Preclinical safety profile of trastuzumab emtansine (T-DM1): Mechanism of action of its cytotoxic component retained with improved tolerability

Toxicology and Applied Pharmacology

Volumn 273, Issue 2, 2013, Pages 298-313

  Poon, Kirsten Achilles ^a   Flagella, Kelly ^a   Beyer, Joseph ^a   Tibbitts, Jay ^b   Kaur, Surinder ^a   Saad, Ola ^a   Yi, Joo Hee ^a   Girish, Sandhya ^a   Dybdal, Noel ^a   Reynolds, Theresa ^a  

^a GENENTECH INC   (United States)

^b UCB Nv   (Belgium)

Author keywords

Ado trastuzumab emtansine; Antibody drug conjugates; Breast cancer; HER2; T DM1; Toxicology

Indexed keywords

EPIDERMAL GROWTH FACTOR RECEPTOR 2; TRASTUZUMAB EMTANSINE;

ANIMAL EXPERIMENT; ANIMAL TISSUE; AREA UNDER THE CURVE; ARTICLE; AUTOPSY; BLEEDING; CELL VACUOLE; DRUG CYTOTOXICITY; DRUG MECHANISM; DRUG SAFETY; DRUG SCREENING; DRUG STRUCTURE; DRUG TOLERABILITY; HAPLORHINI; HUMAN; HYPERPLASIA; HYPERTROPHY; IN VITRO STUDY; MAXIMUM PLASMA CONCENTRATION; METAPHASE; NECROSIS; NERVE FIBER DEGENERATION; NONHUMAN; RAT;

ADO-TRASTUZUMAB EMTANSINE; ANTIBODY-DRUG CONJUGATES; BREAST CANCER; HER2; T-DM1; TOXICOLOGY;

ANIMALS; ANTIBODIES, MONOCLONAL, HUMANIZED; ANTINEOPLASTIC AGENTS; BLOOD PLATELETS; BODY WEIGHT; CYTOTOXINS; DRUG EVALUATION, PRECLINICAL; FEMALE; HUMANS; MACACA FASCICULARIS; MALE; MAYTANSINE; RANDOM ALLOCATION; RATS; RATS, SPRAGUE-DAWLEY;

PRIMATES; RATTUS; RODENTIA;

EID: 84888201843     PISSN: 0041008X     EISSN: 10960333     Source Type: Journal    
DOI: 10.1016/j.taap.2013.09.003     Document Type: Article

References (58)

