Abstract LB-222: Optimization and preclinical characterization of highly potent and stable anti-CD70 ADCs for the potential treatment of CD70 positive cancers

Antibody drug conjugates (ADCs) require coordinated optimization of antibody, linker, and payload to generate potent, specific, and stable cancer therapeutics. CD70 is an attractive ADC tumor target due to its limited expression in normal tissues and over-expression in many solid tumors and hematologic malignancies. Utilizing Ambrx9s site-specific EuCODE technology, we have generated and evaluated multiple ADCs with different combinations of linkers and payloads for treatment of CD70 positive cancers. In vitro activity identified specific CD70 ADCs with picomolar potency/activity against CD70 positive cancer cell lines. Conjugation of drug-linkers at different sites in the antibody and modification of linker design improved in vitro activity and in vivo stability of lead CD70 ADCs. Optimized anti-CD70 ADCs were evaluated for pharmacokinetic profile and demonstrated to be efficacious in reducing tumor burden and significantly prolonging survival in an in vivo orthotopic xenograft model of multiple myeloma. In summary, we have generated encouraging preclinical in vitro and in vivo data with stable, site-specific, DAR = 2 anti-CD70 ADCs for the potential treatment of CD70 positive cancers such as multiple myeloma. Citation Format: Lillian Skidmore, Kari Cox, Jessica Kirtley, Tiep Le, Juhi Firdos, Anthony Manibusan, Shiao-Yan Fang, Andy Beck, Shiva Bhowmik, Nick Knudsen, Jianing Wang, Ying Sun, Armando Ayala, Alyssa Powell, Alan Wahl, Feng Tian, Robin Humphreys. Optimization and preclinical characterization of highly potent and stable anti-CD70 ADCs for the potential treatment of CD70 positive cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-222.