US2015320880A1PendingUtilityA1
Antibody drug conjugates

Assignee: ABRAMS TINYAPriority: Mar 15, 2013Filed: May 20, 2015Published: Nov 12, 2015
Est. expiryMar 15, 2033(~6.7 yrs left)· nominal 20-yr term from priority
Inventors:Tinya Abrams Steven Bruce Cohen Christie P. Fanton Catrin Finner Thomas Huber Kathy Miller Siew Ho Schleyer Kathrin Ulrike Tissot-Daguette
G01N 33/5759G01N 33/575G01N 33/532A61K 47/12C07K 2317/77A61K 9/19A61K 51/1093C07K 2317/76C07K 2317/55C07K 2317/24C07K 16/2863A61K 47/6867A61K 47/26A61K 45/06A61K 47/6889A61K 47/6857A61K 47/6801C07K 2317/33A61K 47/6921A61K 2039/505C07K 2317/34A61K 47/6849C07K 2317/732C07K 2317/565A61K 47/6865C07K 2317/92A61K 9/0019A61K 51/103C07K 2317/73A61P 35/00C07K 2317/21A61K 39/39591A61K 31/537C07K 16/32A61K 47/6855C07K 2317/30A61K 49/00C07K 2317/14A61K 47/48561A61K 47/48715A61K 47/48384A61K 47/68033C07K 16/2803G01N 33/53
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Claims
Abstract

The present invention relates to anti-cKIT antibodies, antibody fragments, antibody drug conjugates, and their uses for the treatment of cancer.
Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . An antibody drug conjugate of the formula
   Ab-(L-(D) m ) n      or a pharmaceutically acceptable salt thereof; wherein   Ab is an antibody or antigen binding fragment thereof that specifically binds to an epitope of human cKIT;   L is a linker;   D is a drug moiety;   m is an integer from 1 to 8; and   n is an integer from 1 to 10.   
     
     
         2 . The antibody drug conjugate of  claim 1 , wherein said n is 3 or 4. 
     
     
         3 . The antibody drug conjugate of  claim 1  or  2 , wherein said antibody or antigen binding fragment thereof specifically binds the extracellular domain of cKIT (SEQ ID NO.160). 
     
     
         4 . The antibody drug conjugate of  claim 1  or  2 , wherein said antibody or antigen binding fragment specifically binds to an epitope of human cKIT at domains 1-3 (SEQ ID NO.155). 
     
     
         5 . The antibody drug conjugate of  claim 1  or  2 , wherein said antibody or antigen binding fragment thereof specifically binds human cKIT at SEQ ID NO. 161 and SEQ ID NO. 162. 
     
     
         6 . The antibody drug conjugate of any of  claims 1 - 3 , wherein said antibody or antigen binding fragment thereof comprises:
 (i) a heavy chain variable region that comprises (a) a HCDR1 (CDR-Complementarity Determining Region) of SEQ ID NO: 76, (b) a HCDR2 of SEQ ID NO: 77, (c) a HCDR3 of SEQ ID NO: 78; and a light chain variable region that comprises: (d) a LCDR1 of SEQ ID NO: 85, (e) a LCDR2 of SEQ ID NO: 86, and (f) a LCDR3 of SEQ ID NO: 87;   (ii) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO: 22, (b) a HCDR2 of SEQ ID NO: 23, (c) a HCDR3 of SEQ ID NO: 24; and a light chain variable region that comprises: (d) a LCDR1 of SEQ ID NO: 31, (e) a LCDR2 of SEQ ID NO: 32, and (f) a LCDR3 of SEQ ID NO: 33;   (iii) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO: 130, (b) a HCDR2 of SEQ ID NO: 131, (c) a HCDR3 of SEQ ID NO: 132; and a light chain variable region that comprises: (d) a LCDR1 of SEQ ID NO: 139, (e) a LCDR2 of SEQ ID NO: 140, and (f) a LCDR3 of SEQ ID NO: 141;   (iv) a heavy chain variable region that comprises: (a) a HCDR1 of SEQ ID NO: 58, (b) a HCDR2 of SEQ ID NO: 59, (c) a HCDR3 of SEQ ID NO: 60; and a light chain variable region that comprises: (d) a LCDR1 of SEQ ID NO: 67, (e) a LCDR2 of SEQ ID NO: 68, and (f) a LCDR3 of SEQ ID NO: 69;   (v) a heavy chain variable region that comprises: (a) a HCDR1 of SEQ ID NO: 40, (b) a HCDR2 of SEQ ID NO: 41, (c) a HCDR3 of SEQ ID NO: 42; and a light chain variable region that comprises: (d) a LCDR1 of SEQ ID NO: 49, (e) a LCDR2 of SEQ ID NO: 50, and (f) a LCDR3 of SEQ ID NO: 51;   (vi) a heavy chain variable region that comprises: (a) a HCDR1 of SEQ ID NO: 94, (b) a HCDR2 of SEQ ID NO: 95, (c) a HCDR3 of SEQ ID NO: 96; and a light chain variable region that comprises: (d) a LCDR1 of SEQ ID NO: 103, (d) a LCDR2 of SEQ ID NO: 104, and (f) a LCDR3 of SEQ ID NO: 105;   (vii) a heavy chain variable region that comprises: (a) a HCDR1 of SEQ ID NO: 112, (b) a HCDR2 of SEQ ID NO: 113, (c) a HCDR3 of SEQ ID NO: 114; and a light chain variable region that comprises: (d) a LCDR1 of SEQ ID NO: 121, (e) a LCDR2 of SEQ ID NO: 122, and (f) a LCDR3 of SEQ ID NO: 123; or   (viii) a heavy chain variable region that comprises: (a) a HCDR1 of SEQ ID NO: 3, (b) a HCDR2 of SEQ ID NO: 4, (c) a HCDR3 of SEQ ID NO: 5; and a light chain variable region that comprises: (d) a LCDR1 of SEQ ID NO: 12, (e) a LCDR2 of SEQ ID NO: 13, and (f) a LCDR3 of SEQ ID NO: 14.   
     
