US2021032364A1PendingUtilityA1

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

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Assignee: NOMOCAN PHARMACEUTICALS LLCPriority: Jul 27, 2017Filed: Jul 26, 2018Published: Feb 4, 2021
Est. expiryJul 27, 2037(~11 yrs left)· nominal 20-yr term from priority
Inventors:Ehsun Sarafraz-YazdiBrad R. Evans
G01N 33/57575A61K 39/0011C07K 2317/34C07K 16/30A61K 31/513C07K 2317/24C07K 16/32A61K 45/06A61K 2039/505C07K 16/28A61P 35/00C07K 2317/734A61K 47/643C07K 2317/21C07K 2317/73C07K 2317/56A61K 31/7068A61K 33/243A61K 31/337C07K 2317/565G01N 33/5748
44
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Claims

Abstract

The present invention relates to certain anti-M(H)DM2/4 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. In particular, described herein are certain 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.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . An antibody or a fragment thereof that specifically binds to an extracellularly accessible epitope of M(H)DM2/4, wherein the antibody or fragment specifically binds to a peptide, wherein the sequence of the peptide consists of MCNTNMSVPTDGAVT (SEQ ID NO:1), TTSQIPASEQE (SEQ ID NO:2), or CPVCRQPIQMIVLTYFP (SEQ ID NO:3). 
     
     
         2 . The antibody or fragment of  claim 1 , wherein the sequence of the peptide is MCNTNMSVPTDGAVT (SEQ ID NO:1). 
     
     
         3 . The antibody or fragment of  claim 1 , wherein the sequence of the peptide is TTSQIPASEQE (SEQ ID NO:2). 
     
     
         4 . The antibody or fragment of  claim 1 , wherein the sequence of the peptide is CPVCRQPIQMIVLTYFP (SEQ ID NO:3). 
     
     
         5 . A humanized antibody or a fragment thereof that specifically binds to HDM2, said antibody or fragment comprising: (i) a heavy chain variable region (VH) comprising VH complementarity determining region (“CDR”) 1, VH CDR2, and VH CDR3; said VH CDR1, VH CDR2 and VH CDR3 being the CDRs of a VH that has an amino acid sequence selected from the group consisting of SEQ ID NO:36, SEQ ID NO:38, and SED ID NO:40; or (ii) a light chain variable region (VL) comprising VL CDR1, VL CDR2, and VL CDR3; said VL CDR1, VL CDR2, and VL CDR3 being the CDRs of a VL that has an amino acid sequence selected from the group consisting of SEQ ID NO:37, SEQ ID NO:39, and SEQ ID NO:41. 
     
     
         6 . The humanized antibody or fragment of  claim 5 , which comprises the VH wherein VH CDR1, VH CDR2 and VH CDR3 are of a VH that has the amino acid sequence of SEQ ID NO:36. 
     
     
         7 . The humanized antibody or fragment of  claim 5  or  6 , which comprises the VL wherein VL CDR1, VL CDR2 and VL CDR3 are of a VL that has the amino acid sequence of SEQ ID NO:37. 
     
     
         8 . The humanized antibody or fragment of  claim 5 , which comprises the VH wherein VH CDR1, VH CDR2 and VH CDR3 are of a VH that has the amino acid sequence of SEQ ID NO:38. 
     
     
         9 . The humanized antibody or fragment of  claim 5  or  8 , which comprises the VL wherein VL CDR1, VL CDR2 and VL CDR3 are of a VL that has the amino acid sequence of SEQ ID NO:39. 
     
     
         10 . The humanized antibody or fragment of  claim 5 , which comprises the VH wherein VH CDR1, VH CDR2 and VH CDR3 are of a VH that has the amino acid sequence of SEQ ID NO:40. 
     
     
         11 . The humanized antibody or fragment of  claim 5  or  10 , which comprises the VL wherein VL CDR1, VL CDR2 and VL CDR3 are of a VL that has the amino acid sequence of SEQ ID NO:41. 
     
