Antibodies to m(h)dm2/4 and their use in diagnosing and treating cancer

Abstract

The present invention relates, inter alia, to certain anti-M(H)DM2/4 antibodies (including chimeric and humanized antibodies) or antigen-binding fragments thereof, pharmaceutical compositions comprising anti-M(H)DM2/4 antibodies or antigen-binding fragments thereof, antibody-drug conjugates comprising anti-M(H)DM2/4 antibodies or antigen-binding fragments thereof bound to a cytotoxic drug, and the use of such antibodies, fragments, compositions and conjugates for treating cancer and/or for preventing metastases. For example, described herein are certain antibodies (including chimeric and humanized antibodies) or antigen-binding fragments thereof that specifically bind to extracellularly accessible epitopes of M(H)DM2/4 and inhibit tumor growth in vivo, pharmaceutical compositions comprising such antibodies or fragments, antibody-drug conjugates comprising such antibodies or fragments, and the use of such antibodies, fragments, compositions and conjugates for treating cancer or for preventing metastasis.

What is claimed is: 
     
         1 . A humanized antibody or a fragment thereof that specifically binds to HDM2 or MDM2, said antibody or fragment comprising:
 (a) a heavy chain variable region (VH) comprising a VH having an amino acid sequence selected from the group consisting of SEQ ID NO:287, SEQ ID NO:291, SEQ ID NO:295, SEQ ID NO:299, SEQ ID NO:305, and SEQ ID NO:309, or a VH having at least 95% sequence identity to the amino acid sequence selected from the group consisting of SEQ ID NO:287, SEQ ID NO:291, SEQ ID NO:295, SEQ ID NO:299, SEQ ID NO:305, and SEQ ID NO:309, and/or   (b) a light chain variable region (VL) comprising a VL having an amino acid sequence selected from the group consisting of SEQ ID NO:289, SEQ ID NO:293, SEQ ID NO:297, SEQ ID NO:301, SEQ ID NO:303; SEQ ID NO:307, and SEQ ID NO:311, or a VL having at least 95% sequence identity to the amino acid sequence selected from the group consisting of SEQ ID NO:289, SEQ ID NO:293, SEQ ID NO:297, SEQ ID NO:301, SEQ ID NO:303; SEQ ID NO:307, and SEQ ID NO:311.   
     
     
         2 . The humanized antibody or fragment of  claim 1 , which comprises a VH having the amino acid sequence of SEQ ID NO:287, or a VH having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:287. 
     
     
         3 . The humanized antibody or fragment of  claim 1 , which comprises a VH having the amino acid sequence of SEQ ID NO:291, or a VH having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:291. 
     
     
         4 . The humanized antibody or fragment of  claim 1 , which comprises a VH having the amino acid sequence of SEQ ID NO:295, or a VH having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:295. 
     
     
         5 . The humanized antibody or fragment of  claim 1 , which comprises a VH having the amino acid sequence of SEQ ID NO:299, or a VH having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:299. 
     
     
         6 . The humanized antibody or fragment of  claim 1 , which comprises a VH having the amino acid sequence of SEQ ID NO:305, or a VH having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:305. 
     
     
         7 . The humanized antibody or fragment of  claim 1 , which comprises a VH having the amino acid sequence of SEQ ID NO:309, or a VH having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:309. 
     
     
         8 . The humanized antibody or fragment of any one of  claims 1 - 7 , which comprises a VL having the amino acid sequence of SEQ ID NO:289, or a VL having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:289. 
     
     
         9 . The humanized antibody or fragment of any one of  claims 1 - 7 , which comprises a VL having the amino acid sequence of SEQ ID NO:293, or a VL having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:293. 
     
     
         10 . The humanized antibody or fragment of any one of  claims 1 - 7 , which comprises a VL having the amino acid sequence of SEQ ID NO:297, or a VL having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:297. 
     
     
         11 . The humanized antibody or fragment of any one of  claims 1 - 7 , which comprises a VL having the amino acid sequence of SEQ ID NO:301, or a VL having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:301. 
     
     
         12 . The humanized antibody or fragment of any one of  claims 1 - 7 , which comprises a VL having the amino acid sequence of SEQ ID NO:303, or a VL having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:303. 
     
     
         13 . The humanized antibody or fragment of any one of  claims 1 - 7 , which comprises a VL having the amino acid sequence of SEQ ID NO:307, or a VL having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:307. 
     
     
         14 . The humanized antibody or fragment of any one of  claims 1 - 7 , which comprises a VL having the amino acid sequence of SEQ ID NO:311, or a VL having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:311. 
     
     
         15 . The humanized antibody or fragment of  claim 1 , which comprises: (i) a VH having the amino acid sequence of SEQ ID NO:299, and (ii) a VL having the amino acid sequence of SEQ ID NO:297. 
     
     
         16 . The humanized antibody or fragment of  claim 1 , which comprises: (a) a heavy chain variable region (VH) comprising a VH having an amino acid sequence selected from the group consisting of SEQ ID NO:287, SEQ ID NO:291, SEQ ID NO:295, and SEQ ID NO:299, and (b) a light chain variable region (VL) comprising a VL having an amino acid sequence selected from the group consisting of SEQ ID NO:289, SEQ ID NO:293, SEQ ID NO:297, SEQ ID NO:301, and SEQ ID NO:303. 
     
     
         17 . The humanized antibody or fragment of  claim 1 , which comprises: (a) a heavy chain variable region (VH) comprising a VH having an amino acid sequence selected from the group consisting of SEQ ID NO:299, SEQ ID NO:305, and SEQ ID NO:309, and (ii) a light chain variable region (VL) comprising a VL having an amino acid sequence selected from the group consisting of SEQ ID NO:297, SEQ ID NO:307, and SEQ ID NO:311. 
     
