Anti-Trop-2 antibody-drug conjugates and uses thereof

Patent metadata

Field	Value
Publication number	US-9770517-B2
Application number	US-201414321171-A
Country	US
Kind code	B2
Filing date	Jul 1, 2014
Priority date	Mar 1, 2002
Publication date	Sep 26, 2017
Grant date	Sep 26, 2017

Abstract

Described herein are compositions and methods of use of antibody-drug conjugates (ADCs) comprising an anti-Trop-2 antibody or antigen-binding fragment thereof, conjugated to one or more cytotoxic drugs. Preferably, the antibody is an RS7, 162-46.2 or MAB650 antibody. More preferably, the antibody is humanized. Preferably the drug is SN-38, pro-2-pyrrolinodoxorubicin, paclitaxel, calichemicin, DM1, DM3, DM4, MMAE, MMAD or MMAF. The compositions and methods are of use to treat Trop-2 expressing cancers, such as breast, ovarian, cervical, endometrial, lung, prostate, colon, stomach, esophageal, bladder, renal, pancreatic, thyroid, epithelial or head-and-neck cancer. Preferably, the cancer is one that is resistant to one or more standard cancer therapies. More preferably, the anti-Trop-2 antibody binds to Trop-2 expressed on normal cells, but administration of the anti-Trop-2 ADC to human cancer patients at a therapeutically effective dosage produces only limited toxicity.

First claim

What is claimed is:

1. A method of treating a Trop-2 expressing cancer comprising administering to a human subject with a Trop-2 expressing cancer an antibody-drug conjugate (ADC) comprising:
(i) an anti-Trop-2 IgG antibody, wherein the anti-Trop-2 antibody thereof comprises 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); and
(ii) a cytotoxic drug conjugated to the anti-Trop-2 IgG antibody at a drug to antibody ratio of at least 6;

wherein the cancer selected from the group consisting of triple-negative breast cancer, metastatic colon cancer, metastatic non-small-cell lung cancer (NSCLC), metastatic pancreatic cancer, metastatic renal cell carcinoma, metastatic gastric cancer, metastatic prostate cancer, metastatic bladder cancer and metastatic small-cell lung cancer and is resistant to treatment with at least one anti-cancer therapy.

2. The method of claim 1 , wherein the anti-Trop-2 antibody is a chimeric, humanized or human antibody.

3. The method of claim 1 , wherein the antibody is an IgG1, IgG2, IgG3 or IgG4 antibody.

4. The method of claim 1 , wherein the drug is selected from the group consisting of an anthracycline, a camptothecin, a tubulin inhibitor, a maytansinoid, a calicheamycin, an auristatin, a nitrogen mustard, an ethylenimine derivative, an alkyl sulfonate, a nitrosourea, a triazene, a folic acid analog, a taxane, a COX-2 inhibitor, a pyrimidine analog, a purine analog, an antibiotic, an enzyme inhibitor, an epipodophyllotoxin, a platinum coordination complex, a vinca alkaloid, a substituted urea, a methyl hydrazine derivative, an adrenocortical suppressant, a hormone antagonist, an antimetabolite, an alkylating agent, an antimitotic, an anti-angiogenic agent, a tyrosine kinase inhibitor, an mTOR inhibitor, a heat shock protein (HSP90) inhibitor, a proteosome inhibitor, an HDAC inhibitor, and a pro-apoptotic agent.

5. The method of claim 1 , wherein the drug is 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, celecoxib, chlorambucil, cisplatinum, COX-2 inhibitors, irinotecan (CPT-11), SN-38, carboplatin, cladribine, camptothecans, crizotinib, cyclophosphamide, cytarabine, dacarbazine, dasatinib, dinaciclib, docetaxel, dactinomycin, daunorubicin, DM1, DM3, DM4, doxorubicin, 2-pyrrolinodoxorubicine (2-PDox), a pro-drug form of 2-PDox (pro-2-PDox), cyano-morpholino doxorubicin, doxorubicin glucuronide, endostatin, epirubicin glucuronide, erlotinib, estramustine, epidophyllotoxin, erlotinib, entinostat, estrogen receptor binding agents, etoposide (VP16), etoposide glucuronide, etoposide phosphate, exemestane, fingolimod, floxuridine (FUdR), 3′,5′-O-dioleoyl-FudR (FUdR-dO), fludarabine, flutamide, farnesyl-protein transferase inhibitors, flavopiridol, fostamatinib, ganetespib, GDC-0834, GS-1101, gefitinib, gemcitabine, hydroxyurea, ibrutinib, idarubicin, idelalisib, ifosfamide, imatinib, lapatinib, lenolidamide, leucovorin, LFM-A13, lomustine, mechlorethamine, melphalan, mercaptopurine, 6-mercaptopurine, methotrexate, mitoxantrone, mithramycin, mitomycin, mitotane, monomethylauristatin F (MMAF), monomethylauristatin D (MMAD), monomethylauristatin E (MMAE), navelbine, neratinib, nilotinib, nitrosurea, olaparib, plicomycin, procarbazine, paclitaxel, PCI-32765, pentostatin, PSI-341, raloxifene, semustine, SN-38, sorafenib, streptozocin, SU11248, sunitinib, tamoxifen, temazolomide, transplatinum, thalidomide, thioguanine, thiotepa, teniposide, topotecan, uracil mustard, vatalanib, vinorelbine, vinblastine, vincristine, vinca alkaloids and ZD1839.

