VARIABLE REGION SEQUENCES OF IL-31 MONOCLONAL ANTIBODIES AND METHODS OF USE

• US 20100008909A1
• Filed: 09/04/2007
• Published: 01/14/2010
• Est. Priority Date: 09/01/2006
• Status: Active Grant

• Current Assignee: Zymogenetics Incorporated (Bristol-Myers Squibb Company)
• Original Assignee: Zymogenetics Incorporated (Bristol-Myers Squibb Company)
• Inventors: Rene, Shirley A., Siadak, Anthony W., Bilsborough, Janine M.
• Granted Patent: US 8,466,262 B2
• Time in Patent Office: Days
• US Class Current: 424/133.100
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• 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 17/14 for baldness or alopecia
• 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 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/244 Interleukins [IL]
• CPC Class Codes: C07K 2317/14 Specific host cells or culture conditions, e.g. components, pH or temperature
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/52 Constant or Fc region; Isotype
• 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 2317/732 Antibody-dependent cellular cytotoxicity [ADCC]
• CPC Class Codes: C07K 2317/734 Complement-dependent cytotoxicity [CDC]
• 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: C12N 5/0602 : Vertebrate cells

Abstract

Novel compositions derived from antigen-binding sites of immunoglobulins having affinity for IL-31 are provided. The compositions exhibit immunological binding properties of antibody molecules capable of binding specifically to a human IL-31. CDR regions derived from same or different immunoglobulin moieties are provided. Also provided are single chain polypeptides wherein VH and VL domains are attached. The sFv molecules can include ancillary polypeptide moieties which can be bioactive, or which provide a site of attachment for other useful moieties. The compositions are useful in specific binding assays, affinity purification schemes, drug or toxin targeting, imaging, and genetic or immunological therapeutics for inflammatory diseases. The invention thus provides novel polypeptides, the DNAs encoding those polypeptides, expression cassettes comprising those DNAs, and methods of inducing the production of the polypeptides. The invention further provides the amino acid sequences of the variable regions of the monoclonal antibodies and use of these monoclonal antibody or antibody fragment in conjunction with an human IgG4 Fc molecule.

Claims

1. A monoclonal antibody or antibody fragment that competes for specifically binding to a polypeptide comprising the amino acid sequence of SEQ ID NO:

2 wherein the monoclonal antibody comprises a light chain variable region and a heavy chain variable region selected from the group consisting of;

a) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

8 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

9;

b) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

10 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

11;

c) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

12 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

13;

d) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

14 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

15;

e) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

16 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

17;

f) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

18 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

19;

g) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

20 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

21;

h) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

22 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

23;

i) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

24 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

25; and

j) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

26 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

27 and wherein the monoclonal antibody or antibody fragment is used in conjunction with an human IgG4 Fc molecule.

9. The monoclonal antibody or antibody fragment according to claim 1, wherein the monoclonal antibody or antibody fragment inhibits, blocks, or neutralizes the interaction of IL-31 (SEQ ID NO:

2) with IL-31RA (SEQ ID NO;

5).

11. The monoclonal antibody or antibody fragment according to claim 1, wherein the monoclonal antibody or antibody fragment is selected from the group consisting of:

(a) a murine monoclonal antibody or antibody fragment;

(b) a humanized antibody or antibody fragment; and

(c) a human monoclonal antibody.

13. The monoclonal antibody or antibody fragment of claim 1, wherein the antibody further comprises PEGylation.

15. The monoclonal antibody or antibody fragment of claim 1, wherein the monoclonal antibody or antibody fragment comprising a light chain variable region and a heavy chain variable region where the monoclonal antibody or antibody fragment is selected from the group consisting of:

a) a monoclonal antibody or antibody fragment that competes for specifically binding to a polypeptide comprising the amino acid sequence of SEQ ID NO;

2 wherein the monoclonal antibody or antibody fragment comprises a light chain variable region and a heavy chain variable region selected from the group consisting of;

i) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

8 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

9; and

ii) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

26 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

27; and

b) a monoclonal antibody or antibody fragment that competes for specifically binding to a polypeptide comprising the amino acid sequence of SEQ ID NO;

2 wherein the monoclonal antibody or antibody fragment comprises a light chain variable region and a heavy chain variable region selected from the group consisting of;

i) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

10 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

11;

ii) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

12 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

13;

iii) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

14 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

15;

iv) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

16 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

17;

v) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

18 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

19;

vi) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

20 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

21;

vii) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

22 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

23; and

vii) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

24 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

25

and wherein the monoclonal antibody or antibody fragment is used in conjunction with an human IgG4 Fc molecule.

17. The monoclonal antibody or method according to claims 15 or 16, wherein the monoclonal antibody or antibody fragment competes for specifically binding to a polypeptide comprising the amino acid sequence of SEQ ID NO:

2 wherein the monoclonal antibody or antibody fragment comprises a light chain variable region and a heavy chain variable region selected from the group consisting of;

a) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

8 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

9; and

b) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

26 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

27.

