Compositions and methods for the diagnosis and treatment of tumor

Abstract

The invention is directed to antibody drug conjugate compositions of matter useful for the diagnosis and treatment of tumors in mammals and to methods of using those compositions of matter for the same.

1 .- 21 . (canceled) 
     
     
         22 . A method of inhibiting the growth of a cell that expresses a protein comprising the amino acid sequence of SEQ ID NO:2, said method comprising contacting said cell with an antibody that comprises three light chain hypervariable regions (HVR-L1, HVR-L2 and HVR-L3) and three heavy chain hypervariable regions (HVR-H1, HVR-H2 and HVR-H3) wherein:
 (a) HVR-L1 comprises the amino acid sequence of SEQ ID NO:119;   (b) HVR-L2 comprises the amino acid sequence of any one of SEQ ID NOS:120-121;   (c) HVR-L3 comprises the amino acid sequence of SEQ ID NO:122;   (d) HVR-H1 comprises the amino acid sequence of SEQ ID NO:123;   (e) HVR-H2 comprises the amino acid sequence of any one of SEQ ID NOS:124-127; and   (f) HVR-H3 comprises the amino acid sequence of any one of SEQ ID NOS:128-183,   
       wherein the antibody is conjugated to a growth inhibitory agent or a cytotoxic agent and wherein the binding of said antibody to said protein causes an inhibition of growth of said cell. 
     
     
         23 .- 78 . (canceled) 
     
     
         79 . The method of  claim 22 , wherein:
 (a) HVR-L1 comprises the amino acid sequence of SEQ ID NO:119;   (b) HVR-L2 comprises the amino acid sequence of SEQ ID NO:121;   (c) HVR-L3 comprises the amino acid sequence of SEQ ID NO:122;   (d) HVR-H1 comprises the amino acid sequence of SEQ ID NO:123;   (e) HVR-H2 comprises the amino acid sequence of SEQ ID NO:125; and   (f) HVR-H3 comprises the amino acid sequence of SEQ ID NO:174.   
     
     
         80 . The method of  claim 79 , wherein the antibody comprises the variable heavy (VH) sequence of SEQ ID NO:206 and the variable light (VL) sequence of SEQ ID NO:211. 
     
     
         81 . The method of  claim 22 , wherein:
 (a) HVR-L1 comprises the amino acid sequence of SEQ ID NO:119;   (b) HVR-L2 comprises the amino acid sequence of SEQ ID NO:121;   (c) HVR-L3 comprises the amino acid sequence of SEQ ID NO:122;   (d) HVR-H1 comprises the amino acid sequence of SEQ ID NO:123;   (e) HVR-H2 comprises the amino acid sequence of SEQ ID NO:126; and   (f) HVR-H3 comprises the amino acid sequence of SEQ ID NO:174.   
     
     
         82 . The method of  claim 81 , wherein the antibody comprises the VH sequence of SEQ ID NO:207 and the VL sequence of SEQ ID NO:211. 
     
     
         83 . The method of  claim 22 , wherein:
 (a) HVR-L1 comprises the amino acid sequence of SEQ ID NO:119;   (b) HVR-L2 comprises the amino acid sequence of SEQ ID NO:121;   (c) HVR-L3 comprises the amino acid sequence of SEQ ID NO:122;   (d) HVR-H1 comprises the amino acid sequence of SEQ ID NO:123;   (e) HVR-H2 comprises the amino acid sequence of SEQ ID NO:125; and   (f) HVR-H3 comprises the amino acid sequence of SEQ ID NO:183.   
     
     
         84 . The method of  claim 83 , wherein the antibody comprises the VH sequence of SEQ ID NO:208 and the VL sequence of SEQ ID NO:211. 
     
     
         85 . The method of  claim 22 , wherein the antibody is a monoclonal antibody. 
     
     
         86 . The method of  claim 22 , wherein the antibody is an antibody fragment. 
     
     
         87 . The method of  claim 22 , wherein the antibody is a chimeric antibody or a humanized antibody. 
     
     
         88 . The method of  claim 22 , wherein the cytotoxic agent is selected from the group consisting of toxins, antibiotics, radioactive isotopes and nucleolytic enzymes. 
     
     
         89 . The method of  claim 22 , wherein the cytotoxic agent is a toxin. 
     
     
         90 . The method of  claim 22 , wherein the toxin is selected from the group consisting of maytansinoid and calicheamicin. 
     
     
         91 . The method of  claim 22 , wherein the antibody is produced in bacteria. 
     
     
         92 . The method of  claim 22 , wherein the antibody is produced in CHO cells. 
     
     
         93 . The method of  claim 22 , wherein the cell is a cancer cell. 
     
     
         94 . The method of  claim 93 , wherein the cancer cell is selected from the group consisting of a breast cancer cell, a colorectal cancer cell, a lung cancer cell, an ovarian cancer cell, a central nervous system cancer cell, a liver cancer cell, a bladder cancer cell, a pancreatic cancer cell, a cervical cancer cell, a melanoma cell and a leukemia cell. 
     
     
         95 . The method of  claim 94 , wherein the cell is an ovarian cancer cell. 
     
     
         96 . The method of  claim 93 , wherein the protein is more abundantly expressed by said cancer cell as compared to a normal cell of the same tissue origin. 
     
     
         97 . The method of  claim 22 , further comprising the step of exposing the cell to radiation treatment or to a chemotherapeutic agent. 
     
