Ado-trastuzumab emtansine (T-DM1): An antibody-drug conjugate (ADC) for HER2-positive breast cancer

Journal of Medicinal Chemistry

Volumn 57, Issue 16, 2014, Pages 6949-6964

  Lambert, John M ^a   Chari, Ravi V J ^a  

^a IMMUNOGEN INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; EPIDERMAL GROWTH FACTOR RECEPTOR 2; ERBB2 PROTEIN, HUMAN; MAYTANSINE; MONOCLONAL ANTIBODY; TRASTUZUMAB EMTANSINE;

ANALOGS AND DERIVATIVES; ANIMAL; BREAST NEOPLASMS; CHEMISTRY; DRUG SCREENING; FEMALE; HUMAN; METABOLISM; MOUSE; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); RAT;

ANIMALS; ANTIBODIES, MONOCLONAL, HUMANIZED; ANTINEOPLASTIC AGENTS; BREAST NEOPLASMS; CLINICAL TRIALS, PHASE I AS TOPIC; CLINICAL TRIALS, PHASE II AS TOPIC; CLINICAL TRIALS, PHASE III AS TOPIC; DRUG SCREENING ASSAYS, ANTITUMOR; FEMALE; HUMANS; MAYTANSINE; MICE; RATS; RECEPTOR, ERBB-2;

EID: 84906874906     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm500766w     Document Type: Article

References (50)

