US2016017053A1PendingUtilityA1

Non-Antagonistic EGFR-Binding Molecules and Immunoconjugates Thereof

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Assignee: IMMUNOGEN INCPriority: Oct 29, 2010Filed: May 8, 2015Published: Jan 21, 2016
Est. expiryOct 29, 2030(~4.3 yrs left)· nominal 20-yr term from priority
Inventors:Julianto SetiadyRajeeva SinghPeter U. ParkLingyun RuiThomas Chittenden
C07K 2317/732A61K 47/6871A61K 2039/505C07K 2317/74G01N 33/74C07K 2317/33C07K 2317/567A61K 47/6849C07K 2317/76G01N 2333/912C07K 2317/565C07K 2317/14C07K 2317/75A61K 47/6851C07K 2317/24C07K 2317/92G01N 2333/71C07K 2317/73A61P 35/00C07K 2317/21C07K 16/2863C07K 16/30A61K 47/48384A61K 47/48646C07K 16/40A61K 47/68033
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Claims

Abstract

Novel anti-cancer agents, including, but not limited to, antibodies and immunoconjugates, that bind to EGFR are provided. Methods of using the agents, antibodies, or immunoconjugates, such as methods of inhibiting tumor growth are further provided.

Claims

exact text as granted — not AI-modified
1 - 74 . (canceled) 
     
     
         75 . An antibody or antigen binding fragment thereof that specifically binds to human EGFR, wherein said antibody or antigen binding fragment thereof comprises:
 a) a heavy chain variable region comprising the heavy chain CDR1 of SEQ ID NO:1, the heavy chain CDR2 of SEQ ID NO:2, 4, or 5, and the heavy chain CDR3 of SEQ ID NO:3; and   b) a light chain variable region comprising the light chain CDR1 of SEQ ID NO:11, the light chain CDR2 of SEQ ID NO:12, and the light chain CDR3 of SEQ ID NO:13.   
     
     
         76 . The antibody or antigen binding fragment thereof of  claim 75 , wherein said antibody or antigen binding fragment thereof comprises:
 a) a heavy chain variable region comprising the heavy chain CDR1 of SEQ ID NO:1, the heavy chain CDR2 of SEQ ID NO:2, and the heavy chain CDR3 of SEQ ID NO:3; and   b) a light chain variable region comprising the light chain CDR1 of SEQ ID NO:11, the light chain CDR2 of SEQ ID NO:12, and the light chain CDR3 of SEQ ID NO:13.   
     
     
         77 . The antibody or antigen binding fragment thereof of  claim 75 , wherein said antibody or antigen binding fragment thereof comprises:
 a) a heavy chain variable region comprising the heavy chain CDR1 of SEQ ID NO:1, the heavy chain CDR2 of SEQ ID NO:5, and the heavy chain CDR3 of SEQ ID NO:3; and   b) a light chain variable region comprising the light chain CDR1 of SEQ ID NO:11, the light chain CDR2 of SEQ ID NO:12, and the light chain CDR3 of SEQ ID NO:13.   
     
     
         78 . The antibody or antigen binding fragment thereof of  claim 75 , wherein said antibody or antigen binding fragment thereof comprises:
 a) a heavy chain variable region comprising the heavy chain CDR1 of SEQ ID NO:1, the heavy chain CDR2 of SEQ ID NO:4, and the heavy chain CDR3 of SEQ ID NO:3; and   b) a light chain variable region comprising the light chain CDR1 of SEQ ID NO:11, the light chain CDR2 of SEQ ID NO:12, and the light chain CDR3 of SEQ ID NO:13.   
     
     
         79 . The antibody or antigen binding fragment thereof of  claim 75 , wherein said antibody or antigen binding fragment thereof comprises the heavy chain variable region of SEQ ID NO:18 and the light chain variable region of SEQ ID NO:22. 
     
     
         80 . The antibody or antigen binding fragment thereof of  claim 75 , wherein said antibody or antigen binding fragment thereof comprises the heavy chain variable region of SEQ ID NO:17 and the light chain variable region of SEQ ID NO:21. 
     
     
         81 . The antibody or antigen binding fragment thereof of  claim 75 , wherein said antibody or antigen binding fragment thereof is rat, non-human, humanized, chimeric, or human. 
     