     
         18 . An antibody or a fragment comprising a light chain variable region (VL) comprising VL complementarity determining region (“CDR”) 1, VL CDR 2, and VL CDR 3, wherein:
 (i) the VL CDR 1 has the amino acid sequence RSSKNLLHSNGITYLY (SEQ ID NO:21), the VL CDR 2 has the amino acid sequence RVSNRAS (SEQ ID NO:236), and the VL CDR 3 has the amino acid sequence AQLLELPYT (SEQ ID NO:23); or 
 (ii) the VL CDR 1 has the amino acid sequence LHSNGITYLYWY (SEQ ID NO:49), the VL CDR 2 has the amino acid sequence LLISRVSNRAS (SEQ ID NO:237), and the VL CDR 3 has the amino acid sequence AQLLELPY (SEQ ID NO:51). 
 
     
     
         19 . The antibody or fragment of  claim 18 , which comprises a heavy chain variable region (VH) comprising VH complementarity determining region (“CDR”) 1, VH CDR 2, and VH CDR 3, wherein:
 (i) the VH CDR 1 has the amino acid sequence GFTFTHY (SEQ ID NO:18), the VH CDR 2 has the amino acid sequence RNKAKGYT (SEQ ID NO:19), and the VH CDR 3 has the amino acid sequence DIGDN (SEQ ID NO:20); 
 (ii) the VH CDR 1 has the amino acid sequence GFTFTHYYMS (SEQ ID NO:42), the VH CDR 2 has the amino acid sequence FIRNKAKGYTAE (SEQ ID NO:45), and the VH CDR 3 has the amino acid sequence DIGDN (SEQ ID NO:20); 
 (iii) the VH CDR 1 has the amino acid sequence HYYMS (SEQ ID NO:43), the VH CDR 2 has the amino acid sequence FIRNKAKGYTAEYSASVKG (SEQ ID NO:46), and the VH CDR 3 has the amino acid sequence DIGDN (SEQ ID NO:20); 
 (iv) the VH CDR 1 has the amino acid sequence THYYMS (SEQ ID NO:44), the VH CDR 2 has the amino acid sequence WLGFIRNKAKGYTAE (SEQ ID NO:47), and the VH CDR 3 has the amino acid sequence ARDIGD (SEQ ID NO:48); or 
 (v) the VH CDR 1 has the amino acid sequence FTFTHYY (SEQ ID NO:144), the VH CDR 2 has the amino acid sequence IRNKAKGYTA (SEQ ID NO:145), and the VH CDR 3 has the amino acid sequence ARDIGDN (SEQ ID NO:146). 
 
     
     
         20 . An antibody or a fragment thereof that specifically binds to HDM2 or MDM2, said antibody or fragment comprising: (a) a heavy chain variable region (VH) having an amino acid sequence of SEQ ID NO:283, or a VH having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:283, and (ii) a light chain variable region (VL) having an amino acid sequence of SEQ ID NO:285, or a VL having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:285. 
     
     
         21 . A chimeric antibody that specifically binds to HDM2 or MDM2, said antibody comprising: (a) a heavy chain having an amino acid sequence of SEQ ID NO:312, or a heavy chain having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:312, and/or (b) a light chain having an amino acid sequence of SEQ ID NO:313, or a light chain having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:313. 
     
     
         22 . The antibody or fragment of any one of  claims 1 - 21 , wherein the antibody is a monoclonal antibody. 
     
     
         23 . The antibody or fragment of any one of  claims 1 - 20 , which is an immunoglobulin. 
     
     
         24 . The antibody or fragment of  claim 23 , wherein the immunoglobulin is an IgG. 
     
     
         25 . The antibody or fragment of  claim 24 , wherein the immunoglobulin is of IgG1 isotype. 
     
     
         26 . The antibody or fragment of any one of  claims 1 - 20 , which comprises an Fc region, and wherein the Fc region is a human IgG1, a human IgG2, a human IgG3, a human IgG4, or a human IgM Fc region. 
     
     
         27 . The antibody or fragment of  claim 26 , wherein the Fc region is a human IgG1. 
     
     
         28 . The antibody or fragment of any one of  claims 1 - 27 , wherein the antibody or fragment mediates complement-dependent cytotoxicity (CDC) or antibody-dependent cell-mediated cytoxicity (ADCC). 
     
     
         29 . The antibody or fragment of  claim 28 , wherein the antibody or fragment mediates complement-dependent cytotoxicity (CDC). 
     
     
         30 . The antibody or fragment of any one of  claims 1 - 20 , which is an Fv fragment, a Fab fragment, a Fab′ fragment, a F(ab′)2 fragment, a single chain antibody molecule, or a single chain Fv (scFv). 
     
     
         31 . The antibody or fragment of any one of  claims 1 - 30 , wherein the HDM2 is an HDM2 variant that lacks a nuclear localization signal domain, an HDM2 variant that lacks the sequence of amino acids 179 to 185 of SEQ ID NO:4, and/or an HDM2 variant that lacks the sequence of amino acids 464 to 471 of SEQ ID NO:4. 
     
     
         32 . The antibody or fragment of any one of  claims 1 - 31 , which is purified. 
     
     
         33 . The antibody or fragment of any one of  claims 1 - 32 , which inhibits tumor cell proliferation in vivo. 
     
     
         34 . An antibody-drug conjugate comprising the antibody or fragment of any one of  claims 1 - 33 , bound to a cytotoxic drug. 
     
     
         35 . A pharmaceutical composition comprising a therapeutically effective amount of the antibody or fragment of any one of  claims 1 - 33  or the antibody-drug conjugate of  claim 34 . 
     
