ANTI-TIGIT ANTIBODIES

• US 20160355589A1
• Filed: 08/17/2015
• Published: 12/08/2016
• Est. Priority Date: 08/19/2014
• Status: Abandoned Application

• Current Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Original Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Inventors: Williams, Sybil M. G., Fayadat-Dilman, Laurence, LaFace, Drake, Raghunathan, Gopalan, Liang, Linda, Seghezzi, Wolfgang
• Application Number:
  US15/121,624
• Publication Number:
  US 20160355589A1
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/507 Comprising a combination of two or more separate antibodies
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/28 against receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: C07K 16/2803 against the immunoglobulin superfamily
• CPC Class Codes: C07K 16/2818 against CD28 or CD152
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/34 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 2317/52 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 2317/73 Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C07K 2317/74 Inducing cell proliferation
• 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: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention relates to anti-TIGIT antibodies, as well as use of these antibodies in the treatment of diseases such as cancer and infectious disease.

Claims

1. An antibody or antigen binding fragment thereof that binds to human TIGIT, wherein the antibody or antigen binding fragment is selected from the group consisting of:

a. an antibody or antigen binding fragment comprising;

a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO;

1, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO;

2, a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO;

3, 79, 80, 81, 82, 83 or 140, a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO;

4, a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO;

5, 65, 66, 67, 68, 69, 70, 71, 72, 73 or 41, and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO;

6, 74, 75, 76, 77, 78 or 142;

b. an antibody or antigen binding fragment comprising;

a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO;

57, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO;

58, a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO;

59, a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO;

60, a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO;

61, and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO;

62; and

c. an antibody or antigen binding fragment comprising;

a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO;

88, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO;

89, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 134, 135 or 147, a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO;

90, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166 or 167, a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO;

91, a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO;

92, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122 or 148, and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO;

93.

2. The antibody or antigen binding fragment of claim 1, wherein the antibody comprises a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:

1, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO;

2, a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO;

3, a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO;

4, a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO;

5, and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO;

6.

3. The antibody or antigen binding fragment of claim 1, wherein the antibody comprises a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:

88, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO;

89, 134 or 135, a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO;

90, a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO;

91, a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO;

92, and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO;

93.

4. The antibody or antigen binding fragment of claim 1, wherein the antibody comprises a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:

88, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO;

134, a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO;

90, a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO;

91, a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO;

92, and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO;

93.

6. The antibody or antigen binding fragment of claim 1, wherein the antibody or antigen binding fragment thereof binds to human TIGIT with a KD value of about 1×

10-9 M to about 1×

10-12 M as determined by surface plasmon resonance (e.g., BIACORE) or a similar technique (e.g. KinExa or OCTET).

10. The antibody or antigen binding fragment of claim 1, which is a humanized antibody comprising two heavy chains and two light chains.

11. The antibody or antigen binding fragment of claim 1, which is a humanized antibody, wherein the antibody comprises a human IgG1 constant domain and a human kappa constant domain.

14. An isolated nucleic acid encoding:

any one of the antibodies or antigen binding fragments of claim 1.

15. An expression vector comprising the isolated nucleic acid of claim 14.

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

18. A composition comprising the antibody or antigen binding fragment of claim 1 and a pharmaceutically acceptable carrier or diluent.

19. The composition of claim 18, further comprising an agent selected from the group consisting of:

a. an anti-PD1 antibody or an antigen binding fragment thereof;

b. an anti-LAG3 antibody or an antigen binding fragment thereof;

c. an anti-VISTA antibody or an antigen binding fragment thereof;

d. an anti-BTLA antibody or an antigen binding fragment thereof;

e. an anti-TIM3 antibody or an antigen binding fragment thereof;

f. an anti-CTLA4 antibody or an antigen binding fragment thereof;

g. an anti-HVEM antibody or an antigen binding fragment thereof;

h. an anti-CD27 antibody or an antigen binding fragment thereof;

i. an anti-CD137 antibody or an antigen binding fragment thereof;

j. an anti-OX40 antibody or an antigen binding fragment thereof;

k. an anti-CD28 antibody or an antigen binding fragment thereof;

l. an anti-PDL1 antibody or an antigen binding fragment thereof;

m. an anti-PDL2 antibody or an antigen binding fragment thereof;

n. an anti-GITR antibody or an antigen binding fragment thereof;

o. an anti-ICOS antibody or an antigen binding fragment thereof;

p. an anti-SIRPα

antibody or an antigen binding fragment thereof;

q. an anti-ILT2 antibody or an antigen binding fragment thereof;

r. an anti-ILT3 antibody or an antigen binding fragment thereof;

s. an anti-ILT4 antibody or an antigen binding fragment thereof; and

t. an anti-ILT5 antibody or an antigen binding fragment thereof.