1. Adcetris [package insert]. Bothell, WA: Seattle Genetics; 2012.
2. Alley S.C., Okeley N.M., Senter P.D. Antibody-drug conjugates: targeted drug delivery for cancer. Curr. Opin. Chem. Biol. 2010, 14:529-537.
3. Blackwell K.L., Burstein H.J., Storniolo A.M., Rugo H., Sledge G., Koehler M., Ellis C., Casey M., Vukelja S., Bischoff J., Baselga J., O'Shaughnessy J. Randomized study of lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J. Clin. Oncol. 2010, 28:1124-1130.
4. Blättler W.A., Chari R.V.J. Drugs to enhance the therapeutic potency of anticancer antibodies: antibody-drug conjugates as tumor-activated prodrugs. Anticancer Agents: Frontiers in Cancer Chemotherapy 2001, 317-338. American Chemical Society, Washington, DC. I. Ojima, G. Vite, K. Altmann (Eds.).
5. Burris H.A., 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.
6. Cabanillas F., Rodriguez V., Hall S.W., Burgess M.A., Bodey G.P., Freireich E.J. Phase I study of maytansine using a 3-day schedule. Cancer Treat. Rep. 1978, 62:425-428.
7. Carrasco-Triguero M., Yi J.H., Dere R., Qiu Z.J., Lei C., Li Y., Mahood C., Wang B., Leipold D., Poon K.A., Kaur S. Immunogenicity assays for antibody-drug conjugates: case study with ado-trastuzumab emtansine. Bioanalysis 2013, 5:1007-1023.
8. Cassady J.M., Chan K.K., Floss H.G., Leistner E. Recent developments in the maytansinoid antitumor agents. Chem. Pharm. Bull. (Tokyo) 2004, 52:1-26.
9. Chabner B.A., Levine A.S., Johnson B.L., Young R.C. Initial clinical trials of maytansine, an antitumor plant alkaloid. Cancer Treat. Rep. 1978, 62:429-433.
10. Chahinian A.P., Nogeire C., Ohnuma T., Greenberg M.L., Sivak M., Jaffrey I.S., Holland J.F. Phase I study of weekly maytansine given by IV bolus or 24-hour infusion. Cancer Treat. Rep. 1979, 63:1953-1960.
11. 50 Concentration Response Assays [Internet] [cited 2013 Apr 25]. Available from:. http://www.chantest.com/screening-services/safety-services/pre-clinical-safety/herg-concentration-response-assay.
12. Chari R.V. Targeted cancer therapy: conferring specificity to cytotoxic drugs. Acc. Chem. Res. 2008, 41:98-107.
13. Dawood S., Broglio K., Buzdar A.U., Hortobagyi G.N., Giordano S.H. Prognosis of women with metastatic breast cancer by HER2 status and trastuzumab treatment: an institutional-based review. J. Clin. Oncol. 2010, 28:92-98.
14. De Keulenaer G.W., Doggen K., Lemmens K. The vulnerability of the heart as a pluricellular paracrine organ: lessons from unexpected triggers of heart failure in targeted ErbB2 anticancer therapy. Circ. Res. 2010, 106:35-46.
15. Dere R., Yi J.H., Lei C., Saad O.M., Huang C., Li Y., Baudys J., Kaur S. PK assays for antibody-drug conjugates: case study with ado-trastuzumab emtansine. Bioanalysis 2013, 5:1025-1040.
16. Eagan R.T., Ingle J.N., Rubin J., Frytak S., Moertel C.G. Early clinical study of an intermittent schedule for maytansine (NSC-153858): brief communication. J. Natl. Cancer Inst. 1978, 60:93-96.
17. Erickson H.K., Park P.U., Widdison W.C., Kovtun Y.V., Garrett L.M., Hoffman K., Lutz R.J., Goldmacher V.S., Blättler W.A. Antibody-maytansinoid conjugates are activated in targeted cancer cells by lysosomal degradation and linker-dependent intracellular processing. Cancer Res. 2006, 66:4426-4433.
18. Erickson H.K., Widdison W.C., Mayo M.F., Whiteman K., Audette C., Wilhelm S.D., Singh R. Tumor delivery and in vivo processing of disulfide-linked and thioether-linked antibody-maytansinoid conjugates. Bioconjug. Chem. 2010, 21:84-92.
19. Girish S., Gupta M., Wang B., Lu D., Krop I.E., Vogel C.L., Burris H.A., 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.
20. Goldmacher V.S., Blättler W.A., Lambert J.M., Chari R.V.J. Immunotoxins and antibody-drug conjugates for cancer treatment. Biomedical Aspects of Drug Targeting 2002, 291-310. Kluwer Academic Publishers, Boston, Massachusetts. V.R. Muzykantov, V.P. Torchilin (Eds.).
