Utilizing a mouse cross-reactive model system to better understand antibody-drug conjugate pharmacokinetics, biodistribution and efficacy

Antibody-drug conjugates (ADCs) are designed to deliver a potent cytotoxic payload directly to tumors, thus limiting exposure in normal tissues. However, target antigen expression on normal tissues can lead to lower systemic ADC exposures, resulting in sub-efficacious concentrations at the tumor site as well as heterogeneous distribution within tumors. Traditional preclinical efficacy studies performed in rodent models using ADCs with non-cross-reactive antibodies have been of limited translational relevance, and a better understanding of the factors that impact ADC dose and activity remains to be elucidated. To examine relationships between variables that could influence ADC efficacy, we generated a cross-reactive model system that utilized a chimeric anti-murine folate receptor α (FRα) antibody (designated rmFR1-12) that binds both mouse and human FRα, and can be conjugated to either maytansinoid (DM) or indolinobenzodiazepine (IGN) payloads. This model system was predicted to have substantial target-mediated drug disposition (TMDD) due to normal tissue expression of FRα. An rmFR1-12-s-SPDB-DM4 ADC was made using tritium-labeled DM4 and administered to tumor-bearing mice in order to assess ADC pharmacokinetics (PK), biodistribution, and efficacy. This approach allowed tracking of the ADC at multiple levels – whole animal, organ, tumor, and cell. Studies were undertaken that assessed the impact of xenograft antigen expression, ADC dose, and ADC drug-to-antibody ratio (DAR) on the PK, biodistribution, and efficacy of the rmFR1-12-s-SPDB-DM4 conjugate. The results showed that TMDD significantly impacted the PK, biodistribution, and activity of the conjugate relative to a non-cross-reactive ADC, with lower ADC doses being more severely impacted than higher doses. Antigen expression positively correlated with local ADC exposure and efficacy. Decreasing the DAR (by co-dosing naked antibody with the ADC) increased systemic exposure. A positive correlation between systemic exposure and dose of naked antibody was observed. Factors that impacted local exposure included: the type of tissue (normal vs tumor), presence or absence of FRα expression on normal tissue, and dose of naked antibody. Of note, in the naked antibody plus ADC study, efficacy did not correlate with local exposure - suggesting that ADC distribution within tumors is of similar importance as the amount of ADC delivered. Overall, these findings underscore the importance of accounting for site, and extent of, normal tissue target expression with respect to ADC PK/PD, and the data generated from these studies are currently being used to build a multiscale physiologically based PK model of a cross-reactive ADC. Citation Format: Leanne Lanieri, Rassol Laleau, Bahar Matin, Jenny Lee, Steven Boule, Paulin Salomon, Luke Harris, Michael Miller, Nicholas C. Yoder, Yulius Setiady, Neeraj Kohli, Thomas A. Keating, Jan Pinkas, Richard Gregory. Utilizing a mouse cross-reactive model system to better understand antibody-drug conjugate pharmacokinetics, biodistribution and 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 229.