1. Colomer, R.; Shamon, L. A.; Tsai, M. S.; Lupu, R. Herceptin: from the bench to the clinic Cancer Invest. 2001, 19, 49-56
2. Pegram, M. D.; Konecny, G. E.; O'Callaghan, C.; Beryt, M.; Pietras, R.; Slamon, D. J. Rational combinations of trastuzumab with chemotherapeutic drugs used in the treatment of breast cancer J. Natl. Cancer Inst. 2004, 96, 739-749
3. Shepard, H. M.; Lewis, G. D.; Sarup, J. C.; Fendly, B. M.; Maneval, D.; Mordenti, J.; Figari, I.; Kotts, C. E.; Palladino, M. A., Jr.; Ullrich, A. Monoclonal antibody therapy of human cancer: taking the HER2 protooncogene to the clinic J. Clin. Immunol. 1991, 11, 117-127
4. Spector, N. L.; Blackwell, K. L. Understanding the mechanisms behind trastuzumab therapy for human epidermal growth factor receptor 2-positive breast cancer J. Clin. Oncol. 2009, 27, 5838-5847
5. Slamon, D. J.; Leyland-Jones, B.; Shak, S.; Fuchs, H.; Paton, V.; Bajamonde, A.; Fleming, T.; Eiermann, W.; Wolter, J.; Pegram, M.; Baselga, J.; Norton, L. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2 N. Engl. J. Med. 2001, 344, 783-792
6. Nahta, R.; Esteva, F. J. HER-2-targeted therapy: lessons learned and future directions Clin. Cancer Res. 2003, 9, 5078-5084
7. Metzger-Filho, O.; Winer, E. P.; Krop, I. Pertuzumab: optimizing HER2 blockade Clin. Cancer Res. 2013, 19, 5552-5556
8. Chari, R. V.; Miller, M. L.; Widdison, W. C. Antibody-drug conjugates: an emerging concept in cancer therapy Angew. Chem., Int. Ed. 2014, 53, 3796-3827
9. Blattler, W. A.; Chari, R. V. J. Methods of treatment using anti-ERBB antibody-maytansinoid conjugates. U.S. Patent 8,337,856, 2012.
10. Sedlacek, H. H. Antibodies as Carriers of Cytotoxicity; Karger: Basel, Switzerland, 1992; pp 1-145.
11. Chari Ravi, V. J. Targeted cancer therapy: conferring specificity to cytotoxic drugs Acc. Chem. Res. 2008, 41, 98-107
12. Kupchan, S. M.; Komoda, Y.; Branfman, A. R.; Sneden, A. T.; Court, W. A.; Thomas, G. J.; Hintz, H. P.; Smith, R. M.; Karim, A.; Howie, G. A.; Verma, A. K.; Nagao, Y.; Dailey, R. G., Jr.; Zimmerly, V. A.; Sumner, W. C., Jr. The maytansinoids. Isolation, structural elucidation, and chemical interrelation of novel ansa macrolides J. Org. Chem. 1977, 42, 2349-2357
13. Widdison, W. C.; Wilhelm, S. D.; Cavanagh, E. E.; Whiteman, K. R.; Leece, B. A.; Kovtun, Y.; Goldmacher, V. S.; Xie, H.; Steeves, R. M.; Lutz, R. J.; Zhao, R.; Wang, L.; Blattler, W. A.; Chari, R. V. Semisynthetic maytansine analogues for the targeted treatment of cancer J. Med. Chem. 2006, 49, 4392-4408
14. Issell, B. F.; Crooke, S. T. Maytansine Cancer Treat. Rev. 1978, 5, 199-207
15. Kupchan, S. M.; Sneden, A. T.; Branfman, A. R.; Howie, G. A.; Rebhun, L. I.; McIvor, W. E.; Wang, R. W.; Schnaitman, T. C. Structural requirements for antileukemic activity among the naturally occurring and semisynthetic maytansinoids J. Med. Chem. 1978, 21, 31-37
16. Chari, R. V.; Martell, B. A.; Gross, J. L.; Cook, S. B.; Shah, S. A.; Blattler, W. A.; McKenzie, S. J.; Goldmacher, V. S. Immunoconjugates containing novel maytansinoids: promising anticancer drugs Cancer Res. 1992, 52, 127-131
17. Kellogg, B. A.; Garrett, L.; Kovtun, Y.; Lai, K. C.; Leece, B.; Miller, M.; Payne, G.; Steeves, R.; Whiteman, K. R.; Widdison, W.; Xie, H.; Singh, R.; Chari, R. V.; Lambert, J. M.; Lutz, R. J. Disulfide-linked antibody-maytansinoid conjugates: optimization of in vivo activity by varying the steric hindrance at carbon atoms adjacent to the disulfide linkage Bioconjugate Chem. 2011, 22, 717-727
18. Wakankar, A.; Chen, Y.; Gokarn, Y.; Jacobson, F. S. Analytical methods for physicochemical characterization of antibody drug conjugates mAbs 2011, 3, 161-172
19. Wakankar, A. A.; Feeney, M. B.; Rivera, J.; Chen, Y.; Kim, M.; Sharma, V. K.; Wang, Y. J. Physicochemical stability of the antibody-drug conjugate trastuzumab-DM1: changes due to modification and conjugation processes Bioconjugate Chem. 2010, 21, 1588-1595
20. Lewis Phillips, G. D.; Li, G.; Dugger, D. L.; Crocker, L. M.; Parsons, K. L.; Mai, E.; Blattler, W. A.; Lambert, J. M.; Chari, R. V.; Lutz, R. J.; Wong, W. L.; Jacobson, F. S.; Koeppen, H.; Schwall, R. H.; Kenkare-Mitra, S. R.; Spencer, S. D.; Sliwkowski, M. X. Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate Cancer Res. 2008, 68, 9280-9290
