Antibodies to MAdCAM

• US 20070166308A1
• Filed: 07/10/2006
• Published: 07/19/2007
• Est. Priority Date: 01/09/2004
• Status: Active Grant

• Current Assignee: Amgen Fremont Inc. (Amgen Inc.), Pfizer Inc.
• Original Assignee: Amgen Fremont Inc. (Amgen Inc.)
• Inventors: Kellermann, Sirid-Aimee, Pullen, Nicholas, Haak-Frendscho, Mary, Green, Larry, Molloy, Elizabeth
• Granted Patent: US 7,932,372 B2
• Time in Patent Office: Days
• US Class Current: 424/144.100
• 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 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/10 of the bladder
• 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 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/04 for non-specific disorders of the connective tissue
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/16 : Otologicals
• 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 3/02 : Nutrients, e.g. vitamins, minerals
• 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 31/14 : for RNA 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 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 39/00 : General protective or antinoxious agents
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 5/16 : for decreasing, blocking or antagonising the activity of the thyroid hormones
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• 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 14/70503 : Immunoglobulin superfamily
• CPC Class Codes: C07K 16/2803 : against the immunoglobulin superfamily
• 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 2317/34 : Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C07K 2317/51 : Complete heavy chain or Fd fragment, i.e. VH + CH1
• CPC Class Codes: C07K 2317/515 : Complete light chain, i.e. VL + CL
• 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 2317/76 : 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
• CPC Class Codes: G01N 2333/70503 : Immunoglobulin superfamily, e.g. VCAMs, PECAM, LFA-3
• CPC Class Codes: G01N 2333/70546 : Integrin superfamily, e.g. VLAs, leuCAM, GPIIb/GPIIIa, LPAM
• CPC Class Codes: G01N 33/56972 : White blood cells
• CPC Class Codes: G01N 33/6854 : Immunoglobulins

Abstract

The present invention relates to antibodies including human antibodies and antigen-binding portions thereof that specifically bind to MAdCAM, preferably human MAdCAM and that function to inhibit MAdCAM. The invention also relates to human anti-MAdCAM antibodies and antigen-binding portions thereof. The invention also relates to antibodies that are chimeric, bispecific, derivatized, single chain antibodies or portions of fusion proteins. The invention also relates to isolated heavy and light chain immunoglobulins derived from human anti-MAdCAM antibodies and nucleic acid molecules encoding such immunoglobulins. The present invention also relates to methods of making human anti-MAdCAM antibodies, compositions comprising these antibodies and methods of using the antibodies and compositions for diagnosis and treatment. The invention also provides gene therapy methods using nucleic acid molecules encoding the heavy and/or light immunoglobulin molecules that comprise the human anti-MAdCAM antibodies. The invention also relates to transgenic animals or plants comprising nucleic acid molecules of the invention.

Claims

1. A human monoclonal antibody or an antigen-binding portion thereof that specifically binds to Mucosal Adressin Cell Adhesion Molecule (MAdCAM).

2. The human monoclonal antibody or antigen-binding portion according to claim 1, wherein said antibody or portion possesses at least one of the following properties:

(a) binds to human cells;

(b) has a selectivity for MAdCAM over VCAM or fibronectin of at least 100 fold;

(c) binds to human MAdCAM with a K_d of 3×

10<sup>−

10</sup> M or less;

or

(d) inhibits the binding of α

₄β

₇ expressing cells to human 10 MAdCAM.

(e) inhibits the recruitment of lymphocytes to gastrointestinal lymphoid tissue.

3. The human monoclonal antibody or antigen-binding portion according to claim 2, wherein said antibody or portion binds human MAdCAM with a K_d of 3×

10<sup>−

10</sup> M or less and inhibits α

₄ β

₇ binding to human MAdCAM.