     
         36 . A method of treating cancer in a subject in need thereof, said method comprising administering to the subject: (i) the antibody or fragment of any one of  claims 1 - 33 , (ii) the antibody-drug conjugate of  claim 34 , or (iii) the pharmaceutical composition of  claim 35 . 
     
     
         37 . A method of inhibiting or preventing metastasis in a subject having a cancer, said method comprising administering to the subject: (i) the antibody or fragment of any one of  claims 1 - 33 , (ii) the antibody-drug conjugate of  claim 34 , or (iii) the pharmaceutical composition of  claim 35 . 
     
     
         38 . A method of preventing cancer recurrence or preventing cancer relapse in a subject in need thereof, said method comprising administering to the subject: (i) the antibody or fragment of any one of  claims 1 - 33 , (ii) the antibody-drug conjugate of  claim 34 , or (iii) the pharmaceutical composition of  claim 35 . 
     
     
         39 . A method of treating cancer in a subject who has experienced an accelerated rate of cancer growth in response to administration to the subject of an inhibitor of one or more inhibitory checkpoint molecules, said method comprising administering to the subject: (i) an antibody or a fragment thereof that specifically binds to an extracellularly accessible epitope of M(H)DM2/4, or an antibody-drug conjugate comprising the antibody or fragment bound to a cytotoxic drug, wherein said antibody or fragment is not bound to a cell-penetrating peptide, (ii) an antibody or a fragment thereof that specifically binds to an extracellularly accessible epitope of M(H)DM2/4, wherein said antibody or fragment is not bound to a cytotoxic component, (iii) the antibody or fragment of any one of  claims 1 - 33 , (iv) the antibody-drug conjugate of  claim 34 , or (v) the pharmaceutical composition of  claim 35 . 
     
     
         40 . The method of  claim 39 , wherein the one or more inhibitory checkpoint molecules are selected from the group consisting of: CTLA-4, PD-1, PD-L1, and PD-L2. 
     
     
         41 . The method of  claim 39 , wherein the one or more inhibitory checkpoint molecules is PD-1. 
     
     
         42 . The method of  claim 39 , wherein the inhibitor of one or more inhibitory checkpoint molecules is an inhibitory antibody to PD-1. 
     
     
         43 . The method of any one of  claims 36 - 42 , wherein said method comprises administering to the subject the antibody or fragment of any one of  claims 1 - 33 . 
     
     
         44 . The method of any one of  claims 36 - 42 , said method comprising administering to the subject the pharmaceutical composition of  claim 35 . 
     
     
         45 . The method of  claim 43  or  44 , wherein the antibody or fragment is not bound to a cell-penetrating peptide. 
     
     
         46 . The method of any one of  claims 36 - 42 , said method comprising administering to the subject the antibody or fragment thereof that specifically binds to an extracellularly accessible epitope of M(H)DM2/4, wherein said antibody or fragment is not bound to a cell-penetrating peptide. 
     
     
         47 . The method of any one of  claims 36 - 42 , said method comprising administering to the subject the antibody or fragment thereof that specifically binds to an extracellularly accessible epitope of M(H)DM2/4, wherein said antibody or fragment is not bound to a cytotoxic component. 
     
     
         48 . The method of  claim 46  or  47 , wherein the antibody or fragment is a humanized antibody or a fragment thereof that specifically binds to an extracellularly accessible epitope of M(H)DM2/4. 
     
     
         49 . The method of  claim 46  or  47 , wherein the antibody or fragment is a human antibody or a fragment thereof that specifically binds to an extracellularly accessible epitope of M(H)DM2/4. 
     
     
         50 . The method of  claim 46  or  47 , wherein the antibody or fragment is a chimeric antibody. 
     
     
         51 . The method of any one of  claims 46 - 50 , wherein the antibody or fragment is a monoclonal antibody or a fragment thereof that specifically binds to an extracellularly accessible epitope of M(H)DM2/4. 
     
     
         52 . The method of any one of  claims 46 - 51 , wherein the antibody or fragment is an immunoglobulin. 
     
     
         53 . The method of  claim 52 , wherein the immunoglobulin is an IgG. 
     
     
         54 . The method of  claim 53 , wherein the immunoglobulin is of IgG1 isotype. 
     
     
         55 . The method of  claim 53 , wherein the immunoglobulin is of IgG3 isotype. 
     
     
         56 . The method of any one of  claims 46 - 51 , wherein the antibody or fragment comprises an Fc region, and wherein the Fc region is a human IgG1, a human IgG2, a human IgG3, a human IgG4, or a human IgM Fc region. 
     
     
         57 . The method of any one of  claims 46 - 56 , wherein the antibody or fragment mediates complement-dependent cytotoxicity (CDC) or antibody-dependent cell-mediated cytoxicity (ADCC). 
     
     
         58 . The method of  claim 57 , wherein the antibody or fragment mediates complement-dependent cytotoxicity (CDC). 
     
     
         59 . The method of any one of  claims 46 - 51 , wherein the antibody or fragment is an Fv fragment, a Fab fragment, a Fab′ fragment, a F(ab′) 2 fragment, a single chain antibody molecule, or a single chain Fv (scFv). 
     
     
         60 . The method of any one of  claims 46 - 59 , wherein the antibody or fragment specifically binds to a peptide, wherein the sequence of the peptide is MCNTNMSVPTDGAVT (SEQ ID NO:1). 
     
     
         61 . The method of any one of  claims 46 - 59 , wherein the antibody or fragment specifically binds to a peptide, wherein the sequence of the peptide is TTSQIPASEQE (SEQ ID NO:2). 
     
     
         62 . The method of any one of  claims 46 - 59 , wherein the antibody or fragment specifically binds to a peptide, wherein the sequence of the peptide is CPVCRQPIQMIVLTYFP (SEQ ID NO:3). 
     
