TY - JOUR T1 - Exposure-Efficacy Analysis of Antibody-Drug Conjugates Delivering an Excessive Level of Payload to Tissues JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.119.087023 SP - dmd.119.087023 AU - Donglu Zhang AU - Peter S Dragovich AU - Shang-Fan Yu AU - Yong Ma AU - Thomas H Pillow AU - Jack D Sadowsky AU - Dian Su AU - Wei Wang AU - Andrew Polson AU - S Cyrus Khojasteh AU - Cornelis ECA Hop Y1 - 2019/01/01 UR - http://dmd.aspetjournals.org/content/early/2019/07/29/dmd.119.087023.abstract N2 - Antibody-drug conjugates (ADCs) contain a disease-receptor antibody and a payload drug connected via a linker. The rate and extent of payload delivery depend on both tumor properties and ADC characteristics. In this study, we utilized different linkers, attachment sites, and doses to modulate payload delivery of several ADCs bearing maytansinoids (e.g., DM1), auristatins (e.g., MMAE), and DNA alkylating agents (e.g., pyrrolo[2,1-c][1,4]benzodiazepine-dimer, PBD) as payloads in HER2- or CD22-expressing xenograft models. The associated tumor growth inhibition, ADC stability and exposure data were also collected and analyzed from these dosed animals. The trend analysis results suggest that intratumor payload exposures that were directly related the combination of conjugate linker and dose correlate with the corresponding efficacies of three payload types in two antigen-expressing xenograft models. These preliminary correlations also suggest that a minimal threshold concentration of intratumor payload is required to support sustained efficacy. In addition, an ADC can deliver an excessive level of payload to tumors that does not enhance efficacy ('Plateau' effect). In contrast to tumor payload concentrations, the assessments of systemic exposures of total antibody (Tab) as well as the linker, dose, site of attachment, plasma stability, and drug-to-antibody ratio (DAR) changes of these ADCs did not consistently rationalize the observed ADC efficacies. The requirement of a threshold payload concentration for efficacy is further supported by dose fractionation studies with DM1-, MMAE- and PBD-containing ADCs, which demonstrated that single dose regimens showed better efficacies than fractionated dosing. Overall, this study demonstrates that (1) the linker and dose together determine the tissue payload concentration that correlates with the anti-tumor efficacy of ADCs and (2) an ADC can deliver an unnecessary level of payload to tumors in xenograft models.SIGNIFICANCE STATEMENT The ADC linker and dose together determines intratumor payload delivery. The trend analysis supported correlation of tumor growth inhibition efficacy with payload tissue concentrations but not with systemic ADC exposures. An ADC could deliver excess level of payload to tumors. ER -