Antibody drug conjugates for ablating hematopoietic stem cells

• US 11,357,864 B2
• Filed: 12/19/2017
• Issued: 06/14/2022
• Est. Priority Date: 12/21/2016
• Status: Active Grant

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: Wen, Ben, Boitano, Anthony E., Burger, Matthew, Cellitti, Susan E., Cooke, Michael P., Finner, Catrin, Geierstanger, Bernhard Hubert, Jin, Yunho, Lee-Hoeflich, Si Tuen, Pham, HongNgoc Thi, Schleyer, Siew Ho, Tissot, Kathrin, Uno, Tetsuo
• Primary Examiner(s): Haddad, Maher M
• Application Number:
  US16/470,897
• Publication Number:
  US 20190321483A1
• Time in Patent Office: 1,638 Days
• Field of Search: None
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 38/07 Tetrapeptides
• CPC Class Codes: A61K 38/12 Cyclic peptides , e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 47/6803 Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
• CPC Class Codes: A61K 47/6831 Fungal toxins, e.g. alpha sarcine, mitogillin, zinniol or restrictocin
• CPC Class Codes: A61K 47/6849 the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 2317/55 Fab or Fab'
• CPC Class Codes: C07K 2317/73 Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C07K 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Abstract

The present invention provides antibody drug conjugates, wherein an antibody or antibody fragment that specifically binds to human cKIT is linked to a drug moiety, optionally through a linker. The present invention further provides pharmaceutical compositions comprising the antibody drug conjugates; and methods of making and using such pharmaceutical compositions for ablating hematopoietic stem cells in a patient in need thereof.

Claims

1. A conjugate of Formula (I) or a pharmaceutically acceptable salt thereof;

A-(L_B-(D)_n)_y 

 

Formula (I)

wherein;

A is an antibody fragment that specifically binds to human cKIT, wherein the antibody fragment is selected from any of the following;

(1) a Fab or Fab′

comprising (i) a heavy chain variable region that comprises (a) a HCDR1 (Heavy Chain Complementarity Determining Region

     1) of SEQ ID NO;

1, (b) a HCDR2 (Heavy Chain Complementarity Determining Region

     2) of SEQ ID NO;

2, and (c) a HCDR3 (Heavy Chain Complementarity Determining Region

     3) of SEQ ID NO;

3; and

(ii) a light chain variable region that comprises;

(d) a LCDR1 (Light Chain Complementarity Determining Region

     1) of SEQ ID NO;

16, (e) a LCDR2 (Light Chain Complementarity Determining Region

     2) of SEQ ID NO;

17, and (f) a LCDR3 (Light Chain Complementarity Determining Region

     3) of SEQ ID NO;

18;

(2) a Fab or Fab′

comprising (i) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO;

4, (b) a HCDR2 of SEQ ID NO;

5, (c) a HCDR3 of SEQ ID NO;

3; and

(ii) a light chain variable region that comprises;

(d) a LCDR1 of SEQ ID NO;

19, (e) a LCDR2 of SEQ ID NO;

20, and (f) a LCDR3 of SEQ ID NO;

21;

(3) a Fab or Fab′

comprising (i) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO;

6, (b) a HCDR2 of SEQ ID NO;

2, (c) a HCDR3 of SEQ ID NO;

3; and

(ii) a light chain variable region that comprises;

(d) a LCDR1 of SEQ ID NO;

16, (e) a LCDR2 of SEQ ID NO;

17, and (f) a LCDR3 of SEQ ID NO;

18;

(4) a Fab or Fab′

comprising (i) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO;

7, (b) a HCDR2 of SEQ ID NO;

8, (c) a HCDR3 of SEQ ID NO;

9; and

(ii) a light chain variable region that comprises;

(d) a LCDR1 of SEQ ID NO;

22, (e) a LCDR2 of SEQ ID NO;

20, and (f) a LCDR3 of SEQ ID NO;

18;

(5) a Fab or Fab′

comprising (i) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO;

27, (b) a HCDR2 of SEQ ID NO;

28, (c) a HCDR3 of SEQ ID NO;

29; and

(ii) a light chain variable region that comprises;

(d) a LCDR1 of SEQ ID NO;

42, (e) a LCDR2 of SEQ ID NO;

17, and (f) a LCDR3 of SEQ ID NO;

43;

(6) a Fab or Fab′

comprising (i) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO;

30, (b) a HCDR2 of SEQ ID NO;