     
         63 . The method of any one of  claims 46 - 59 , wherein the antibody or a fragment comprises a heavy chain variable region (VH) comprising VH complementarity determining region (“CDR”) 1, VH CDR 2, and VH CDR 3, wherein:
 (i) the VH CDR 1 has the amino acid sequence GFTFTHY (SEQ ID NO:18), the VH CDR 2 has the amino acid sequence RNKAKGYT (SEQ ID NO:19), and the VH CDR 3 has the amino acid sequence DIGDN (SEQ ID NO:20); 
 (ii) the VH CDR 1 has the amino acid sequence GFTFTHYYMS (SEQ ID NO:42), the VH CDR 2 has the amino acid sequence FIRNKAKGYTAE (SEQ ID NO:45), and the VH CDR 3 has the amino acid sequence DIGDN (SEQ ID NO:20); 
 (iii) the VH CDR 1 has the amino acid sequence HYYMS (SEQ ID NO:43), the VH CDR 2 has the amino acid sequence FIRNKAKGYTAEYSASVKG (SEQ ID NO:46), and the VH CDR 3 has the amino acid sequence DIGDN (SEQ ID NO:20); 
 (iv) the VH CDR 1 has the amino acid sequence THYYMS (SEQ ID NO:44), the VH CDR 2 has the amino acid sequence WLGFIRNKAKGYTAE (SEQ ID NO:47), and the VH CDR 3 has the amino acid sequence ARDIGD (SEQ ID NO:48); or 
 (v) the VH CDR 1 has the amino acid sequence FTFTHYY (SEQ ID NO:144), the VH CDR 2 has the amino acid sequence IRNKAKGYTA (SEQ ID NO:145), and the VH CDR 3 has the amino acid sequence ARDIGDN (SEQ ID NO:146). 
 
     
     
         64 . The method of any one of  claims 46 - 59 , wherein the antibody or a fragment comprises a heavy chain variable region (VH) comprising VH complementarity determining region (“CDR”) 1, VH CDR 2, and VH CDR 3, wherein:
 (i) the VH CDR 1 has the amino acid sequence GDTLSGS (SEQ ID NO:24), the VH CDR 2 has the amino acid sequence HLNRGT (SEQ ID NO:25), and the VH CDR 3 has the amino acid sequence SPGFAY (SEQ ID NO:26); 
 (ii) the VH CDR 1 has the amino acid sequence GDTLSGSWMH (SEQ ID NO:52), the VH CDR 2 has the amino acid sequence EIHLNRGTTN (SEQ ID NO:55), and the VH CDR 3 has the amino acid sequence SPGFAY (SEQ ID NO:26); 
 (iii) the VH CDR 1 has the amino acid sequence GSWMH (SEQ ID NO:53), the VH CDR 2 has the amino acid sequence EIHLNRGTTNYNEKFKG (SEQ ID NO:56), and the VH CDR 3 has the amino acid sequence SPGFAY (SEQ ID NO:26); 
 (iv) the VH CDR 1 has the amino acid sequence SGSWMH (SEQ ID NO:54), the VH CDR 2 has the amino acid sequence WIGEIHLNRGTTN (SEQ ID NO:57), and the VH CDR 3 has the amino acid sequence ARSPGFA (SEQ ID NO:58); or 
 (v) the VH CDR 1 has the amino acid sequence GDTLSGSW (SEQ ID NO:148), the VH CDR 2 has the amino acid sequence IHLNRGTT (SEQ ID NO:143), and the VH CDR 3 has the amino acid sequence ARSPGFA (SEQ ID NO:58). 
 
     
     
         65 . The method of any one of  claims 46 - 59 , wherein the antibody or a fragment comprises a heavy chain variable region (VH) comprising VH complementarity determining region (“CDR”) 1, VH CDR 2, and VH CDR 3, wherein:
 (i) the VH CDR 1 has the amino acid sequence GYTFTSY (SEQ ID NO:30), the VH CDR 2 has the amino acid sequence NPRNGG (SEQ ID NO:31), and the VH CDR 3 has the amino acid sequence SGYYAMDY (SEQ ID NO:32); 
 (ii) the VH CDR 1 has the amino acid sequence GYTFTSYYMY (SEQ ID NO:62), the VH CDR 2 has the amino acid sequence GINPRNGGTN (SEQ ID NO:65), and the VH CDR 3 has the amino acid sequence SGYYAMDY (SEQ ID NO:32); 
 (iii) the VH CDR 1 has the amino acid sequence SYYMY (SEQ ID NO:63), the VH CDR 2 has the amino acid sequence GINPRNGGTNFNEKFKN (SEQ ID NO:66), and the VH CDR 3 has the amino acid sequence SGYYAMDY (SEQ ID NO:32); or 
 (iv) the VH CDR 1 has the amino acid sequence TSYYMY (SEQ ID NO:64), the VH CDR 2 has the amino acid sequence WIGGINPRNGGTN (SEQ ID NO:67), and the VH CDR 3 has the amino acid sequence TRSGYYAMD (SEQ ID NO:68). 
 