     
         12 . An antibody or a fragment thereof that specifically binds to HDM2, said antibody or fragment comprising 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). 
 
     
     
         13 . An antibody or a fragment thereof that specifically binds to HDM2, said antibody or fragment comprising 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). 
 
     
     
         14 . An antibody or a fragment thereof that specifically binds to HDM2, said antibody or fragment comprising 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). 
 
     
     
         15 . The antibody or fragment of  claim 12 , 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). 
 
     
     
         16 . The antibody or fragment of  claim 13 , 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). 
 
     
     
         17 . The antibody or fragment of  claim 14 , 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). 
 
     
     
         18 . The antibody or fragment of  claim 12 , which comprises a VH having the amino acid sequence of SEQ ID NO:36, or a VH having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:36. 
     
     
         19 . The antibody or fragment of  claim 1 ,  12  or  18 , which comprises a light chain variable region (VL) having the amino acid sequence of SEQ ID NO:37, or a VL having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:37. 
     
     
         20 . The antibody or fragment of  claim 13 , which comprises a VH having the amino acid sequence of SEQ ID NO:38, or a VH having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:38. 
     
     
         21 . The antibody or fragment of  claim 1 ,  13  or  20 , which comprises a VL having the amino acid sequence of SEQ ID NO:39, or a VL having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:39. 
     
     
         22 . The antibody or fragment of  claim 14 , which comprises a VH having the amino acid sequence of SEQ ID NO:40, or a VH having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:40. 
     
     
         23 . The antibody or fragment of  claim 1 ,  14  or  22 , which comprises a VL having the amino acid sequence of SEQ ID NO:41, or a VL having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:41. 
     
     
         24 . The antibody or fragment of any one of  claims 1 - 4  and  12 - 23 , wherein the antibody is a humanized antibody. 
     
     
         25 . The antibody or fragment of any one of  claims 1 - 4  and  12 - 23 , wherein the antibody is a human antibody. 
     
     
         26 . The antibody or fragment of any one of  claims 1 - 4  and  12 - 23 , wherein the antibody is a chimeric antibody. 
     
     
         27 . The antibody or fragment of any one of  claims 1 - 26 , wherein the antibody is a monoclonal antibody. 
     
     
         28 . The antibody or fragment of any one of  claims 1 - 27 , which is an immunoglobulin. 
     
     
         29 . The antibody or fragment of  claim 28 , wherein the immunoglobulin is an IgG. 
     
     
         30 . The antibody or fragment of  claim 28 , wherein the immunoglobulin is of IgG1 isotype. 
     
     
         31 . The antibody or fragment of  claim 28 , wherein the immunoglobulin is of IgG3 isotype. 
     
     
         32 . The antibody or fragment of any one of  claims 1 - 28 , 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. 
     
     
         33 . The antibody or fragment of  claim 32 , wherein the antibody or fragment mediates complement-dependent cytotoxicity (CDC) or antibody-dependent cell-mediated cytoxicity (ADCC). 
     
     
         34 . The antibody or fragment of  claim 33 , wherein the antibody or fragment mediates complement-dependent cytotoxicity (CDC). 
     
     
         35 . The antibody or fragment of any one of  claims 1 - 27 , 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). 
     
     
         36 . The antibody or fragment of any one of  claims 5 - 23 , 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. 
     
     
         37 . The antibody or fragment of any one of  claims 1 - 36 , which is purified. 
     
     
         38 . The antibody or fragment of any one of  claims 1 - 37 , which inhibits tumor cell proliferation in vivo. 
     
     
         39 . An antibody or a fragment thereof that competes for binding to M(H)DM2/4 with the antibody or fragment of any one of  claims 1 - 38 . 
     