18. The monoclonal antibody or method according to claims 15 or 16, wherein the monoclonal antibody or antibody fragment competes for specifically binding to a polypeptide comprising the amino acid sequence of SEQ ID NO:

2 wherein the monoclonal antibody or antibody fragment comprises a light chain variable region and a heavy chain variable region selected from the group consisting of;

a)) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

10 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

11;

b) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

12 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

13;

c) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

14 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

15;

d) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

16 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

17;

e) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

18 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

19;

f) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

20 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

21;

g) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

22 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

23; and

h) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

24 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

25 and wherein the monoclonal antibody or antibody fragment is used in conjunction with an human IgG4 Fc molecule.

2. A method of reducing, blocking, inhibiting, or neutralizing inflammation in a mammal comprising administering to the mammal an monoclonal antibody or antibody fragment that competes for specifically binding to a polypeptide comprising the amino acid sequence of SEQ ID NO:

2 wherein the monoclonal antibody comprises a light chain variable region and a heavy chain variable region selected from the group consisting of;

a) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

8 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

9;

b) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

10 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

11;

c) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

12 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

13;

d) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

14 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

15;

e) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

16 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

17;

f) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

18 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

19;

g) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

20 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

21;

h) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

22 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

23;

i) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

24 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

25; and

j) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

26 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

27 and wherein the monoclonal antibody or antibody fragment is used in conjunction with an human IgG4 Fc molecule.

3. The method of claim 2, wherein administration of the antibody to the mammal reduces, blocks, inhibits, or neutralizes production of pro-inflammatory chemokines.

4. The method of claim 2, wherein the pro-inflammatory chemokines are TARC or MDC.

10. The method of claims 2, 5, or 8 wherein the monoclonal antibody or antibody fragment inhibits, blocks, or neutralizes the interaction of IL-31 (SEQ ID NO:

2) with IL-31RA (SEQ ID NO;

5).

12. The method of claims 2, 5, or 8, wherein the monoclonal antibody or antibody fragment is selected from the group consisting of:

(a) a murine monoclonal antibody or antibody fragment;

(b) a humanized antibody or antibody fragment; and

(c) a human monoclonal antibody.

14. The method of claims 2, 5, or 8, wherein, wherein the antibody further comprises PEGylation.

16. The method according to claims 2, 5, or 8 wherein the monoclonal antibody or antibody fragment comprising a light chain variable region and a heavy chain variable region where the monoclonal antibody or antibody fragment is selected from the group consisting of:

a) a monoclonal antibody or antibody fragment that competes for specifically binding to a polypeptide comprising the amino acid sequence of SEQ ID NO;

2 wherein the monoclonal antibody or antibody fragment comprises a light chain variable region and a heavy chain variable region selected from the group consisting of;

i) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

8 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

9; and

ii) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

26 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

27; and

b) a monoclonal antibody or antibody fragment that competes for specifically binding to a polypeptide comprising the amino acid sequence of SEQ ID NO;

2 wherein the monoclonal antibody or antibody fragment comprises a light chain variable region and a heavy chain variable region selected from the group consisting of;

i) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

10 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

11;

ii) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

12 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

13;

iii) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

14 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

15;

iv) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

16 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

17;

v) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

18 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

19;

vi) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

20 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

21;

vii) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

22 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

23; and

vii) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

24 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

25

and wherein the monoclonal antibody or antibody fragment is used in conjunction with an human IgG4 Fc molecule.

5. A method of reducing, blocking, inhibiting, or neutralizing pruritis in a mammal comprising administering to the mammal an monoclonal antibody or antibody fragment that competes for specifically binding to a polypeptide comprising the amino acid sequence of SEQ ID NO:

2 wherein the monoclonal antibody comprises a light chain variable region and a heavy chain variable region selected from the group consisting of;

a) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

8 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

9;

b) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

10 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

11;

c) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

12 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

13;

d) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

14 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

15;

e) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

16 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

17;

f) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

18 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

19;

g) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

20 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

21;

h) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

22 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

23;

i) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

24 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

25; and

j) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

26 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

27 and wherein the monoclonal antibody or antibody fragment is used in conjunction with an human IgG4 Fc molecule.

6. The method of claim 5, wherein administration of the monoclonal antibody or antibody fragment reduces, blocks, inhibits, or neutralizes dermatitis.

7. The method of claim 5, wherein the dermatitis is atopic dermatitis or prurigo nodularis.

8. A method of reducing, blocking, inhibiting, or neutralizing scratching in a mammal comprising administering to the mammal an monoclonal antibody or antibody fragment that competes for specifically binding to a polypeptide comprising the amino acid sequence of SEQ ID NO:

2 wherein the monoclonal antibody comprises a light chain variable region and a heavy chain variable region selected from the group consisting of;

a) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

8 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

9;

b) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

10 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

11;

c) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

12 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

13;

d) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

14 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

15;

e) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

16 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

17;

f) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

18 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

19;

g) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

22 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

21;

h) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

22 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

23;

i) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

24 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

25; and

j) a light chain variable region comprising the amino acid sequence of SEQ ID NO;

26 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO;

27 and wherein the monoclonal antibody or antibody fragment is used in conjunction with an human IgG4 Fc molecule.