4. A hybridoma cell line that produces the human monoclonal antibody according to claim 1, wherein the hybridoma is selected from the group consisting of 1.7.2 (ECACC Accession No. 03090901), 1.8.2 (ECACC Accession No. 03090902), 6.14.2 (ECACC Accession No. 03090903), 6.22.2 (ECACC Accession No. 03090904), 6.34.2 (ECACC Accession No. 03090905), 6.67.1 (ECACC Accession No. 03090906), 6.73.2 (ECACC Accession No. 03090907), 6.77.1 (ECACC Accession No. 03090908), 7.16.6 (ECACC Accession No. 03090909), 7.20.5 (ECACC Accession No. 03090910), 7.26.4 (ECACC Accession No. 03090911), and 9.8.2 (ECACC Accession No. 03090912).

5. The human monoclonal antibody produced by the hybridoma cell line according to claim 4 or an antigen-binding portion of said monoclonal antibody.

6. The human monoclonal antibody according to claim 5, wherein the heavy chain C-terminal lysine is cleaved.

7. The human monoclonal antibody or antigen-binding portion thereof according to either of claims 1 or 5, wherein said antibody or antigen-binding portion inhibits binding of human MAdCAM to α

₄β

₇, and wherein the antibody or portion thereof has at least one of the following properties;

(a) cross-competes with a reference antibody for binding to MAdCAM;

(b) competes with a reference antibody for binding to MAdCAM;

(c) binds to the same epitope of MAdCAM as a reference antibody;

(d) binds to MAdCAM with substantially the same K_d as a reference antibody;

(e) binds to MAdCAM with substantially the same off rate as a reference antibody;

wherein the reference antibody is selected from the group consisting of;

monoclonal antibody 1.7.2, monoclonal antibody 1.8.2, monoclonal antibody 6.14.2, monoclonal antibody 6.22.2, monoclonal antibody 6.34.2, monoclonal antibody 6.67.1, monoclonal antibody 6.73.2, monoclonal antibody 6.77.1, monoclonal antibody 7.16.6, monoclonal antibody 7.20.5, monoclonal antibody 7.26.4, monoclonal antibody 9.8.2, monoclonal antibody 6.22.2-mod, monoclonal antibody 6.34.2-mod, monoclonal antibody 6.67.1-mod, monoclonal antibody 6.77.1-mod and monoclonal antibody 7.26.4-mod.

12. The human monoclonal antibody or antigen-binding portion according to claim 1, wherein the heavy chain variable region, the light chain variable region or both are at least 90% identical in amino acid sequence to the corresponding region or regions of a monoclonal antibody selected from the group consisting of:

monoclonal antibody 1.7.2, monoclonal antibody 1.8.2, monoclonal antibody 6.14.2, monoclonal antibody 6.22.2, monoclonal antibody 6.34.2, monoclonal antibody 6.67.1, monoclonal antibody 6.73.2, monoclonal antibody 6.77.1, monoclonal antibody 7.16.6, monoclonal antibody 7.20.5, monoclonal antibody 7.26.4 monoclonal antibody 9.8.2, monoclonal antibody 6.22.2-mod, monoclonal antibody 6.34.2-mod, monoclonal antibody 6.67.1-mod, monoclonal antibody 6.77.1-mod and monoclonal antibody 7.26.4-mod.

16. The monoclonal antibody according to any one of claims 1-3 and 5-15 that is an immunoglobulin G (IgG), an IgM, an IgE, and IgA or an IgD molecule, a humanized antibody, a chimeric antibody or a bispecific antibody.

17. The antigen-binding portion according to any one of claims 1-3, 5-7 and 9-16 which is an Fab fragment, an F(ab′

)₂ fragment, an F_V fragment or a single chain antibody.

18. A pharmaceutical composition comprising an effective amount of the monoclonal antibody or antigen-binding portion thereof according to any one of claims 1-3 and 5-17 and a pharmaceutically acceptable carrier.

19. A method of treating inflammatory disease in a subject in need thereof, comprising the step of administering to said subject the monoclonal antibody or antigen-binding portion thereof according to any one of claims 1-3 and 5-17 wherein said antibody or antigen-binding portion inhibits binding of MAdCAM to α

₄β

₇.