31, (c) a HCDR3 of SEQ ID NO;

29; and

(ii) a light chain variable region that comprises;

(d) a LCDR1 of SEQ ID NO;

44, (e) a LCDR2 of SEQ ID NO;

20, and (f) a LCDR3 of SEQ ID NO;

45;

(7) a Fab or Fab′

comprising (i) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO;

32, (b) a HCDR2 of SEQ ID NO;

28, (c) a HCDR3 of SEQ ID NO;

29; and

(ii) a light chain variable region that comprises;

(d) a LCDR1 of SEQ ID NO;

42, (e) a LCDR2 of SEQ ID NO;

17, and (f) a LCDR3 of SEQ ID NO;

43;

(8) a Fab or Fab′

comprising (i) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO;

33, (b) a HCDR2 of SEQ ID NO;

34, (c) a HCDR3 of SEQ ID NO;

35; and

(ii) a light chain variable region that comprises;

(d) a LCDR1 of SEQ ID NO;

46, (e) a LCDR2 of SEQ ID NO;

20, and (f) a LCDR3 of SEQ ID NO;

43;

(9) a Fab or Fab′

comprising (i) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO;

60, (b) a HCDR2 of SEQ ID NO;

61, (c) a HCDR3 of SEQ ID NO;

62; and

(ii) a light chain variable region that comprises;

(d) a LCDR1 of SEQ ID NO;

75, (e) a LCDR2 of SEQ ID NO;

76, and (f) a LCDR3 of SEQ ID NO;

77;

(10) a Fab or Fab′

comprising (i) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO;

63, (b) a HCDR2 of SEQ ID NO;

64, (c) a HCDR3 of SEQ ID NO;

62; and

(ii) a light chain variable region that comprises;

(d) a LCDR1 of SEQ ID NO;

78, (e) a LCDR2 of SEQ ID NO;

79, and (f) a LCDR3 of SEQ ID NO;

80;

(11) a Fab or Fab′

comprising (i) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO;

65, (b) a HCDR2 of SEQ ID NO;

61, (c) a HCDR3 of SEQ ID NO;

62; and

(ii) a light chain variable region that comprises;

(d) a LCDR1 of SEQ ID NO;

75, (e) a LCDR2 of SEQ ID NO;

76, and (f) a LCDR3 of SEQ ID NO;

77;

(12) a Fab or Fab′

comprising (i) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO;

66, (b) a HCDR2 of SEQ ID NO;

67, (c) a HCDR3 of SEQ ID NO;

68; and

(ii) a light chain variable region that comprises;

(d) a LCDR1 of SEQ ID NO;

81, (e) a LCDR2 of SEQ ID NO;

79, and (f) a LCDR3 of SEQ ID NO;

77;

(13) a Fab or Fab′

comprising (i) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO;

86, (b) a HCDR2 of SEQ ID NO;

87, (c) a HCDR3 of SEQ ID NO;

88; and

(ii) a light chain variable region that comprises;

(d) a LCDR1 of SEQ ID NO;

101, (e) a LCDR2 of SEQ ID NO;

102, and (f) a LCDR3 of SEQ ID NO;

103;

(14) a Fab or Fab′

comprising (i) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO;

89, (b) a HCDR2 of SEQ ID NO;

90, (c) a HCDR3 of SEQ ID NO;

88; and

(ii) a light chain variable region that comprises;

(d) a LCDR1 of SEQ ID NO;

104, (e) a LCDR2 of SEQ ID NO;

105, and (f) a LCDR3 of SEQ ID NO;

106;

(15) a Fab or Fab′

comprising (i) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO;

91, (b) a HCDR2 of SEQ ID NO;

87, (c) a HCDR3 of SEQ ID NO;

88; and

(ii) a light chain variable region that comprises;

(d) a LCDR1 of SEQ ID NO;

101, (e) a LCDR2 of SEQ ID NO;

102, and (f) a LCDR3 of SEQ ID NO;

103;

(16) a Fab or Fab′

comprising (i) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO;

92, (b) a HCDR2 of SEQ ID NO;

93, (c) a HCDR3 of SEQ ID NO;

94; and

(ii) a light chain variable region that comprises;

(d) a LCDR1 of SEQ ID NO;

107, (e) a LCDR2 of SEQ ID NO;

105, and (f) a LCDR3 of SEQ ID NO;

103;

