Improving the therapeutic index in cancer therapy by using antibody-drug conjugates designed with a moderately cytotoxic drug

Molecular Pharmaceutics

Volumn 12, Issue 6, 2015, Pages 1836-1847

  Govindan, Serengulam V ^a   Cardillo, Thomas M ^a   Rossi, Edmund A ^a   Trisal, Preeti ^a   McBride, William J ^a   Sharkey, Robert M ^a   Goldenberg, David M ^a,b  

^a IMMUNOMEDICS INC   (United States)

^b CENTER FOR MOLECULAR MEDICINE AND IMMUNOLOGY   (United States)

Author keywords

antibody drug conjugate; CEACAM5 antigen; clinical safety and efficacy; drug antibody ratio; preclinical efficacy and tolerability; SN 38

Indexed keywords

BEVACIZUMAB; LABETUZUMAB; LABETUZUMAB GOVITECAN; ANTIBODY CONJUGATE; ANTINEOPLASTIC AGENT; CAMPTOTHECIN; IRINOTECAN; MONOCLONAL ANTIBODY;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTINEOPLASTIC ACTIVITY; ARTICLE; CANCER THERAPY; COLON CARCINOMA; DRUG CONJUGATION; DRUG DESIGN; DRUG DISTRIBUTION; DRUG DOSE ESCALATION; DRUG DOSE INCREASE; DRUG EFFICACY; DRUG STRUCTURE; DRUG TOLERABILITY; FEMALE; HUMAN; HUMAN CELL; MALE; METASTATIC COLORECTAL CANCER; MOUSE; NONHUMAN; PHASE 1 CLINICAL TRIAL; PRIORITY JOURNAL; RABBIT; TUMOR XENOGRAFT; ANALOGS AND DERIVATIVES; ANIMAL; CHEMISTRY; CLINICAL TRIAL; COLONIC NEOPLASMS; NUDE MOUSE; TUMOR CELL LINE;

ANIMALS; ANTIBODIES, MONOCLONAL; ANTINEOPLASTIC AGENTS; BEVACIZUMAB; CAMPTOTHECIN; CELL LINE, TUMOR; COLONIC NEOPLASMS; FEMALE; HUMANS; IMMUNOCONJUGATES; MICE; MICE, NUDE; RABBITS;

EID: 84930660992     PISSN: 15438384     EISSN: 15438392     Source Type: Journal    
DOI: 10.1021/mp5006195     Document Type: Article

References (56)