20. The method of claim 19, wherein the inflammatory disease is inflammatory disease of the gastrointestinal tract.

21. The method of claim 20, wherein the inflammatory disease of the gastrointestinal tract is selected from the group consisting of inflammatory bowel disease, Crohn'"'"'s disease, ulcerative colitis, diverticula disease, gastritis, liver disease, primary biliary sclerosis and sclerosing cholangitis.

22. The method of claim 20, wherein the inflammatory bowel disease is Crohn'"'"'s disease, ulcerative colitis or both.

23. The method of claim 20, wherein the inflammatory diseases are insulin-dependent diabetes and graft versus host disease.

24. An isolated cell line that produces the monoclonal antibody or antigen-binding portion according to any one of claims 1-3 and 5-17 or the heavy chain or light chain of said antibody or of said portion thereof.

25. The cell line according to either of claims 4 or 24 that produces an antibody selected from the group consisting of:

1.7.2, 1.8.2, 6.14.2, 6.22.2, 6.34.2, 6.67.1, 6.73.2, 6.77.1, 7.16.6, 7.20.5, 7.26.4 and 9.8.2, or an antibody comprising the amino acid sequences of one of said antibodies.

26. The cell line according to claim 25 that produces a monoclonal antibody selected from the group consisting of:

6.22.2-mod, 6.34.2-mod, 6.67.1-mod, 6.77.1-mod and 7.26.4-mod or an antibody comprising the amino acid sequences of one of said antibodies.

27. An isolated nucleic acid molecule comprising a nucleotide sequence that encodes the heavy chain or an antigen-binding portion thereof or the light chain or an antigen-binding portion thereof of an antibody according to any one of claims 1-3 and 5-17.

28. A vector comprising the nucleic acid molecule according to claim 27, wherein the vector optionally comprises an expression control sequence operably linked to the nucleic acid molecule.

29. A host cell comprising the vector according to claim 28 or the nucleic acid molecule according to claim 27.

30. A host cell according to claim 29 comprising a nucleic acid molecule encoding the heavy chain or an antigen-binding portion thereof and a nucleic acid molecule encoding the light chain or an antigen-binding portion thereof of an antibody or antigen-binding portion according to any one of claims 1-3 and 5-17.

31. A method for producing a human monoclonal antibody or antigen-binding portion thereof that specifically binds MAdCAM, comprising culturing the host cell according to claim 29 or 30 or the cell line according to either of claims 4 or 24 under suitable conditions and recovering said antibody or antigen-binding portion.

32. A non-human transgenic animal or transgenic plant comprising (a) nucleic acid molecule encoding the heavy chain or an antigen-binding portion thereof;

(b) a nucleic acid molecule encoding the light chain or an antigen-binding portion thereof;

or (c) both (a) and (b) of an antibody according to any one of claims 1-3 or 5-17, wherein the non-human transgenic animal or transgenic plant expresses said heavy chain or light chain or both.

33. A method of isolating an antibody or antigen-binding portion thereof that specifically binds to MAdCAM, comprising the step of isolating the antibody from the non-human transgenic animal or transgenic plant according to claim 32.

37. A method of inhibiting α

₄ β

₇ binding to cells expressing human MAdCAM comprising contacting the cells with the monoclonal antibody according to any one of claims 1-3 and 5-17 or an antigen-binding portion thereof.

38. A method for inhibiting MAdCAM-mediated leukocyte-endothelial cell adhesion comprising contacting the endothelial cells with the monoclonal antibody according to any one of claims 1-3 and 5-17 or an antigen-binding portion thereof.

39. A method for inhibiting MAdCAM-mediated leukocyte adhesion, migration and infiltration into tissues comprising the step of contacting the endothelial cells with the monoclonal antibody according to any one of claims 1-3 and 5-17 or an antigen-binding portion thereof.

40. A method for inhibiting α

₄ β

₇/MAdCAM-dependent cellular adhesion comprising the step of contacting cells expressing human MAdCAM with the monoclonal antibody according to any one of claims 1-3 and 5-17 or antigen-binding portion thereof.

41. A method for inhibiting the MAdCAM-mediated recruitment of lymphocytes to gastrointestinal lymphoid tissue comprising the step of contacting cells expressing human MAdCAM with the monoclonal antibody according to any one of claims 1-3 and 5-17 or antigen-binding portion thereof.

