Combining anti-HLA-DR or anti-Trop-2 antibodies with microtubule inhibitors, PARP inhibitors, bruton kinase inhibitors or phosphoinositide 3-kinase inhibitors significantly improves therapeutic outcome in cancer
The present invention relates to combination therapy with drugs, such as microtubule inhibitors, PARP inhibitors, Bruton kinase inhibitors or PI3K inhibitors, with antibodies or immunoconjugates against HLA-DR or Trop-2. Where immunoconjugates are used, they preferably incorporate SN-38 or pro-2PDOX. The immunoconjugate may be administered at a dosage of between 1 mg/kg and 18 mg/kg, preferably 4, 6, 8, 9, 10, 12, 16 or 18 mg/kg, more preferably 8 or 10 mg/kg. The combination therapy can reduce solid tumors in size, reduce or eliminate metastases and is effective to treat cancers resistant to standard therapies, such as radiation therapy, chemotherapy or immunotherapy. Preferably, the combination therapy has an additive effect on inhibiting tumor growth. Most preferably, the combination therapy has a synergistic effect on inhibiting tumor growth.
1. A method of treating a Trop-2 expressing cancer, comprising:
a) administering to a human subject with a Trop-2 expressing cancer an immunoconjugate comprising an anti-Trop-2 antibody conjugated to SN-38;
b) administering to the subject at least one therapeutic agent selected from the group consisting of a PARP inhibitor and a microtubule inhibitor, wherein the PARP inhibitor is olaparib, rucaparib, or talazoparib, wherein the microtubule inhibitor is paclitaxel or eribulin mesylate;
wherein the combination of the immunoconjugate and the therapeutic agent has a synergistic effect in inhibiting tumor growth.
2. The method of claim 1 , wherein the anti-Trop-2 antibody is hRS7.
3. The method of claim 1 , wherein the SN-38 is conjugated to the anti-Trop-2 antibody via a CL2A linker.
4. The method of claim 1 , wherein the therapeutic agent is a PARP inhibitor.
5. The method of claim 1 , wherein the PARP inhibitor is olaparib.
6. The method of claim 1 , wherein the immunoconjugate is administered at a dosage of between 3 mg/kg and 18 mg/kg, and wherein the patient has failed to respond to at least one other therapy, prior to treatment with the ADC immunoconjugate.
7. The method of claim 6 , wherein the dosage is selected from the group consisting of 3 mg/kg, 4 mg/kg, 6 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 12 mg/kg, 16 mg/kg and 18 mg/kg.
8. The method of claim 1 , wherein the immunoconjugate is administered at a dosage of between 8 and 10 mg/kg.
9. The method of claim 1 , wherein the cancer is a solid tumor and the treatment results in a reduction in tumor size of at least 15%, at least 20%, at least 30%, or at least 40%.
10. The method of claim 1 , wherein the cancer is metastatic.
11. The method of claim 10 , further comprising reducing in size or eliminating the metastases.
12. The method of claim 1 , wherein the cancer is refractory to other therapies but responds to the combination of the immunoconjugate and the therapeutic agent.
13. The method of claim 1 , wherein the patient has failed to respond to therapy with irinotecan, prior to treatment with the immunoconjugate.
14. The method of claim 1 , wherein the antibody is an IgG1 or IgG4 antibody.
15. The method of claim 1 , wherein the antibody has an allotype selected from the group consisting of G1m3, G1m3,1, G1m3,2, G1m3,1,2, nG1m1, nG1m1,2 and Km3 allotypes.
16. The method of claim 1 , further comprising administering to the subject one or more additional therapeutic modalities selected from the group consisting of unconjugated antibodies, radiolabeled antibodies, drug-conjugated antibodies, toxin-conjugated antibodies, gene therapy, chemotherapy, therapeutic peptides, cytokine therapy, oligonucleotides, localized radiation therapy, surgery and interference RNA therapy.
17. The method of claim 16 , wherein the therapeutic modality comprises treatment with an agent selected from the group consisting of 5-fluorouracil, afatinib, aplidin, azaribine, anastrozole, anthracyclines, axitinib, AVL-101, AVL-291, bendamustine, bleomycin, bortezomib, bosutinib, bryostatin-1, busulfan, calicheamycin, camptothecin, carboplatin, 10-hydroxycamptothecin, carmustine, celebrex, chlorambucil, cisplatin (CDDP), Cox-2 inhibitors, irinotecan (CPT-11), SN-38, carboplatin, cladribine, camptothecans, cyclophosphamide, crizotinib, cytarabine, dacarbazine, dasatinib, dinaciclib, docetaxel, dactinomycin, daunorubicin, doxorubicin, 2-pyrrolinodoxorubicine (2P-DOX), cyanomorpholino doxorubicin, doxorubicin glucuronide, epirubicin glucuronide, erlotinib, estramustine, epidophyllotoxin, erlotinib, entinostat, estrogen receptor binding agents, etoposide (VP16), etoposide glucuronide, etoposide phosphate, exemestane, fingolimod, flavopiridol, floxuridine (FUdR), 3′,5′-O-dioleoyl-FudR (FUdR-dO), fludarabine, flutamide, farnesyl-protein transferase inhibitors, 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 (an aqueous form of DTIC), transplatinum, thalidomide, thioguanine, thiotepa, teniposide, topotecan, uracil mustard, vatalanib, vinorelbine, vinblastine, vincristine, vinca alkaloids and ZD1839.
18. The method of claim 1 , wherein the cancer is selected from the group consisting of colon cancer, stomach cancer, esophageal cancer, kidney cancer, breast cancer, lung cancer, pancreatic cancer, urinary bladder cancer, urothelial cancer, ovarian cancer, uterine cancer, cervical cancer, testicular cancer, prostate cancer, liver cancer, and rectal cancer.
19. The method of claim 1 , wherein the cancer is selected from the group consisting of triple-negative breast cancer, ovarian cancer, endometrial cancer, urothelial cancer, non-small-cell lung cancer, small-cell lung cancer and metastatic colorectal cancer.