Preclinical safety profile of trastuzumab emtansine (T-DM1): mechanism of action of its cytotoxic component retained with improved tolerability.
Toxicol Appl Pharmacol
; 273(2): 298-313, 2013 Dec 01.
Article
em En
| MEDLINE
| ID: mdl-24035823
ABSTRACT
Trastuzumab emtansine (T-DM1) is the first antibody-drug conjugate (ADC) approved for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. The therapeutic premise of ADCs is based on the hypothesis that targeted delivery of potent cytotoxic drugs to tumors will provide better tolerability and efficacy compared with non-targeted delivery, where poor tolerability can limit efficacious doses. Here, we 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. Therefore, antigen-dependent and non-antigen-dependent toxicity was evaluated in monkeys and rats, respectively, in both single- and repeat-dose studies; toxicity of DM1 was assessed in rats only. T-DM1 was well tolerated at doses up to 40 mg/kg (~4400 µg DM1/m(2)) and 30 mg/kg (~ 6000 µg DM1/m(2)) in rats and monkeys, respectively. In contrast, DM1 was only tolerated up to 0.2mg/kg (1600 µg DM1/m(2)). This suggests that at least two-fold higher doses of the cytotoxic agent are tolerated in T-DM1, supporting the premise of ADCs to improve the therapeutic 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 origin 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.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Plaquetas
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Citotoxinas
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Anticorpos Monoclonais Humanizados
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Maitansina
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Antineoplásicos
Tipo de estudo:
Clinical_trials
Limite:
Animals
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Female
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Humans
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Male
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article