Abstract 223: Antibody intracellular activated drug conjugate (AiADC) as novel ADC technology

Abstract

Abstract Antibody drug conjugate (ADC) consisting of antibody and modifier (potent cytotoxic drug with chemical linker) is expected to selectively eliminate cancer cells expressing corresponding cell-surface antigen. More than 60 ADCs are in clinical trials and about 75 percent of its modifiers are based on three series (auristatin, maytansine, and pyrrolobenzodiazepine). Whereas some ADCs show promising clinical benefits, several ADCs may not have shown maximum value of ADC due to their narrow therapeutic windows. The function of modifiers impacts on total characteristics of ADC such as the efficacy, tolerability, and pharmacokinetics (PK). Therefore, further exploration of new types of modifier for ADC technology platform is needed. We designed hydrophilic modifiers which can be activated only inside of target cells. The ADC consisting of certain IgG1 monoclonal antibodies and this modifier (DSP-ADC) showed selective and potent cytotoxicity to target cells with IC50s at picomolar range. The DSP-ADC with the average drug-to-antibody ratio (DAR) of 7-8 was stable in blood circulation and showed favorable PK profiles in mice. Additionally, administration of the DSP-ADC led to dose-dependent suppression of cancer cell proliferation in mice xenograft models and achieved complete remissions at 3 mg/kg without body weight reduction. The toxicity studies of DSP-ADC in rats showed no effect on hematologic parameters up to 100 mg/kg. These modifiers are applicable to various monoclonal antibodies. Taken together, our modifiers can be fundamental component for ADC technology. We present here the novel ADC technology named as antibody intracellular activated drug conjugate (AiADC). Citation Format: Atsushi Suwa, Kazuo Komiya, Kenta Kadotsuji, Shoko Ochiai, Yosuke Takanashi, Eiji Sugaru, Hitoshi Ban. Antibody intracellular activated drug conjugate (AiADC) as novel ADC technology [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 223.