(17) a Fab or Fab′

comprising a heavy chain variable region (VH) that comprises SEQ ID NO;

10, and a light chain variable region (VL) that comprises SEQ ID NO;

23;

(18) a Fab or Fab′

comprising a VH that comprises SEQ ID NO;

36, and a VL that comprises SEQ ID NO;

47;

(19) a Fab or Fab′

comprising a VH that comprises SEQ ID NO;

69, and a VL that comprises SEQ ID NO;

82;

(20) a Fab or Fab′

comprising a VH that comprises SEQ ID NO;

95, and a VL that comprises SEQ ID NO;

108;

(21) a Fab′

comprising a heavy chain that that comprises SEQ ID NO;

14, and a light chain that comprises SEQ ID NO;

25;

(22) a Fab′

comprising a heavy chain that that comprises SEQ ID NO;

40, and a light chain that comprises SEQ ID NO;

49;

(23) a Fab′

comprising a heavy chain that that comprises SEQ ID NO;

73, and a light chain that comprises SEQ ID NO;

84;

(24) a Fab′

comprising a heavy chain that that comprises SEQ ID NO;

99, and a light chain that comprises SEQ ID NO;

110;

(25) a Fab comprising a heavy chain that comprises SEQ ID NO;

118, and a light chain that comprises SEQ ID NO;

122;

(26) a Fab comprising a heavy chain that comprises SEQ ID NO;

118, and a light chain that comprises SEQ ID NO;

123;

(27) a Fab comprising a heavy chain that comprises SEQ ID NO;

124, and a light chain that comprises SEQ ID NO;

128;

(28) a Fab comprising a heavy chain that comprises SEQ ID NO;

124, and a light chain that comprises SEQ ID NO;

129;

(29) a Fab comprising a heavy chain that comprises SEQ ID NO;

130, and a light chain that comprises SEQ ID NO;

134;

(30) a Fab comprising a heavy chain that comprises SEQ ID NO;

130, and a light chain that comprises SEQ ID NO;

135;

(31) a Fab comprising a heavy chain that comprises SEQ ID NO;

136, and a light chain that comprises SEQ ID NO;

140;

(32) a Fab comprising a heavy chain that comprises SEQ ID NO;

141, and a light chain that comprises SEQ ID NO;

145;

(33) a Fab comprising a heavy chain that comprises an amino acid sequence selected from SEQ ID NO;

119, 120 or 121, and a light chain comprising the amino acid sequence of SEQ ID NO;

25;

(34) a Fab comprising a heavy chain that comprises an amino acid sequence selected from SEQ ID NO;

125, 126, or 127, and a light chain comprising the amino acid sequence of SEQ ID NO;

49;

(35) a Fab comprising a heavy chain that comprises an amino acid sequence selected from SEQ ID NO;

137, 138, or 139, and a light chain comprising the amino acid sequence of SEQ ID NO;

84;

or

(36) a Fab comprising a heavy chain that comprises an amino acid sequence selected from SEQ ID NO;

142, 143, or 144, and a light chain comprising the amino acid sequence of SEQ ID NO;

110;

L_B is a linker;

D is a cytotoxic agent;

n is an integer from 1 to 10; and

y is an integer from 1 to 10.

2. The conjugate of claim 1, wherein y is 1, 2, 3 or 4.

3. The conjugate of claim 1, wherein each D is a cytotoxic agent independently selected from an auristatin, an amanitin, a maytansinoid or a saporin.

4. The conjugate of claim 1, wherein each L_B is independently selected from a cleavable linker or a non-cleavable linker.

5. The conjugate of claim 1, wherein the Formula (I) is selected from:

6. The conjugate of claim 1, wherein the antibody fragment specifically binds to the extracellular domain of human cKIT (SEQ ID NO:

112).

7. The conjugate of claim 1, wherein the antibody fragment specifically binds to an epitope in domains 1-3 of human cKIT (SEQ ID NO:

113).

8. The conjugate of claim 1, wherein the antibody fragment is a human or humanized Fab or Fab′

.

9. The conjugate of claim 1, wherein the antibody fragment is a Fab′

and the linker (LB) is attached to a native cysteine residue in the hinge region of the Fab′

.