     
         7 . The antibody drug conjugate of any of the preceding claims in which at least one amino acid within a CDR is substituted by a corresponding residue of a corresponding CDR of another anti-cKIT antibody in Table 1. 
     
     
         8 . The antibody drug conjugate of any of the preceding claims in which one or two amino acids within a CDR have been modified, deleted or substituted. 
     
     
         9 . The antibody drug conjugate of any of the preceding claims that retains at least 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% identity over either the variable light or variable heavy region. 
     
     
         10 . The antibody drug conjugate of any of the preceding claims wherein the antibody is a monoclonal antibody, a chimeric antibody, a humanized antibody, a human engineered antibody, a human antibody, a single chain antibody (scFv) or an antibody fragment. 
     
     
         11 . The antibody drug conjugate of any one of  claims 1 - 10 , wherein said linker (L) is selected from the group consisting of a cleavable linker, a non-cleavable linker, a hydrophilic linker, a procharged linker and a dicarboxylic acid based linker. 
     
     
         12 . The antibody drug conjugate of  claim 11 , wherein the linker is derived from a cross-linking reagent selected from the group consisting of N-succinimidyl-3-(2-pyridyldithio)propionate (SPDP), N-succinimidyl 4-(2-pyridyldithio)pentanoate (SPP), N-succinimidyl 4-(2-pyridyldithio)butanoate (SPDB), N-succinimidyl-4-(2-pyridyldithio)2-sulfo-butanoate (sulfo-SPDB), N-succinimidyl iodoacetate (SIA), N-succinimidyl(4-iodoacetyl)aminobenzoate (SIAB), maleimide PEG NHS, N-succinimidyl 4-(maleimidomethyl) cyclohexanecarboxylate (SMCC), N-sulfosuccinimidyl 4-(maleimidomethyl) cyclohexanecarboxylate (sulfo-SMCC) or 2,5-dioxopyrrolidin-1-yl 17-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-5,8,11,14-tetraoxo-4,7,10,13-tetraazaheptadecan-1-oate (CX1-1). 
     
     
         13 . The antibody drug conjugate of  claim 12 , wherein said linker is derived from the cross-linking reagent N-succinimidyl 4-(maleimidomethyl) cyclohexanecarboxylate (SMCC). 
     
