Anti-cd79b antibodies and immunoconjugates and methods of use

Abstract

The present invention is directed to compositions of matter useful for the treatment of hematopoietic tumor in mammals and to methods of using those compositions of matter for the same.

1 . An anti-CD79b antibody comprising:
 (i) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 131;   (ii) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 132;   (iii) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 133;   (iv) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 134;   (v) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 135; and   (vi) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 138.   
     
     
         2 .- 65 . (canceled) 
     
     
         66 . The anti-CD79b antibody of  claim 1 , wherein the anti-CD79b antibody comprises a light chain variable domain (VL) comprising the sequence of SEQ ID NO: 188 and a heavy chain variable domain (VH) comprising the sequence of (SEQ ID NO: 189. 
     
     
         67 . The anti-CD79b antibody of  claim 1 , wherein the anti-CD79b antibody comprises a light chain comprising the sequence of SEQ ID NO: 305 and a heavy chain comprising the sequence of SEQ ID NO: 306. 
     
     
         68 .- 134 . (canceled) 
     
     
         135 . The anti-CD79b antibody of  claim 1 , wherein the anti-CD79b antibody is a monoclonal antibody or a bispecific antibody. 
     
     
         136 . The anti-CD79b antibody of  claim 1 , wherein the anti-CD79b antibody is an antibody fragment. 
     
     
         137 . The anti-CD79b antibody of  claim 1 , wherein the antibody fragment is a Fab fragment. 
     
     
         138 .- 258 . (canceled) 
     
     
         259 . An isolated polynucleotide encoding the anti-CD79b antibody of  claim 1 . 
     
     
         260 . An isolated vector comprising the isolated polynucleotide of  claim 259 . 
     
     
         261 . An isolated host cell comprising the isolated vector of  claim 260 . 
     
     
         262 . The isolated host cell of  claim 261 , which is a eukaryotic host cell. 
     
     
         263 . A pharmaceutical composition comprising the anti-CD79b antibody of  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         264 . The anti-CD79b antibody of  claim 1 , wherein the anti-CD79b antibody is fused to an albumin binding peptide. 
     
     
         265 . The anti-CD79b antibody of  claim 264 , wherein the albumin binding peptide comprises the sequence of any of SEQ ID NOs: 246-250. 
     
     
         266 . An immunoconjugate comprising the anti-CD79b antibody of  claim 1  covalently attached to a capture label, a detection label, or a solid support. 
     
     
         267 . An immunoconjugate comprising the anti-CD79b antibody of  claim 1  covalently attached to a cytotoxic agent. 
     
     
         268 . The immunoconjugate of  claim 267 , wherein the cytotoxic agent is selected from the group consisting of a toxin, a chemotherapeutic agent, a drug moiety, an antibiotic, a radioactive isotope, and a nucleolytic enzyme. 
     
     
         269 . An immunoconjugate comprising the formula Ab-(L-D) p , wherein:
 (a) Ab is the anti-CD79b antibody of  claim 1 ;   (b) L is a linker moiety;   (c) D is a drug moiety; and   (d) p ranges from about 1 to about 20.   
     
     
         270 . The immunoconjugate of  claim 269 , wherein L comprises a linker selected from one or more of 6-maleimidocaproyl (MC), maleimidopropanoyl (MP), valine-citrulline (val-cit), alanine-phenylalanine (ala-phe), p-aminobenzyloxycarbonyl (PAB), N-Succinimidyl 4-(2-pyridylthio) pentanoate (SPP), N-succinimidyl 4-(N-maleimidomethyl) cyclohexane-1 carboxylate (SMCC), 4-(2-Pyridyldithio) butyric acid-N-hydroxysuccinimide ester (SPDB), bis-maleimido-trioxyethylene glycol (BMPEO), and N-succinimidyl (4-iodo-acetyl) aminobenzoate (SIAB). 
     
     
         271 . The immunoconjugate of  claim 269 , wherein D is selected from the group consisting of a maytansinoid, an auristatin, and a dolastatin. 
     
     
         272 . The immunoconjugate of  claim 271 , wherein D is an auristatin comprising formula DE or DF: 
       
         
           
           
               
               
           
         
         wherein R 2  and R 6  are each methyl; R 3  and R 4  are each isopropyl; R 5  is H or methyl; R 7  is sec-butyl; each R 8  is independently selected from CH 3 , O—CH 3 , OH, and H; R 9  is H; R 10  is aryl; Z is —O— or —NH—; R 11  is H, C 1 -C 8  alkyl, or —(CH 2 ) 2 —O—(CH 2 ) 2 —O—(CH 2 ) 2 —O—CH 3 ; and R 18  is —C(R 8 ) 2 —C(R 8 ) 2 -aryl; and 
         wherein the wavy line indicates the attachment site to linker moiety L. 
       
