Antibodies against mica and/or micb and uses thereof

Abstract

The disclosure provides antibodies that specifically bind human MICA/B and methods of use thereof. In some aspects, the disclosure is directed to methods of treating a cancer in a subject, comprising administering to the subject an anti-MICA/B antibody.

1 . An antibody that specifically binds to human MHC class I polypeptide-related sequence A (MICA) and/or human MHC class I polypeptide-related sequence B (MICB), comprising a heavy chain variable region (VH) and a light chain variable region (VL); wherein the VH comprises a VH complementarity determining region (CDR) 1, a VH-CDR2, and a VH-CDR3 and the VL comprises a VL-CDR1, a VL-CDR2, and a VL-CDR3; wherein the VH-CDR3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 7, 17, 27, 37, and 47. 
     
     
         2 . The antibody of  claim 1 , wherein:
 (a) the VH-CDR2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 6, 16, 26, 36, and 46;   (b) the VH-CDR1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 5, 15, 25, 35, and 45;   (c) the VL-CDR1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 8, 18, 28, 38, and 48;   (d) the VL-CDR2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 9, 19, 29, 39, and 49;   (e) the VL-CDR3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 10, 20, 30, 40, and 50; or   (f) any combination of (a)-(e).   
     
     
         3 - 6 . (canceled) 
     
     
         7 . The antibody of  claim 1 , wherein
 (a) the VH-CDR1 comprises the amino acid sequence set forth in SEQ ID NO:5, the VH-CDR2 comprises the amino acid sequence set forth in SEQ ID NO:6, the VH-CDR3 comprises the amino acid sequence set forth in SEQ ID NO:7, the VL-CDR1 comprises the amino acid sequence set forth in SEQ ID NO:8, the VL-CDR2 comprises the amino acid sequence set forth in SEQ ID NO:9, and the VL-CDR3 comprises the amino acid sequence set forth in SEQ ID NO:10;   (b) the VH-CDR1 comprises the amino acid sequence set forth in SEQ ID NO:15, the VH-CDR2 comprises the amino acid sequence set forth in SEQ ID NO:16, the VH-CDR3 comprises the amino acid sequence set forth in SEQ ID NO:17, the VL-CDR1 comprises the amino acid sequence set forth in SEQ ID NO:18, the VL-CDR2 comprises the amino acid sequence set forth in SEQ ID NO:19, and the VL-CDR3 comprises the amino acid sequence set forth in SEQ ID NO:20;   (c) the VH-CDR1 comprises the amino acid sequence set forth in SEQ ID NO:25, the VH-CDR2 comprises the amino acid sequence set forth in SEQ ID NO:26, the VH-CDR3 comprises the amino acid sequence set forth in SEQ ID NO:27, the VL-CDR1 comprises the amino acid sequence set forth in SEQ ID NO:28, the VL-CDR2 comprises the amino acid sequence set forth in SEQ ID NO:29, and the VL-CDR3 comprises the amino acid sequence set forth in SEQ ID NO:30;   (d) the VH-CDR1 comprises the amino acid sequence set forth in SEQ ID NO:35, the VH-CDR2 comprises the amino acid sequence set forth in SEQ ID NO:36, the VH-CDR3 comprises the amino acid sequence set forth in SEQ ID NO:37, the VL-CDR1 comprises the amino acid sequence set forth in SEQ ID NO:38, the VL-CDR2 comprises the amino acid sequence set forth in SEQ ID NO:39, and the VL-CDR3 comprises the amino acid sequence set forth in SEQ ID NO:40; or   (e) the VH-CDR1 comprises the amino acid sequence set forth in SEQ ID NO:45, the VH-CDR2 comprises the amino acid sequence set forth in SEQ ID NO:46, the VH-CDR3 comprises the amino acid sequence set forth in SEQ ID NO:47, the VL-CDR1 comprises the amino acid sequence set forth in SEQ ID NO:48, the VL-CDR2 comprises the amino acid sequence set forth in SEQ ID NO:49, and the VL-CDR3 comprises the amino acid sequence set forth in SEQ ID NO:50.   
     
     
         8 . The antibody of  claim 1 , wherein the antibody has one or more properties selected from the group consisting of:
 (a) the antibody inhibits shedding of MICA by a tumor cell;   (b) the antibody increases membrane bound MICA on a tumor cell;   (c) the antibody reduces soluble MICA level in the serum in a patient;   (d) the antibody mediates enhanced ADCC and/or ADCP;   (e) the antibody mediates enhanced antigen processing and/or cross-presentation by a cell;   (f) the antibody inhibits tumor growth and/or metastasis;   (g) the antibody reduces tumor volume;   (h) the antibody increases progression-free survival;   (i) the antibody increases overall survival; and   (j) any combination thereof.   
     
     
         9 . The antibody of any one of  claim 1 , wherein:
 (a) the VH comprises an amino acid sequence having at least about 70% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 12, 22, 32, and 42;   (b) the VL comprises an amino acid sequence having at least about 70% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 4, 14, 24, 34, and 44; or   (c) both (a) and (b).   
     