     
         14 . The antibody drug conjugate of any one of  claims 1 - 13 , wherein said drug moiety (D) is selected from a group consisting of a V-ATPase inhibitor, a pro-apoptotic agent, a Bcl2 inhibitor, an MCL1 inhibitor, a HSP90 inhibitor, an IAP inhibitor, an mTor inhibitor, a microtubule stabilizer, a microtubule destabilizer, an auristatin, a dolastatin, a maytansinoid, a MetAP (methionine aminopeptidase), an inhibitor of nuclear export of proteins CRM1, a DPPIV inhibitor, proteasome inhibitors, inhibitors of phosphoryl transfer reactions in mitochondria, a protein synthesis inhibitor, a kinase inhibitor, a CDK2 inhibitor, a CDK9 inhibitor, a kinesin inhibitor, an HDAC inhibitor, a DNA damaging agent, a DNA alkylating agent, a DNA intercalator, a DNA minor groove binder and a DHFR inhibitor. 
     
     
         15 . The antibody drug conjugate of  claim 14 , wherein the drug moiety is a maytansinoid. 
     
     
         16 . The antibody drug conjugate of  claim 15 , wherein the maytansinoid is N(2′)-deacetyl-N(2′)-(3-mercapto-1-oxopropyl)-maytansine (DM1) or N(2′)-deacetyl-N2-(4-mercapto-4-methyl-1-oxopentyl)-maytansine (DM4). 
     
     
         17 . The antibody drug conjugate of any of the preceding claims in combination with another therapeutic agent. 
     
     
         18 . The antibody drug conjugate of any of the preceding claims in combination with a therapeutic agent listed in Table 16. 
     
     
         19 . An antibody drug conjugate of the formula 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; wherein; 
         Ab is an antibody or antigen binding fragment thereof that specifically binds to human cKIT, and at least n number of primary amines; and n is an integer from 1 to 10. 
       
     
     
         20 . The antibody drug conjugate of  claim 19 , wherein said antibody or antigen binding fragment specifically binds to an epitope of human cKIT at domains 1-3 (SEQ ID NO.155). 
     
     
         21 . The antibody drug conjugate of  claim 19 , wherein said antibody or antigen binding fragment thereof specifically binds human cKIT at SEQ ID NO. 161 and SEQ ID NO. 162. 
     
     
         22 . The antibody drug conjugate of  claim 19 , wherein said Ab is an antibody or antigen binding fragment thereof comprises:
 (i) a heavy chain variable region that comprises (a) a HCDR1 (CDR-Complementarity Determining Region) of SEQ ID NO: 76, (b) a HCDR2 of SEQ ID NO: 77, (c) a HCDR3 of SEQ ID NO: 78; and a light chain variable region that comprises: (d) a LCDR1 of SEQ ID NO: 85, (e) a LCDR2 of SEQ ID NO: 86, and (f) a LCDR3 of SEQ ID NO: 87;   (ii) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO: 22, (b) a HCDR2 of SEQ ID NO: 23, (c) a HCDR3 of SEQ ID NO: 24; and a light chain variable region that comprises: (d) a LCDR1 of SEQ ID NO: 31, (e) a LCDR2 of SEQ ID NO: 32, and (f) a LCDR3 of SEQ ID NO: 33;   (iii) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO: 130, (b) a HCDR2 of SEQ ID NO: 131, (c) a HCDR3 of SEQ ID NO: 132; and a light chain variable region that comprises: (d) a LCDR1 of SEQ ID NO: 139, (e) a LCDR2 of SEQ ID NO: 140, and (f) a LCDR3 of SEQ ID NO: 141;   (iv) a heavy chain variable region that comprises: (a) a HCDR1 of SEQ ID NO: 58, (b) a HCDR2 of SEQ ID NO: 59, (c) a HCDR3 of SEQ ID NO: 60; and a light chain variable region that comprises: (d) a LCDR1 of SEQ ID NO: 67, (e) a LCDR2 of SEQ ID NO: 68, and (f) a LCDR3 of SEQ ID NO: 69;   (v) a heavy chain variable region that comprises: (a) a HCDR1 of SEQ ID NO: 40, (b) a HCDR2 of SEQ ID NO: 41, (c) a HCDR3 of SEQ ID NO: 42; and a light chain variable region that comprises: (d) a LCDR1 of SEQ ID NO: 49, (e) a LCDR2 of SEQ ID NO: 50, and (f) a LCDR3 of SEQ ID NO: 51;   (vi) a heavy chain variable region that comprises: (a) a HCDR1 of SEQ ID NO: 94, (b) a HCDR2 of SEQ ID NO: 95, (c) a HCDR3 of SEQ ID NO: 96; and a light chain variable region that comprises: (d) a LCDR1 of SEQ ID NO: 103, (d) a LCDR2 of SEQ ID NO: 104, and (f) a LCDR3 of SEQ ID NO: 105;   (vii) a heavy chain variable region that comprises: (a) a HCDR1 of SEQ ID NO: 112, (b) a HCDR2 of SEQ ID NO: 113, (c) a HCDR3 of SEQ ID NO: 114; and a light chain variable region that comprises: (d) a LCDR1 of SEQ ID NO: 121, (e) a LCDR2 of SEQ ID NO: 122, and (f) a LCDR3 of SEQ ID NO: 123; or   (viii) a heavy chain variable region that comprises: (a) a HCDR1 of SEQ ID NO: 3, (b) a HCDR2 of SEQ ID NO: 4, (c) a HCDR3 of SEQ ID NO: 5; and a light chain variable region that comprises: (d) a LCDR1 of SEQ ID NO: 12, (e) a LCDR2 of SEQ ID NO: 13, and (f) a LCDR3 of SEQ ID NO: 14.   
     
