ANTIBODIES TO TIGIT

• US 20160176963A1
• Filed: 12/22/2015
• Published: 06/23/2016
• Est. Priority Date: 12/23/2014
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Ardourel, Daniel F., Maurer, Mark F., Chen, Tseng-hui Timothy, Devaux, Brigitte, Srinivasan, Mohan, Julien, Susan H., Sheppard, Paul O., Chakraborty, Indrani
• Granted Patent: US 10,189,902 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• 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 2317/31 multispecific
• 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 2317/76 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 provides antibodies, or antigen binding fragments thereof, that bind to human TIGIT (T cell immunoreceptor with Ig and ITIM domains), as well as uses of these antibodies or fragments in therapeutic applications, such as in the treatment of cancer or chronic viral infection. Such method of treatment include combination therapy with inhibitors of other immunomodulatory receptor interactions, such as the PD-1/PD-L1 interaction. The invention further provides polynucleotides encoding the heavy and/or light chain variable region of the antibodies, expression vectors comprising the polynucleotides encoding the heavy and/or light chain variable region of the antibodies, cells comprising the vectors, and methods of making the antibodies or fragments by expressing them from the cells.

Claims

1. An isolated antibody, or antigen binding fragment thereof, that competes for binding to human TIGIT (T cell immunoreceptor with Ig and ITIM domains) with one or more antibodies selected from the group consisting of 11G11, 10D7, 15A6 and 22G2.

11. A nucleic acid encoding the heavy and/or light chain variable region of the antibody or fragment of claim 1.

12. An expression vector comprising the nucleic acid of claim 11.

13. A host cell transformed with an expression vector of claim 12.

14. A method of producing an anti-TIGIT antibody or antigen binding fragment thereof comprising culturing the host cell of claim 13 under conditions that allows production of the antibody or fragment, and purifying the antibody from the cell.

15. A method of enhancing an antigen-specific T cell response in a subject in need thereof comprising contacting the T cell with the antibody or fragment of claim 1 such that an antigen-specific T cell response is enhanced.

16. The method of claim 15 wherein the subject has a tumor or a chronic viral infection and an immune response against the tumor or viral infection is enhanced.

17. A method of reducing or depleting regulatory T cells in a tumor of a subject in need thereof comprising administering an effective amount of an antibody or fragment of claim 1 such that the number of regulatory T cells in a tumor is reduced.

18. A method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of the antibody or fragment of claim 1.

19. The method of claim 18 further comprising administering one or more additional therapeutic agents selected from the group consisting of an anti-PD-1 antibody, an anti-LAG-3 antibody, an anti-CTLA-4 antibody, or an anti-PD-L1 antibody.

20. A bispecific antibody comprising a first antigen binding domain and a second antigen binding domain, wherein:

first antigen binding domain is from an anti-huTIGIT antibody of claim 1; and

b) the second antigen binding domain is from an antibody selected from the group consisting of an anti-PD-1 antibody, an anti-LAG-3 antibody, an anti-CTLA-4 antibody, and an anti-PD-L1 antibody.

21. The method of treating cancer of claim 18 further comprising administering an antagonist anti-TIGIT antibody, or antigen binding fragment thereof, to a subject having a tumor if and only if the tumor comprises one or more of the following:

a) high levels of infiltrating TIGIT⁺ T cells and/or NK cells;

b) elevated expression of PVR and/or Nectin-2 on tumor cells or tumor infiltrating myeloid cells; and

c) a Fusobacterium nucleatum infection.

2. An isolated antibody, or antigen binding fragment thereof, that binds to TIGIT (human T cell immunoreceptor with Ig and ITIM domains) at:

a) an epitope comprising one or more of residues E60, I109, L65, N70, F107, T117, I68, H76 and N58 (antibody 22G2) of huTIGIT (SEQ ID NO;

     1);

b) an epitope comprising one or more of residues G74, N70, H76, L65, L73, Q56, I68, H111 and P114 (antibody 11G11);

or

c) an epitope comprising one or more of residues H76, G74, L65, N58, I68, Q139, G135, L73, F107, N70, E60, H134, A132 and I109 (antibody 15A6).

3. The isolated antibody or fragment of claim 2 that binds to TIGIT at:

a) an epitope comprising the sequence NWEQQDQLLAICNADLGWH (SEQ ID NO;

     38) and/or FCIYHTYPDGT (SEQ ID NO;

     39) (antibody 22G2);

b) an epitope comprising the sequence QVNWEQQDQLLAICNADLGWH (SEQ ID NO;

     40) and/or HTYP (SEQ ID NO;

     41) (antibody 11G11);

or

c) an epitope comprising the sequence NWEQQDQLLAICNADLGWH (SEQ ID NO;

     38), FCI, and/or AEHGARFQ (SEQ ID NO;

     43) (antibody 15A6).

4. The isolated antibody or fragment of claim 3 that binds to TIGIT at an epitope comprising the sequence LLAICNADLGWH (SEQ ID NO:

44).

5. An isolated antibody, or antigen binding fragment thereof, that binds to TIGIT (human T cell immunoreceptor with Ig and ITIM domains) wherein the antibody heavy chain variable domain is derived from human V region germline sequence V4-39, V4-61, or V1-69.

6. An isolated antibody, or antigen binding fragment thereof, that binds to TIGIT (human T cell immunoreceptor with Ig and ITIM domains) comprising:

a) a heavy chain variable domain comprising;

i) CDRH1 comprising the sequence of SEQ ID NO.;

14, 20, 26, or 32;

ii) CDRH2 comprising the sequence of SEQ ID NO.;

15, 21, 27, or 33; and

iii) CDRH3 comprising the sequence of SEQ ID NO.;

16, 22, 28, or 34; and

b) a light chain variable domain comprising;

iv) CDRL1 comprising the sequence of SEQ ID NO.;

17, 23, 29, or 35;

v) CDRL2 comprising the sequence of SEQ ID NO.;

18, 24, 30, or 36; and

vi) CDRL3 comprising the sequence of SEQ ID NO.;

19, 25, 31, or 37.

7. The isolated antibody or fragment of claim 6 wherein:

a) the heavy chain variable domain has at least 80% sequence identity with the sequence of SEQ ID NOs;

2, 3, 4, 5, 7, 8, 10 or 12; and

b) the light chain variable domain has at least 80% sequence identity with the sequence of SEQ ID NOs;

6, 9, 11, or 13.

8. The isolated antibody or fragment of claim 6 comprising heavy and light chain variable domains comprising a specific combination of CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 sequences selected from the group consisting of:

a) SEQ ID NOs;

14-19 (antibody 15A6);

b) SEQ ID NOs;

20-25 (antibody 22G2);

c) SEQ ID NOs;

26-31 (antibody 11G11); and

d) SEQ ID NOs;

32-37 (antibody 10D7).

9. The isolated antibody of claim 6 wherein the antibody is a human IgG1 Fc variant with reduced or eliminated effector function.

10. The isolated antibody or fragment claim 9 comprising the following mutations:

L234A, L235E, G237A, A330S and P331S (SEQ ID NO;

     48) by EU numbering.