Antibody and checkpoint inhibitor combination therapy
The present invention provides a combination therapy for treatment of a tumour in a subject. The combination therapy comprises administration of (i) an antibody directed against cancer stem cells and (ii) a checkpoint inhibitor.
1. A method of treating a colorectal tumour in a subject, wherein the tumor comprises cancer stem cells that express LGR5, the method comprising a combination therapy comprising administration of (i) an antibody directed against leucine-rich repeat containing G-protein-coupled receptor 5 (LGR5), wherein the antibody comprises a heavy chain CDR1 having amino acids GYSFTAYW (SEQ ID NO:1), a heavy chain CDR2 having amino acids ILPGSDST (SEQ ID NO:2), a heavy chain CDR3 having amino acids ARSGYYGSSQY (SEQ ID NO:3), a light chain CDR1 having amino acids ESVDSYGNSF (SEQ ID NO:4), a light chain CDR2 having amino acids LTS (SEQ ID NO:5), and a light chain CDR3 having amino acids QQNAEDPRT (SEQ ID NO:6), and (ii) a checkpoint inhibitor, wherein the inhibitor is an antibody that binds to PD-1.
2. The method as claimed in claim 1 in which the antibody comprises a heavy chain variable domain comprising SEQ ID NOs: 7 or 8.
3. The method as claimed in claim 1 in which the antibody comprises a light chain variable domain comprising SEQ ID NOs: 9 or 10.
4. The method as claimed in claim 1 in which the antibody that binds to PD-1 is selected from the group consisting of pembrolizumab, nivolumab and combinations thereof.
5. The method as claimed in claim 1 in which the combination therapy is administered in conjunction with standard of cancer care.
6. The method as claimed in claim 5 in which standard of cancer care comprises administration of a chemotherapeutic agent or combination of chemotherapeutic agents.
7. The method as claimed in claim 6 in which the chemotherapeutic agent is selected from the group consisting of cyclophosphamide, methotrexate, 5-fluorouracil, doxorubicin, mustine, vincristine, procarbazine, prednisolone, bleomycin, vinblastine, dacarbazine, etoposide, cisplatin, epirubicin, capecitabine, leucovorin, folinic acid, oxaliplatin, gemcitabine, protein bound paclitaxel, irinotecan and combinations thereof.
8. The method as claimed in claim 6 in which the standard of care comprises 5-fluorouracil+leucovorin+irinotecan.
9. The method as claimed in claim 6 wherein the chemotherapeutic agent is a vascular disrupting agent.
10. The method as claimed in claim 9 wherein the vascular disrupting agent is 2-methyl-7-hydroxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxybenzofuran (BNC105) or disodium [6-methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)-1-benzofuran-7-yl] phosphate (BNC105P).
11. The method as claimed in claim 1 wherein the colorectal tumour is metastatic colorectal cancer tumour.