     
         23 . The antibody drug conjugate of any of the preceding claims in which at least one amino acid within a CDR is substituted by a corresponding residue of a corresponding CDR of another anti-cKIT antibody of Table 1. 
     
     
         24 . The antibody drug conjugate of any of the preceding claims in which one or two amino acids within a CDR have been modified, deleted or substituted. 
     
     
         25 . The antibody drug conjugate of any of the preceding claims that retains at least 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% identity over either the variable light or variable heavy region. 
     
     
         26 . The antibody drug conjugate of any of  claims 19 - 25 , wherein the antibody is a monoclonal antibody, a chimeric antibody, a humanized antibody, a human engineered antibody, a human antibody, a single chain antibody (scFv) or an antibody fragment. 
     
     
         27 . The antibody drug conjugate of any of  claims 19 - 25 , wherein said n is an integer from 2 to 8. 
     
     
         28 . The antibody drug conjugate of any of  claims 19 - 25 , wherein said n is an integer from 3 to 4. 
     
     
         29 . The antibody drug conjugate of any of  claims 19 - 28  in combination with another therapeutic agent. 
     
     
         30 . The antibody drug conjugate of any of  claims 19 - 28  in combination with a therapeutic agent listed in Table 16. 
     
     
         31 . A pharmaceutical composition comprising the antibody drug conjugate of any one of  claims 1 - 28  and a pharmaceutically acceptable carrier. 
     
     
         32 . The pharmaceutical composition of  claim 31  wherein said composition is prepared as a lyophilisate. 
     
     
         33 . The pharmaceutical composition of  claim 32 , wherein said lyophilisate comprises the antibody drug conjugate of any one of  claims 1  to  28 , sodium succinate, and polysorbate 20. 
     
     
         34 . A method of treating an cKIT positive cancer in a patient in need thereof, comprising administering to said patient the antibody drug conjugate of any of  claims 1 - 28 , or the pharmaceutical composition of  claims 31 - 33 . 
     
     
         35 . The method of  claim 34 , wherein said cancer is selected from the group consisting of gastrointestinal stromal tumors (GIST), small cell lung cancer (SCLC), acute myeloid leukemia (AML), melanoma, mast cell leukemia (MCL), mastocytosis, neurofibromatosis, breast cancer, non-small cell lung cancer (NSCLC) and pancreatic cancer. 
     
     
         36 . The method of  claim 35 , wherein the antibody drug conjugate or the pharmaceutical composition is administered in combination with another therapeutic agent. 
     
     
         37 . The method of  claim 36 , wherein the antibody drug conjugate or the pharmaceutical composition is administered in combination with a therapeutic listed in Table 16. 
     
     
         38 . The antibody drug conjugate of any of  claims 1 - 28  for use as a medicament. 
     
     
         39 . The antibody drug conjugate of any of  claims 1 - 28 , or the pharmaceutical composition of any of  claims 31 - 33 , for use in the treatment of a cKIT positive cancer. 
     
     
         40 . The antibody drug conjugate of  claim 39  administered in combination with another therapeutic agent. 
     
     
         41 . The antibody drug conjugate of  claim 40  administered in combination with a therapeutic agent listed in Table 16. 
     
     
         42 . A nucleic acid that encodes the antibody or antigen binding fragment of any of  claims 1 - 28 . 
     
     
         43 . A vector comprising the nucleic acid of  claim 42 . 
     
