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T-DM1): Mechanism of Action of Its Cytotoxic Component Retained with Improved Tolerability

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T-DM1): Mechanism of Action of Its Cytotoxic Component Retained with Improved Tolerability View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Toxicology and Applied Pharmacology 273 (2013) 298–313 Contents lists available at ScienceDirect Toxicology and Applied Pharmacology journal homepage: www.elsevier.com/locate/ytaap Preclinical safety profile of trastuzumab emtansine (T-DM1): Mechanism of action of its cytotoxic component retained with improved tolerability Kirsten Achilles Poon a,⁎, Kelly Flagella a,JosephBeyera, Jay Tibbitts b, Surinder Kaur a,OlaSaada,Joo-HeeYia, Sandhya Girish a,NoelDybdala,1, Theresa Reynolds a,1 a Genentech, Inc., South San Francisco, CA, USA b UCB, Brussels, Belgium article info abstract Article history: Trastuzumab emtansine (T-DM1) is the first antibody-drug conjugate (ADC) approved for patients with human Received 13 June 2013 epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. The therapeutic premise of ADCs is Revised 30 August 2013 based on the hypothesis that targeted delivery of potent cytotoxic drugs to tumors will provide better tolerability Accepted 3 September 2013 and efficacy compared with non-targeted delivery, where poor tolerability can limit efficacious doses. Here, we Available online 12 September 2013 present results from preclinical studies characterizing the toxicity profile of T-DM1, including limited assessment of unconjugated DM1. T-DM1 binds primate ErbB2 and human HER2 but not the rodent homolog c-neu. There- Keywords: Breast cancer fore, antigen-dependent and non-antigen-dependent toxicity was evaluated in monkeys and rats, respectively, in HER2 both single- and repeat-dose studies; toxicity of DM1 was assessed in rats only. T-DM1 was well tolerated at Ado-trastuzumab emtansine doses up to 40 mg/kg (~4400 μgDM1/m2) and 30 mg/kg (~6000 μgDM1/m2) in rats and monkeys, respective- T-DM1 ly. In contrast, DM1 was only tolerated up to 0.2 mg/kg (1600 μgDM1/m2). This suggests that at least two-fold Toxicology higher doses of the cytotoxic agent are tolerated in T-DM1, supporting the premise of ADCs to improve the ther- Antibody-drug conjugates apeutic index. In addition, T-DM1 and DM1 safety profiles were similar and consistent with the mechanism of action of DM1 (i.e., microtubule disruption). Findings included hepatic, bone marrow/hematologic (primarily platelet), lymphoid organ, and neuronal toxicities, and increased numbers of cells of epithelial and phagocytic or- igin in metaphase arrest. These adverse effects did not worsen with chronic dosing in monkeys and are consistent with those reported in T-DM1-treated patients to date. © 2013 The Authors. Published by Elsevier Inc. Open access under CC BY-NC-ND license. Introduction domain of the receptor, has made HER2 a suitable target for antibody therapy. The human epidermal growth factor receptor 2 (HER2, also known Trastuzumab (Herceptin®, Genentech, Inc., South San Francisco, CA) as ErbB2) is a transmembrane receptor tyrosine kinase that is part of a is a humanized monoclonal antibody directed against subdomain IV of complex signal transduction network involved in cell differentiation, the extracellular region of HER2 and is indicated for the treatment of proliferation, and survival (Yarden and Sliwkowski, 2001). HER2 is HER2-overexpressing breast cancer and HER2-overexpressing meta- expressed in normal epithelial tissues at relatively low levels in healthy static gastric or gastroesophageal junction adenocarcinoma (Herceptin adults (Press et al., 1990), but it is overexpressed in approximately 20% package insert, 2010; Herceptin Summary of Product Characteristics, of tumors from patients with breast cancer (Dawood et al., 2010; Ross 2010). The mechanisms of action are thought to include one or more et al., 2009). HER2-positive breast tumors are associated with aggres- of the following: interference with signal transduction pathways, sive growth and poor clinical outcomes (Slamon et al., 1987, 1989). impairment of extracellular domain (ECD) cleavage, inhibition of DNA The association between HER2 overexpression and tumor pathogenesis repair, decreased angiogenesis, induction of cell cycle arrest, and in breast cancer, together with the accessibility of the extracellular activation of antibody-dependent cellular cytotoxicity (Hudis, 2007; Sliwkowski et al., 1999; Spector and Blackwell, 2009). Although trastuzumab provides substantial benefits for many patients with HER2-positive breast cancer, a proportion have tumors that either do not respond to trastuzumab or relapse following initial response to treatment (Nahta et al., 2006; Slamon et al., 2001). Following relapse, HER2 overexpression is still present (Spector et al., 2005), suggesting ⁎ Corresponding author at: Development Sciences, 1 DNA Way, South San Francisco, CA that these tumors could still be responsive to treatment with HER2- 94080, USA. Fax: +1 650 225 2797. E-mail address: [email protected] (K.A. Poon). targeted agents. Indeed, two phase III clinical trials have shown in pa- 1 These authors contributed equally to this work. tients with tumors that progressed on trastuzumab-containing therapy 0041-008X © 2013 The Authors. Published by Elsevier Inc. Open access under CC BY-NC-ND license. http://dx.doi.org/10.1016/j.taap.2013.09.003 K.A. Poon et al. / Toxicology and Applied Pharmacology 273 (2013) 298–313 299 that the addition of trastuzumab to subsequent therapy resulted in that resulted in equivalent DM1 doses based on body surface area significantly improved clinical outcomes (Blackwell et al., 2010; von (μg DM1/m2). Minckwitz et al., 2009, 2011). An alternative to targeted antibody therapy and/or systemic chemo- Methods therapy is the use of antibody-drug conjugates (ADCs). ADCs are created by chemically linking a cytotoxic agent to a monoclonal antibody that General animal information. All procedures in animals described targets a tumor-enriched or tumor-specific protein. Tumor-specific below were performed in compliance with the Animal Welfare Act, delivery of potent cytotoxic agents has the potential to ameliorate the the Guide for the Care and Use of Laboratory Animals, and the Office systemic toxicity associated with many chemotherapies (Alley et al., of Laboratory Animal Welfare. Protocols were reviewed by the Institu- 2010; Lambert, 2005; Wu and Senter, 2005). tional Animal Care and Use Committees of the relevant facility; either Trastuzumab emtansine (T-DM1, Kadcyla™, Genentech, Inc., South Genentech, Inc. (South San Francisco, CA), or Covance, Inc. (Madison, San Francisco, CA) is an ADC composed of trastuzumab, a nonreducible WI). Sprague–Dawley rats were obtained from Charles River Laborato- thioether linker (4-[N-maleimidomethyl]-cyclohexane-1-carbonyl ries (Portage, MI, or Hollister, CA). Cynomolgus monkeys (Macaca [MCC]) (Lewis Phillips et al., 2008), and the cytotoxic agent DM1 fascicularis) were obtained from Three Springs Scientific, Inc. (Perkasie, (N2′-deacetyl-N2′-(3-mercapto-1-oxopropyl) maytansine) (Blättler PA), or Covance Research Products, Inc. (Alice, TX). All animals were and Chari, 2001; Cassady et al., 2004; Goldmacher et al., 2002) individually housed in stainless-steel cages and were provided with (Fig. 1). DM1 is derived from the highly potent antitumor agent food supplements (that did not require analysis) and various cage- maytansine and inhibits microtubule polymerization (Cabanillas enrichment devices. Monkeys were commingled to provide psycholog- et al., 1978; Chabner et al., 1978; Eagan et al., 1978; Issell and ical enrichment. Animals were assigned to dose groups using a stratified Crooke, 1978; Remillard et al., 1975). T-DM1 comprises trastuzumab randomization scheme based on individual body weight. For scheduled with zero to eight DM1 molecules linked via MCC, primarily to lysine or unscheduled necropsies, rats were euthanized with isoflurane residues, and has an average drug-to-antibody ratio (DAR) of ap- followed by an overdose of a ketamine/xylazine cocktail or sodium proximately 3.5 (Krop et al., 2010). After T-DM1 binds to HER2 on pentobarbital; monkeys were terminally sedated with sodium pento- the cell surface, the T-DM1/HER2 complex is internalized via endo- barbital and euthanized by exsanguination. cytosis and degraded in lysosomes, ultimately leading to the intra- cellular release of lysine-MCC-DM1 (lys-MCC-DM1) (Chari, 2008; Intravenous dose formulations. T-DM1 was formulated in a vehicle Erickson et al., 2006, 2010). In the phase III EMILIA study, patients composed of 10 mM succinate, 100 mg/mL trehalose, and 0.1% polysor- with HER2-positive, metastatic breast cancer previously treated with bate 20, pH 5.0. DM1 was formulated in the T-DM1 vehicle plus 0.5% trastuzumab and a taxane received treatment with either T-DM1 or dimethyl adipimidate and 1 mM ethylenediaminetetraacetic acid. The lapatinib plus capecitabine. Patients who received T-DM1 had significant- average DAR was 3.4 for all studies, with the exception of the repeat- ly improved clinical outcomes compared with patients treated with dose (every 3 weeks [q3w] × eight doses) monkey study where the lapatinib plus capecitabine (Verma et al., 2012). Median progression- DAR was 3.8. free survival was 9.6 months versus 6.4 months in the T-DM1 and con- trol arms, respectively (hazard ratio = 0.65; 95% confidence interval Parameters for the evaluation of toxicity. Toxicity indices consisted of [CI]: 0.55 − 0.77; p b 0.001). Median overall survival also improved daily clinical observations, body weight, food consumption, clinical and was 30.9 months
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