Combining radioimmunotherapy and antibody-drug conjugates for improved cancer therapy
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.
1. A pharmaceutical composition comprising
a) an anti-Trop-2 antibody or antigen-binding fragment thereof conjugated to a first therapeutic agent, wherein the anti-Trop-2 antibody or 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); and
b) an anti-pancreatic cancer mucin antibody or antigen-binding fragment thereof conjugated to a second therapeutic agent, wherein the anti-pancreatic cancer mucin antibody or fragment thereof binds to the same epitope as an anti-pancreatic cancer mucin 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).
2. The pharmaceutical composition of claim 1 , wherein the first therapeutic agent is a chemotherapeutic drug and the second therapeutic agent is a radionuclide.
3. The pharmaceutical composition of claim 1 , wherein the first therapeutic agent is SN-38 and the second therapeutic agent is 90 Y.
4. The pharmaceutical composition of claim 2 , 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.
5. The pharmaceutical composition of claim 2 , 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, 80m 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 Ir, 194 Ir, 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.
6. The pharmaceutical composition of claim 1 , wherein the anti-pancreatic cancer mucin 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).
7. The pharmaceutical composition of claim 1 , wherein the anti-Trop-2 antibody or 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).
8. The pharmaceutical composition of claim 1 , wherein the anti-Trop-2 antibody or fragment thereof and the anti-pancreatic cancer mucin antibody or fragment thereof are separate antibodies or fragments thereof.
9. The pharmaceutical composition of claim 1 , wherein the anti-Trop-2 antibody or fragment thereof and the anti-pancreatic cancer mucin antibody or fragment thereof are attached to each other.
10. The pharmaceutical composition of claim 1 , wherein the anti-Trop-2 antibody or fragment thereof and the anti-pancreatic cancer mucin antibody or fragment thereof are chimeric, humanized or human antibodies or fragments thereof.
11. The composition of claim 1 , wherein the first and second therapeutic agents are selected from the group consisting of a radionuclide, a chemotherapeutic drug, a toxin, an immunomodulator, a hormone, a hormone antagonist, an enzyme, an siRNA, an RNAi, a photoactive therapeutic agent, an anti-angiogenic agent and a pro-apoptotic agent.
12. The composition of claim 11 , wherein the toxin is selected from the group consisting of ricin, abrin, alpha toxin, saporin, ribonuclease (RNase), DNase I, Staphylococcal enterotoxin-A, pokeweed antiviral protein, gelonin, diphtheria toxin, Pseudomonas exotoxin, and Pseudomonas endotoxin.
13. The composition of claim 11 , wherein the immunomodulator is selected from the group consisting of a cytokine, a stem cell growth factor, a lymphotoxin, a hematopoietic factor, a colony stimulating factor (CSF), an interferon (IFN), erythropoietin, thrombopoietin.