43. The human monoclonal antibody or antigen-binding portion according to claim 1, wherein the antibody comprises:

(a) a heavy chain amino acid sequence that is at least 90% identical to the heavy chain amino acid sequence of a monoclonal antibody selected from the group consisting of;

1.7.2, 1.8.2, 6.14.2, 6.22.2, 6.34.2, 6.67.1, 6.73.2, 6.77.1, 7.16.6, 7.20.5, 7.26.4, 9.8.2, 6.22.2-mod, 6.34.2-mod, 6.67.1-mod, 6.77.1-mod and 7.26.4-mod;

(b) a light chain amino acid sequence that is at least 90% identical to the light chain amino acid sequence of a monoclonal antibody selected from the group consisting of;

1.7.2, 1.8.2, 6.14.2, 6.22.2, 6.34.2, 6.67.1, 6.73.2, 6.77.1, 7.16.6, 7.20.5, 7.26.4, 9.8.2, 6.22.2-mod, 6.34.2-mod, 6.67.1-mod, 6.77.1-mod and 7.26.4-mod;

(c) both (a) and (b);

or

(d) either (a), (b) or (c), with or without the signal sequence.

44. A method for diagnosing a disorder characterized by circulating soluble human MAdCAM comprising the steps of:

(1) contacting a biological sample with the monoclonal antibody according to any one of claims 1-3 and 5-17 or antigen-binding portion and (2) detecting binding.

45. A method for detecting inflammation in a subject comprising the steps of:

(1) administering to said subject the monoclonal antibody or antigen-binding portion according to any one of claims 1-3 and 5-17 wherein said antibody or portion thereof is detectably labeled and (2) detecting binding.

46. A diagnostic kit comprising the monoclonal antibody according to any one of claims 1-3 and 5-17 or antigen-binding portion.

47. The pharmaceutical composition according to claim 18 further comprising one or more additional anti-inflammatory or immunomodulatory agents.

48. The pharmaceutical composition according to claim 47, wherein the one or more additional anti-inflammatory or immunomodulatory agents are selected from the group consisting of:

corticosteroids, aminosalicylates, azathioprine, methotrexate, cyclosporin, FK506, IL-10, GM-CSF, rapamycin, anti-TNFα

agents and adhesion molecule antagonists.

49. A vaccine comprising an effective amount of the human antibody thereof according to any one of claims 1-3 and 5-17 or antigen-binding portion and a pharmaceutically acceptable carrier.

50. The vaccine according to claim 49, wherein the vaccine is mucosal.

8. A monoclonal antibody that specifically binds MAdCAM, wherein the antibody is selected from the group consisting of:

(a) an antibody comprising the amino acid sequences set forth in SEQ ID NO;

2 and SEQ ID NO;

4, without the signal sequences;

(b) an antibody comprising the amino acid sequences set forth in SEQ ID NO;

6 and SEQ ID NO;

8, without the signal sequences;

(c) an antibody comprising the amino acid sequences set forth in SEQ ID NO;

10 and SEQ ID NO;

12, without the signal sequences;

(d) an antibody comprising the amino acid sequences set forth in SEQ ID NO;

14 and SEQ ID NO;

16, without the signal sequences;

(e) an antibody comprising the amino acid sequences set forth in SEQ ID NO;

18 and SEQ ID NO;

20, without the signal sequences;

(f) an antibody comprising the amino acid sequences set forth in SEQ ID NO;

22 and SEQ ID NO;

24, without the signal sequences;

(g) an antibody comprising the amino acid sequences set forth in SEQ ID NO;

26 and SEQ ID NO;

28, without the signal sequences;

(h) an antibody comprising the amino acid sequences set forth in SEQ ID NO;

30 and SEQ ID NO;

32, without the signal sequences;

(i) an antibody comprising the amino acid sequences set forth in SEQ ID NO;

34 and SEQ ID NO;

36, without the signal sequences;

(j) an antibody comprising the amino acid sequences set forth in SEQ ID NO;

38 and SEQ ID NO;