     
     
         66 . The method of  claim 63 , wherein the antibody or fragment further comprises a light chain variable region (VL) comprising VL complementarity determining region (“CDR”) 1, VL CDR 2, and VL CDR 3, wherein:
 (i) the VL CDR 1 has the amino acid sequence RSSKNLLHSNGITYLY (SEQ ID NO:21), the VL CDR 2 has the amino acid sequence RVSNLAS (SEQ ID NO:22), and the VL CDR 3 has the amino acid sequence AQLLELPYT (SEQ ID NO:23); 
 (ii) the VL CDR 1 has the amino acid sequence LHSNGITYLYWY (SEQ ID NO:49), the VL CDR 2 has the amino acid sequence LLISRVSNLA (SEQ ID NO:50), and the VL CDR 3 has the amino acid sequence AQLLELPY (SEQ ID NO:51); or 
 (iii) the VL CDR 1 has the amino acid sequence KNLLHSNGITY (SEQ ID NO:147), the VL CDR 2 has the amino acid sequence RVS, and the VL CDR 3 has the amino acid sequence AQLLELPYT (SEQ ID NO:23). 
 
     
     
         67 . The method of  claim 63 , wherein the antibody or fragment comprises a light chain variable region (VL) comprising VL complementarity determining region (“CDR”) 1, VL CDR 2, and VL CDR 3, wherein:
 (i) the VL CDR 1 has the amino acid sequence RSSKNLLHSNGITYLY (SEQ ID NO:21), the VL CDR 2 has the amino acid sequence RVSNRAS (SEQ ID NO:236), and the VL CDR 3 has the amino acid sequence AQLLELPYT (SEQ ID NO:23); or 
 (ii) the VL CDR 1 has the amino acid sequence LHSNGITYLYWY (SEQ ID NO:49), the VL CDR 2 has the amino acid sequence LLISRVSNRAS (SEQ ID NO:237), and the VL CDR 3 has the amino acid sequence AQLLELPY (SEQ ID NO:51). 
 
     
     
         68 . The method of  claim 64 , wherein the antibody or fragment further comprises a light chain variable region (VL) comprising VL complementarity determining region (“CDR”) 1, VL CDR 2, and VL CDR 3, wherein:
 (i) the VL CDR 1 has the amino acid sequence RSSKSLLHSNGNSYLY (SEQ ID NO:27), the VL CDR 2 has the amino acid sequence RMSNLAS (SEQ ID NO:28), and the VL CDR 3 has the amino acid sequence MQHLEYPFT (SEQ ID NO:29); 
 (ii) the VL CDR 1 has the amino acid sequence LHSNGNSYLYWF (SEQ ID NO:59), the VL CDR 2 has the amino acid sequence LLIYRMSNLA (SEQ ID NO:60), and the VL CDR 3 has the amino acid sequence MQHLEYPF (SEQ ID NO:61); or 
 (iii) the VL CDR 1 has the amino acid sequence KSLLHSNGNSY (SEQ ID NO:141), the VL CDR 2 has the amino acid sequence RMS, and the VL CDR 3 has the amino acid sequence MQHLEYPFT (SEQ ID NO:29). 
 
     
     
         69 . The method of  claim 65 , wherein the antibody or fragment further comprises a light chain variable region (VL) comprising VL complementarity determining region (“CDR”) 1, VL CDR 2, and VL CDR 3, wherein:
 (i) the VL CDR 1 has the amino acid sequence RASQDISNFLN (SEQ ID NO:33), the VL CDR 2 has the amino acid sequence YTSRLHS (SEQ ID NO:34), and the VL CDR 3 has the amino acid sequence QQGNTLPRT (SEQ ID NO:35); or 
 (ii) the VL CDR 1 has the amino acid sequence SNFLNWY (SEQ ID NO:69), the VL CDR 2 has the amino acid sequence LLIYYTSRLH (SEQ ID NO:70), and the VL CDR 3 has the amino acid sequence QQGNTLPR (SEQ ID NO:71). 
 
     
     
         70 . The method of any one of  claims 46 - 59 , wherein the extracellularly accessible epitope of M(H)DM2/4 is within amino acids 19 to 50 of SEQ ID NO:4. 
     
     
         71 . The method of any one of  claims 46 - 59 , wherein the extracellularly accessible epitope of M(H)DM2/4 is within amino acids 154 to 167 of SEQ ID NO:4. 
     
     
         72 . The method of any one of  claims 46 - 59 , wherein the extracellularly accessible epitope of M(H)DM2/4 is within amino acids 1 to 60 of SEQ ID NO:4. 
     
     
         73 . The method of any one of  claims 46 - 59 , wherein the extracellularly accessible epitope of M(H)DM2/4 is within amino acids 26 to 60 of SEQ ID NO:4. 
     
     
         74 . The method of any one of  claims 46 - 59 , wherein the extracellularly accessible epitope of M(H)DM2/4 is within amino acids 101 to 200 of SEQ ID NO:4. 
     
     
         75 . The method of any one of  claims 46 - 59 , wherein the extracellularly accessible epitope of M(H)DM2/4 is within amino acids 50 to 60 of SEQ ID NO:4. 
     
     
         76 . The method of any one of  claims 46 - 59 , wherein the extracellularly accessible epitope of M(H)DM2/4 is within the terminal 60 amino acids at the C-terminus of the HDM2 on the plasma membrane of the cancer cells. 
     
     
         77 . The method of any one of  claims 46 - 59 , wherein the antibody or fragment competes for binding to M(H)DM2/4 with mouse anti-HDM2 antibody OP145. 
     
     
         78 . The method of any one of  claims 46 - 59 , wherein the antibody or fragment competes for binding to M(H)DM2/4 with mouse anti-HDM2 antibody 965 (SMP14). 
     
     
         79 . The method of any one of  claims 46 - 59 , wherein the antibody or fragment competes for binding to M(H)DM2/4 with rabbit anti-HDM2 antibody sc-813 (N-20). 
     
     
         80 . The method of any one of  claims 46 - 59 , wherein the antibody or fragment competes for binding to M(H)DM2/4 with rabbit anti-HDM2 antibody sc-812 (C-18). 
     
