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- W4362480005 abstract "<div>Abstract<p>Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate consisting of the anti-HER2 antibody trastuzumab linked via a nonreducible thioether linker to the maytansinoid antitubulin agent DM1. T-DM1 has shown favorable safety and efficacy in patients with HER2-positive metastatic breast cancer. In previous animal studies, T-DM1 exhibited better pharmacokinetics (PK) and slightly more efficacy than several disulfide-linked versions. The efficacy findings are unique, as other disulfide-linked antibody–drug conjugates (ADC) have shown greater efficacy than thioether-linked designs. To explore this further, the <i>in vitro</i> and <i>in vivo</i> activity, PK, and target cell activation of T-DM1 and the disulfide-linked T-SPP-DM1 were examined. Both ADCs showed high <i>in vitro</i> potency, with T-DM1 displaying greater potency in two of four breast cancer cell lines. <i>In vitro</i> target cell processing of T-DM1 and T-SPP-DM1 produced lysine-<i>N<sup>ϵ</sup></i>-MCC-DM1, and lysine-<i>N<sup>ϵ</sup></i>-SPP-DM1 and DM1, respectively; <i>in vivo</i> studies confirmed these results. The <i>in vitro</i> processing rates for the two conjugate to their respective catabolites were similar. <i>In vivo</i>, the potencies of the conjugates were similar, and T-SPP-DM1 had a faster plasma clearance than T-DM1. Slower T-DM1 clearance translated to higher overall tumor concentrations (conjugate plus catabolites), but unexpectedly, similar levels of tumor catabolite. These results indicate that, although the ADC linker can have clear impact on the PK and the chemical nature of the catabolites formed, both linkers seem to offer the same payload delivery to the tumor. <i>Mol Cancer Ther; 11(5); 1133–42. ©2012 AACR</i>.</p></div>" @default.
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- W4362480005 date "2023-04-03" @default.
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- W4362480005 title "Data from The Effect of Different Linkers on Target Cell Catabolism and Pharmacokinetics/Pharmacodynamics of Trastuzumab Maytansinoid Conjugates" @default.
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