10. The conjugate of claim 1, wherein the conjugate has a half-life less than about 24-48 hours.

11. The conjugate of claim 1, wherein the conjugate does not induce mast cell degranulation.

12. A pharmaceutical composition comprising the conjugate of claim 1 and a pharmaceutically acceptable carrier.

13. A method of ablating hematopoietic stem cells in a patient in need thereof, the method comprising administering to the patient an effective amount of the pharmaceutical composition of claim 12.

14. The method of claim 13, wherein the patient is a hematopoietic stem cell transplantation recipient.

15. The method of claim 14, wherein the method is performed before hematopoietic stem cell transplantation to the patient.

16. A method of conditioning a hematopoietic stem cell transplantation patient, the method comprising:

administering to the patient an effective amount of the pharmaceutical composition of claim 12, and allowing a sufficient period of time for the conjugates to clear from the patient'"'"'s circulation before performing hematopoietic stem cell transplantation to the patient.

17. The method of claim 16, wherein the patient has an inherited immunodeficient disease, an autoimmune disorder, a hematopoietic disorder, or an inborn error of metabolism.

18. The method of claim 17, wherein the hematopoietic disorder is selected from:

Acute myeloid leukemia (AML), Acute lymphoblastic leukemia (ALL), acute monocytic leukemia (AMoL), Chronic myeloid leukemia (CIVIL), Chronic lymphocytic leukemia (CLL), Myeloproliferative disorders, Myelodysplastic syndromes, Multiple myeloma, Non-Hodgkin lymphoma, Hodgkin disease, Aplastic anemia, Pure red cell aplasia, Paroxysmal nocturnal hemoglobinuria, Fanconi anemi, Thalassemia major, Sickle cell anemia, Severe combined immunodeficiency, Wiskott-Aldrich syndrome, Hemophagocytic lymphohistiocytosis.

19. The method of claim 17, wherein the inborn error of metabolism is selected from mucopolysaccharidosis, Gaucher disease, metachromatic leukodystrophies, or adrenoleukodystrophies.

20. The method of claim 16, wherein the patient has a non-malignant disease or condition selected from Severe aplastic anemia (SAA), Wiskott Aldrich Syndrome, Hurlers Syndrome, FHL, CGD, Kostmanns syndrome, Severe immunodeficiency syndrome (SCID), other autoimmune disorders such as SLE, Multiple sclerosis, IBD, Crolms Disease, Sjogrens syndrome, vasculitis, Lupus, Myasthenia Gravis, Wegeners disease, inborn errors of metabolism and/or other immunodeficiencies.

21. The method of claim 16, wherein the patient has a malignant disease or condition selected from myelodysplastic syndromes (MDS), acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), acute monocytic leukemia (AMoL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), hairy cell leukemia (HCL), T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, adult T-cell leukemia, Precursor T-cell leukemia/lymphoma, Burkitt lymphoma, follicular lymphoma, diffuse large B cell lymphoma, mantle cell lymphoma, B-cell chronic lymphocytic leukemia/lymphoma, MALT lymphoma, Mycosis fungoides, Peripheral T-cell lymphoma not otherwise specified, Nodular sclerosis form of Hodgkin lymphoma Mixed-cellularity subtype of Hodgkin lymphoma.

22. An antibody or antibody fragment that specifically binds to human cKIT, wherein the antibody or antibody fragment is selected from any of the following:

(1) an antibody or antibody fragment comprising (i) a heavy chain variable region that comprises (a) a HCDR1 (Heavy Chain Complementarity Determining Region

     1) of SEQ ID NO;

1, (b) a HCDR2 (Heavy Chain Complementarity Determining Region

     2) of SEQ ID NO;

2, and (c) a HCDR3 (Heavy Chain Complementarity Determining Region

     3) of SEQ ID NO;

3; and

(ii) a light chain variable region that comprises;

(d) a LCDR1 (Light Chain Complementarity Determining Region

     1) of SEQ ID NO;

16, (e) a LCDR2 (Light Chain Complementarity Determining Region

     2) of SEQ ID NO;

17, and (f) a LCDR3 (Light Chain Complementarity Determining Region

     3) of SEQ ID NO;

18;

(2) an antibody or antibody fragment comprising (i) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO;

4, (b) a HCDR2 of SEQ ID NO;

5, (c) a HCDR3 of SEQ ID NO;

3; and

(ii) a light chain variable region that comprises;

(d) a LCDR1 of SEQ ID NO;

19, (e) a LCDR2 of SEQ ID NO;

20, and (f) a LCDR3 of SEQ ID NO;

21;

(3) an antibody or antibody fragment comprising (i) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO;

