Antibodies that bind to MHC class I polypeptide-related sequence A

• US 10,106,611 B2
• Filed: 12/05/2014
• Issued: 10/23/2018
• Est. Priority Date: 12/06/2013
• Status: Active Grant

• Current Assignee: Dana-Farber Cancer Institute
• Original Assignee: Dana-Farber Cancer Institute
• Inventors: Wucherpfennig, Kai W., Dranoff, Glenn, Hodi, F. Stephen, Franz, Bettina, May, Jr., Kenneth F., Harvey, Christopher
• Primary Examiner(s): Roark, Jessica H
• Application Number:
  US15/100,060
• Publication Number:
  US 20170022275A1
• Time in Patent Office: 1,418 Days
• 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 39/39558 against tumor tissues, cells, antigens
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/2833 against MHC-molecules, e.g. HLA-molecules
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• 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 2317/56 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 2317/76 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

Abstract

The present disclosure provides, in part, compositions comprising peptides immunospecifically binds to MHC class I polypeptide-related sequence A (MICA).

Claims

1. An antibody or antibody fragment that immunospecifically binds to MEW class I polypeptide-related sequence A (MICA), wherein the antibody or antibody fragment comprises

(i) a heavy chain variable (V_H) region comprising V_H CDR1, V_H CDR2, and V_H CDR3 as shown in the V_H of sequence of SEQ ID NO:

168;

(ii) a light chain variable (V_L) region comprising V_L CDR1, V_L CDR2, and V_L CDR3 as shown in the V_L of sequence of SEQ ID NO;

170; and

(iii) a heterologous constant region or a heterologous F_c region.

2. The antibody or antibody fragment of claim 1, wherein the antibody or antibody fragment comprises a V_H region comprising an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98% or 99% A identical to SEQ ID NO:

168.

3. The antibody or antibody fragment of claim 1, wherein the antibody or antibody fragment comprises a V_L region comprising an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98% or 99% A identical to SEQ ID NO:

170.

4. The antibody or antibody fragment of claim 1, wherein the V_H region comprises

a V_H CDR1 comprising SEQ ID NO:

172;

a V_H CDR2 comprising SEQ ID NO;

174; and

a V_H CDR3 comprising SEQ ID NO;

176.

5. The antibody or antibody fragment of claim 1, wherein the

a V_L region comprises

a V_L CDR1 comprising SEQ ID NO:

179,

a V_L CDR2 comprising SEQ ID NO;

181, and

a V_L CDR3 comprising SEQ ID NO;

183.

6. The antibody or antibody fragment of claim 1, wherein the V_H region comprises the amino acid sequence shown in SEQ ID NO:

168 or a variant thereof with 5 or fewer conservative amino acid substitutions in residues that are not within a CDR.

7. The antibody or antibody fragment of claim 1, wherein the V_L region comprises the amino acid sequence shown in SEQ ID NO:

170 or a variant thereof with 5 or fewer conservative amino acid substitutions in residues that are not within a CDR.

8. The antibody or antibody fragment of claim 1, wherein the antibody or antibody fragment binds to an epitope of human MHC class I polypeptide-related sequence A (MICA) comprising the amino acid sequence TCRASSFYPR (SEQ ID NO:

189).

9. The antibody or antibody fragment of claim 1, wherein the antibody or antibody fragment,

(a) binds to MICA α

3 domain;

(b) reduces sMICA levels;

(c) inhibits shedding of MICA from tumor cells;

(d) inhibits sMICA mediated downregulation of the NKG2D receptor on NK cells;

(e) increases NK cell mediated lysis of tumor cells;

or

(f) a combination of one or more of (a)-(e).

10. The antibody or antibody fragment of claim 1, wherein the V_H region comprises the amino acid sequence of SEQ ID NO:

168; and

the V_L region comprises the amino acid sequence of SEQ ID NO;

170.

11. The antibody or antibody fragment of claim 1, wherein the antibody is human, humanized or chimeric.

12. A pharmaceutical composition comprising the antibody or antibody fragment of claim 1.

13. The pharmaceutical composition of claim 12, further comprising an anti-cancer therapeutic.

14. The pharmaceutical composition of claim 13, wherein the anti-cancer therapeutic is selected from the group consisting of,

(a) an histone deacetylase inhibitor (HDAC) selected from the group consisting of hydroxamic acid, vorinostat, suberoylanilide hydroxamic acid (SAHA), trichostatin A (TSA), LAQ824, panobinostat (LBH589), belinostat (PXD101), ITF2357 italfarmaco SpA, cyclic tetrapeptide, depsipeptide (romidepsin, FK228), benzamide;

entinostat (SNDX-275/MS-275), MGCD0103, short-chain aliphatic acids, valproic acid, phenyl butyrate, AN-9, pivanex, CHR-3996, and CHR-2845;

(b) a proteasome inhibitor selected from the group consisting of bortezomib, NPI-0052, carfilzomib (PR-171), CEP 18770, and MLN9708;

(c) anti-CTLA-4 antibody or peptide, an anti-PD-1 antibody or peptide, an anti-PDL-1 antibody or peptide, an anti-OX40 antibody or peptide, an anti-GITR antibody or peptide, an anti-LAG-3 antibody or peptide, and an anti-TIM-3 antibody or peptide; and

(d) a combination (a), (b) and/or (c).

