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- W4361258005 abstract "<div>Abstract<p>Antibody-drug conjugates (ADC) comprise targeting antibodies armed with potent small-molecule payloads. ADCs demonstrate specific cell killing in clinic, but the basis of their antitumor activity is not fully understood. In this study, we investigated the degree to which payload release predicts ADC activity <i>in vitro</i> and <i>in vivo</i>. ADCs were generated to target different receptors on the anaplastic large cell lymphoma line L-82, but delivered the same cytotoxic payload (monomethyl auristatin E, MMAE), and we found that the intracellular concentration of released MMAE correlated with <i>in vitro</i> ADC-mediated cytotoxicity independent of target expression or drug:antibody ratios. Intratumoral MMAE concentrations consistently correlated with the extent of tumor growth inhibition in tumor xenograft models. In addition, we developed a robust admixed tumor model consisting of CD30<sup>+</sup> and CD30<sup>−</sup> cancer cells to study how heterogeneity of target antigen expression, a phenomenon often observed in cancer specimens, affects the treatment response. CD30-targeting ADC delivering membrane permeable MMAE or pyrrolobenzodiazepine dimers demonstrated potent bystander killing of neighboring CD30<sup>−</sup> cells. In contrast, a less membrane permeable payload, MMAF, failed to mediate bystander killing <i>in vivo</i>, suggesting local diffusion and distribution of released payloads represents a potential mechanism of ADC-mediated bystander killing. Collectively, our findings establish that the biophysical properties and amount of released payloads are chief factors determining the overall ADC potency and bystander killing. <i>Cancer Res; 76(9); 2710–9. ©2016 AACR</i>.</p></div>" @default.
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- W4361258005 date "2023-03-31" @default.
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- W4361258005 title "Data from Intracellular Released Payload Influences Potency and Bystander-Killing Effects of Antibody-Drug Conjugates in Preclinical Models" @default.
- W4361258005 doi "https://doi.org/10.1158/0008-5472.c.6508011" @default.
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