Abstract
Purpose
Trastuzumab emtansine (T-DM1), an antibody–drug conjugate (ADC) comprised of trastuzumab linked to the antimitotic agent DM1, has shown promising results in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. Investigations of the mechanisms of the action of ADCs, including T-DM1, have been primarily descriptive or semiquantitative. However, quantitative pharmacokinetic/pharmacodynamic (PK/PD) analysis may provide insights into their complex behavior. The analyses described herein applied PK/PD modeling to nonclinical studies of maytansinoid conjugates.
Methods
The maytansinoid conjugates T-DM1 and T-SPP-DM1, with thioether and disulfide linkers, respectively, were tested in mouse efficacy, PK, and tumor uptake studies. 3[H]DM1-bearing ADCs were used to facilitate the quantitation of the ADCs in plasma, as well as ADC and ADC catabolites in tumors. Three mechanistic PK/PD models were used to characterize plasma ADC, tumor ADC, and tumor catabolite concentrations. Tumor catabolite concentrations were used to fit tumor response. Model parameters were estimated using R software and nonlinear least squares regression.
Results
Plasma ADC-associated DM1 concentrations of T-DM1 decreased more slowly than those of T-SPP-DM1, likely due to slower DM1 release. A comparison of the mechanistic models found that the best model allowed catabolism and catabolite exit rates to differ between ADCs, that T-DM1 exhibited both faster tumor catabolism and catabolite exit rate from tumors than T-SPP-DM1; findings inconsistent with expected behavior based on the physicochemical nature of the respective catabolites. Tumor catabolite concentrations adequately described tumor response with both ADCs showing similar potency.
Conclusion
Mechanistic PK/PD studies described herein provided results that confirmed and challenged current hypotheses, and suggested new areas of investigation.
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Abbreviations
- ADC:
-
Antibody–drug conjugate
- DAR:
-
Drug-to-antibody ratio
- HER2:
-
Human epidermal growth factor receptor 2
- HPLC:
-
High-performance liquid chromatography
- LSC:
-
Liquid scintillation counting
- MCC:
-
4-(N-maleimidomethyl) cyclohexane-1 carboxylate
- MOA:
-
Mechanism of action
- PK/PD:
-
Pharmacokinetic/pharmacodynamic
- SPP:
-
N-succinimidyl 4-(2-pyridyldithio) pentanoate
- T-DM1:
-
Trastuzumab emtansine
References
Krop IE, Beeram M, Modi S, Jones SF, Holden SN, Yu W, Girish S, Tibbitts J, Yi JH, Sliwkowski MX, Jacobson F, Lutzker SG, Burris HA (2010) Phase I study of trastuzumab-DM1, a HER2 antibody–drug conjugate, given every 3 weeks to patients with HER2-positive metastatic breast cancer. J Clin Oncol 28:2698–2704
Younes A, Bartlett NL, Leonard JP, Kennedy DA, Lynch CM, Sievers EL, Forero-Torres A (2010) Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med 363:1812–1821
Burris HA III, Rugo HS, Vukelja SJ, Vogel CL, Borson RA, Limentani S, Tan-Chiu E, Krop IE, Michaelson RA, Girish S, Amler L, Zheng M, Chu YW, Klencke B, O’Shaughnessy JA (2011) 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 29:398–405
Senter PD (2009) Potent antibody drug conjugates for cancer therapy. Curr Opin Chem Biol 13:235–244
Junttila TT, Li G, Parsons K, Lewis Phillips G, Sliwkowski MX (2011) 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 128:347–356
Erickson HK, Park PU, Widdison WC, Kovtun YV, Garrett LM, Hoffman K, Lutz RJ, Goldmacher VS, Blättler WA (2006) Antibody-maytansinoid conjugates are activated in targeted cancer cells by lysosomal degradation and linker-dependent intracellular processing. Cancer Res 66:4426–4433
Erickson HK, Widdison WC, Mayo MF, Whiteman K, Audette C, Wilhelm SD, Singh R (2010) Tumor delivery and in vivo processing of disulfide-linked and thioether-linked antibody-maytansinoid conjugates. Bioconjug Chem 21:84–92
Erickson HK, Lewis-Phillips GD, Leipold DD, Provenzano CA, Mai E, Johnson HA, Gunter B, Audette CA, Gupta M, Pinkas J, Tibbitts J (2012) The effect of different linkers on target cell catabolism and pharmacokinetics/pharmacodynamics of trastuzumab maytansinoid conjugates. Mol Cancer Ther 11:1133–1142
Alley SC, Zhang X, Okeley NM, Anderson M, Law CL, Senter PD, Benjamin DR (2009) The pharmacologic basis for antibody-auristatin conjugate activity. J Pharmacol Exp Ther 330:932–938
Okeley NM, Miyamoto JB, Zhang X, Sanderson RJ, Benjamin DR, Sievers EL, Senter PD, Alley SC (2010) Intracellular activation of SGN-35, a potent anti-CD30 antibody–drug conjugate. Clin Cancer Res 16:888–897