1. Lambert, J. M.; Chari, R. V. Ado-trastuzumab emtansine (T-DM1): An antibody-drug conjugate (ADC) for HER2-positive breast cancer J. Med. Chem. 2014, 57, 6949-6964
2. Younes, A.; Yasothan, U.; Kirkpatrick, P. Brentuximab vedotin Nature Rev. Drug Discovery 2011, 11, 19-20
3. Chari, R. V.; Miller, M. L.; Widdison, W. C. Antibody-drug conjugates: an emerging concept in cancer therapy Angew. Chem., Int. Ed. Engl. 2014, 53, 3796-3827
4. Ducry, L.; Stump, B. Antibody-drug conjugates: linking cytotoxic payloads to monoclonal antibodies Bioconjugate Chem. 2010, 21, 5-13
5. Sievers, E. L.; Senter, P. D. Antibody-drug conjugates in cancer therapy Annu. Rev. Med. 2013, 64, 15-29
6. Hamblett, K. J.; Senter, P. D.; Chace, D. F.; Sun, M. M.; Lenox, J.; Cerveny, C. G.; Kissler, K. M.; Bernhardt, S. X.; Kopcha, A. K.; Zabinski, R. F.; Meyer, D. L.; Francisco, J. A. Effects of drug loading on the antitumor activity of a monoclonal antibody drug conjugate Clin. Cancer Res. 2004, 10, 7063-7070
7. Behrens, C. R.; Liu, B. Methods for site-specific drug conjugation to antibodies mAbs 2014, 6, 46-53
8. Panowksi, S.; Bhakta, S.; Raab, H.; Polakis, P.; Junutula, J. R. Site-specific antibody drug conjugates for cancer therapy mAbs 2014, 6, 34-45
9. Iyer, L.; Ratain, M. J. Clinical pharmacology of camptothecins Cancer Chemother. Pharmacol. 1998, 42 (Suppl) S31-S43
10. Mathijssen, R. H.; van Alphen, R. J.; Verweij, J.; Loos, W. J.; Nooter, K.; Stoter, G.; Sparreboom, A. Clinical pharmacokinetics and metabolism of irinotecan (CPT-11) Clin. Cancer Res. 2001, 7, 2182-2194
11. Dotan, E.; Berlin, J.; Starodub, A.; Guarino, M. J.; Cohen, S. J.; Maliakal, P. P.; Govindan, S. V.; Wegener, W. A.; Sharkey, R. M.; Goldenberg, D. M. Activity of IMMU-130 anti-CEACAM5-SN-38 antibody-drug conjugate (ADC) on metastatic colorectal cancer (mCRC) having relapsed after CPT-11: Phase I study. J. Clin. Oncol. 2014, 32, 5s (suppl)) 3106.
12. Segal, N. H.; Dotan, E.; Berlin, J. D.; Starodub, A. N.; Guarino, M. J.; Saltz, L. B.; Maliakal, P. P.; Govindan, S. V.; Wegener, W. A.; Sharkey, R. M.; Goldenberg, D. M. IMMU-130, an SN-38 antibody-drug conjugate (ADC) targeting CEACAM5, is therapeutically active in metastatic colorectal cancer (mCRC): Initial clinical results of two Phase I studies. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research, San Diego, Apr 5-9, 2014; AACR: Philadelphia, 2014; Abstract CT211.
13. Starodub, A. N.; Ocean, A. O.; Shah, M. A.; Vahdat, L. T.; Chuang, E.; Guarino, M. J.; Picozzi, V. J.; Thomas, S. S.; Maliakal, P. P.; Govindan, S. V.; Wegener, W. A.; Sharkey, R. M.; Goldenberg, D. M. SN-38 antibody-drug conjugate (ADC) targeting Trop-2, IMMU-132, as a novel platform for the therapy of diverse metastatic solid cancers: Initial clinical results. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research, San Diego, Apr 5-9, 2014; AACR: Philadelphia, 2014; Abstract CT206.
14. Trail, P. A.; Willner, D.; Lasch, S. J.; Henderson, A. J.; Hofstead, S.; Casazza, A. M.; Firestone, R. A.; Hellstrom, I.; Hellstrom, K. E. Cure of xenografted human carcinomas by BR96-doxorubicin immunoconjugates Science 1993, 261, 212-215
15. Tolcher, A. W.; Sugarman, S.; Gelmon, K. A.; Cohen, R.; Saleh, M.; Isaacs, C.; Young, L.; Healey, D.; Onetto, N.; Slichenmyer, W. Randomized phase II study of BR96-doxorubicin conjugate in patients with metastatic breast cancer J. Clin. Oncol. 1999, 17, 478-484
16. Shimizu, Y.; Nagata, H.; Kikuchi, Y.; Umezawa, S.; Hasumi, K.; Yokokura, T. Cytotoxic agents active against mucinous adenocarcinoma of the ovary Oncol. Rep. 1998, 5, 99-101