21. Gupta M., Wang B., Carrothers T., LoRusso P.M., Chu Y.-W., Shih T., Loecke D., Joshi A., Saad O., Yi J.-H., Girish S. Effects of trastuzumab emtansine (T-DM1) on QT interval and safety of pertuzumab plus T-DM1 in patients with previously treated human epidermal growth factor receptor 2-positive metastatic breast cancer. Clin. Pharmacol. Drug Dev. 2013, 2:11-24.
22. Herceptin [package insert]. South San Francisco, CA: Genentech, Inc.; 2010. Accessed November 7, 2012.
23. Herceptin European Summary of Product Characteristics [Internet] [cited 2013 Apr 25]. Available from:. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000278/WC500074922.pdf.
24. Hudis C.A. Trastuzumab - mechanism of action and use in clinical practice. N. Engl. J. Med. 2007, 357:39-51.
25. Issell B.F., Crooke S.T. Maytansine. Cancer Treat. Rev. 1978, 5:199-207.
26. Kadcyla [package insert]. South San Francisco, CA: Genentech, Inc.; 2013.
27. Klein P.M., Dybdal N. Trastuzumab and cardiac dysfunction: update on preclinical studies. Semin. Oncol. 2003, 30(5 Suppl. 16):49-53.
28. 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 3weeks to patients with HER2-positive metastatic breast cancer. J. Clin. Oncol. 2010, 28:2698-2704.
29. 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., 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.
30. Lambert J.M. Drug-conjugated monoclonal antibodies for the treatment of cancer. Curr. Opin. Pharmacol. 2005, 5:543-549.
31. Lewis Phillips G.D., Li G., Dugger D.L., Crocker L.M., Parsons K.L., Mai E., Blättler 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.
32. Lopus M., Oroudjev E., Wilson L., Wilhelm S., Widdison W., Chari R., Jordan M.A. Maytansine and cellular metabolites of antibody-maytansinoid conjugates strongly suppress microtubule dynamics by binding to microtubules. Mol. Cancer Ther. 2010, 9:2689-2699.
33. Mahapatra K., Darbonne W., Bumbaca D., Shen B., Du X., Tibbitts J., Olsen S., Sliwkowski M., Girish S., Hartley D., Dambach D., Ramakrishnan V., Uppal H. T-DM1-induced thrombocytopenia results from impaired platelet production in a HER2-independent manner [abstract]. Mol. Cancer Ther. 2011, 10(11 Suppl.):A135.
34. Mugera G.M., Ward J.M. Acute toxicity of maytansine in F344 rats. Cancer Treat. Rep. 1977, 61:1333-1338.
35. Nahta R., Yu D., Hung M.C., Hortobagyi G.N., Esteva F.J. Mechanisms of disease: understanding resistance to HER2-targeted therapy in human breast cancer. Nat. Clin. Pract. Oncol. 2006, 3:269-280.
36. Oroudjev E., Lopus M., Wilson L., Audette C., Provenzano C., Erickson H., Kovtun Y., Chari R., Jordan M.A. Maytansinoid-antibody conjugates induce mitotic arrest by suppressing microtubule dynamic instability. Mol. Cancer Ther. 2010, 9:2700-2713.
37. Park S.B., Krishnan A.V., Lin C.S., Goldstein D., Friedlander M., Kiernan M.C. Mechanisms underlying chemotherapy-induced neurotoxicity and the potential for neuroprotective strategies. Curr. Med. Chem. 2008, 15:3081-3094.
38. Press M.F., Cordon-Cardo C., Slamon D.J. Expression of the HER-2/neu proto-oncogene in normal human adult and fetal tissues. Oncogene 1990, 5:953-962.
39. Raschi E., Ceccarini L., De Ponti F., Recanatini M. hERG-related drug toxicity and models for predicting hERG liability and QT prolongation. Expert Opin. Drug Metab. Toxicol. 2009, 5:1005-1021.
40. Rebert C.S., Pryor G.T., Frick M.S. Effects of vincristine, maytansine, and cis-platinum on behavioral and electrophysiological indices of neurotoxicity in the rat. J. Appl. Toxicol. 1984, 4:330-338.
41. Redfern W.S., Carlsson L., Davis A.S., Lynch W.G., MacKenzie I., Palethrope S., Siegl P.K., Strang I., Sullivan A.T., Wallis R., Camm A.J., Hammond T.G. Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. Cardiovasc. Res. 2003, 58:32-45.