Doronina SO, Mendelsohn BA, Bovee TD, Cerveny CG, Alley SC, Meyer DL, Oflazoglu E, Toki BE, Sanderson RJ, Zabinski RF, Wahl AF, Senter PD (2006) Enhanced activity of monomethylauristatin F through monoclonal antibody delivery: effects of linker technology on efficacy and toxicity. Bioconjug Chem 17:114–124
Derendorf H, Lesko LJ, Chaikin P, Colburn WA, Lee P, Miller R, Powell R, Rhodes G, Stanski D, Venitz J (2000) Pharmacokinetic/pharmacodynamic modeling in drug research and development. J Clin Pharmacol 40:1399–1418
Danhof M, de Lange EC, Della Pasqua OE, Ploeger BA, Voskuyl RA (2008) Mechanism-based pharmacokinetic-pharmacodynamic (PK/PD) modeling in translational drug research. Trends Pharmacol Sci 29:186–191
Friberg LE, Brindley CJ, Karlsson MO, Devlin AJ (2000) Models of schedule dependent hematological toxicity 2′-deoxy-2′-methylidinecytidine (DMDC). Eur J Clin Pharmacol 56:567–574
Yamazaki S, Skaptason J, Romero D, Lee JH, Zou HY, Christensen JG, Koup JR, Smith BJ, Koudriakova T (2008) Pharmacokinetic-pharmacodynamic modeling of biomarker response and tumor growth inhibition to an orally available cMet kinase inhibitor in human tumor xenograft mouse models. Drug Metab Dispos 36:1267–1274
Wang S, Zhou Q, Gallo JM (2009) Demonstration of the equivalent pharmacokinetic/pharmacodynamic dosing strategy in a multiple-dose strategy of gefitinib. Mol Cancer Ther 8:1438–1447
Lewis Phillips GD, Li G, Dugger DL, Crocker LM, Parsons KL, Mai E, Blättler WA, Lambert JM, Chari RVJ, Lutz RJ, Wong WLT, Jacobson FS, Koeppen H, Schwall RH, Kenkare-Mitra SR, Spencer SD, Sliwkowski MX (2008) Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody–cytotoxic drug conjugate. Cancer Res 68:9280–9290
Shen B-Q, Bumbaca D, Saad O, Yue Q, Pastuskovas CV, Khojasteh SC, Tibbitts J, Kaur S, Wang B, Chu Y-W, LoRusso PM, Girish S (2012) Catabolic fate and pharmacokinetic characterization of Trastuzumab emtansine (T-DM1): an emphasis on preclinical and clinical catabolism. Curr Drug Metab 13:901–910
Jumbe NL, Yan X, Leipold DD, Crocker L, Dugger D, Mai E, Sliwkowski MX, Fielder PJ, Tibbitts J (2010) Modeling the efficacy of trastuzumab-DM1, an antibody drug conjugate, in mice. J Pharmacokinet Pharmacodyn 37:221–242
Simeoni M, Magni P, Cammia C, De Nicolao G, Croci V, Pesenti E, Germani M, Poggesi I, Rocchetti M (2004) Predictive pharmacokinetic-pharmacodynamic modeling of tumor growth kinetics in xenograft models after administration of anticancer agents. Cancer Res 64:1094–1101
Karlsson MO, Savic RM (2007) Diagnosing model diagnostics. Clin Pharmacol Ther 82:17–20
Austin CD, De Maziere AM, Pisacane PI, van Dijk SM, Eigenbrot C, Sliwkowski MX, Klumperman J, Scheller RH (2004) Endocytosis and sorting of ErbB2 and the site of action of cancer therapeutics trastuzumab and geldanamycin. Molec Biol Cell 15:5268–5282
Shah DK, Haddish-Berhan N, Betts A (2012) Bench to bedside translation of antibody drug conjugates using a multiscale mechanistic PK/PD model: a case study with brentuximab-vedotin. J Pharmacokinet Pharmacodyn 39:643–659
Erickson HK, Park PU, Widdison WC, Kovtun YV, Garrett LM, Hoffman K, Lutz RJ, Goldmacher VS, Blättler WA (2006) Antibody-maytansinoid conjugates are activated in targeted cancer cells by lysosomal degradation and linker dependent intracellular processing. Cancer Res 66(8):4426–4433
Chudasama VL, Stark FS, Harrold JM, Tibbetts J, Girish SR, Gupta M, Frey N, Mager DE (2012) Semi-mechanistic population pharmacokinetic model of multivalent trastuzumab emtansine in patients with metastatic breast cancer. Clin Pharmacol Ther 92(4):520–527
Acknowledgments
The authors would like to acknowledge Frank-Peter Theil, Saroja Ramanujan, Victor Goldmacher, and the Genentech In vivo Studies Group for their contributions to this work. Financial support for research was provided by Genentech, Inc. and Immunogen, Inc. Leipold, Lewis Phillips, and Mai are employees of Genentech. Tibbitts was an employee of Genentech at the time of this work. Johnson is an employee of Immunogen. Provenzano and Erickson were employees of Immunogen at the time of this work. Wada is an employee of Quantitative Solutions.
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Wada, R., Erickson, H.K., Lewis Phillips, G.D. et al. Mechanistic pharmacokinetic/pharmacodynamic modeling of in vivo tumor uptake, catabolism, and tumor response of trastuzumab maytansinoid conjugates. Cancer Chemother Pharmacol 74, 969–980 (2014). https://doi.org/10.1007/s00280-014-2561-2
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DOI: https://doi.org/10.1007/s00280-014-2561-2