Efficacy of anti-trop-2-sn-38 antibody drug conjugates for therapy of tumors relapsed/refractory to checkpoint inhibitors

Abstract

The present invention relates to therapeutic ADCs comprising SN-38 attached to an anti-Trop-2 antibody or antigen-binding antibody fragment, more particularly sacituzumab govitecan. The ADC is administered to a subject with a Trop-2 positive cancer that is resistant to or relapsed from prior treatment with a checkpoint inhibitor. The therapy is effective to treat cancers that are resistant to checkpoint inhibitors.

We claim: 
     
         1 . A method of treating a human cancer that expresses Trop-2 comprising:
 a. administering to a human patient with a cancer that expresses Trop-2 an antibody-drug conjugate (ADC) comprising SN-38 conjugated to a linker moiety attached to an anti-TROP-2 antibody or antigen-binding fragment thereof,   b. administering to the patient a first checkpoint inhibitor antibody that binds to CTLA-4; and   c. administering to the patient a second checkpoint inhibitor antibody that binds to PD-1 or PD-L1.   
     
     
         2 . The method of  claim 1 , wherein the patient has relapsed from or is refractory to treatment with any checkpoint inhibitor antibody prior to treatment with the ADC, the first checkpoint inhibitor antibody and the second checkpoint inhibitor antibody. 
     
     
         3 . The method of  claim 1 , wherein the first checkpoint inhibitor antibody is selected from the group consisting of ipilimumab and tremilimumab. 
     
     
         4 . The method of  claim 1 , wherein second checkpoint inhibitor antibody is selected from the group consisting of MPDL3280A, atezolizumab, pembrolizumab, nivolumab, pidilizumab, MDX-1105, durvalumab and BMS-936559. 
     
     
         5 . The method of  claim 1 , wherein the anti-Trop-2 antibody is an hRS7 antibody comprising the light chain CDR sequences CDR1 (KASQDVSIAVA, SEQ ID NO:1); CDR2 (SASYRYT, SEQ ID NO:2); and CDR3 (QQHYITPLT, SEQ ID NO:3) and the heavy chain CDR sequences CDR1 (NYGMN, SEQ ID NO:4); CDR2 (WINTYTGEPTYTDDFKG, SEQ ID NO:5) and CDR3 (GGFGSSYWYFDV, SEQ ID NO:6). 
     
     
         6 . The method of  claim 1 , wherein the linker is CL2A and the structure of the ADC is MAb-CL2A-SN-38 
       
         
           
           
               
               
           
         
       
     
     
         7 . The method of  claim 1 , wherein the cancer is selected from the group consisting of colorectal, lung, stomach, urothelial, renal, pancreatic, breast, ovarian, uterine, esophageal and prostatic cancer. 
     
     
         8 . The method of  claim 1 , wherein the cancer is selected from the group consisting of triple-negative breast cancer, metastatic breast cancer, metastatic non-small-cell lung cancer, metastatic small-cell lung cancer, metastatic endometrial cancer, metastatic urothelial cancer and metastatic pancreatic cancer. 
     
     
         9 . The method of  claim 1 , wherein the cancer is metastatic urothelial cancer and the patient is cisplatin-ineligible. 
     
     
         10 . The method of  claim 1 , wherein the ADC is administered at a dosage of between 3 mg/kg and 18 mg/kg. 
     
     
         11 . The method of  claim 1 , wherein the ADC is administered at a dosage of between 8 mg/kg and 12 mg/kg. 
     
     
         12 . The method of  claim 1 , wherein the ADC is administered at a dosage of between 8 mg/kg and 10 mg/kg. 
     
     
         13 . The method of  claim 1 , wherein the ADC is administered at a dosage of 10 mg/kg. 
     
     
         14 . The method of  claim 1 , wherein the treatment results in a reduction in tumor size of at least 15%, at least 20%, at least 30%, or at least 40%. 
     
     
         15 . The method of  claim 1 , wherein the ADC comprises 6 to 8 molecules of SN-38 conjugated to the antibody or antigen-binding fragment thereof. 
     
     
         16 . The method of  claim 1 , wherein the cancer is metastatic. 
     
     
         17 . The method of  claim 17 , further comprising reducing in size or eliminating the metastases. 
     
     
         18 . The method of  claim 1 , further comprising administering to the patient at least one other anti-cancer therapy selected from the group consisting of surgery, external radiation, radioimmunotherapy, immunotherapy, chemotherapy, antisense therapy, interference RNA therapy, treatment with a therapeutic agent and gene therapy. 
     
     
         19 . The method of claim  22 , wherein the therapeutic agent is a drug, toxin, immunomodulator, second antibody, antigen-binding fragment of a second antibody, pro-apoptotic agent, toxin, RNase, hormone, radionuclide, anti-angiogenic agent, siRNA, RNAi, chemotherapeutic agent, cytokine, chemokine, prodrug or enzyme. 
     
     
         20 . The method of claim  23 , wherein the drug is selected from the group consisting of 5-fluorouracil, afatinib, aplidin, azaribine, anastrozole, axitinib, AVL-101, AVL-291, bendamustine, bleomycin, bortezomib, bosutinib, bryostatin-1, busulfan, calicheamycin, camptothecin, carboplatin, 10-hydroxycamptothecin, carmustine, celecoxib, chlorambucil, cisplatin, irinotecan, SN-38, carboplatin, cladribine, crizotinib, cyclophosphamide, cytarabine, dacarbazine, dasatinib, dinaciclib, docetaxel, dactinomycin, daunorubicin, doxorubicin, 2-pyrrolinodoxorubicine, cyano-morpholino doxorubicin, doxorubicin glucuronide, epirubicin glucuronide, erlotinib, estramustine, epidophyllotoxin, erlotinib, entinostat, etoposide, exemestane, fingolimod, floxuridine, 3′,5′-O-dioleoyl-floxuridine, fludarabine, flutamide, flavopiridol, fostamatinib, ganetespib, GDC-0834, GS-1101, gefitinib, gemcitabine, hydroxyurea, ibrutinib, idarubicin, idelalisib, ifosfamide, imatinib, L-asparaginase, lapatinib, lenolidamide, leucovorin, LFM-A13, lomustine, mechlorethamine, melphalan, mercaptopurine, 6-mercaptopurine, methotrexate, mitoxantrone, mithramycin, mitomycin, mitotane, navelbine, neratinib, nilotinib, nitrosurea, olaparib, plicomycin, procarbazine, paclitaxel, PCI-32765, pentostatin, PSI-341, raloxifene, semustine, sorafenib, streptozocin, SU11248, sunitinib, tamoxifen, temazolomide, transplatin, thalidomide, thioguanine, thiotepa, teniposide, topotecan, uracil mustard, vatalanib, vinorelbine, vinblastine, vincristine and ZD1839.