IP-10 ANTIBODIES AND THEIR USES

• US 20100077497A1
• Filed: 05/27/2009
• Published: 03/25/2010
• Est. Priority Date: 12/10/2003
• Status: Active Grant

• Current Assignee: ER Squibb & Sons LLC (Bristol-Myers Squibb Company)
• Original Assignee: Medarex Incorporated (Bristol-Myers Squibb Company)
• Inventors: LANE, Thomas E., PASSMORE, David, DESHPANDE, Shrikant, LIU, Michael T., RANGAN, Vangipuram, SRINIVASAN, Mohan, KEIRSTEAD, Hans S., WANG, Changyu, HUANG, Haichun, CARDARELLI, Josephine M.
• Granted Patent: US 8,258,266 B2
• Time in Patent Office: Days
• US Class Current: 800/18
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/16 Central respiratory analeptics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 31/14 : for RNA viruses
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 31/22 : for herpes viruses
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/14 : Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07K 14/522 : Alpha-chemokines, e.g. NAP-2, ENA-78, GRO-alpha/MGSA/NAP-3, GRO-beta/MIP-2alpha, GRO-gamma/MIP-2beta, IP-10, GCP-2, MIG, PBSF, PF-4, KC
• CPC Class Codes: C07K 16/24 : against cytokines, lymphokines or interferons
• CPC Class Codes: C07K 2317/21 : from primates, e.g. man
• CPC Class Codes: C07K 2317/33 : Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
• CPC Class Codes: C07K 2317/56 : variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 : Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/567 : Framework region [FR]
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Abstract

The present invention provides isolated monoclonal antibodies, particularly human antibodies, that bind to IP-10 with high affinity, inhibit the binding of IP-10 to its receptor, inhibit IP-10-induced calcium flux and inhibit IP-10-induced cell migration. Nucleic acid molecules encoding the antibodies of the invention, expression vectors, host cells and methods for expressing the antibodies of the invention are also provided. Immunoconjugates, bispecific molecules and pharmaceutical compositions comprising the antibodies of the invention are also provided. The invention also provides methods for inhibiting IP-10 activity using the antibodies of the invention, including methods for treating various inflammatory and autoimmune diseases.

Claims

1. An isolated monoclonal antibody, or antigen binding portion thereof, which binds human IP-10, wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:

39.

13. An isolated nucleic acid molecule encoding the antibody, or antigen-binding portion thereof, of claim 1, 2, or 5.

14. An expression vector comprising the nucleic acid molecule of claim 17.

15. A host cell comprising the expression vector of claim 14.

17. A method of inhibiting an inflammatory or autoimmune response mediated by activated T cells or NK cells comprising contacting the T cells or NK cells with the antibody, or antigen-binding portion thereof, of claim 1, 2, or 5, such that the inflammatory or autoimmune response is inhibited.

2. An isolated monoclonal antibody, or antigen binding portion thereof, which binds human IP-10, wherein the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:

88.

3. An isolated monoclonal antibody, or antigen binding portion thereof, which binds human IP-10, wherein the heavy and light chain variable regions comprise the amino acid sequences set forth in SEQ ID NOs:

39 and 88, respectively.

4. An isolated monoclonal antibody, or antigen binding portion thereof, which binds human IP-10, wherein the heavy and light chain variable regions are encoded by the nucleotide sequences set forth in SEQ ID NOs:

103 and 114, respectively.

5. An isolated monoclonal antibody, or antigen binding portion thereof, which binds human IP-10, comprising:

(a) a heavy chain variable region CDR1 comprising SEQ ID NO;

5;

(b) a heavy chain variable region CDR2 comprising SEQ ID NO;

17;

(c) a heavy chain variable region CDR3 comprising SEQ ID NO;

28;

(d) a light chain variable region CDR1 comprising SEQ ID NO;

55;

(e) a light chain variable region CDR2 comprising SEQ ID NO;

66; and

(f) a light chain variable region CDR3 comprising SEQ ID NO;

77.

6. An isolated human antibody, or antigen-binding portion thereof, that competes for binding to human IP-10 with the antibody of claim 5.

7. The antibody, or antigen binding portion thereof, of claim 5, wherein the antibody is selected from the group consisting of a human antibody, a humanized antibody, a bispecific antibody, and a chimeric antibody.

8. The antibody, or antigen binding portion thereof, of claim 5, wherein the antigen binding portion is selected from the group consisting of a Fab, Fab'"'"'2, and ScFv.

9. The antibody, or antigen binding portion thereof, of claim 5, wherein the antibody isotype is selected from the group consisting of an IgG1, an IgG2, an IgG3, an IgG4, an IgM, an IgA1, an IgA2, an IgAsec, an IgD, and an IgE antibody.

10. A composition comprising the antibody, or antigen-binding portion thereof, of claim 5, and a pharmaceutically acceptable carrier.

11. A bispecific molecule comprising the antibody, or antigen-binding portion thereof, of claim 5, linked to a second functional moiety having a different binding specificity than said antibody, or antigen binding portion thereof.

12. A hybridoma prepared from a transgenic mouse comprising human immunoglobulin heavy and light chain transgenes, wherein the mouse expresses the antibody of claim 5.

16. A transgenic mouse comprising human immunoglobulin heavy and light chain transgenes, wherein the mouse expresses the antibody of claim 5.

18. A method of treating an inflammatory or autoimmune disease in a subject, comprising administering to the subject the antibody, or antigen-binding portion thereof, of claim 5 such that the inflammatory or autoimmune disease in the subject is treated.

19. A method of treating a viral or bacterial infection in a subject, comprising administering to the subject the antibody, or antigen-binding portion thereof, of claim 5, such that the viral or bacterial infection in the subject is treated.