     
         81 . The method of any one of  claims 46 - 59 , wherein the antibody or fragment competes for binding to M(H)DM2/4 with mouse anti-HDM2 antibody M01, clone 1A7. 
     
     
         82 . The method of any one of  claims 46 - 59 , wherein the antibody or fragment competes for binding to M(H)DM2/4 with a humanized antibody or a fragment that specifically binds to HDM2 or MDM2, said antibody or fragment comprising: (a) a heavy chain variable region (VH) comprising a VH having an amino acid sequence selected from the group consisting of SEQ ID NO:287, SEQ ID NO:291, SEQ ID NO:295, and SEQ ID NO:299, and (b) a light chain variable region (VL) comprising a VL having an amino acid sequence selected from the group consisting of SEQ ID NO:289, SEQ ID NO:293, SEQ ID NO:297, SEQ ID NO:301, and SEQ ID NO:303. 
     
     
         83 . The method of any one of  claims 46 - 59 , wherein the antibody or fragment competes for binding to M(H)DM2/4 with a humanized antibody or a fragment that specifically binds to HDM2 or MDM2, said antibody or fragment comprising: (a) a heavy chain variable region (VH) comprising a VH having an amino acid sequence selected from the group consisting of SEQ ID NO:299, SEQ ID NO:305, and SEQ ID NO:309, and (b) a light chain variable region (VL) comprising a VL having an amino acid sequence selected from the group consisting of SEQ ID SEQ ID NO:297, SEQ ID NO:307, and SEQ ID NO:311. 
     
     
         84 . The method of any one of  claims 46 - 59 , wherein the antibody or fragment competes for binding to M(H)DM2/4 with an antibody or a fragment that specifically binds to HDM2 or MDM2, said antibody or fragment comprising: (a) a heavy chain variable region (VH) having an amino acid sequence of SEQ ID NO:283, and (ii) a light chain variable region (VL) having an amino acid sequence of SEQ ID NO:285. 
     
     
         85 . The method of any one of  claims 46 - 59 , wherein the antibody or fragment competes for binding to M(H)DM2/4 with a chimeric antibody that specifically binds to HDM2 or MDM2, said antibody comprising: (a) a heavy chain having an amino acid sequence of SEQ ID NO:312, and (ii) a light chain having an amino acid sequence of SEQ ID NO:313. 
     
     
         86 . The method of any one of  claims 46 - 85 , wherein the M(H)DM2/4 is an HDM2 variant that lacks a nuclear localization signal domain, an HDM2 variant that lacks the sequence of amino acids 179 to 185 of SEQ ID NO:4, and/or an HDM2 variant that lacks the sequence of amino acids 464 to 471 of SEQ ID NO:4. 
     
     
         87 . The method of any one of  claims 46 - 86 , wherein the antibody or fragment is purified. 
     
     
         88 . The method of any one of  claims 36 - 42 , said method comprising administering to the subject an antibody-drug conjugate, said antibody-drug conjugate comprising the antibody or a fragment thereof that specifically binds to an extracellularly accessible epitope of M(H)DM2/4 bound to a cytotoxic drug, wherein said antibody or fragment is not bound to a cell-penetrating peptide. 
     
     
         89 . The method of any one of  claims 36 - 87 , wherein the antibody or fragment is not bound to a cytotoxic drug. 
     
     
         90 . The method of any one of  claims 36 - 89 , wherein the cancer is a type of cancer that is known to metastasize. 
     
     
         91 . The method of any one of  claims 36 - 90 , wherein the cancer is an advanced stage cancer. 
     
     
         92 . The method of any one of  claims 36 - 91 , wherein the cancer is a metastatic cancer. 
     
     
         93 . The method of any one of  claims 36 - 92 , wherein the cancer is a solid cancer. 
     
     
         94 . The method of  claim 93 , wherein the cancer is a lung cancer, a cervical cancer, an endometrial cancer, an ovarian cancer, a pancreatic cancer, a melanoma, a breast cancer, a colon cancer, a bladder cancer, an astrocytic neoplasm, a glioblastoma, or a pediatric Rhabdomyosarcoma. 
     
     
         95 . The method of  claim 94 , wherein the cancer is a pancreatic cancer, a lung cancer, or a colon cancer. 
     
     
         96 . The method of  claim 93 , wherein the cancer is a bladder cancer, a breast cancer, a lung cancer, a colon cancer, a melanoma, a sarcoma, an ovarian cancer, a glioma, a head and neck cancer, an urothelial cancer, a pancreatic cancer, a squamous cell carcinoma of the hypopharynx. 
     
     
         97 . The method of  claim 96 , wherein the breast cancer is a triple negative breast cancer. 
     
     
         98 . The method of  claim 96 , wherein the sarcoma is an endometrial stromal sarcoma. 
     
     
         99 . The method of any one of  claims 36 - 92 , wherein the cancer is a non-solid cancer. 
     
     
         100 . The method of  claim 99 , wherein the cancer is a leukemia or a lymphoma. 
     
     
         101 . The method of any one of  claims 36 - 100 , wherein the antibody or fragment is administered intravenously, intraperitoneally, intramuscularly, subcutaneously, or intratumorally. 
     
     
         102 . The method of any one of  claims 36 - 101 , further comprising administering to the subject a cancer therapy different from said antibody or fragment or antibody-drug conjugate. 
     
     
         103 . The method of  claim 102 , wherein the cancer therapy is a chemotherapy. 
     
     
         104 . The method of  claim 103 , wherein the chemotherapy is gemcitabine. 
     
     
         105 . The method of  claim 103 , wherein the chemotherapy is nab-paclitaxel. 
     
     
         106 . The method of  claim 103 , wherein the chemotherapy is cisplatin. 
     
     
         107 . The method of  claim 103 , wherein the chemotherapy is 5-FU. 
     