     
         40 . An antibody or a fragment thereof that (i) competes for binding to a peptide of sequence SEQ ID NO:1 with a mouse anti-HDM2 IgG1 antibody comprising a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO:36, and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO:37; or (ii) competes for binding to a peptide of SEQ ID NO:2 with a mouse anti-HDM2 IgG3 antibody comprising a VH having the amino acid sequence of SEQ ID NO:38, and a VL having the amino acid sequence of SEQ ID NO:39; or (iii) competes for binding to a peptide of SEQ ID NO:3 with a mouse IgM antibody comprising a VH having the amino acid sequence of SEQ ID NO:40, and a VL having the amino acid sequence of SEQ ID NO:41. 
     
     
         41 . An antibody-drug conjugate comprising the antibody or fragment of any one of  claims 1 - 40 , bound to a cytotoxic drug. 
     
     
         42 . A pharmaceutical composition comprising a therapeutically effective amount of the antibody or fragment of any one of  claims 1 - 40  or the antibody-drug conjugate of  claim 41 . 
     
     
         43 . A method of treating cancer in a subject in need thereof, 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) the antibody or fragment of any one of  claims 1 - 40 , (iii) the antibody-drug conjugate of  claim 41 , or (iv) the pharmaceutical composition of  claim 42 . 
     
     
         44 . A method of treating cancer in a subject in need thereof, said method comprising administering to the subject: 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. 
     
     
         45 . A method of inhibiting or preventing metastasis in a subject having a cancer, 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) the antibody or fragment of any one of  claims 1 - 40 , (iii) the antibody-drug conjugate of  claim 41 , or (iv) the pharmaceutical composition of  claim 42 . 
     
     
         46 . A method of inhibiting or preventing metastasis in a subject having a cancer, said method comprising administering to the subject 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. 
     
     
         47 . A method of preventing cancer recurrence or preventing cancer relapse in a subject in need thereof, 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) the antibody or fragment of any one of  claims 1 - 40 , (iii) the antibody-drug conjugate of  claim 41 , or (iv) the pharmaceutical composition of  claim 42 . 
     
     
         48 . A method of preventing cancer recurrence or preventing cancer relapse in a subject having a cancer, said method comprising administering to the subject: 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. 
     
     
         49 . A method of increasing survival in a subject having a cancer relative to a subject not treated with anti-M(H)DM2/4 antibody or fragment, 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) the antibody or fragment of any one of  claims 1 - 40 , (iii) the antibody-drug conjugate of  claim 41 , or (iv) the pharmaceutical composition of  claim 42 . 
     
     
         50 . A method of increasing survival in a subject having a cancer relative to a subject not treated with anti-M(H)DM2/4 antibody or fragment, said method comprising administering to the subject: 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. 
     
     
         51 . The method of any one of  claims 43 - 50 , wherein said method comprises administering to the subject the antibody or fragment of any one of  claims 1 - 40 . 
     
     
         52 . The method of any one of  claims 43 ,  45 ,  47 , and  49 , said method comprising administering to the subject the antibody or fragment of any one of  claims 1 - 40 , the antibody-drug conjugate of  claim 41 , or the pharmaceutical composition of  claim 42 . 
     
     
         53 . The method of  claim 52 , wherein the antibody or fragment is not bound to a cell-penetrating peptide. 
     
     
         54 . The method of any one of  claims 43 ,  45 ,  47 , and  49 , said method comprising administering to the subject the 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 cell-penetrating peptide. 
     
     
         55 . The method of any one of  claims 43 - 52  and  56 , 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. 
     
     
         56 . The method of any one of  claims 43 - 50  and  54 , 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. 
     
     
         57 . The method of any one of  claims 43 - 50  and  54 , wherein the antibody or fragment is a chimeric antibody. 
     
     
         58 . The method of any one of  claims 43 - 50 , and  54 - 57 , 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. 
     
     
         59 . The method of any one of  claims 43 - 50 , and  54 - 58 , wherein the antibody or fragment is an immunoglobulin. 
     
     
         60 . The method of  claim 59 , wherein the immunoglobulin is an IgG. 
     
     
         61 . The method of  claim 59 , wherein the immunoglobulin is of IgG1 isotype. 
     