40, without the signal sequences;

(k) an antibody comprising the amino acid sequences set forth in SEQ ED NO;

42 and SEQ ID NO;

44, without the signal sequences;

(l) an antibody comprising the amino acid sequences set forth in SEQ ID NO;

46 and SEQ ID NO;

48, without the signal sequences;

(m) an antibody comprising the amino acid sequences set forth in SEQ ID NO;

52 and SEQ ID NO;

54, without the signal sequences;

(n) an antibody comprising the amino acid sequences set forth in SEQ ID NO;

56 and SEQ ID NO;

58, without the signal sequences;

(o) an antibody comprising the amino acid sequences set forth in SEQ ID NO;

60 and SEQ ID NO;

62, without the signal sequences;

(p) an antibody comprising the amino acid sequences set forth in SEQ ID NO;

64 and SEQ ID NO;

66, without the signal sequences; and

(q) an antibody comprising the amino acid sequences set forth in SEQ ID NO;

42 and SEQ ID NO;

68, without the signal sequences.

9. A monoclonal antibody or an antigen-binding portion thereof, wherein the heavy chain of said antibody or portion thereof comprises the heavy chain CDR1, CDR2 and CDR3 or wherein the light chain comprises the light chain CDR1, CDR2 and CDR3 of a monoclonal antibody selected from the group consisting of:

1.7.2, 1.8.2, 6.14.2, 6.22.2, 6.34.2, 6.67.1, 6.73.2, 6.77.1, 7.16.6, 7.20.5, 7.26.4, 9.8.2, 6.22.2-mod, 6.34.2-mod, 6.67.1-mod, 6.77.1-mod and 7.26.4-mod.

10. The monoclonal antibody or antigen-binding portion according to claim 9, wherein said antibody or portion comprises a heavy chain that utilizes a human VH 1-18 gene, a human VH 3-15 gene, a human VH 3-21 gene, a human VH 3-23 gene, a human VH 3-30 gene, a human VH 3-33 gene or a human VH 4-4 gene.

11. The monoclonal antibody or an antigen-binding portion thereof according to claim 10, wherein said antibody or portion comprises a light chain that utilizes a human V_K A2 gene, a human V_K A3 gene, a human V_K A26 gene, a human V_K B3 gene, a human V_K O12 gene or a human V_K O18 gene.

13. A monoclonal antibody or an antigen-binding portion thereof that specifically binds MAdCAM, wherein:

(a) the heavy chain comprises the heavy chain CDR1, CDR2 and CDR3 amino acid sequences of a reference antibody selected from the group consisting of;

1.7.2, 1.8.2, 6.14.2, 6.22.2, 6.34.2, 6.67.1, 6.73.2, 6.77.1, 7.16.6, 7.20.5, 7.26.4, 9.8.2, 6.22.2-mod, 6.34.2-mod, 6.67.1-mod, 6.77.1-mod and 7.26.4-mod

(b) the light chain comprises the light chain CDR1, CDR2 and CDR3 amino acid sequences of a reference antibody selected from the group consisting of;

1.7.2, 1.8.2, 6.14.2, 6.22.2, 6.34.2, 6.67.1, 6.73.2, 6.77.1, 7.16.6, 7.20.5, 7.26.4, 9.8.2, 6.22.2-mod, 6.34.2-mod, 6.67.1-mod, 6.77.1-mod and 7.26.4-mod

(c) the antibody comprises a heavy chain of (a) and a light chain of (b); and

(d) the antibody of (c) wherein the heavy chain and light chain CDR amino acid sequences are selected from the same reference antibody.

14. The monoclonal antibody or antigen-binding portion according to claim 13, wherein the heavy chain, the light chain or both comprise the amino acid sequence from the beginning of the CDR1 through the end of the CDR3 of the heavy chain, the light chain or both, respectively, of the reference antibody.