     
     
         273 . The immunoconjugate of  claim 271 , wherein D is monomethyl auristatin E (MMAE) or monomethyl auristatin F (MMAF). 
     
     
         274 . The immunoconjugate of  claim 273 , wherein the immunoconjugate comprises the formula Ab-(L-MMAE) p , and wherein p ranges from about 2 to about 5. 
     
     
         275 . The immunoconjugate of  claim 273 , wherein the immunoconjugate comprises the formula Ab-(L-MMAF) p , and wherein p ranges from about 2 to about 5. 
     
     
         276 . The immunoconjugate of  claim 271 , wherein D is a dolastatin. 
     
     
         277 . The immunoconjugate of  claim 271 , wherein D is a maytansinoid. 
     
     
         278 . The immunoconjugate of  claim 277 , wherein the maytansinoid is selected from DM1, DM3, and DM4. 
     
     
         279 . The immunoconjugate of  claim 269 , wherein L comprises one or more of val-cit, MC, PAB, and MC-PAB. 
     
     
         280 . The immunoconjugate of  claim 269 , wherein L comprises MC-val-cit-PAB. 
     
     
         281 . The immunoconjugate of  claim 269 , wherein the immunoconjugate comprises a structure selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein Val is valine and Cit is citrulline. 
       
     
     
         282 . The immunoconjugate of  claim 269 , wherein the immunoconjugate comprises the structure 
       
         
           
           
               
               
           
         
       
     
     
         283 . The immunoconjugate of  claim 269 , wherein p ranges from about 1 to about 8. 
     
     
         284 . The immunoconjugate of  claim 269 , wherein p ranges from about 2 to about 5. 
     
     
         285 . The immunoconjugate of  claim 269 , wherein p ranges from about 3 to about 4. 
     
     
         286 . A pharmaceutical composition comprising the immunoconjugate of  claim 269 , and a pharmaceutically acceptable carrier. 
     
     
         287 . A method of inhibiting the growth of a cell that expresses CD79b, comprising contacting the cell with an effective amount of the immunoconjugate of  claim 269 . 
     
     
         288 . A method of treating a proliferative disorder in a subject, comprising administering to the subject an effective amount of the immunoconjugate of  claim 269 . 
     
     
         289 . The method of  claim 288 , wherein the proliferative disorder is cancer. 
     
     
         290 . The method of  claim 289 , wherein the cancer is a B cell proliferative disorder. 
     
     
         291 . The method of  claim 290 , wherein said B cell proliferative disorder is selected from the group consisting of lymphoma, myeloma, non-Hodgkin's lymphoma (NHL), aggressive NHL, relapsed aggressive NHL, indolent lymphoma, relapsed indolent NHL, relapsed NHL, refractory NHL, refractory indolent NHL, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma, leukemia, hairy cell leukemia (HCL), acute lymphocytic leukemia (ALL), and mantle cell lymphoma. 
     
     
         292 . The method of  claim 291 , wherein the B cell proliferative disorder is NHL. 
     
     
         293 . The method of  claim 291 , wherein the B cell proliferative disorder is DLBCL. 
     
     
         294 . The method of  claim 291 , wherein the B cell proliferative disorder is relapsed NHL or refractory NHL. 
     
     
         295 . The method of  claim 291 , wherein the B cell proliferative disorder is FL. 
     
     
         296 . The method of  claim 288 , further comprising administering to the subject an effective amount of another therapeutic agent. 
     
     
         297 . The method of  claim 296 , wherein the therapeutic agent is selected from the group consisting of an antibody, a chemotherapeutic agent, a cytotoxic agent, an anti-angiogenic agent, an immunosuppressive agent, a prodrug, a cytokine, a cytokine antagonist, cytotoxic radiotherapy, a corticosteroid, a cancer vaccine, and a growth-inhibitory agent. 
     
     
         298 . The method of  claim 296 , wherein the therapeutic agent is selected from one or more of tamoxifen, letrozole, exemestane, anastrozole, irinotecan, cetuximab, fulvestrant, vinorelbine, erlotinib, bevacizumab, cyclophosphamide, hydroxydaunorubicin, vincristine, imatinib mesylate, sorafenib, lapatinib, trastuzumab, cisplatin, gemcitabine, methotrexate, vinblastine, carboplatin, paclitaxel, 5-fluorouracil, doxorubicin, bortezomib, melphalan, prednisone, prednisolone, and docetaxel. 
     