20. The composition of claim 19, wherein the anti-PD1 antibody or an antigen binding fragment thereof is selected from the group consisting of:

pembrolizumab or an antigen binding fragment thereof and nivolumab or an antigen binding fragment thereof.

22. A method of treating cancer in a human subject, comprising administering to the subject an effective amount of the antibody or antigen binding fragment of claim 1, optionally in association with a further therapeutic agent or therapeutic procedure.

23. A method of treating an infection or infectious disease in a human subject, comprising administering to the subject an effective amount of the antibody or antigen binding fragment of claim 1, optionally in association with a further therapeutic agent or therapeutic procedure.

24. A vaccine comprising the antibody or antigen binding fragment of claim 1 and an antigen.

5. An antibody or antigen binding fragment thereof that binds to human TIGIT comprising a light chain immunoglobulin, a heavy chain immunoglobulin or both a light chain and a heavy chain immunoglobulin selected from the group consisting of:

a. an antibody or antigen binding fragment thereof comprising a variable heavy chain comprising the amino acid sequence of SEQ ID NO;

7 and/or a variable light chain comprising the amino acid sequence of SEQ ID NO;

8;

b. an antibody or antigen binding fragment thereof comprising a variable heavy chain comprising the amino acid sequence of SEQ ID NO;

63 and/or a variable light chain comprising the amino acid sequence of SEQ ID NO;

64;

c. an antibody or antigen binding fragment thereof comprising a variable heavy chain comprising the amino acid sequence of SEQ ID NO;

94 and/or a variable light chain comprising the amino acid sequence of SEQ ID NO;

95;

d. an antibody or antigen binding fragment thereof comprising a variable heavy chain selected from the group consisting of SEQ ID NOs;

9-24, 37-47 and 63 and/or a variable light chain selected from the group consisting of any one of SEQ ID NOs;

25-30, 48-52 and 64;

e. an antibody or antigen binding fragment thereof comprising a variable heavy chain selected from the group consisting of SEQ ID NOs;

124-129 and/or a variable light chain selected from the group consisting of any one of SEQ ID NOs;

130-133;

f. an antibody or antigen binding fragment thereof comprising a variable heavy chain comprising the amino acid sequence of SEQ ID NO;

128 and/or a variable light chain comprising the amino acid sequence of SEQ ID NO;

132;

g. an antibody or antigen binding fragment thereof comprising a variable heavy chain comprising the amino acid sequence of SEQ ID NO;

127 and/or a variable light chain comprising the amino acid sequence of SEQ ID NO;

130; and

h. an antibody or antigen binding fragment thereof comprising a variable heavy chain comprising the amino acid sequence of SEQ ID NO;

128 and/or a variable light chain comprising the amino acid sequence of SEQ ID NO;

133;

i. an antibody or antigen binding fragment thereof comprising a variable heavy chain comprising the amino acid sequence of SEQ ID NO;

143 and/or a variable light chain comprising the amino acid sequence of SEQ ID NO;

145;

j. an antibody or antigen binding fragment thereof comprising a variable heavy chain comprising the amino acid sequence of SEQ ID NO;

149 and/or a variable light chain comprising the amino acid sequence of SEQ ID NO;

151;

k. an antibody or antigen binding fragment thereof comprising a variable heavy chain comprising the amino acid sequence of SEQ ID NO;

144 and/or a variable light chain comprising the amino acid sequence of SEQ ID NO;

146;

l. an antibody or antigen binding fragment thereof comprising a variable heavy chain comprising the amino acid sequence of SEQ ID NO;

150 and/or a variable light chain comprising the amino acid sequence of SEQ ID NO;

152;

m. an antibody or antigen binding fragment thereof comprising a variable heavy chain comprising at least 90%, 95%, 96%, 97%, 98% or 99% identity any one of SEQ ID NOs;

7, 9-24, 37-47 and 63 and/or a variable light chain comprising at least 90%, 95%, 96%, 97%, 98% or 99% identity to any one of SEQ ID NOs;

8, 25-30, 48-52 and 64;

n. an antibody or antigen binding fragment thereof comprising a variable heavy chain comprising at least 90%, 95%, 96%, 97%, 98% or 99% identity any one of SEQ ID NOs;

7, 9-24, 37-47 and 63 and/or a variable light chain comprising at least 90%, 95%, 95%, 96%, 97%, 98% or 99% identity to any one of SEQ ID NOs;

8, 25-30, 48-52 and 64, wherein any sequence variations occur in the framework regions of the antibody;

o. an antibody or antigen binding fragment thereof comprising a variable heavy chain comprising at least 90%, 95%, 96%, 97%, 98% or 99% identity any one of SEQ ID NOs;

