Combining Radioimmunotherapy and Antibody-Drug Conjugates for Improved Cancer Therapy

Abstract

Described herein are compositions and methods of use of radionuclide-antibody conjugates (for RAIT) and drug-antibody conjugates (ADC). The combination of RAIT and ADC was more efficacious than either RAIT alone, ADC alone, or the sum of effects of RAIT and ADC. The unexpected synergy resulted in decreased tumor growth rate and increased survival, with a high incidence of tumor-free survival in Capan-1 human pancreatic cancer xenografts in nude mice.

What is claimed is: 
     
         1 . A method of treating a cancer that expresses Trop-2 and MUC-5ac comprising
 a) administering to a subject with a cancer that expresses Trop-2 and MUC-5ac an anti-Trop-2 antibody or antigen-binding fragment thereof conjugated to a chemotherapeutic drug; and   b) administering to said subject an anti-MUC-5ac antibody or antigen-binding fragment thereof conjugated to a radionuclide;   
       wherein the combination of drug-conjugated anti-Trop-2 and radionuclide-conjugated anti-MUC-5ac antibodies is effective to treat the cancer. 
     
     
         2 . The method of  claim 1 , wherein the anti-Trop-2 antibody or antigen-binding fragment thereof binds to the same epitope as an anti-Trop-2 antibody comprising the light chain CDR sequences CDR1 (KASQDVSIAVA, SEQ ID NO:7); CDR2 (SASYRYT, SEQ ID NO:8); and CDR3 (QQHYITPLT, SEQ ID NO:9) and the heavy chain CDR sequences CDR1 (NYGMN, SEQ ID NO: 10); CDR2 (WINTYTGEPTYTDDFKG, SEQ ID NO: 11) and CDR3 (GGFGSSYWYFDV, SEQ ID NO: 12). 
     
     
         3 . The method of  claim 1 , wherein the anti-MUC-5ac antibody or fragment thereof binds to the same epitope as an anti-MUC-5ac antibody comprising the light complementarity determining region (CDR) sequences CDR1 (SASSSVSSSYLY, SEQ ID NO: 1); CDR2 (STSNLAS, SEQ ID NO:2); and CDR3 (HQWNRYPYT, SEQ ID NO:3); and the heavy chain CDR sequences CDR1 (SYVLH, SEQ ID NO:4); CDR2 (YINPYNDGTQYNEKFKG, SEQ ID NO:5) and CDR3 (GFGGSYGFAY, SEQ ID NO:6). 
     
     
         4 . The method of  claim 1 , wherein the anti-Trop-2 antibody or antigen-binding fragment thereof comprises the light chain CDR sequences CDR1 (KASQDVSIAVA, SEQ ID NO:7); CDR2 (SASYRYT, SEQ ID NO:8); and CDR3 (QQHYITPLT, SEQ ID NO:9) and the heavy chain CDR sequences CDR1 (NYGMN, SEQ ID NO: 10); CDR2 (WINTYTGEPTYTDDFKG, SEQ ID NO: 11) and CDR3 (GGFGSSYWYFDV, SEQ ID NO: 12). 
     
     
         5 . The method of  claim 1 , wherein the anti-MUC-5ac antibody or fragment thereof comprises the light complementarity determining region (CDR) sequences CDR1 (SASSSVSSSYLY, SEQ ID NO: 1); CDR2 (STSNLAS, SEQ ID NO:2); and CDR3 (HQWNRYPYT, SEQ ID NO:3); and the heavy chain CDR sequences CDR1 (SYVLH, SEQ ID NO:4); CDR2 (YINPYNDGTQYNEKFKG, SEQ ID NO:5) and CDR3 (GFGGSYGFAY, SEQ ID NO:6). 
     
     
         6 . The method of  claim 1 , wherein the chemotherapeutic drug is selected from the group consisting of nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas, gemcitabine, triazenes, folic acid analogs, anthracyclines, taxanes, COX-2 inhibitors, pyrimidine analogs, purine analogs, antibiotics, enzyme inhibitors, epipodophyllotoxins, platinum coordination complexes, vinca alkaloids, substituted ureas, methyl hydrazine derivatives, adrenocortical suppressants, hormone antagonists, endostatin, taxols, camptothecins, SN-38, doxorubicin, doxorubicin analogs, antimetabolites, alkylating agents, antimitotics, anti-angiogenic agents, tyrosine kinase inhibitors, mTOR inhibitors, heat shock protein (HSP90) inhibitors, proteosome inhibitors, HDAC inhibitors, pro-apoptotic agents, methotrexate and CPT-11. 
     