     
         108 . The method of  claim 103 , wherein the chemotherapy is paclitaxel. 
     
     
         109 . The method of  claim 103 , wherein the cancer is a pancreatic cancer, and wherein the chemotherapy is a combination of gemcitabine and nab-paclitaxel. 
     
     
         110 . The method of  claim 109 , wherein the gemcitabine and nab-paclitaxel are administered in doses that are lower than doses used when gemcitabine and nab-paclitaxel are administered not in combination with an anti-cancer antibody. 
     
     
         111 . The method of  claim 109 , wherein the subject is human, and wherein the gemcitabine is administered in a dose that is equal to or less than 1,000 mg/m2, and the nab-paclitaxel is administered in a dose that is equal to or less than 125 mg/m2. 
     
     
         112 . The method of  claim 109 , wherein the subject is human, and wherein gemcitabine is administered in a dose that is equal to or less than 500 mg/m2, and the nab-paclitaxel is administered in a dose that is equal to or less than 62.5 mg/m2. 
     
     
         113 . The method of any one of  claims 109 - 112 , wherein the combination of gemcitabine and nab-paclitaxel is administered with a frequency of every 2 weeks or less. 
     
     
         115 . The method of any one of  claims 36 - 113 , wherein the subject is a human. 
     
     
         116 . The method of  claim 102 , wherein the cancer therapy is an immunotherapy. 
     
     
         117 . The method of  claim 116 , wherein the immunotherapy is an inhibitor of one or more inhibitory checkpoint molecules. 
     
     
         118 . The method of  claim 117 , wherein the one or more inhibitory checkpoint molecules are selected from the group consisting of: CTLA-4, PD-1, PD-L1, PD-L2, TIM-3, OX40, and LAG-3. 
     
     
         119 . The method of  claim 102 , wherein the cancer therapy is an inhibitor of one or more of: EGFR, KRAS, STK11, ALK, BRAF, ERBB2, RET, ROS1, B2M, HLA, POLE, IGF-1, ERK/MAPK, PI3K/AKT, TGF-β, DNMT3A, IFNγ, JAK1/JAK2/JAK3, CD274, PTEN, ART, and CDK. 
     
     
         120 . The method of  claim 102 , wherein the cancer therapy is a peptide inhibitor of p53-M(H)DM2/4 interaction.or a small molecule inhibitor of p53-M(H)DM2/4 interaction. 
     
     
         121 . The method of any one of  claims 36 - 101 , wherein the antibody or fragment is administered as a monotherapy. 
     
     
         122 . A method of selecting and treating a subject having a cancer, said method comprising:
 (a) identifying a subject having a cancer wherein an antibody or a fragment thereof that specifically binds to an extracellularly accessible epitope of M(H)DM2/4 binds to the surface of an intact cell of the cancer; and   (b) administering to the subject: (i) the antibody or fragment of any one of  claims 1 - 33 , (ii) the antibody-drug conjugate of  claim 34 , or (iii) the pharmaceutical composition of  claim 35 .   
     
     
         123 . The method of  claim 122 , which further comprises before step (b) a step of determining whether the antibody or fragment thereof that specifically binds to an extracellularly accessible epitope of M(H)DM2/4 binds to the surface of intact cells of the cancer, wherein the antibody or fragment thereof that specifically binds to an extracellularly accessible epitope of M(H)DM2/4 is the antibody or fragment of any one of  claims 1 - 33 . 
     
     
         124 . The method of  claim 123 , which further comprises before the determining step the step of obtaining intact cells of the cancer. 
     
     
         125 . A method of diagnosing cancer in a subject, said method comprising:
 (a) detecting whether the antibody or fragment of any one of  claims 1 - 33  binds to the surface of intact cells of the subject; and   (b) diagnosing the subject with cancer if binding is detected in step (a).   
     
     
         126 . The method of  claim 125 , which is an ex vivo method. 
     
     
         127 . The method of  claim 125 , further comprising obtaining intact cells from the subject before step (a). 
     
     
         128 . The method of  claim 125 , which comprises administering the antibody or fragment to the subject before the detecting in step (a), and wherein the detecting is performed by in vivo imaging of the subject. 
     
     
         129 . The method of any one of  claims 122 - 128 , wherein, in step (a), the antibody or fragment is labeled. 
     
     
         130 . The method of any one of  claims 122 - 129 , wherein the subject is a human. 
     
     
         131 . The antibody or a fragment thereof of any one of  claims 1 - 33 , wherein the antibody or fragment specifically binds to an extracellularly accessible epitope of HDM2. 
     
     
         132 . The method of any one of  claims 36 - 130 , said method comprising administering to the subject the antibody or fragment that specifically binds to an extracellularly accessible epitope of HDM2. 
     
     
         133 . A method of treating cancer in a subject who has experienced an accelerated rate of cancer growth in response to administration to the subject of an inhibitor of one or more inhibitory checkpoint molecules, said method comprising:
 (a) identifying a subject who (i) has experienced accelerated rate of cancer growth in response to administration to the subject of an inhibitor of one or more inhibitory checkpoint molecules, and (ii) has a cancer wherein an antibody or a fragment thereof that specifically binds to an extracellularly accessible epitope of M(H)DM2/4 binds to the surface of intact cells of the cancer; and   (b) administering to the subject: (i) an antibody or a fragment thereof that specifically binds to an extracellularly accessible epitope of M(H)DM2/4, or an antibody-drug conjugate comprising the antibody or fragment bound to a cytotoxic drug, wherein said antibody or fragment is not bound to a cell-penetrating peptide, (ii) an antibody or a fragment thereof that specifically binds to an extracellularly accessible epitope of M(H)DM2/4, wherein said antibody or fragment is not bound to a cytotoxic component, (iii) the antibody or fragment of any one of  claims 1 - 33 , (iv) the antibody-drug conjugate of  claim 34 , or (v) the pharmaceutical composition of  claim 35 .   
     