     
         10 - 12 . (canceled) 
     
     
         13 . The antibody of  claim 1 , wherein
 (a) the VH comprises the amino acid sequence set forth in SEQ ID NO:2 and the VL comprises the amino acid sequence set forth in SEQ ID NO:4;   (b) the VH comprises the amino acid sequence set forth in SEQ ID NO:12 and the VL comprises the amino acid sequence set forth in SEQ ID NO:14;   (c) the VH comprises the amino acid sequence set forth in SEQ ID NO:22 and the VL comprises the amino acid sequence set forth in SEQ ID NO:24;   (d) the VH comprises the amino acid sequence set forth in SEQ ID NO:32 and the VL comprises the amino acid sequence set forth in SEQ ID NO:34; or   (e) the VH comprises the amino acid sequence set forth in SEQ ID NO:42 and the VL comprises the amino acid sequence set forth in SEQ ID NO:44.   
     
     
         14 . The antibody of  claim 1 , wherein:
 (a) the antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:58, and a light chain comprising the amino acid sequence set forth in SEQ ID NO:60;   (b) the antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:130, and a light chain comprising the amino acid sequence set forth in SEQ ID NO:60;   (c) the antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:62, and a light chain comprising the amino acid sequence set forth in SEQ ID NO:64;   (d) the antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:66, and a light chain comprising the amino acid sequence set forth in SEQ ID NO:68; or   (e) the antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:70, and a light chain comprising the amino acid sequence set forth in SEQ ID NO:72.   
     
     
         15 . The antibody of  claim 1 , wherein the antibody binds an epitope on human MICA, wherein the epitope comprises:
 (a) one or more amino acid residues of human MICA selected from the group consisting of G254, D255, L257, Y264, W267, and any combination thereof corresponding to SEQ ID NO: 51, as determined by yeast surface display;   (b) amino acid residues G254, D255, L257, Y264, and W267 corresponding to SEQ ID NO: 51, as determined by yeast surface display;   (c) amino acid residues W150-M163 corresponding to SEQ ID NO: 51, as determined by hydrogen/deuterium exchange mass spectrometry (HDX-MS);   (d) amino acid residues Y231-T238 corresponding to SEQ ID NO: 51, as determined by hydrogen/deuterium exchange mass spectrometry (HDX-MS);   (e) amino acid residues D255-Q265 corresponding to SEQ ID NO: 51, as determined by hydrogen/deuterium exchange mass spectrometry (HDX-MS)   (f) amino acid residues W253-W267 corresponding to SEQ ID NO: 51, as determined by hydrogen/deuterium exchange mass spectrometry (HDX-MS);   (g) amino acid residues L201-N220 corresponding to SEQ ID NO:51, as determined by hydrogen/deuterium exchange mass spectrometry (HDX-MS);   (h) amino acid residues T238-Q252 corresponding to SEQ ID NO:51, as determined by hydrogen/deuterium exchange mass spectrometry (HDX-MS);   (i) amino acid residues L201-N220 and T238-Q252 corresponding to SEQ ID NO:51, as determined by hydrogen/deuterium exchange mass spectrometry (HDX-MS);   (i) amino acid residues R240, Q241, D242, V244, and R279 corresponding to SEQ ID NO:51, as determined by yeast surface display;   (j) amino acid residues P258, G260, G262, and Y264 corresponding to SEQ ID NO:51, as determined by yeast surface display; or   (k) any combination thereof.   
     
     
         16 - 29 . (canceled) 
     
     
         30 . The antibody of  claim 1 , wherein the antibody specifically binds human MICA with:
 (a) a K D  of about 1×10 −4  M M or less, wherein K D  is measured by surface plasmon resonance (Biacore) analysis,   (b) an on rate (kon) of about 1×10 −4  M 1/Ms or more, wherein the kon rate is measured by surface plasmon resonance (Biacore) analysis;   (c) an off rate (koff) of about 1×10 −4  M l/s or less, wherein the koff is measured by surface plasmon resonance (Biacore) analysis; or   (d) any combination of (a)-(c).   
     
     
         31 - 32 . (canceled) 
     
     
         33 . The antibody of  claim 1 , wherein the antibody is selected from the group consisting of an IgG1, an IgG2, an IgG3, an IgG4 or a variant thereof. 
     
     
         34 . (canceled) 
     
     
         35 . The antibody of  claim 1 , which is non-fucosylated or hypo-fucosylated. 
     
     
         36 . The antibody of  claim 1 , wherein the antibody comprises a constant region in the heavy chain, and wherein the constant region comprises a G to A mutation at a position that corresponds to residue 234 in SEQ ID NO: 58. 
     
     
         37 . The antibody of  claim 1 , wherein the antibody is a human antibody, a humanized antibody, or a chimeric antibody. 
     
     
         38 - 47 . (canceled) 
     
     
         48 . A polynucleotide or a set of polynucleotides encoding the antibody of  claim 1 . 
     
     
         49 . A vector or a set of vectors comprising the polynucleotide or the set of polynucleotides of  claim 48 . 
     
     
         50 . A host cell comprising, the polynucleotide or the set of polynucleotides of  claim 48 . 
     
     
         51 . An immunoconjugate comprising the antibody of  claim 1  and a therapeutic agent. 
     
     
         52 - 54 . (canceled) 
     
     
         55 . A pharmaceutical composition comprising the antibody of  claim 1 . 
     
     
         56 - 71 . (canceled) 
     
     
         72 . A method of treating a cancer in a subject in need thereof, comprising administering to the subject the antibody of  claim 1 . 
     
     
         73 - 107 . (canceled) 
     
     
         108 . A method of preparing an antibody comprising expressing the polynucleotide or the set of polynucleotides of  claim 48  in a host cell under suitable conditions. 
     
     
         109 . (canceled)