17. Govindan, S. V.; Cardillo, T. M.; Sharkey, R. M.; Tat, F.; Gold, D. V.; Goldenberg, D. M. Milatuzumab-SN-38 conjugates for the treatment of CD74+ cancers Mol. Cancer Ther. 2013, 12, 968-978
18. Sharkey, R. M.; Juweid, M.; Shevitz, J.; Behr, T.; Dunn, R.; Swayne, L. C.; Wong, G. Y.; Blumenthal, R. D.; Griffiths, G. L.; Siegel, J. A. Evaluation of a complementarity-determining region-grafted (humanized) anti-carcinoembryonic antigen monoclonal antibody in preclinical and clinical studies Cancer Res. 1995, 55, 5935s-5945s
19. Goldenberg, D. M.; Morschhauser, F.; Wegener, W. A. Veltuzumab (humanized anti-CD20 monoclonal antibody): characterization, current clinical results, and future prospects 4 Leuk. Lymphoma 2010, 51, 747-755
20. Cardillo, T. M.; Govindan, S. V.; Sharkey, R. M.; Trisal, P.; Goldenberg, D. M. Humanized anti-Trop-2 IgG-SN-38 conjugate for effective treatment of diverse epithelial cancers: preclinical studies in human cancer xenograft models and monkeys Clin. Cancer Res. 2011, 17, 3157-3169
21. Sharkey, R. M.; Govindan, S. V.; Cardillo, T. M.; Goldenberg, D. M. Epratuzumab-SN-38: a new antibody-drug conjugate for the therapy of hematologic malignancies Mol. Cancer Ther. 2012, 11, 224-234
22. Govindan, S. V.; Cardillo, T. M.; Moon, S. J.; Hansen, H. J.; Goldenberg, D. M. CEACAM5-targeted therapy of human colonic and pancreatic cancer xenografts with potent labetuzumab-SN-38 immunoconjugates Clin. Cancer Res. 2009, 15, 6052-6061
23. Moon, S. J.; Govindan, S. V.; Cardillo, T. M.; DSouza, C. A.; Hansen, H. J.; Goldenberg, D. M. Antibody conjugates of 7-ethyl-10-hydroxycamptothecin (SN-38) for targeted cancer chemotherapy J. Med. Chem. 2008, 51, 6916-6926
24. Sharkey, R. M.; Weadock, K. S.; Natale, A.; Haywood, L.; Aninipot, R.; Blumenthal, R. D.; Goldenberg, D. M. Successful radioimmunotherapy for lung metastasis of human colonic cancer in nude mice J. Natl. Cancer Inst 1991, 83, 627-632
25. Heskamp, S.; Boerman, O. C.; Molkenboer-Kuenen, J. D.; Oyen, W. J.; van der Graaf, W. T.; van Laarhoven, H. W. Bevacizumab reduces tumor targeting of antiepidermal growth factor and anti-insulin-like growth factor 1 receptor antibodies Int. J. Cancer 2013, 133, 307-314
26. Sharkey, R. M.; Motta-Hennessy, C.; Gansow, O. A.; Brechbiel, M. W.; Fand, I.; Griffiths, G. L.; Jones, A. L.; Goldenberg, D. M. Selection of a DTPA chelate conjugate for monoclonal antibody targeting to a human colonic tumor in nude mice Int. J. Cancer 1990, 46, 79-85
27. de Bruijn, P.; de Jonge, M. J.; Verweij, J.; Loos, W. J.; Nooter, K.; Stoter, G.; Sparreboom, A. Femtomole quantitation of 7-ethyl-10-hydroxycamptothecine (SN-38) in plasma samples by reversed-phase high-performance liquid chromatography Anal. Biochem. 1999, 269, 174-178
28. Wakankar, A.; Chen, Y.; Gokarn, Y.; Jacobson, F. S. Analytical methods for physicochemical characterization of antibody drug conjugates mAbs 2011, 3, 161-172
29. Govindan, S. V.; Cardillo, T. M.; Moon, S.-J.; Tat, F.; Sheerin, A.; Zalath, M.; Nair, A.; Sharkey, R. M.; Goldenberg, D. M. Efficacious therapies of two human pancreatic cancer xenografts and an aggressive human lymphoma xenograft with redesigned antibody-SN-38 conjugates. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research, Washington, DC, Apr 17-21, 2010; AACR: Philadelphia, 2010; Abstract 2438.
30. Huang, T. L.; Szekacs, A.; Uematsu, T.; Kuwano, E.; Parkinson, A.; Hammock, B. D. Hydrolysis of carbonates, thiocarbonates, carbamates, and carboxylic esters of α-naphthol, β-naphthol, and p -nitrophenol by human, rat, and mouse liver carboxylesterases Pharm. Res. 1993, 10, 639-648