     
         134 . The method of  claim 133 , which further comprises before step (b) a step of determining whether the antibody or fragment thereof that specifically binds to an extracellularly accessible epitope of M(H)DM2/4 binds to the surface of intact cells of the cancer, wherein the antibody or fragment is the antibody or fragment of any one of  claims 1 - 33 . 
     
     
         135 . The method of  claim 134 , which further comprises before the determining step the step of obtaining intact cells of the cancer. 
     
     
         136 . The method of any one of  claims 133 - 135 , wherein step (a) further comprises selecting a subject who has a gene amplification of M(H)DM2/4. 
     
     
         137 . The method of any one of  claims 133 - 136 , wherein step (a) further comprises selecting a subject who has an increased protein expression of M(H)DM2/4 in the cells of the cancer relative to the level of protein expression of M(H)DM2/4 in normal cells. 
     
     
         138 . The method of any one of  claims 133 - 137 , wherein step (a) further comprises selecting a subject who has a cancer wherein there is an increased binding of an antibody or a fragment thereof that specifically binds to an extracellularly accessible epitope of M(H)DM2/4 to the surface of intact cells of the cancer relative to the binding of the antibody or fragment thereof to the surface of intact normal cells. 
     
     
         139 . A method of treating cancer in a subject who is a hyper-progressor in response to administration of an inhibitor of one or more inhibitory checkpoint molecules, said method comprising:
 (a) identifying a subject, wherein the subject has (i) a cancer wherein an antibody or a fragment thereof that specifically binds to an extracellularly accessible epitope of M(H)DM2/4 binds to the surface of intact cells of the cancer, and (ii) a gene amplification of M(H)DM2/4, or an increased protein expression of M(H)DM2/4 in the cells of the cancer relative to the level of protein expression of M(H)DM2/4 in normal cells; and   (b) administering to the subject: (i) an antibody or a fragment thereof that specifically binds to an extracellularly accessible epitope of M(H)DM2/4, or an antibody-drug conjugate comprising the antibody or fragment bound to a cytotoxic drug, wherein said antibody or fragment is not bound to a cell-penetrating peptide, (ii) an antibody or a fragment thereof that specifically binds to an extracellularly accessible epitope of M(H)DM2/4, wherein said antibody or fragment is not bound to a cytotoxic component, (iii) the antibody or fragment of any one of  claims 1 - 33 , (iv) the antibody-drug conjugate of  claim 34 , or (v) the pharmaceutical composition of  claim 35 .   
     
     
         140 . The method of  claim 139 , which further comprises before step (b) a step of determining whether the antibody or fragment thereof that specifically binds to an extracellularly accessible epitope of M(H)DM2/4 binds to the surface of intact cells of the cancer, wherein the antibody or fragment is the antibody or fragment of any one of  claims 1 - 33 . 
     
     
         141 . The method of  claim 133 , which further comprises before the determining step the step of obtaining intact cells of the cancer. 
     
     
         142 . The method of any one of  claims 139 - 141 , wherein step (a) further comprises selecting a subject who has a gene amplification of M(H)DM2/4. 
     
     
         143 . The method of any one of  claims 139 - 142 , wherein step (a) further comprises selecting a subject who has an increased binding of an antibody or a fragment thereof that specifically binds to an extracellularly accessible epitope of M(H)DM2/4 to the surface of intact cells of the cancer relative to its binding to the surface of intact normal cells. 
     
     
         144 . A method of diagnosing a hyper-progressive disease in a subject who has cancer, said method comprising:
 (a) determining whether a gene amplification of M(H)DM2/4 is present in the cells of the cancer of the subject;   (b) determining whether an antibody or a fragment thereof that specifically binds to an extracellularly accessible epitope of M(H)DM2/4 binds to the surface of intact cells of the cancer of the subject; and   (c) diagnosing the subject with the hyper-progressive disease if the gene amplification is determined to be present in step (a) and binding is detected in step (b).   
     
     
         145 . The method of  claim 144 , which is an ex vivo method. 
     
     
         146 . The method of  claim 144  or  145 , further comprising obtaining intact cells from the subject before step (b). 
     
     
         147 . The method of  claim 144 , which comprises administering the antibody or fragment to the subject before the detecting in step (b), and wherein the detecting is performed by in vivo imaging of the subject. 
     
     
         148 . The method of any one of  claims 144 - 147 , wherein, in step (b), the antibody or fragment is labeled. 
     
     
         149 . The method of any one of  claims 144 - 148 , wherein the antibody or fragment is the antibody or fragment of any one of  claims 1 - 33 . 
     
     
         150 . The method of any one of  claims 133 - 149 , wherein the subject is a human. 
     
     
         151 . A vaccine composition comprising: (i) an immunogenic amount of a peptide, wherein the amino acid sequence of the peptide is MCNTNMSVPTDGAVT (SEQ ID NO:1), TTSQIPASEQE (SEQ ID NO:2), or CPVCRQPIQMIVLTYFP (SEQ ID NO:3), or a polynucleotide encoding the peptide; and (ii) a pharmaceutically acceptable carrier. 
     
     
         152 . The vaccine composition of  claim 151 , wherein the peptide is purified. 
     
     
         153 . The vaccine composition of  claim 151  or  152 , further comprising an adjuvant. 
     
     
         154 . A method of vaccinating a subject at risk for developing cancer or a subject who has been diagnosed with cancer by administering to the subject the vaccine composition of any one of  claims 151 - 153 .