6, (b) a HCDR2 of SEQ ID NO;

2, (c) a HCDR3 of SEQ ID NO;

3; and

(ii) a light chain variable region that comprises;

(d) a LCDR1 of SEQ ID NO;

16, (e) a LCDR2 of SEQ ID NO;

17, and (f) a LCDR3 of SEQ ID NO;

18;

(4) an antibody or antibody fragment comprising (i) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO;

7, (b) a HCDR2 of SEQ ID NO;

8, (c) a HCDR3 of SEQ ID NO;

9; and

(ii) a light chain variable region that comprises;

(d) a LCDR1 of SEQ ID NO;

22, (e) a LCDR2 of SEQ ID NO;

20, and (f) a LCDR3 of SEQ ID NO;

18;

(5) an antibody or antibody fragment comprising (i) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO;

27, (b) a HCDR2 of SEQ ID NO;

28, (c) a HCDR3 of SEQ ID NO;

29; and

(ii) a light chain variable region that comprises;

(d) a LCDR1 of SEQ ID NO;

42, (e) a LCDR2 of SEQ ID NO;

17, and (f) a LCDR3 of SEQ ID NO;

43;

(6) an antibody or antibody fragment comprising (i) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO;

30, (b) a HCDR2 of SEQ ID NO;

31, (c) a HCDR3 of SEQ ID NO;

29; and

(ii) a light chain variable region that comprises;

(d) a LCDR1 of SEQ ID NO;

44, (e) a LCDR2 of SEQ ID NO;

20, and (f) a LCDR3 of SEQ ID NO;

45;

(7) an antibody or antibody fragment comprising (i) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO;

32, (b) a HCDR2 of SEQ ID NO;

28, (c) a HCDR3 of SEQ ID NO;

29; and

(ii) a light chain variable region that comprises;

(d) a LCDR1 of SEQ ID NO;

42, (e) a LCDR2 of SEQ ID NO;

17, and (f) a LCDR3 of SEQ ID NO;

43;

(8) an antibody or antibody fragment comprising (i) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO;

33, (b) a HCDR2 of SEQ ID NO;

34, (c) a HCDR3 of SEQ ID NO;

35; and

(ii) a light chain variable region that comprises;

(d) a LCDR1 of SEQ ID NO;

46, (e) a LCDR2 of SEQ ID NO;

20, and (f) a LCDR3 of SEQ ID NO;

43;

(9) an antibody or antibody fragment comprising (i) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO;

60, (b) a HCDR2 of SEQ ID NO;

61, (c) a HCDR3 of SEQ ID NO;

62; and

(ii) a light chain variable region that comprises;

(d) a LCDR1 of SEQ ID NO;

75, (e) a LCDR2 of SEQ ID NO;

76, and (f) a LCDR3 of SEQ ID NO;

77;

(10) an antibody or antibody fragment comprising (i) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO;

63, (b) a HCDR2 of SEQ ID NO;

64, (c) a HCDR3 of SEQ ID NO;

62; and

(ii) a light chain variable region that comprises;

(d) a LCDR1 of SEQ ID NO;

78, (e) a LCDR2 of SEQ ID NO;

79, and (f) a LCDR3 of SEQ ID NO;

80;

(11) an antibody or antibody fragment comprising (i) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO;

65, (b) a HCDR2 of SEQ ID NO;

61, (c) a HCDR3 of SEQ ID NO;

62; and

(ii) a light chain variable region that comprises;

(d) a LCDR1 of SEQ ID NO;

75, (e) a LCDR2 of SEQ ID NO;

76, and (f) a LCDR3 of SEQ ID NO;

77;

(12) an antibody or antibody fragment comprising (i) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO;

66, (b) a HCDR2 of SEQ ID NO;

67, (c) a HCDR3 of SEQ ID NO;

68; and

(ii) a light chain variable region that comprises;

(d) a LCDR1 of SEQ ID NO;

81, (e) a LCDR2 of SEQ ID NO;

79, and (f) a LCDR3 of SEQ ID NO;

77;

(13) an antibody or antibody fragment comprising (i) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO;

86, (b) a HCDR2 of SEQ ID NO;

87, (c) a HCDR3 of SEQ ID NO;

88; and

(ii) a light chain variable region that comprises;

(d) a LCDR1 of SEQ ID NO;

101, (e) a LCDR2 of SEQ ID NO;