     
         62 . The method of  claim 59 , wherein the immunoglobulin is of IgG3 isotype. 
     
     
         63 . The method of any one of  claims 43 - 50 , and  54 - 59 , 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. 
     
     
         64 . The method of  claim 63 , wherein the antibody or fragment mediates complement-dependent cytotoxicity (CDC) or antibody-dependent cell-mediated cytoxicity (ADCC). 
     
     
         65 . The method of  claim 64 , wherein the antibody or fragment mediates complement-dependent cytotoxicity (CDC). 
     
     
         66 . The method of any one of  claims 43 - 50 , and  54 - 58 , 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). 
     
     
         67 . The method of any one of  claims 43 - 50 , and  54 - 66 , wherein the extracellularly accessible epitope of M(H)DM2/4 is within amino acids 19 to 50 of SEQ ID NO:4. 
     
     
         68 . The method of any one of  claims 43 - 50 , and  54 - 66 , wherein the extracellularly accessible epitope of M(H)DM2/4 is within amino acids 154 to 167 of SEQ ID NO:4. 
     
     
         69 . The method of any one of  claims 43 - 52 , and  56 - 68 , wherein the extracellularly accessible epitope of M(H)DM2/4 is within amino acids 1 to 60 of SEQ ID NO:4. 
     
     
         70 . The method of any one of  claims 43 - 50 , and  54 - 66 , wherein the extracellularly accessible epitope of M(H)DM2/4 is within amino acids 26 to 60 of SEQ ID NO:4. 
     
     
         71 . The method of any one of  claims 43 - 50 , and  54 - 66 , wherein the extracellularly accessible epitope of M(H)DM2/4 is within amino acids 101 to 200 of SEQ ID NO:4. 
     
     
         72 . The method of any one of  claims 43 - 50 , and  54 - 66 , wherein the extracellularly accessible epitope of M(H)DM2/4 is within amino acids 50 to 60 of SEQ ID NO:4. 
     
     
         73 . The method of any one of  claims 43 - 50 , and  54 - 66 , 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. 
     
     
         74 . The method of any one of  claims 43 - 50 , and  54 - 66 , wherein the antibody or fragment competes for binding to M(H)DM2/4 with mouse anti-HDM2 antibody OP145. 
     
     
         75 . The method of any one of  claims 43 - 50 , and  54 - 66 , wherein the antibody or fragment competes for binding to M(H)DM2/4 with mouse anti-HDM2 antibody 965 (SMP14). 
     
     
         76 . The method of any one of  claims 43 - 50 , and  54 - 66 , wherein the antibody or fragment competes for binding to M(H)DM2/4 with rabbit anti-HDM2 antibody sc-813 (N-20). 
     
     
         77 . The method of any one of  claims 43 - 50 , and  54 - 66 , wherein the antibody or fragment competes for binding to M(H)DM2/4 with rabbit anti-HDM2 antibody sc-812 (C-18). 
     
     
         78 . The method of any one of  claims 43 - 50 , and  54 - 66 , wherein the antibody or fragment competes for binding to M(H)DM2/4 with mouse anti-HDM2 antibody M01, clone 1A7. 
     
     
         79 . The method of any one of  claims 43 - 50 , and  54 - 78 , 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. 
     
     
         80 . The method of any one of  claims 43 - 50 , and  54 - 79 , wherein the antibody or fragment is purified. 
     
     
         81 . The method of any one of  claims 43 ,  45 ,  47 , and  49 , 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. 
     
     
         82 . The method of any one of  claims 54 - 80 , wherein the antibody or fragment is not bound to a cytotoxic drug. 
     
     
         83 . The method of any one of  claims 43 - 82 , wherein the cancer is a type of cancer that is known to metastasize. 
     
     
         84 . The method of any one of  claims 43 - 83 , wherein the cancer is an advanced stage cancer. 
     
     
         85 . The method of any one of  claims 43 - 84 , wherein the cancer is a metastatic cancer. 
     
     
         86 . The method of any one of  claims 43 - 85 , wherein the cancer is a solid cancer. 
     