31. Danks, M. K.; Morton, C. L.; Krull, E. J.; Cheshire, P. J.; Richmond, L. B.; Naeve, C. W.; Pawlik, C. A.; Houghton, P. J.; Potter, P. M. Comparison of activation of CPT-11 by rabbit and human carboxylesterases for use in enzyme/prodrug therapy Clin. Cancer Res. 1999, 5, 917-924
32. Gupta, E.; Lestingi, T. M.; Mick, R.; Ramirez, J.; Vokes, E. E.; Ratain, M. J. Metabolic fate of irinotecan in humans: correlation of glucuronidation with diarrhea Cancer Res. 1994, 54, 3723-3725
33. Goldenberg, D. M.; Sharkey, R. M.; Primus, F. J. Carcinoembryonic antigen in histopathology: immunoperoxidase staining of conventional tissue sections J. Natl. Cancer Inst. 1976, 57, 11-22
34. Hammarström, S. The carcinoembryonic antigen (CEA) family: structures, suggested functions and expression in normal and malignant tissues Semin. Cancer Biol. 1999, 9, 67-81
35. Shively, J. E.; Beatty, J. D. CEA-related antigens: molecular biology and clinical significance Crit. Rev. Oncol. Hematol. 1985, 2, 355-399
36. Thompson, J. A.; Grunert, F.; Zimmermann, W. Carcinoembryonic antigen gene family: molecular biology and clinical perspectives J. Clin. Lab. Anal. 1991, 5, 344-366
37. Hansen, H. J.; Goldenberg, D. M.; Newman, E. S.; Grebenau, R.; Sharkey, R. M. Characterization of second-generation monoclonal antibodies against carcinoembryonic antigen Cancer 1993, 71, 3478-3485
38. Beauchemin, N.; Draber, P.; Dveksler, G.; Gold, P.; Gray-Owen, S.; Grunert, F.; Hammarstrom, S.; Holmes, K. V.; Karlsson, A.; Kuroki, M.; Lin, S. H.; Lucka, L.; Najjar, S. M.; Neumaier, M.; Obrink, B.; Shively, J. E.; Skubitz, K. M.; Stanners, C. P.; Thomas, P.; Thompson, J. A.; Virji, M.; von, K. S.; Wagener, C.; Watt, S.; Zimmermann, W. Redefined nomenclature for members of the carcinoembryonic antigen family Exp. Cell Res. 1999, 252, 243-249
39. Blumenthal, R. D.; Osorio, L.; Hayes, M. K.; Horak, I. D.; Hansen, H. J.; Goldenberg, D. M. Carcinoembryonic antigen antibody inhibits lung metastasis and augments chemotherapy in a human colonic carcinoma xenograft Cancer Immunol. Immunother. 2005, 54, 315-327
40. Stein, R.; Goldenberg, D. M. A humanized monoclonal antibody to carcinoembryonic antigen, labetuzumab, inhibits tumor growth and sensitizes human medullary thyroid cancer xenografts to dacarbazine chemotherapy Mol. Cancer Ther. 2004, 3, 1559-1564
41. Hajjar, G.; Sharkey, R. M.; Burton, J.; Zhang, C. H.; Yeldell, D.; Matthies, A.; Alavi, A.; Losman, M. J.; Brenner, A.; Goldenberg, D. M. Phase I radioimmunotherapy trial with iodine-131-labeled humanized MN-14 anti-carcinoembryonic antigen monoclonal antibody in patients with metastatic gastrointestinal and colorectal cancer Clin. Colorectal Cancer 2002, 2, 31-42
42. Juweid, M. E.; Hajjar, G.; Stein, R.; Sharkey, R. M.; Herskovic, T.; Swayne, L. C.; Suleiman, S.; Pereira, M.; Rubin, A. D.; Goldenberg, D. M. Initial experience with high-dose radioimmunotherapy of metastatic medullary thyroid cancer using 131I-MN-14 F(ab)2 anti-carcinoembryonic antigen MAb and AHSCR J. Nucl. Med. 2000, 41, 93-103
43. Liersch, T.; Meller, J.; Kulle, B.; Behr, T. M.; Markus, P.; Langer, C.; Ghadimi, B. M.; Wegener, W. A.; Kovacs, J.; Horak, I. D.; Becker, H.; Goldenberg, D. M. Phase II trial of carcinoembryonic antigen radioimmunotherapy with 131I-labetuzumab after salvage resection of colorectal metastases in the liver: five-year safety and efficacy results J. Clin. Oncol. 2005, 23, 6763-6770
44. Liersch, T.; Meller, J.; Bittrich, M.; Kulle, B.; Becker, H.; Goldenberg, D. M. Update of carcinoembryonic antigen radioimmunotherapy with (131)I-labetuzumab after salvage resection of colorectal liver metastases: comparison of outcome to a contemporaneous control group Ann. Surg. Oncol. 2007, 14, 2577-2590
