Antibodies that bind to MHC class I polypeptide-related sequence A
The present disclosure provides, in part, compositions comprising peptides immunospecifically binds to MHC class I polypeptide-related sequence A (MICA).
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 α3 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 α3 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 α3 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 .