124-129 and/or a variable light chain comprising at least 90%, 95%, 96%, 97%, 98% or 99% identity to any one of SEQ ID NOs;

130-133; and

p. an antibody or antigen binding fragment thereof comprising a variable heavy chain comprising at least 90%, 95%, 96%, 97%, 98% or 99% identity any one of SEQ ID NOs;

124-129 and/or a variable light chain comprising at least 90%, 95%, 95%, 96%, 97%, 98% or 99% identity to any one of SEQ ID NOs;

130-133, wherein any sequence variations occur in the framework regions of the antibody;

q. an antibody or antigen binding fragment thereof comprising a variable heavy chain comprising at least 90%, 95%, 96%, 97%, 98% or 99% identity SEQ ID NO;

128 and/or a variable light chain comprising at least 90%, 95%, 96%, 97%, 98% or 99% identity to any one of SEQ ID NOs;

132;

r. an antibody or antigen binding fragment thereof comprising a variable heavy chain comprising at least 90%, 95%, 96%, 97%, 98% or 99% identity SEQ ID NO;

128 and/or a variable light chain comprising at least 90%, 95%, 96%, 97%, 98% or 99% identity to any one of SEQ ID NOs;

132, wherein any sequence variations occur in the framework regions of the antibody;

s. an antibody or antigen binding fragment thereof comprising a variable heavy chain comprising at least 90%, 95%, 96%, 97%, 98% or 99% identity SEQ ID NO;

127 and/or a variable light chain comprising at least 90%, 95%, 96%, 97%, 98% or 99% identity to any one of SEQ ID NOs;

130;

t. an antibody or antigen binding fragment thereof comprising a variable heavy chain comprising at least 90%, 95%, 96%, 97%, 98% or 99% identity SEQ ID NO;

127 and/or a variable light chain comprising at least 90%, 95%, 96%, 97%, 98% or 99% identity to any one of SEQ ID NOs;

130, wherein any sequence variations occur in the framework regions of the antibody;

u. an antibody or antigen binding fragment thereof comprising a variable heavy chain comprising at least 90%, 95%, 96%, 97%, 98% or 99% identity SEQ ID NO;

128 and/or a variable light chain comprising at least 90%, 95%, 96%, 97%, 98% or 99% identity to any one of SEQ ID NOs;

133;

v. an antibody or antigen binding fragment thereof comprising a variable heavy chain comprising at least 90%, 95%, 96%, 97%, 98% or 99% identity SEQ ID NO;

128 and/or a variable light chain comprising at least 90%, 95%, 96%, 97%, 98% or 99% identity to any one of SEQ ID NOs;

133, wherein any sequence variations occur in the framework regions of the antibody.

7. An antibody or antigen binding fragment thereof that binds to the same epitope of human TIGIT as an antibody selected from the group consisting of:

a. an antibody comprising the variable heavy chain of SEQ ID NO;

7 and the variable light chain of SEQ ID NO;

8,

b. an antibody comprising the variable heavy chain of SEQ ID NO;

63 and the variable light chain of SEQ ID NO;

64, and

c. an antibody comprising the variable heavy chain of SEQ ID NO;

94 and the variable light chain of SEQ ID NO;

95;

wherein the antibody or fragment thereof has at least one of the following characteristics;

i. binds to human TIGIT with a KD value of about 1×

10-9 M to about 1×

10-12 M as determined by surface plasmon resonance (e.g., BIACORE) or a similar technique (e.g. KinExa or OCTET);

ii. cross-reacts with cynomolgous and rhesus TIGIT;

iii. blocks binding of human TIGIT to human CD155 and human CD112;

iv. increases T cell activation;

v. stimulates antigen-specific T-cell production of IL-2 and IFNγ

;

vi. blocks induction of T cell suppression of activation induced by TIGIT ligation with cognate ligands CD155 and CD112.

8. The antibody or antigen binding fragment of claim 7, wherein the antibody binds to an epitope comprising the following regions of human TIGIT (SEQ ID NO:

31);

residues 54-57, 68-70 and 76-81.

9. The antibody or antigen binding fragment of claim 7, wherein the antibody binds to an epitope comprising the following regions of human TIGIT (SEQ ID NO:

31);

residues 53-57, 60-65, 68-70, 72-81, 94-95, and 109-119.

12. (canceled)

13. An isolated polypeptide comprising the amino acid sequence of any one of SEQ ID NOs:

7-30, 37-52, 63-64, 94-95 or 124-133, 136-139, 143-146, 149-151.

17. (canceled)

21. (canceled)

25. (canceled)

26. (canceled)

27. (canceled)

28. (canceled)

29. (canceled)

30. (canceled)

31. (canceled)

32. (canceled)

33. (canceled)

34. (canceled)