45. Sharkey, R. M.; Goldenberg, D. M.; Murthy, S.; Pinsky, H.; Vagg, R.; Pawlyk, D.; Siegel, J. A.; Wong, G. Y.; Gascon, P.; Izon, D. O. Clinical evaluation of tumor targeting with a high-affinity, anticarcinoembryonic-antigen-specific, murine monoclonal antibody, MN-14 Cancer 1993, 71, 2082-2096
46. Ford, C. H.; Tsaltas, G. C.; Osborne, P. A.; Addetia, K. Novel flow cytometric analysis of the progress and route of internalization of a monoclonal anti-carcinoembryonic antigen (CEA) antibody Cytometry 1996, 23, 228-240
47. Shih, L. B.; Goldenberg, D. M.; Xuan, H.; Lu, H. W.; Mattes, M. J.; Hall, T. C. Internalization of an intact doxorubicin immunoconjugate Cancer Immunol. Immunother. 1994, 38, 92-98
48. Tsaltas, G.; Ford, C. H.; Gallant, M. Demonstration of monoclonal anti-carcinoembryonic antigen (CEA) antibody internalization by electron microscopy, western blotting and radioimmunoassay Anticancer Res. 1992, 12, 2133-2142
49. Stein, R.; Govindan, S. V.; Hayes, M.; Griffiths, G. L.; Hansen, H. J.; Horak, I. D.; Goldenberg, D. M. Advantage of a residualizing iodine radiolabel in the therapy of a colon cancer xenograft targeted with an anticarcinoembryonic antigen monoclonal antibody Clin. Cancer Res. 2005, 11, 2727-2734
50. Zhao, H.; Lee, C.; Sai, P.; Choe, Y. H.; Boro, M.; Pendri, A.; Guan, S.; Greenwald, R. B. 20- O -Acylcamptothecin derivatives: evidence for lactone stabilization J. Org. Chem. 2000, 65, 4601-4606
51. Goldenberg, D. M.; Cardillo, T. M.; Sharkey, R. M.; McBride, W. J.; Rossi, E. A.; Chang, C.-H.; Govindan, S. V. SN-38 Antibody-drug conjugates as a novel platform for solid cancer therapy: preclinical science. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research, San Diego, Apr 5-9, 2014; AACR: Philadelphia, 2014; Abstract 2904.
52. Pal, A.; Khan, S.; Wang, Y. F.; Kamath, N.; Sarkar, A. K.; Ahmad, A.; Sheikh, S.; Ali, S.; Carbonaro, D.; Zhang, A.; Ahmad, I. Preclinical safety, pharmacokinetics and antitumor efficacy profile of liposome-entrapped SN-38 formulation Anticancer Res. 2005, 25, 331-341
53. Patnaik, A.; Papadopoulos, K. P.; Tolcher, A. W.; Beeram, M.; Urien, S.; Schaaf, L. J.; Tahiri, S.; Bekaii-Saab, T.; Lokiec, F. M.; Rezai, K.; Buchbinder, A. Phase I dose-escalation study of EZN-2208 (PEG-SN38), a novel conjugate of poly(ethylene) glycol and SN38, administered weekly in patients with advanced cancer Cancer Chemother. Pharmacol. 2013, 71, 1499-1506
54. Hamaguchi, T.; Doi, T.; Eguchi-Nakajima, T.; Kato, K.; Yamada, Y.; Shimada, Y.; Fuse, N.; Ohtsu, A.; Matsumoto, S.; Takanashi, M.; Matsumura, Y. Phase I study of NK012, a novel SN-38-incorporating micellar nanoparticle, in adult patients with solid tumors Clin. Cancer Res. 2010, 16, 5058-5066
55. Vergote, I. B.; Garcia, A.; Micha, J.; Pippitt, C.; Bendell, J.; Spitz, D.; Reed, N.; Dark, G.; Fracasso, P. M.; Ibrahim, E. N.; Armenio, V. A.; Duska, L.; Poole, C.; Gennigens, C.; Dirix, L. Y.; Leung, A. C.; Zhao, C.; Soufi-Mahjoubi, R.; Rustin, G. Randomized multicenter phase II trial comparing two schedules of etirinotecan pegol (NKTR-102) in women with recurrent platinum-resistant/refractory epithelial ovarian cancer J. Clin. Oncol. 2013, 31, 4060-4066
56. Boghaert, E. R.; Khandke, K.; Sridharan, L.; Armellino, D.; Dougher, M.; Dijoseph, J. F.; Kunz, A.; Hamann, P. R.; Sridharan, A.; Jones, S.; Discafani, C.; Damle, N. K. Tumoricidal effect of calicheamicin immunoconjugates using a passive targeting strategy Int. J. Oncol. 2006, 28, 675-684