     
         82 . The antibody or antigen binding fragment thereof of  claim 81 , wherein said humanized antibody or antigen binding fragment thereof is resurfaced. 
     
     
         83 . The antibody or antigen binding fragment thereof of  claim 75 , wherein said antibody comprises the full length heavy chain of SEQ ID NO:25 and the full length light chain of SEQ ID NO:26. 
     
     
         84 . The antibody or antigen binding fragment thereof of  claim 75 , which is a full length antibody. 
     
     
         85 . The antibody or antigen binding fragment thereof of  claim 75 , which is an antigen binding fragment. 
     
     
         86 . The antibody or antigen binding fragment thereof of  claim 75 , wherein said antibody or antigen binding fragment thereof comprises a Fab, Fab′, F(ab′)2, single chain Fv or scFv, disulfide linked Fv, intrabody, IgGΔCH2, minibody, F(ab′)3, tetrabody, triabody, diabody, DVD-Ig, mAb2, (scFv)2, or scFv-Fc. 
     
     
         87 . The antibody or antigen binding fragment thereof of  claim 75 , wherein said antibody or antigen binding fragment thereof binds to human or macaque EGFR with a Kd of about 1.0 to about 10 nM. 
     
     
         88 . The antibody or antigen binding fragment thereof of  claim 75 , wherein said antibody or antigen binding fragment thereof binds to human or macaque EGFR with a Kd of about 1.0 nM or better. 
     
     
         89 . The antibody or antigen binding fragment thereof of  claim 75 , wherein the antibody or antigen binding fragment thereof is produced by the hybridoma deposited with the ATCC on Oct. 21, 2010 and having ATCC deposit no. PTA-11423. 
     
     
         90 . An isolated cell producing the antibody of  claim 75 . 
     
     
         91 . A method of making the antibody of  claim 75 , comprising (a) culturing a cell that produces said antibody; and (b) isolating said antibody from said cultured cell. 
     
     
         92 . A pharmaceutical composition comprising the antibody or antigen binding fragment thereof of  claim 75  and a pharmaceutically acceptable carrier. 
     
     
         93 . A diagnostic reagent comprising the antibody or antigen binding fragment thereof of  claim 75  and further comprising a label. 
     
     
         94 . An immunoconjugate having the formula (A)-(L)-(C), wherein:
 (A) is an antibody or antigen binding fragment thereof that specifically binds to human EGFR comprising a heavy chain variable region comprising the heavy chain CDR1 of SEQ ID NO:1, the heavy chain CDR2 of SEQ ID NO:2, 4, or 5, and the heavy chain CDR3 of SEQ ID NO:3; and a light chain variable region comprising the light chain CDR1 of SEQ ID NO:11, the light chain CDR2 of SEQ ID NO:12, and the light chain CDR3 of SEQ ID NO:13;   (L) is a linker;   (C) is a cytotoxic agent; and   wherein (L) links (A) to (C).   
     
     
         95 . The immunoconjugate of  claim 94 , wherein (A) comprises a heavy chain variable region comprising the heavy chain CDR1 of SEQ ID NO:1, the heavy chain CDR2 of SEQ ID NO:2, and the heavy chain CDR3 of SEQ ID NO:3; and the light chain variable region comprising the light chain CDR1 of SEQ ID NO:11, the light chain CDR2 of SEQ ID NO:12, and the light chain CDR3 of SEQ ID NO:13. 
     
     
         96 . The immunoconjugate of  claim 94 , wherein (A) comprises a heavy chain variable region comprising the heavy chain CDR1 of SEQ ID NO:1, the heavy chain CDR2 of SEQ ID NO:5, and the heavy chain CDR3 of SEQ ID NO:3; and the light chain variable region comprising the light chain CDR1 of SEQ ID NO:11, the light chain CDR2 of SEQ ID NO:12, and the light chain CDR3 of SEQ ID NO:13. 
     
     
         97 . The immunoconjugate of  claim 94 , wherein (A) comprises the heavy chain variable domain of SEQ ID NO:18 and the light chain variable domain of SEQ ID NO:22. 
     