     
         98 . A method of inhibiting the growth of a cell that expresses a protein comprising the amino acid sequence of SEQ ID NO:2, said method comprising contacting said cell with an antibody drug conjugate comprising an antibody covalently attached by a linker to one or more toxin drug moieties, the compound having the formula:
   Ab-(L-D) p      
       or a pharmaceutically acceptable salt or solvate thereof, wherein:
 Ab is an antibody that comprises three light chain hypervariable regions (HVR-L1, HVR-L2 and HVR-L3) and three heavy chain hypervariable regions (HVR-H1, HVR-H2 and HVR-H3) wherein: 
 (a) HVR-L1 comprises the amino acid sequence of SEQ ID NO:119; 
 (b) HVR-L2 comprises the amino acid sequence of any one of SEQ ID NOS:120-121; 
 (c) HVR-L3 comprises the amino acid sequence of SEQ ID NO:122; 
 (d) HVR-H1 comprises the amino acid sequence of SEQ ID NO:123; 
 (e) HVR-H2 comprises the amino acid sequence of any one of SEQ ID NOS:124-127; and 
 (f) HVR-H3 comprises the amino acid sequence of any one of SEQ ID NOS:128-183; 
 L is a linker; 
 D is a toxin drug moiety selected from; and 
 p is 1 to about 20. 
 
     
     
         99 . The method of  claim 98 , wherein:
 (a) HVR-L1 comprises the amino acid sequence of SEQ ID NO:119;   (b) HVR-L2 comprises the amino acid sequence of SEQ ID NO:121;   (c) HVR-L3 comprises the amino acid sequence of SEQ ID NO:122;   (d) HVR-H1 comprises the amino acid sequence of SEQ ID NO:123;   (e) HVR-H2 comprises the amino acid sequence of SEQ ID NO:125; and   (f) HVR-H3 comprises the amino acid sequence of SEQ ID NO:174.   
     
     
         100 . The method of  claim 99 , wherein the antibody comprises the variable heavy (VH) sequence of SEQ ID NO:206 and the variable light (VL) sequence of SEQ ID NO:211. 
     
     
         101 . The method of  claim 98 , wherein:
 (a) HVR-L1 comprises the amino acid sequence of SEQ ID NO:119;   (b) HVR-L2 comprises the amino acid sequence of SEQ ID NO:121;   (c) HVR-L3 comprises the amino acid sequence of SEQ ID NO:122;   (d) HVR-H1 comprises the amino acid sequence of SEQ ID NO:123;   (e) HVR-H2 comprises the amino acid sequence of SEQ ID NO:126; and   (f) HVR-H3 comprises the amino acid sequence of SEQ ID NO:174.   
     
     
         102 . The method of  claim 101 , wherein the antibody comprises the VH sequence of SEQ ID NO:207 and the VL sequence of SEQ ID NO:211. 
     
     
         103 . The method of  claim 98 , wherein:
 (a) HVR-L1 comprises the amino acid sequence of SEQ ID NO:119;   (b) HVR-L2 comprises the amino acid sequence of SEQ ID NO:121;   (c) HVR-L3 comprises the amino acid sequence of SEQ ID NO:122;   (d) HVR-H1 comprises the amino acid sequence of SEQ ID NO:123;   (e) HVR-H2 comprises the amino acid sequence of SEQ ID NO:125; and   (f) HVR-H3 comprises the amino acid sequence of SEQ ID NO:183.   
     
     
         104 . The method of  claim 103 , wherein the antibody comprises the VH sequence of SEQ ID NO:208 and the VL sequence of SEQ ID NO:211. 
     
     
         105 . The method of  claim 98 , wherein D is a maytansinoid. 
     
     
         106 . The method of  claim 105 , wherein the maytansinoid is DM1. 
     
     
         107 . The method of  claim 98 , wherein D is an auristatin. 
     
     
         108 . The method of  claim 107 , wherein the auristatin is MMAE or MMAF. 
     
     
         109 . The method of  claim 98 , wherein L is MC-val-cit-PAB or MC. 
     
     
         110 . The method of  claim 98 , wherein L is SMCC, SPP, or BMPEO. 
     
     
         111 . The method of any one of  claims 98 - 104 , wherein the antibody drug conjugate is selected from the formula: Ab-MC-val-cit-PAB-MMAE, Ab-MC-val-cit-PAB-MMAF, Ab-MC-MMAE, Ab-MC-MMAF, Ab-SPP-DM1, and Ab-SMCC-DM1. 
     
     
         112 . The method of  claim 100 , wherein the antibody drug conjugate is Ab-MC-val-cit-PAB-MMAE. 
     
     
         113 . The method of  claim 102 , wherein the antibody drug conjugate is Ab-MC-val-cit-PAB-MMAE. 
     
     
         114 . The method of  claim 104 , wherein the antibody drug conjugate is Ab-MC-val-cit-PAB-MMAE. 
     
     
         115 . The method of  claim 98 , wherein the antibody is attached to the linker through a cysteine thiol of the antibody. 
     
     
         116 . The method of any one of  claims 98 - 104  or, wherein the antibody further comprises a V H  acceptor human consensus framework sequence of any one of SEQ ID NOS:184-193 and a V L  acceptor human consensus framework sequence of any one of SEQ ID NOS:194-197. 
     
     
         117 . The method of any one of  claims 94 - 104 , wherein the antibody is an antibody fragment. 
     
     
         118 . The method of any one of  claims 94 - 104 , wherein the antibody is a chimeric or a humanized antibody.