42. Remillard S., Rebhun L.I., Howie G.A., Kupchan S.M. Antimitotic activity of the potent tumor inhibitor maytansine. Science 1975, 189:1002-1005.
43. Ross J.S., Slodkowska E.A., Symmans W.F., Pusztai L., Ravdin P.M., Hortobagyi G.N. The HER-2 receptor and breast cancer: ten years of targeted anti-HER-2 therapy and personalized medicine. Oncologist 2009, 14:320-368.
44. Seidman A., Hudis C., Pierri M.K., Shak S., Paton V., Ashby M., Murphy M., Stewart S.J., Keefe D. Cardiac dysfunction in the trastuzumab clinical trials experience. J. Clin. Oncol. 2002, 20:1215-1221.
45. Sieber S.M., Whang-Peng J., Botkin C., Knutsen T. Teratogenic and cytogenetic effects of some plant-derived antitumor agents (vincristine, colchicine, maytansine, VP-16-213 and VM-26) in mice. Teratology 1978, 18:31-47.
46. Slamon D.J., Clark G.M., Wong S.G., Levin W.J., Ullrich A., McGuire W.L. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987, 235:177-182.
47. Slamon D.J., Godolphin W., Jones L.A., Holt J.A., Wong S.G., Keith D.E., Levin W.J., Stuart S.G., Udove J., Ullrich A. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 1989, 244:707-712.
48. 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.
49. Sliwkowski M.X., Lofgren J.A., Lewis G.D., Hotaling T.E., Fendly B.M., Fox J.A. Nonclinical studies addressing the mechanism of action of trastuzumab (Herceptin). Semin. Oncol. 1999, 26:60-70.
50. 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.
51. Spector N.L., Xia W., Burris H., Hurwitz H., Dees E.C., Dowlati A., O'Neil B., Overmoyer B., Marcom P.K., Blackwell K.L., Smith D.A., Koch K.M., Stead A., Mangum S., Ellis M.J., Liu L., Man A.K., Bremer T.M., Harris J., Bacus S. Study of the biologic effects of lapatinib, a reversible inhibitor of ErbB1 and ErbB2 tyrosine kinases, on tumor growth and survival pathways in patients with advanced malignancies. J. Clin. Oncol. 2005, 23:2502-2512.
52. Swanson S.J., Bussiere J. Immunogenicity assessment in non-clinical species. Curr. Opin. Microbiol. 2012, 15:337-347.
53. Tolcher A.W., Ochoa L., Hammond L.A., Patnaik A., Edwards T., Takimoto C., Smith L., de Bono J., Schwartz G., Mays T., Jonak Z.L., Johnson R., DeWitte M., Martino H., Audette C., Maes K., Chari R.V., Lambert J.M., Rowinsky E.K. Cantuzumab mertansine, a maytansinoid immunoconjugate directed to the CanAg antigen: a phase I, pharmacokinetic, and biologic correlative study. J. Clin. Oncol. 2003, 21:211-222.
54. Verma S., Miles D., Gianni L., Krop I.E., Welslau M., Baselga J., Pegram M., Oh D.Y., Diéras 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. the EMILIA Study Group.
55. von Minckwitz G., du Bois A., Schmidt M., Maass N., Cufer T., de Jongh F.E., Maartense E., Zielinski C., Kaufmann M., Bauer W., Baumann K.H., Clemens M.R., Duerr R., Uleer C., Andersson M., Stein R.C., Nekljudova V., Loibl S. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a German breast group 26/breast international group 03-05 study. J. Clin. Oncol. 2009, 27:1999-2006.
56. von Minckwitz G., Schwedler K., Schmidt M., Barinoff J., Mundhenke C., Cufer T., Maartense E., de Jongh F.E., Baumann K.H., Bischoff J., Harbeck N., Lück H.J., Maass N., Zielinski C., Andersson M., Stein R.C., Nekljudova V., Loibl S. Trastuzumab beyond progression: overall survival analysis of the GBG 26/BIG 3-05 phase III study in HER2-positive breast cancer. Eur. J. Cancer 2011, 47:2273-2281. GBG 26/BIG 03-05 study group and participating investigators.
57. Wu A.M., Senter P.D. Arming antibodies: prospects and challenges for immunoconjugates. Nat. Biotechnol. 2005, 23:1137-1146.
58. Yarden Y., Sliwkowski M.X. Untangling the ErbB signalling network. Nat. Rev. Mol. Cell Biol. 2001, 2:127-137.