     
         98 . The immunoconjugate of  claim 94 , wherein (L) is selected from the group consisting of: a cleavable linker, a non-cleavable linker, a hydrophilic linker, and a dicarboxylic acid based linker. 
     
     
         99 . The immunoconjugate of  claim 98 , wherein (L) is a linker selected from the group consisting of: N-succinimidyl 4-(2-pyridyldithio)pentanoate (SPP), N-succinimidyl 4-(2-pyridyldithio)butanoate (SPDB), N-succinimidyl 4-(2-pyridyldithio)-2-sulfobutanoate (sulfo-SPDB), N-succinimidyl 4-(maleimidomethyl) cyclohexanecarboxylate (SMCC), N-sulfosuccinimidyl 4-(maleimidomethyl) cyclohexanecarboxylate (sulfoSMCC), N-succinimidyl-4-(iodoacetyl)-aminobenzoate (SIAB), and N-succinimidyl-[(N-maleimidopropionamido)-tetraethyleneglycol]ester (NHS-PEG4-maleimide). 
     
     
         100 . The immunoconjugate of  claim 94 , wherein (C) is a cytotoxic agent selected from the group consisting of: a maytansinoid, a maytansinoid analog, benzodiazepine, taxoid, CC-1065, CC-1065 analog, duocarmycin, duocarmycin analog, calicheamicin, dolastatin, dolastatin analog, auristatin, tomaymycin derivative, doxorubicin, leptomycin derivative, methotrexate, cisplatin, carboplatin, daunorubicin, vincristine, vinblastine, melphalan, mitomycin C, chlorambucil and morpholino doxorubicin, or a prodrug of the cytotoxic agent. 
     
     
         101 . The immunoconjugate of  claim 100 , wherein said immunoconjugate comprises multiple (C) with an average of 2 to 8 (C) per (A). 
     
     
         102 . The immunoconjugate of  claim 101 , wherein (C) is a maytansinoid. 
     
     
         103 . The immunoconjugate of  claim 102 , wherein (C) is N(2′)-deacetyl-N(2′)-(3-mercapto-1-oxopropyl)-maytansine (DM1) or N(2′)-deacetyl-N(2′)-(4-mercapto-4-methyl-1-oxopentyl)-maytansine (DM4). 
     
     
         104 . The immunoconjugate of  claim 103 , wherein (L) is a N-succinimidyl 4-(maleimidomethyl) cyclohexanecarboxylate (SMCC) linker, and wherein (C) is the cytotoxic agent N(2′)-deacetyl-N(2′)-(3-mercapto-1-oxopropyl)-maytansine (DM1). 
     
     
         105 . The immunoconjugate of  claim 103 , wherein (L) is a N-succinimidyl 442-pyridyldithio) butanoate (SPDB) linker, and wherein (C) is the cytotoxic agent N(2′)-deacetyl-N(2′)-(4-mercapto-4-methyl-1-oxopentyl)-maytansine (DM4). 
     
     
         106 . The immunoconjugate of  claim 94 , wherein:
 (A) is an antibody or antigen binding fragment thereof comprising the heavy chain variable region of SEQ ID NO:18 and the light chain variable region of SEQ ID NO:22;   (L) is a N-succinimidyl 4-(maleimidomethyl) cyclohexanecarboxylate (SMCC) linker; and   (C) is the cytotoxic agent N(2)-deacetyl-N(2′)-(3-mercapto-1-oxopropyl)-maytansine (DM1).   
     
     
         107 . The immunoconjugate of  claim 94 , wherein:
 (A) is an antibody or antigen binding fragment thereof comprising the heavy chain variable region of SEQ ID NO:18 and the light chain variable region of SEQ ID NO:22;   (L) is a N-succinimidyl 4-(2-pyridyldithio) butanoate (SPDB) linker; and   (C) is the cytotoxic agent N(2′)-deacetyl-N(2′)-(4-mercapto-4-methyl-1-oxopentyl)-maytansine (DM4).   
     
     
         108 . A pharmaceutical composition comprising the immunoconjugate of  claim 94  and a pharmaceutically acceptable carrier. 
     
     
         109 . A kit comprising the immunoconjugate of  claim 94 . 
     
     
         110 . A diagnostic reagent comprising the immunoconjugate of  claim 94  and further comprising a label.

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