102, and (f) a LCDR3 of SEQ ID NO;

103;

(14) an antibody or antibody fragment comprising (i) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO;

89, (b) a HCDR2 of SEQ ID NO;

90, (c) a HCDR3 of SEQ ID NO;

88; and

(ii) a light chain variable region that comprises;

(d) a LCDR1 of SEQ ID NO;

104, (e) a LCDR2 of SEQ ID NO;

105, and (f) a LCDR3 of SEQ ID NO;

106;

(15) an antibody or antibody fragment comprising (i) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO;

91, (b) a HCDR2 of SEQ ID NO;

87, (c) a HCDR3 of SEQ ID NO;

88; and

(ii) a light chain variable region that comprises;

(d) a LCDR1 of SEQ ID NO;

101, (e) a LCDR2 of SEQ ID NO;

102, and (f) a LCDR3 of SEQ ID NO;

103;

(16) an antibody or antibody fragment comprising (i) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO;

92, (b) a HCDR2 of SEQ ID NO;

93, (c) a HCDR3 of SEQ ID NO;

94; and

(ii) a light chain variable region that comprises;

(d) a LCDR1 of SEQ ID NO;

107, (e) a LCDR2 of SEQ ID NO;

105, and (f) a LCDR3 of SEQ ID NO;

103;

(17) an antibody or antibody fragment comprising a heavy chain variable region (VH) that comprises SEQ ID NO;

10, and a light chain variable region (VL) that comprises SEQ ID NO;

23;

(18) an antibody or antibody fragment comprising a VH that comprises SEQ ID NO;

36, and a VL that comprises SEQ ID NO;

47;

(19) an antibody or antibody fragment comprising a VH that comprises SEQ ID NO;

69, and a VL that comprises SEQ ID NO;

82;

(20) an antibody or antibody fragment comprising a VH that comprises SEQ ID NO;

95, and a VL that comprises SEQ ID NO;

108;

(21) an antibody or antibody fragment comprising a heavy chain that that comprises SEQ ID NO;

14, and a light chain that comprises SEQ ID NO;

25;

(22) an antibody or antibody fragment comprising a heavy chain that that comprises SEQ ID NO;

40, and a light chain that comprises SEQ ID NO;

49;

(23) an antibody or antibody fragment comprising a heavy chain that that comprises SEQ ID NO;

73, and a light chain that comprises SEQ ID NO;

84;

(24) an antibody or antibody fragment comprising a heavy chain that that comprises SEQ ID NO;

99, and a light chain that comprises SEQ ID NO;

110;

(25) an antibody or antibody fragment comprising a heavy chain that comprises SEQ ID NO;

118, and a light chain that comprises SEQ ID NO;

122;

(26) an antibody or antibody fragment comprising a heavy chain that comprises SEQ ID NO;

118, and a light chain that comprises SEQ ID NO;

123;

(27) an antibody or antibody fragment comprising a heavy chain that comprises SEQ ID NO;

124, and a light chain that comprises SEQ ID NO;

128;

(28) an antibody or antibody fragment comprising a heavy chain that comprises SEQ ID NO;

124, and a light chain that comprises SEQ ID NO;

129;

(29) an antibody or antibody fragment comprising a heavy chain that comprises SEQ ID NO;

130, and a light chain that comprises SEQ ID NO;

134;

(30) an antibody or antibody fragment comprising a heavy chain that comprises SEQ ID NO;

130, and a light chain that comprises SEQ ID NO;

135;

(31) an antibody or antibody fragment comprising a heavy chain that comprises SEQ ID NO;

136, and a light chain that comprises SEQ ID NO;

140;

(32) an antibody or antibody fragment comprising a heavy chain that comprises SEQ ID NO;

141, and a light chain that comprises SEQ ID NO;

145;

(33) an antibody comprising a heavy chain that that comprises SEQ ID NO;

12, and a light chain that comprises SEQ ID NO;

25;

(34) an antibody comprising a heavy chain that that comprises SEQ ID NO;

38, and a light chain that comprises SEQ ID NO;

49;

(35) an antibody comprising a heavy chain that that comprises SEQ ID NO;

71, and a light chain that comprises SEQ ID NO;

84;

or

(36) an antibody comprising a heavy chain that that comprises SEQ ID NO;

97, and a light chain that comprises SEQ ID NO;

110.

23. A nucleic acid encoding an antibody or antibody fragment of claim 22.