21. Erickson, H. K.; Lewis Phillips, G. D.; Leipold, D. D.; Provenzano, C. A.; Mai, E.; Johnson, H. A.; Gunter, B.; Audette, C. A.; Gupta, M.; Pinkas, J.; Tibbitts, J. The effect of different linkers on target cell catabolism and pharmacokinetics/pharmacodynamics of trastuzumab maytansinoid conjugates Mol. Cancer Ther. 2012, 11, 1133-1142
22. Junttila, T. T.; Li, G.; Parsons, K.; Phillips, G. L.; Sliwkowski, M. X. Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer Breast Cancer Res. Treat. 2011, 128, 347-356
23. Barok, M.; Tanner, M.; Koninki, K.; Isola, J. Trastuzumab-DM1 is highly effective in preclinical models of HER2-positive gastric cancer Cancer Lett. 2011, 306, 171-179
24. Kovtun, Y. V.; Audette, C. A.; Mayo, M. F.; Jones, G. E.; Doherty, H.; Maloney, E. K.; Erickson, H. K.; Sun, X.; Wilhelm, S.; Ab, O.; Lai, K. C.; Widdison, W. C.; Kellogg, B.; Johnson, H.; Pinkas, J.; Lutz, R. J.; Singh, R.; Goldmacher, V. S.; Chari, R. V. Antibody-maytansinoid conjugates designed to bypass multidrug resistance Cancer Res. 2010, 70, 2528-2537
25. Guo, J.; Li, G.; Lewis Phillips, G. D. Role of multidrug resistance transporters in the biological response to trastuzumab-cytotoxic drug conjugates Cancer Res. 2010, 70 (Suppl. 1) Abstract 618
26. Jumbe, N. L.; Xin, Y.; Leipold, D. D.; Crocker, L.; Dugger, D.; Mai, E.; Sliwkowski, M. X.; Fielder, P. J.; Tibbitts, J. Modeling the efficacy of trastuzumab-DM1, an antibody drug conjugate, in mice J. Pharmacokinet. Pharmacodyn. 2010, 37, 221-242
27. Kaur, S.; Xu, K.; Saad, O. M.; Dere, R. C.; Carrasco-Triguero, M. Bioanalytical assay strategies for the development of antibody-drug conjugate biotherapeutics Bioanalysis 2013, 5, 201-226
28. Poon, K. A.; Flagella, K.; Beyer, J.; Tibbitts, J.; Kaur, S.; Saad, O.; Yi, J. H.; Girish, S.; Dybdal, N.; Reynolds, T. Preclinical safety profile of trastuzumab emtansine (T-DM1): mechanism of action of its cytotoxic component retained with improved tolerability Toxicol. Appl. Pharmacol. 2013, 273, 298-313
29. Sun, X.; Widdison, W.; Mayo, M.; Wilhelm, S.; Leece, B.; Chari, R.; Singh, R.; Erickson, H. Design of antibody-maytansinoid conjugates allows for efficient detoxification via liver metabolism Bioconjugate Chem. 2011, 22, 728-735
30. Fishkin, N.; Maloney, E. K.; Chari, R. V.; Singh, R. A novel pathway for maytansinoid release from thioether linked antibody-drug conjugates (ADCs) under oxidative conditions Chem. Commun. 2011, 47, 10752-10754
31. Krop, I. E.; Beeram, M.; Modi, S.; Jones, S. F.; Holden, S. N.; Yu, W.; Girish, S.; Tibbitts, J.; Yi, J. H.; Sliwkowski, M. X.; Jacobson, F.; Lutzker, S. G.; Burris, H. A. Phase I study of trastuzumab-DM1, an HER2 antibody-drug conjugate, given every 3 weeks to patients with HER2-positive metastatic breast cancer J. Clin. Oncol. 2010, 28, 2698-2704
32. Baselga, J. Phase I and II clinical trials of trastuzumab Ann. Oncol. 2001, 12 (Suppl. 1) S49-S55
33. Beeram, M.; Krop, I. E.; Burris, H. A.; Girish, S. R.; Yu, W.; Lu, M. W.; Holden, S. N.; Modi, S. A phase 1 study of weekly dosing of trastuzumab emtansine (T-DM1) in patients with advanced human epidermal growth factor 2-positive breast cancer Cancer 2012, 118, 5733-5740
34. Burris, H. A., 3rd; Rugo, H. S.; Vukelja, S. J.; Vogel, C. L.; Borson, R. A.; Limentani, S.; Tan-Chiu, E.; Krop, I. E.; Michaelson, R. A.; Girish, S.; Amler, L.; Zheng, M.; Chu, Y. W.; Klencke, B.; O'Shaughnessy, J. A. Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy J. Clin. Oncol. 2011, 29, 398-405
35. Krop, I. E.; LoRusso, P.; Miller, K. D.; Modi, S.; Yardley, D.; Rodriguez, G.; Guardino, E.; Lu, M.; Zheng, M.; Girish, S.; Amler, L.; Winer, E. P.; Rugo, H. S. A phase II study of trastuzumab emtansine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer who were previously treated with trastuzumab, lapatinib, an anthracycline, a taxane, and capecitabine J. Clin. Oncol. 2012, 30, 3234-3241
36. Hurvitz, S. A.; Dirix, L.; Kocsis, J.; Bianchi, G. V.; Lu, J.; Vinholes, J.; Guardino, E.; Song, C.; Tong, B.; Ng, V.; Chu, Y. W.; Perez, E. A. Phase II randomized study of trastuzumab emtansine versus trastuzumab plus docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer J. Clin. Oncol. 2013, 31, 1157-1163