19. An isolated antibody that binds to human IL31, wherein said antibody is a humanized antibody derived from the monoclonal antibody produced by the hybridoma deposited with the American Type Culture Collection having the ATCC Patent Deposit Designation selected from:

a) ATCC Patent Deposit Designation PTA-6815;

b) ATCC Patent Deposit Designation PTA-6816;

c) ATCC Patent Deposit Designation PTA-6829;

d) ATCC Patent Deposit Designation PTA-6830;

e) ATCC Patent Deposit Designation PTA-6831;

f) ATCC Patent Deposit Designation PTA-6871;

g) ATCC Patent Deposit Designation PTA-6872;

h) ATCC Patent Deposit Designation PTA-6875; and

i) ATCC Patent Deposit Designation PTA-6873;

and wherein said antibody comprises a heavy chain immunoglobulin constant domain which is a human IgG4. In an embodiment, the human IgG4 constant domain is a mutated form stable in solution and with little or no complement activating activity. In a particular embodiment, the heavy chain immunoglobulin constant region domain is a human IgG4 constant domain with a Ser to Pro mutation at position 241 (Kabat numbering).

20. The isolated antibody according to claim 19, wherein the immunoglobulin light chain constant region domain is selected from the group consisting of the constant region of a kappa or lambda human immunoglobulin light chain.

21. An isolated antibody as disclosed herein wherein

a) the heavy chain variable domain comprises first CDR sequence consisting of amino acid sequence SEQ ID NO:

51, a second CDR sequence consisting of SEQ ID NO;

52 or SEQ ID NO;

57, and a third CDR sequence consisting of SEQ ID NO;

53; and

b) the light chain variable domain comprises first CDR sequence consisting of amino acid sequence SEQ ID NO;

54, a second CDR sequence consisting of SEQ ID NO;

55, and a third CDR sequence consisting of SEQ ID NO;

56.

22. An isolated antibody as disclosed herein wherein

a) the heavy chain variable domain comprises first CDR sequence consisting of amino acid sequence SEQ ID NO:

51, a second CDR sequence consisting of SEQ ID NO;

58, and a third CDR sequence consisting of SEQ ID NO;

59; and

b) the light chain variable domain comprises first CDR sequence consisting of amino acid sequence SEQ ID NO;

60, a second CDR sequence consisting of SEQ ID NO;

61, and a third CDR sequence consisting of SEQ ID NO;

62.

23. An isolated antibody as disclosed herein wherein

a) the heavy chain variable domain comprises first CDR sequence consisting of amino acid sequence SEQ ID NO:

63, a second CDR sequence consisting of SEQ ID NO;

64, and a third CDR sequence consisting of SEQ ID NO;

65; and

b) the light chain variable domain comprises first CDR sequence consisting of amino acid sequence SEQ ID NO;

66, a second CDR sequence consisting of SEQ ID NO;

67, and a third CDR sequence consisting of SEQ ID NO;

68.

24. An isolated antibody as disclosed herein wherein

a) the heavy chain variable domain comprises first CDR sequence consisting of amino acid sequence SEQ ID NO:

69, a second CDR sequence consisting of SEQ ID NO;

70 or SEQ ID NO;

79, and a third CDR sequence consisting of SEQ ID NO;

71; and

b) the light chain variable domain comprises first CDR sequence consisting of amino acid sequence SEQ ID NO;

72, a second CDR sequence consisting of SEQ ID NO;

73, and a third CDR sequence consisting of SEQ ID NO;

74.

25. An isolated antibody as disclosed herein wherein

a) the heavy chain variable domain comprises first CDR sequence consisting of amino acid sequence SEQ ID NO:

75, a second CDR sequence consisting of SEQ ID NO;

76, and a third CDR sequence consisting of SEQ ID NO;

65; and

b) the light chain variable domain comprises first CDR sequence consisting of amino acid sequence SEQ ID NO;

77, a second CDR sequence consisting of SEQ ID NO;

78, and a third CDR sequence consisting of SEQ ID NO;

68.

26. An isolated antibody as disclosed herein wherein

a) the heavy chain variable domain comprises first CDR sequence consisting of amino acid sequence SEQ ID NO:

80, a second CDR sequence consisting of SEQ ID NO;

817, and a third CDR sequence consisting of SEQ ID NO;

82; and

b) the light chain variable domain comprises first CDR sequence consisting of amino acid sequence SEQ ID NO;

83, a second CDR sequence consisting of SEQ ID NO;

84, and a third CDR sequence consisting of SEQ ID NO;

85.