R contains from 1 to 20 carbon atoms; and when &#x2014;X is &#x2014;OH, R contains from 4 to 20 carbon atoms.

Particles for immunoassays and methods for treating the same

Tertiary amine compounds for use in immunoassays

The invention is directed to human IL-4 muteins numbered in accordance with wild-type IL-4 having T cell activating activity, but having reduced endothelial cell activating activity. In particular, the invention is related to human IL-4 muteins wherein the surface-exposed residues of the D helix of the wild-type IL-4 are mutated whereby the resulting mutein causes T cell proliferation, and causes reduced IL-6 secretion from HUVECs, relative to wild-type IL-4. This invention realizes a less toxic IL-4 mutant that allows greater therapeutic use of this interleukin. Further, the invention is directed to IL-4 muteins having single, double and triple mutations represented by the designators R121A, R121D, R121E, R121F, R121H, R121I, R121K, R121N, R121P, R121T, R121W; Y124A, Y124Q, Y124R, Y124S, Y124T; Y124A/S125A, T13D/R121E; and R121T/E122F/Y124Q, when numbered in accordance with wild type IL-4 (His&equals;1). The invention also includes polynucleotides coding for the muteins of the invention, vectors containing the polynucleotides, transformed host cells, pharmaceutical compositions comprising the muteins, and therapeutic methods of treatment.

Polynucleotides encoding T-cell selective interleukin-4 agonists

This invention realizes a less toxic IL-4 mutant that allows greater therapeutic use of interleukin 4. Further, the invention is directed to IL-4 muteins having single and double mutations represented by the designators R121E and T13D/R121E, numbered in accordance with wild type IL-4 (His&equals;1). The invention also includes polynucleotides coding for the muteins of the invention, vectors containing the polynucleotides, transformed host cells, pharmaceutical compositions comprising the muteins, and therapeutic methods of treatment.

T-cell selective interleukin-4 agonists

A recombinant human IL-4 mutein numbered in accordance with wild-type IL-4 wherein the mutein comprises at least one amino acid substitution in the binding surface of either the A- or C-alpha helices of the wild-type IL-4 whereby the mutein binds to the IL-4R&agr; receptor with at least greater affinity than native IL-4. The substitution is more preferably selected from the group of positions consisting of, in the A-helix, positions 13 and 16, and in the C-helix, positions 81 and 89. A most preferred embodiment is the recombinant human IL-4 mutein wherein the substitution at position 13 is Thr to Asp. Pharmaceutical compositions, amino acid and polynucleotide sequences encoding the muteins, transformed host cells, antibodies to the muteins, and methods of treatment are also described.

DNA encoding high affinity interleukin-4 muteins

This invention is directed to recombinant human IL-4 muteins numbered in accordance with wild-type IL-4 wherein the muteins comprise at least one amino acid substitution selected from the group consisting of substitutions at positions 13, 16, 81 and 89 of the wild-type IL-4, whereby the mutein binds to the IL-4R.alpha. receptor with at least greater affinity than native IL-4. The invention is further directed to recombinant human IL-4 antagonist muteins numbered in accordance with wild-type IL-4 wherein the muteins comprise substitutions R121D and Y124D in the D-helix of said wild-type IL-4; and at least one amino acid substitution selected from the group consisting of substitutions at positions 13, 16, 81 and 89 of said wild-type IL-4, whereby the mutein binds to the IL-4R.alpha. receptor with at least greater affinity than native IL-4. The invention is also directed to pharmaceutical compositions comprising individual muteins in combination with pharmaceutically acceptable carriers.

High-affinity interleukin-4 muteins

The invention is directed to human IL-4 muteins numbered in accordance with wild-type IL-4 having T cell activating activity, but having reduced endothelial cell activating activity. In particular, the invention is related to human IL-4 muteins wherein the surface-exposed residues of the D helix of the wild-type IL-4 are mutated whereby the resulting mutein causes T cell proliferation, and causes reduced IL-6 secretion from HUVECs, relative to wild-type IL-4. This invention realizes a less toxic IL-4 mutant that allows greater therapeutic use of this interleukin. Further, the invention is directed to IL-4 muteins having single, double and triple mutations represented by the designators R121A, R121D, R121E, R121F, R121H, R1211, R121K, R121N, R121P, R121T, R121W; Y124A, Y124Q, Y124R, Y124S, Y124T; Y124A/S125A, T13D/R121E; and R121T/E122F/Y124Q, when numbered in accordance with wild type IL-4 (His=1). The invention also includes polynucleotides coding for the muteins of the invention, vectors containing the polynucleotides, transformed host cells, pharmaceutical compositions comprising the muteins, and therapeutic methods of treatment.

Growing community of inventors

Carmel, IN, United States of America

Armen B Shanafelt