Catabolic Fate and Pharmacokinetic Characterization of Trastuzumab Emtansine (T-DM1): an Emphasis on Preclinical and Clinical Catabolism

Abstract

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate in clinical development for the treatment of human epidermal growth factor receptor 2 (HER2)-positive cancers. Herein, we describe a series of studies to assess T-DM1 absorption, distribution, metabolism, and excretion (ADME) in rats as well as to assess human exposure to T-DM1 catabolites. Following administration of unlabeled and radiolabeled T-DM1 in female Sprague Dawley rats as a single dose, plasma, urine, bile and feces were assessed for mass balance, profiling and identification of catabolites. In rats, the major circulating species in plasma was T-DM1, while DM1 concentrations were low (1.08 to 15.6 ng/mL). The major catabolites found circulating in rat plasma were DM1, [N-maleimidomethyl] cyclohexane-1- carboxylate-DM1 (MCC-DM1), and Lysine-MCC-DM1. These catabolites identified in rats were also detected in plasma samples from patients with HER2-positive metastatic breast cancer who received single-agent T-DM1 (3.6 mg/kg every 3 weeks) in a phase 2 clinical study. There was no evidence of tissue accumulation in rats or catabolite accumulation in human plasma following multiple dosing. In rats, T-DM1 was distributed nonspecifically to the organs without accumulation. The major pathway of DM1-containing catabolite elimination in rats was the fecal/biliary route, with up to 80% of radioactivity recovered in the feces and 50% in the bile. The rat T-DM1 ADME profile is likely similar to the human profile, although there may be differences since trastuzumab does not bind the rat HER2- like receptor. Further research is necessary to more fully understand the T-DM1 ADME profile in humans.

ADME of Antibody–Maytansinoid Conjugates

“…The anti-CanAg-SMCC-[ 3 H]DM1 conjugate with an uncleavable linker was found to have a similar distribution profile in tumor-bearing mice as shown above (Fig. 3c) for a disulfide-linked conjugate (unpublished data), and was also similar to the tissue distribution reported for labeled maytansinoid in nontumorbearing rats following administration of a single bolus administration of T-[ 3 H]DM1 (30,31). In the study with T-DM1 (31), up to 80% of the radioactivity was recovered in the feces over 7 days consistent with the hepatobiliary route for maytansinoid elimination.…”

Absorption, Distribution, Metabolism, and Excretion Considerations for the Development of Antibody-Drug Conjugates

“…The thiosuccinimide linkage may undergo a maleimide elimination reaction and transfer the drug linker to other components of the plasma with reactive thiol (Shen et al, 2012a). This transfer has been observed for ADCs; however, the circulating concentrations of these species are appreciably lower than that of ADC, suggesting that other mechanisms may compete with maleimide transfer such as proteolytic cleavage in cells or hydrolysis of the linker.…”

“…Based on preclinical data, the major elimination pathway of DM1-containing catabolites in rats after ado-trastuzumab emtansine administration is the fecal/biliary route. About 80% of radioactivity was recovered in the feces, and 50% was recovered in the bile (Shen et al, 2012a). A clinical excretion study of brentuximab vedotin showed that over a 1-week period the primary excretion route of MMAE was via feces, which accounted for approximately 72% of the recovered MMAE, with the remaining MMAE recovered in urine (Han et al, 2013a).…”

“…Among these analytes, most drug developers measure TAb to monitor the total antibody-driven activity, ADC or conjugated small molecule to monitor the ADC-driven activity, and released small-molecule drug to monitor the unconjugated drug activity. Exploratory evaluations may be needed if multiple species are released from the ADC, such as in the case of T-DM1 (Shen et al, 2012a) and maleimide transfer for brentuximab vedotin (CDER, 2011). As with other protein-based therapeutics, antitherapeutic antibodies are also routinely monitored.…”

“…Engineering of the antibody to direct conjugation to specific sites, the use of different residues, and the introduction of chemical sites of conjugation have been explored (Junutula et al, 2008;Shen et al, 2012b;Kung Sutherland et al, 2013). The druglinker technology continues to be advanced by the modification of the chemistry at the site of antibody conjugation to confer stability (Shen et al, 2012a;Lyon et al, 2013), the introduction of chemical entities that mask the physiochemical properties of the drug-linker to improve ADC pharmacokinetics (PK) (Kovtun et al, 2010;Burke et al, 2014), and the introduction of novel linkers .…”