     
         7 . The method of  claim 1 , wherein the radionuclide is selected from the group consisting of  11 C,  13 N,  15 O,  32 P,  33 P,  47 Sc,  51 Cr,  57 Co,  58 Co,  59 Fe,  62 Cu,  67 Cu,  67 Ga,  67 Ga,  75 Br,  75 Se,  75 Se,  76 Br,  77 As,  77 Br,  80 Br,  89 Sr,  90 Y,  95 Ru,  97 Ru,  99 Mo,  99m Tc,  103m Rh,  103 Ru,  105 Rh,  105 Ru,  107 Hg,  109 Pd,  109 Pt,  111 Ag,  111 In,  113m In,  119 Sb,  121m Te,  122m Te,  125 I,  125m Te,  126 I,  131 I,  133 I,  142 Pr,  143 Pr,  149 Pm,  152 Dy,  153 Sm,  161 Ho,  161 Tb,  165 Tm,  166 Dy,  166 Ho,  167 Tm,  168 Tm,  169 Er,  169 Yb,  177 Lu,  186 Re,  188 Re,  189m Os,  189 Re,  192 I,  194 I,  197 Pt,  198 Au,  199 Au,  199 Au,  201 Tl,  203 Hg,  211 At,  211 Bi,  211 Pb,  212 Bi,  212 Pb,  213 Bi,  215 Po,  217 At,  219 Rn,  221 Fr,  223 Ra,  21 Ac,  225 Ac and  255 Fm. 
     
     
         8 . The method of  claim 1 , wherein the anti-Trop-2 antibody or fragment thereof and the anti-MUC-5ac antibody or fragment thereof are administered sequentially or concurrently. 
     
     
         9 . The method of  claim 1 , wherein the anti-Trop-2 antibody or fragment thereof and the anti-MUC-5ac antibody or fragment thereof are conjugated together. 
     
     
         10 . The method of  claim 1 , wherein the anti-Trop-2 antibody or fragment thereof and the anti-MUC-5ac antibody or fragment thereof are chimeric, humanized or human antibodies or fragments thereof. 
     
     
         11 . The method of  claim 1 , further comprising administering to the subject a therapeutic agent selected from the group consisting of a chemotherapeutic drug, an immunomodulator, a hormone, a hormone antagonist, an enzyme, an siRNA, an RNAi, a photoactive therapeutic agent, an anti-angiogenic agent, a pro-apoptotic agent, an antibody and an antigen-binding antibody fragment. 
     
     
         12 . The method of  claim 12 , wherein the immunomodulator is selected from the group consisting of a cytokine, a lymphokine, a monokine, a stem cell growth factor, a lymphotoxin, a hematopoietic factor, a colony stimulating factor (CSF), an interferon (IFN), parathyroid hormone, thyroxin, insulin, proinsulin, relaxin, prorelaxin, follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), luteinizing hormone (LH), hepatic growth factor, prostaglandin, fibroblast growth factor, prolactin, placental lactogen, OB protein, a transforming growth factor (TGF), TGF-α, TGF-β, insulin-like growth factor (ILGF), erythropoietin, thrombopoietin, TNF-α, TNF-β, mouse gonadotropin-associated peptide, inhibin, activin, vascular endothelial growth factor, integrin, interleukin (IL), granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), interferon-α, interferon-β, interferon-γ, S1 factor, IL-1, IL-1cc, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18 IL-21 and IL-25, LIF, kit-ligand, FLT-3, angiostatin, thrombospondin and endostatin. 
     
     
         13 . The method of  claim 11 , wherein the chemotherapeutic drug is selected from the group consisting of nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas, gemcitabine, triazenes, folic acid analogs, anthracyclines, taxanes, COX-2 inhibitors, pyrimidine analogs, purine analogs, antibiotics, enzyme inhibitors, epipodophyllotoxins, platinum coordination complexes, vinca alkaloids, substituted ureas, methyl hydrazine derivatives, adrenocortical suppressants, hormone antagonists, endostatin, taxols, camptothecins, SN-38, doxorubicin, doxorubicin analogs, antimetabolites, alkylating agents, antimitotics, anti-angiogenic agents, tyrosine kinase inhibitors, mTOR inhibitors, heat shock protein (HSP90) inhibitors, proteosome inhibitors, HDAC inhibitors, pro-apoptotic agents, methotrexate and CPT-11. 
     
     
         14 . The method of  claim 11 , wherein the antibody or antigen-binding antibody fragment binds to an antigen selected from the group consisting of CA19.9, DUPAN2, SPAN1, Nd2, B72.3, CC49, Le a , Le(y), CEACAM5, CEACAM6, CSAp, MUC-1, MUC-2, MUC-3, MUC-4, MUC-5ac, MUC-16, MUC-17, HLA-DR, CD40, CD74, CD138, HER2/neu, EGFR, EGP-1, EGP-2, VEGF, PlGF, insulin-like growth factor, tenascin, platelet-derived growth factor, IL-6, bcl-2, K-ras, p53 and cMET.