     
         87 . The method of  claim 86 , 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. 
     
     
         88 . The method of  claim 87 , wherein the cancer is a pancreatic cancer, a lung cancer, or a colon cancer. 
     
     
         89 . The method of any one of  claims 43 - 85 , wherein the cancer is a non-solid cancer. 
     
     
         90 . The method of  claim 89 , wherein the cancer is a leukemia or a lymphoma. 
     
     
         91 . The method of any one of  claims 43 - 90 , wherein the antibody or fragment is administered intravenously, intraperitoneally, intramuscularly, subcutaneously, or intratumorally. 
     
     
         92 . The method of any one of  claims 43 - 91 , further comprising administering to the subject a cancer therapy different from said antibody or fragment or antibody-drug conjugate. 
     
     
         93 . The method of  claim 92 , wherein the cancer therapy is a chemotherapy. 
     
     
         94 . The method of  claim 93 , wherein the chemotherapy is gemcitabine. 
     
     
         95 . The method of  claim 93 , wherein the chemotherapy is nab-paclitaxel. 
     
     
         96 . The method of  claim 93 , wherein the chemotherapy is cisplatin. 
     
     
         97 . The method of  claim 93 , wherein the chemotherapy is 5-FU. 
     
     
         98 . The method of  claim 93 , wherein the chemotherapy is paclitaxel. 
     
     
         99 . The method of  claim 93 , wherein the cancer is a pancreatic cancer, and wherein the chemotherapy is a combination of gemcitabine and nab-paclitaxel. 
     
     
         100 . The method of  claim 99 , 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. 
     
     
         101 . The method of  claim 99 , 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. 
     
     
         102 . The method of  claim 99 , 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. 
     
     
         103 . The method of any one of  claims 99 - 102 , wherein the combination of gemcitabine and nab-paclitaxel is administered with a frequency of every 2 weeks or less. 
     
     
         104 . The method of any one of  claims 43 - 100 , wherein the subject is a human. 
     
     
         105 . The method of  claim 92 , wherein the cancer therapy is an immunotherapy. 
     
     
         106 . The method of  claim 105 , wherein the immunotherapy is an inhibitor of one or more inhibitory checkpoint molecules. 
     
     
         107 . The method of  claim 106 , 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. 
     
     
         108 . A method of selecting and treating a subject having a cancer, said method comprising:
 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   administering to the subject: (i) 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 cell-penetrating peptide, or an antibody-drug conjugate comprising the antibody or fragment bound to a cytotoxic drug, (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 - 40 , (iv) the antibody-drug conjugate of  claim 41 , or (v) the pharmaceutical composition of  claim 42 .   
     
     
         109 . The method of  claim 108 , 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 - 40 . 
     
     
         110 . The method of  claim 109 , which further comprises before the determining step the step of obtaining intact cells of the cancer. 
     
     
         111 . A method of diagnosing cancer in a subject, said method comprising:
 (a) detecting whether the antibody or fragment of any one of  claims 1 - 40  binds to the surface of intact cells of the subject; and   (b) diagnosing the subject with cancer if binding is detected in step (a).   
     
     
         112 . The method of  claim 111 , which is an ex vivo method. 
     
     
         113 . The method of  claim 111 , further comprising obtaining intact cells from the subject before step (a). 
     
     
         114 . The method of  claim 111 , 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. 
     
     
         115 . The method of any one of  claims 108 - 114 , wherein, in step (a), the antibody or fragment is labeled. 
     
     
         116 . The method of any one of  claims 108 - 114 , wherein the subject is a human. 
     
     
         117 . The antibody or a fragment thereof of any one of  claims 1 - 4 , wherein the antibody or a fragment thereof specifically binds to an extracellularly accessible epitope of HDM2. 
     
     
         118 . The method of any one of  claims 43 - 50 , said method comprising administering to the subject an antibody or a fragment thereof that specifically binds to an extracellularly accessible epitope of HDM2.

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