     
         44 . A host cell comprising the vector according to  claim 43 . 
     
     
         45 . A process for producing an antibody or antigen binding fragment comprising cultivating the host cell of  claim 44  and recovering the antibody from the culture. 
     
     
         46 . A process for producing an anti-cKIT antibody drug conjugate, the process comprising:
 (a) chemically linking SMCC to a drug moiety DM-1;   (b) conjugating said linker-drug to the antibody recovered from the cell culture of  claim 45 ; and   (c) purifying the antibody drug conjugate.   
     
     
         47 . The antibody drug conjugate made according to  claim 46  having an average maytansinoid to antibody ratio (MAR), measured with a UV spectrophotometer, about 3.5. 
     
     
         48 . An antibody or antigen binding fragment thereof that comprises:
 (i) a heavy chain variable region that comprises (a) a HCDR1 (CDR-Complementarity Determining Region) of SEQ ID NO: 76, (b) a HCDR2 of SEQ ID NO: 77, (c) a HCDR3 of SEQ ID NO: 78; and a light chain variable region that comprises: (d) a LCDR1 of SEQ ID NO: 85, (e) a LCDR2 of SEQ ID NO: 86, and (f) a LCDR3 of SEQ ID NO: 87;   (ii) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO: 22, (b) a HCDR2 of SEQ ID NO: 23, (c) a HCDR3 of SEQ ID NO: 24; and a light chain variable region that comprises: (d) a LCDR1 of SEQ ID NO: 31, (e) a LCDR2 of SEQ ID NO: 32, and (f) a LCDR3 of SEQ ID NO: 33;   (iii) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO: 130, (b) a HCDR2 of SEQ ID NO: 131, (c) a HCDR3 of SEQ ID NO: 132; and a light chain variable region that comprises: (d) a LCDR1 of SEQ ID NO: 139, (e) a LCDR2 of SEQ ID NO: 140, and (f) a LCDR3 of SEQ ID NO: 141;   (iv) a heavy chain variable region that comprises: (a) a HCDR1 of SEQ ID NO: 58, (b) a HCDR2 of SEQ ID NO: 59, (c) a HCDR3 of SEQ ID NO: 60; and a light chain variable region that comprises: (d) a LCDR1 of SEQ ID NO: 67, (e) a LCDR2 of SEQ ID NO: 68, and (f) a LCDR3 of SEQ ID NO: 69;   (v) a heavy chain variable region that comprises: (a) a HCDR1 of SEQ ID NO: 40, (b) a HCDR2 of SEQ ID NO: 41, (c) a HCDR3 of SEQ ID NO: 42; and a light chain variable region that comprises: (d) a LCDR1 of SEQ ID NO: 49, (e) a LCDR2 of SEQ ID NO: 50, and (f) a LCDR3 of SEQ ID NO: 51;   (vi) a heavy chain variable region that comprises: (a) a HCDR1 of SEQ ID NO: 94, (b) a HCDR2 of SEQ ID NO: 95, (c) a HCDR3 of SEQ ID NO: 96; and a light chain variable region that comprises: (d) a LCDR1 of SEQ ID NO: 103, (d) a LCDR2 of SEQ ID NO: 104, and (f) a LCDR3 of SEQ ID NO: 105;   (vii) a heavy chain variable region that comprises: (a) a HCDR1 of SEQ ID NO: 112, (b) a HCDR2 of SEQ ID NO: 113, (c) a HCDR3 of SEQ ID NO: 114; and a light chain variable region that comprises: (d) a LCDR1 of SEQ ID NO: 121, (e) a LCDR2 of SEQ ID NO: 122, and (f) a LCDR3 of SEQ ID NO: 123; or   (viii) a heavy chain variable region that comprises: (a) a HCDR1 of SEQ ID NO: 3, (b) a HCDR2 of SEQ ID NO: 4, (c) a HCDR3 of SEQ ID NO: 5; and a light chain variable region that comprises: (d) a LCDR1 of SEQ ID NO: 12, (e) a LCDR2 of SEQ ID NO: 13, and (f) a LCDR3 of SEQ ID NO: 14.   
     
     
         49 . A diagnostic reagent comprising the antibody or antigen binding fragment thereof of  claim 48  which is labeled. 
     
     
         50 . The diagnostic reagent of  claim 49 , wherein the label is selected from the group consisting of a radiolabel, a fluorophore, a chromophore, an imaging agent, and a metal ion.
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