Abstract 219: The potential benefit of lower drug-antibody ratio (DAR) on antibody-maytansinoid conjugatein vivoefficacy

The majority of antibody-drug conjugates (ADCs) with maytansinoid payloads in development are linked via lysine residues and target an average drug-antibody ratio (DAR) of 3.5. These ADCs demonstrate substantial preclinical potency while maintaining good biophysical and pharmacological properties. However, some targets are expressed in normal tissues at levels that result in target-mediated drug disposition (TMDD), which can impact systemic and tumor ADC exposure and tumor penetration. For targets with TMDD, lowering the DAR of the ADCs may be advantageous. Since ADC tolerability is generally determined by the payload dose, lower DAR ADCs can be dosed at a higher antibody concentration, resulting in an increased conjugate exposure which may improve efficacy by saturating TMDD and/or increasing tumor delivery and penetration of the conjugate. In preclinical cell line xenograft studies, lysine-conjugated 2.0 and 3.5 DAR ADCs had comparable efficacy when dosed by payload concentration. However, the effect of TMDD cannot be captured with these models because the antibody in the ADCs does not cross-react with murine target antigen expressed on normal tissues. To supplement our understanding of the factors that influence ADC activity, we generated a cross-reactive model system that utilizes a chimeric anti-murine folate receptor α (FRα) antibody that binds with similar affinity to mouse and human FRα. Using this cross-reactive system, where the target is also expressed in normal tissues, 2.0 DAR conjugates were more efficacious than 3.5 DAR conjugates when dosed at matched payload concentrations in multiple xenograft models, suggesting that lower DAR can be an effective strategy to compensate for TMDD. Additional studies using xenograft models with varying antigen expression levels are ongoing, and studies designed to assess different conjugation methods of generating lower DAR ADCs are planned. This work highlights some of the many factors that impact ADC activity and demonstrates that the DAR of an ADC should be optimized for each target. Citation Format: Kerstin W. Sinkevicius, Leanne Lanieri, Jenny Lee, Steven Boule, Nicholas C. Yoder, Stuart W. Hicks, Jan Pinkas, Jose F. Ponte, Richard J. Gregory. The potential benefit of lower drug-antibody ratio (DAR) on antibody-maytansinoid conjugate in vivo efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 219.