6. The method of claim 1 , wherein the drug is selected from the group consisting of SN-38, pro-2-pyrrolinodoxorubicin (pro-2-PDox), paclitaxel, calichemicin, DM1, DM3, DM4, MMAE, MMAD and MMAF.

7. The method of claim 1 , wherein the average ratio of drug to antibody is between 6 and 8.

8. The method of claim 1 , wherein the average ratio of drug to antibody is about 6.

9. The method of claim 1 , wherein the cancer is resistant to treatment with a topoisomerase 1 or topoisomerase 2 inhibitor.

10. The method of claim 9 , wherein the cancer is resistant to treatment with irinotecan or SN-38.

11. The method of claim 1 , further comprising treating the subject with one or more therapies selected from the group consisting of surgery, radiation therapy, chemotherapy, an immunomodulator, a cytokine, a chemotherapeutic agent, a pro-apoptotic agent, an anti-angiogenic agent, a cytotoxic agent, a drug, a toxin, a radionuclide, an RNAi, an siRNA, a second antibody, an antigen-binding fragment of a second antibody, and an immunoconjugate.

12. The method of claim 11 , wherein the therapy comprises administration of an anti-Trop-2 agent selected from the group consisting of catumaxomab, VB4-845, IGN-101, adecatumumab, ING-1 and EMD 273 066.

13. The method of claim 11 , wherein the therapy comprises administration of an anti-MUC5ac antibody or antigen-binding antibody fragment.

14. The method of claim 11 , wherein the therapy comprises administration of 90 Y-hPAM4.

15. The method of claim 14 , wherein the cancer is pancreatic cancer.

16. The method of claim 11 , wherein the drug is 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, celecoxib, chlorambucil, cisplatinum, COX-2 inhibitors, irinotecan (CPT-11), SN-38, carboplatin, cladribine, camptothecans, crizotinib, cyclophosphamide, cytarabine, dacarbazine, dasatinib, dinaciclib, docetaxel, dactinomycin, daunorubicin, DM1, DM3, DM4, doxorubicin, 2-pyrrolinodoxorubicine (2-PDox), a pro-drug form of 2-PDox (pro-2-PDox), cyano-morpholino doxorubicin, doxorubicin glucuronide, endostatin, epirubicin glucuronide, erlotinib, estramustine, epidophyllotoxin, erlotinib, entinostat, estrogen receptor binding agents, etoposide (VP16), etoposide glucuronide, etoposide phosphate, exemestane, fingolimod, floxuridine (FUdR), 3′,5′-O-dioleoyl-FudR (FUdR-dO), fludarabine, flutamide, farnesyl-protein transferase inhibitors, flavopiridol, fostamatinib, ganetespib, GDC-0834, GS-1101, gefitinib, gemcitabine, hydroxyurea, ibrutinib, idarubicin, idelalisib, ifosfamide, imatinib, lapatinib, lenolidamide, leucovorin, LFM-A13, lomustine, mechlorethamine, melphalan, mercaptopurine, 6-mercaptopurine, methotrexate, mitoxantrone, mithramycin, mitomycin, mitotane, monomethylauristatin F (MMAF), monomethylauristatin D (MMAD), monomethylauristatin E (MMAE), navelbine, neratinib, nilotinib, nitrosurea, olaparib, plicomycin, procarbazine, paclitaxel, PCI-32765, pentostatin, PSI-341, raloxifene, semustine, SN-38, sorafenib, streptozocin, SU11248, sunitinib, tamoxifen, temazolomide, transplatinum, thalidomide, thioguanine, thiotepa, teniposide, topotecan, uracil mustard, vatalanib, vinorelbine, vinblastine, vincristine, vinca alkaloids and ZD1839.

17. The method of claim 11 , 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 S

Assignees

• Immunomedics Inc

Inventors

• Govindan Serengulam V
• Goldenberg David M

Classifications

• C07K16/303

  Liver or Pancreas · CPC title

• A61K51/1051

  the tumor cell being from breast, e.g. the antibody being herceptin · CPC title

• A61K31/337

  having four-membered rings, e.g. taxol · CPC title

• C07K16/30

  from tumour cells · CPC title

• A61K2039/505

  comprising antibodies · CPC title