15. The monoclonal antibody or antigen-binding portion according to claim 13, wherein said antibody comprises:

(a) a heavy chain comprising the heavy chain variable region amino acid sequence of an antibody selected from the group consisting of;

1.7.2 (SEQ ID NO;

     2);

1.8.2 (SEQ ID NO;

     6);

6.14.2 (SEQ ID NO;

     10);

6.22.2 (SEQ ID NO;

     14);

6.34.2 (SEQ ID NO;

     18);

6.67.1 (SEQ ID NO;

     22);

6.73.2 (SEQ ID NO;

     26);

6.77.1 (SEQ ID NO;

     30);

7.16.6 (SEQ ID NO;

     34);

7.20.5 (SEQ ID NO;

     38);

7.26.4 (SEQ ID NO;

     42); and

9.8.2 (SEQ ID NO;

     46);

6.22.2-mod (SEQ ID NO;

     52);

6.34.2-mod (SEQ ID NO;

     56);

6.67.1-mod (SEQ ID NO;

     60);

6.77.1-mod (SEQ ID NO;

     64); and

7.26.4-mod (SEQ ID NO;

     42);

(b) a light chain comprising the light chain variable region amino acid sequence of an antibody selected from the group consisting of;

1.7.2 (SEQ ID NO;

     4);

1.8.2 (SEQ ID NO;

     8);

6.14.2 (SEQ ID NO;

     12);

6.22.2 (SEQ ID NO;

     16);

6.34.2 (SEQ ID NO;

     20);

6.67.1 (SEQ ID NO;

     24);

6.73.2 (SEQ ID NO;

     28);

6.77.1 (SEQ ID NO;

     32);

7.16.6 (SEQ ID NO;

     36);

7.20.5 (SEQ ID NO;

     40);

7.26.4 (SEQ ID NO;

     44); and

9.8.2 (SEQ ID NO;

     48);

6.22.2-mod (SEQ ID NO;

     54);

6.34.2-mod (SEQ ID NO;

     58);

6.67.1-mod (SEQ ID NO;

     62);

6.77.1-mod (SEQ ID NO;

     66); and

7.26.4-mod (SEQ ID NO;

     68);

or

(c) the heavy chain of (a) and the light chain of (b).

34. A method of treating a subject in need thereof with a human antibody or antigen-binding portion thereof that specifically binds to MAdCAM and inhibits binding to α

₄ β

₇ comprising the steps of;

(a) administering an effective amount of an isolated nucleic acid molecule encoding the heavy chain or an antigen-binding portion thereof, an isolated nucleic acid molecule encoding the light chain or an antigen-binding portion thereof, or nucleic acid molecules encoding the light chain and the heavy chain or antigen-binding portions thereof; and

(b) expressing the nucleic acid molecule.

35. A method for producing a human monoclonal antibody that specifically binds MAdCAM, comprising the steps of:

(a) immunizing a non-human transgenic animal that is capable of producing human antibodies with MAdCAM, with an immunogenic portion of MAdCAM or a with cell or tissue expressing MAdCAM; and

(b) allowing the transgenic animal to mount an immune response to MAdCAM.

36. A human monoclonal antibody produced by the method according to claim 35.

42. A monoclonal antibody or an antigen-binding portion thereof that specifically binds MAdCAM, wherein said antibody or portion thereof comprises one or more of an FR1, FR2, FR3 or FR4 amino acid sequence of a human monoclonal antibody selected from the group consisting of:

1.7.2, 1.8.2, 6.14.2, 6.22.2, 6.34.2, 6.67.1, 6.73.2, 6.77.1, 7.16.6, 7.20.5, 7.26.4 9.8.2, 6.22.2-mod, 6.34.2-mod, 6.67.1-mod, 6.77.1-mod and 7.26.4-mod.

51. A method of detecting the effect of administration of an inhibitory anti-MAdCAM antibody or antigen-binding portion thereof to a subject comprising the steps of:

(a) administering to a subject a human monoclonal antibody that specifically binds to MAdCAM; and

(b) determining whether there is an increase in the levels of circulating α

₄β

₇-expressing leukocytes.

52. The method according to claim 51, wherein said leukocytes are lymphocytes.

53. The method according to claim 51, wherein said increase in the levels of circulating α

₄β

₇-expressing leukocytes is determined by FACS analysis.