     
         299 . The method of  claim 296 , wherein the therapeutic agent is an anti-CD20 antibody. 
     
     
         300 . The method of  claim 296 , wherein the therapeutic agent is an anti-CD20 antibody, and wherein the B cell proliferative disorder is DLBCL. 
     
     
         301 . The method of  claim 296 , wherein the therapeutic agent is an anti-CD20 antibody, and wherein the B cell proliferative disorder is FL. 
     
     
         302 . The method of  claim 299 , wherein the anti-CD20 antibody is rituximab. 
     
     
         303 . The method of  claim 296 , wherein the therapeutic agent is a chemotherapeutic agent. 
     
     
         304 . The method of  claim 303 , wherein the chemotherapeutic agent comprises (i) one or more of cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone; or (ii) one or more of cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisolone. 
     
     
         305 . The method of  claim 303 , wherein the chemotherapeutic agent comprises (i) cyclophosphamide, doxorubicin, and prednisone; or (ii) cyclophosphamide, doxorubicin, and prednisolone. 
     
     
         306 . The method of  claim 299 , further comprising administering to the subject an effective amount of a chemotherapeutic agent. 
     
     
         307 . The method of  claim 306 , wherein the chemotherapeutic agent comprises (i) cyclophosphamide, doxorubicin, and prednisone; or (ii) cyclophosphamide, doxorubicin, and prednisolone. 
     
     
         308 . The method of  claim 307 , wherein the B cell proliferative disorder is NHL. 
     
     
         309 . The method of  claim 307 , wherein the B cell proliferative disorder is DLBCL. 
     
     
         310 . The method of  claim 306 , wherein the anti-CD20 antibody is rituximab. 
     
     
         311 . An in vitro method of determining the presence of CD79b in a biological sample suspected of containing CD79b, said method comprising in vitro exposing said biological sample to the immunoconjugate of  claim 266 , and determining binding of said immunoconjugate to CD79b in said biological sample, wherein binding of said immunoconjugate to CD79b in said biological sample is indicative of the presence of CD79b in said biological sample. 
     
     
         312 . The in vitro method of  claim 311 , wherein the biological sample is from a patient suspected of having a B cell proliferative disorder. 
     
     
         313 . A method for making an anti-CD79b antibody, comprising:
 (i) culturing the isolated host cell of  claim 261  under a condition suitable for expression of the encoded anti-CD79b antibody; and   (ii) isolating the expressed anti-CD79b antibody from said cultured host cell.   
     
     
         314 . A method for making an immunoconjugate comprising the anti-CD79b antibody (Ab) of  claim 1 , and an auristatin or a maytansinoid drug moiety (D), wherein the anti-CD79b antibody is attached through one or more cysteine amino acids of the anti-CD79b antibody by a linker moiety (L) to D; the immunoconjugate comprising Formula I:
   Ab-(L-D) p   I
   
       wherein p ranges from about 1 to about 20;
 the method comprising the steps of:
 (a) reacting a cysteine amino acid of the anti-CD79b antibody with a linker reagent to form antibody-linker intermediate Ab-L; and 
 (b) reacting Ab-L with an activated drug moiety D; whereby the immunoconjugate is formed; 
 
 or comprising the steps of:
 (c) reacting a nucleophilic group of a drug moiety D with a linker reagent to form drug-linker intermediate D-L; and 
 (d) reacting D-L with a cysteine amino acid of the anti-CD79b antibody; 
 
 whereby the immunoconjugate is formed. 
 
     
     
         315 . The method of  claim 314 , further comprising the step of expressing the anti-CD79b antibody in Chinese hamster ovary (CHO) cells before step (a) or step (d). 
     
     
         316 . The method of  claim 315 , further comprising the step of treating the expressed anti-CD79b antibody with a reducing agent before step (a) or step (d). 
     
     
         317 . The method of  claim 316 , wherein the reducing agent is TCEP or DTT. 
     
     
         318 . The method of  claim 316 , further comprising the step of treating the expressed anti-CD79b antibody with an oxidizing agent after treating with the reducing agent. 
     
     
         319 . The method of  claim 318 , wherein the oxidizing agent is copper sulfate, dehydroascorbic acid, or air.