37. Suter, T. M.; Procter, M.; van Veldhuisen, D. J.; Muscholl, M.; Bergh, J.; Carlomagno, C.; Perren, T.; Passalacqua, R.; Bighin, C.; Klijn, J. G.; Ageev, F. T.; Hitre, E.; Groetz, J.; Iwata, H.; Knap, M.; Gnant, M.; Muehlbauer, S.; Spence, A.; Gelber, R. D.; Piccart-Gebhart, M. J. Trastuzumab-associated cardiac adverse effects in the herceptin adjuvant trial J. Clin. Oncol. 2007, 25, 3859-3865
38. Verma, S.; Miles, D.; Gianni, L.; Krop, I. E.; Welslau, M.; Baselga, J.; Pegram, M.; Oh, D. Y.; Dieras, V.; Guardino, E.; Fang, L.; Lu, M. W.; Olsen, S.; Blackwell, K. Trastuzumab emtansine for HER2-positive advanced breast cancer N. Engl. J. Med. 2012, 367, 1783-1791
39. Krop, I. E.; Kim, S. B.; Gonzalez-Martin, A.; LoRusso, P. M.; Ferrero, J. M.; Smitt, M.; Yu, R.; Leung, A.; Wildiers, H. Trastuzumab emtansine versus treatment of physician's choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomized open-label phase 3 trial Lancet Oncol. 2014, 15, 689-699
40. Baselga, J.; Cortes, J.; Kim, S. B.; Im, S. A.; Hegg, R.; Im, Y. H.; Roman, L.; Pedrini, J. L.; Pienkowski, T.; Knott, A.; Clark, E.; Benyunes, M. C.; Ross, G.; Swain, S. M. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer N. Engl. J. Med. 2012, 366, 109-119
41. Phillips, G. D.; Fields, C. T.; Li, G.; Dowbenko, D.; Schaefer, G.; Miller, K.; Andre, F.; Burris, H. A., 3rd; Albain, K. S.; Harbeck, N.; Dieras, V.; Crivellari, D.; Fang, L.; Guardino, E.; Olsen, S. R.; Crocker, L. M.; Sliwkowski, M. X. Dual targeting of HER2-positive cancer with trastuzumab emtansine and pertuzumab: critical role for neuregulin blockade in antitumor response to combination therapy Clin. Cancer Res. 2014, 20, 456-468
42. Lu, D.; Burris, H. A., 3rd; Wang, B.; Dees, E. C.; Cortes, J.; Joshi, A.; Gupta, M.; Yi, J. H.; Chu, Y. W.; Shih, T.; Fang, L.; Girish, S. Drug interaction potential of trastuzumab emtansine (T-DM1) combined with pertuzumab in patients with HER2-positive metastatic breast cancer Curr. Drug Metab. 2012, 13, 911-922
43. Bartsch, R.; Berghoff, A. S.; Preusser, M. Breast cancer brain metastases responding to primary systemic therapy with T-DM1 J. Neuro-Oncol. 2014, 116, 205-206
44. Girish, S.; Gupta, M.; Wang, B.; Lu, D.; Krop, I. E.; Vogel, C. L.; Burris, H. A., III; LoRusso, P. M.; Yi, J. H.; Saad, O.; Tong, B.; Chu, Y. W.; Holden, S.; Joshi, A. Clinical pharmacology of trastuzumab emtansine (T-DM1): an antibody-drug conjugate in development for the treatment of HER2-positive cancer Cancer Chemother. Pharmacol. 2012, 69, 1229-1240
45. Lu, D.; Joshi, A.; Wang, B.; Olsen, S.; Yi, J. H.; Krop, I. E.; Burris, H. A.; Girish, S. An integrated multiple-analyte pharmacokinetic model to characterize trastuzumab emtansine (T-DM1) clearance pathways and to evaluate reduced pharmacokinetic sampling in patients with HER2-positive metastatic breast cancer Clin. Pharmacokinet. 2013, 52, 657-672
46. Chudasama, V. L.; Schaedeli Stark, F.; Harrold, J. M.; Tibbitts, J.; Girish, S. R.; Gupta, M.; Frey, N.; Mager, D. E. Semi-mechanistic population pharmacokinetic model of multivalent trastuzumab emtansine in patients with metastatic breast cancer Clin. Pharmacol. Ther. 2012, 92, 520-527
47. Bender, B. C.; Schaedeli-Stark, F.; Koch, R.; Joshi, A.; Chu, Y. W.; Rugo, H.; Krop, I. E.; Girish, S.; Friberg, L. E.; Gupta, M. A population pharmacokinetic/pharmacodynamic model of thrombocytopenia characterizing the effect of trastuzumab emtansine (T-DM1) on platelet counts in patients with HER2-positive metastatic breast cancer Cancer Chemother. Pharmacol. 2012, 70, 591-601
48. Shen, B. Q.; Bumbaca, D.; Saad, O.; Yue, Q.; Pastuskovas, C. V.; Khojasteh, S. C.; Tibbitts, J.; Kaur, S.; Wang, B.; Chu, Y. W.; LoRusso, P. M.; Girish, S. Catabolic fate and pharmacokinetic characterization of trastuzumab emtansine (T-DM1): an emphasis on preclinical and clinical catabolism Curr. Drug Metab. 2012, 13, 901-910
49. Thon, J. N.; Devine, M. T.; Begonja, A. J.; Tibbitts, J.; Italiano, J. E., Jr. High-content live-cell imaging assay used to establish mechanism of trastuzumab emtansine (T-DM1)-mediated inhibition of platelet production Blood 2012, 120, 1975-1984
50. Sendur, M. A.; Aksoy, S.; Altundag, K. Cardiotoxicity of novel HER2-targeted therapies Curr. Med. Res. Opin. 2013, 29, 1015-1024