Anti-mesothelin immunoconjugates and uses therefor
The present invention provides immunoconjugates composed of antibodies, e.g., monoclonal antibodies, or antibody fragments that bind to mesothelin, that are conjugated to cytotoxic agents, e.g., maytansine, or derivatives thereof, and/or co-administered or formulated with one or more additional anti-cancer agents. The immunoconjugates of the invention can be used in the methods of the invention to treat and/or diagnose and/or monitor cancers, solid tumors, recombinant antigen-binding regions and antibodies and functional fragments containing such antigen-binding regions that are specific for the membrane-anchored, 40 kDa mesothelin polypeptide, which which is overexpressed in several tumors, such as pancreatic and ovarian tumors, mesothelioma and lung cancer cells.
1. A method for treating pancreatic cancer, comprising administering to a subject in need thereof an effective amount of an immunoconjugate, wherein the immunoconjugate comprises a DM4 maytansinoid and a human or humanized antibody or functional fragment thereof comprising an antigen-binding site that is specific for Mesothelin (SEQ ID NO:36), and wherein the antigen-binding site comprises a variable heavy chain comprising complementarity determining regions (CDRs) corresponding to SEQ ID NOS 3, 6, and 9 and a variable light chain comprising complementarity determining regions (CDRs) corresponding to SEQ ID NOS 12, 15, and 19, and wherein the DM4 maytansinoid and the human or humanized antibody or functional fragment thereof are linked by an SPDB linker, and wherein the effective amount is from 0.05 mg DM4 maytansinoid/kg body weight up to 0.2 mg DM4 maytansinoid/kg body weight.
2. The method according to claim 1 , wherein the immunoconjugate is administered together with one or more anti-cancer agents to potentiate the effect of the immunoconjugate, the one or more anti-cancer agents, or both.
3. The method according to claim 2 , wherein the anti-cancer agent is selected from the group consisting of gemcitabine, paclitaxel, docetaxel, cisplatin, carboplatin, doxorubicin, and liposomal doxorubicin.
4. The method according to claim 1 , wherein the human or humanized antibody or functional fragment thereof comprises a variable heavy chain of SEQ ID NO: 23 and a variable light chain of SEQ ID NO: 27.