15. An isolated nucleic acid encoding the V_H region of the antibody or antibody fragment of claim 1.

16. An isolated nucleic acid encoding the V_L region of the antibody or antibody fragment of claim 1.

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

18. An antibody or antibody fragment that immunospecifically binds to MEW class I polypeptide-related sequence A (MICA), wherein the antibody or antibody fragment comprises

(i) a heavy chain variable (V_H) region comprising V_H CDR1, V_H CDR2, and V_H CDR3 as shown in the V_H of sequence of SEQ ID NO:

168;

(ii) a light chain variable (VL) region comprising V_L CDR1, V_L CDR2, and V_L CDR3 as shown in the V_L of sequence of SEQ ID NO;

170;

wherein the V_H region comprises one or more amino acid residue modifications within one or more framework regions compared to the framework regions of SEQ ID NO;

168, and/or the V_L region comprises one or more amino acid residue modifications within one or more framework regions compared to the framework regions of SEQ ID NO;

170.

19. The antibody or antibody fragment of claim 18, wherein the antibody or antibody fragment comprises

(i) a V_H region comprising an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:

168;

or

(ii) a V_L region comprising an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO;

170.

20. The antibody or antibody fragment of claim 18, wherein the antibody or antibody fragment binds to an epitope of human MHC class I polypeptide-related sequence A (MICA) comprising the amino acid sequence TCRASSFYPR (SEQ ID NO:

189).

21. The antibody or antibody fragment of claim 18, wherein the antibody or antibody fragment,

(a) binds to MICA α

3 domain;

(b) reduces sMICA levels;

(c) inhibits shedding of MICA from tumor cells;

(d) inhibits sMICA mediated downregulation of the NKG2D receptor on NK cells;

(e) increases NK cell mediated lysis of tumor cells;

or

(f) a combination of one or more of (a)-(e).

22. The antibody or antibody fragment of claim 18, wherein the antibody is human, humanized or chimeric.

23. A pharmaceutical composition comprising the antibody or antibody fragment of claim 18.

24. The pharmaceutical composition of claim 23, further comprising an anti-cancer therapeutic.

25. An isolated nucleic acid encoding the V_H region of the antibody or antibody fragment of claim 18.

26. An isolated nucleic acid encoding the V_L region of the antibody or antibody fragment of claim 18.

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

28. An antibody fragment that immunospecifically binds to MHC class I polypeptide-related sequence A (MICA), wherein the antibody fragment comprises

(i) a heavy chain variable (V_H) region comprising V_H CDR1, V_H CDR2, and V_H CDR3 as shown in the V_H of sequence of SEQ ID NO:

168; and

(ii) a light chain variable (V_L) region comprising V_L CDR1, V_L CDR2, and V_L CDR3 as shown in the V_L of sequence of SEQ ID NO;

170.

29. The antibody fragment of claim 28, wherein the antibody fragment is a Fab fragment, a F(ab′

)₂ fragment, a F_V fragment, a scF_V fragment, a diabody or a linear antibody.

30. The antibody fragment of claim 28, wherein the antibody fragment comprises

(i) a V_H region comprising an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:

168;

or

(ii) a V_L region comprising an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO;

170.

31. The antibody fragment of claim 28, wherein the antibody fragment binds to an epitope of human MHC class I polypeptide-related sequence A (MICA) comprising the amino acid sequence TCRASSFYPR (SEQ ID NO:

189).

32. The antibody fragment of claim 28, wherein the antibody fragment,

(a) binds to MICA α

3 domain;

(b) reduces sMiCA levels;

(c) ihibits shedding of MICA from tumor cells;

(d) inhibits sMICA mediated downregulation of the NKG2D receptor on NK cells;

(e) increases NK cell mediated lysis of tumor cells;

or

(f) a combination of one or more of (a)-(e).

33. The antibody fragment of claim 28, wherein the V_H region comprises the amino acid sequence of SEQ ID NO:

168; and

the V_L region comprises the amino acid sequence of SEQ ID NO;

170.

34. A pharmaceutical composition comprising the antibody fragment of claim 28.

35. The pharmaceutical composition of claim 34, further comprising an anti-cancer therapeutic.

36. A method of treating cancer in a subject comprising administering to the subject a therapeutically effective amount of the antibody fragment of claim 28.