Abstract
Abstract Folate receptor α (FRα) is an antigen that is overexpressed on the cell surface of solid tumors including ovarian cancer. The differential expression on cancer cells makes FRα an attractive target for antibody-drug conjugates (ADCs), and an ADC targeting FRα, Mirvetuximab soravtansine, has demonstrated promising activity and safety profiles in the clinic. Here, we employed a new linker (NL) to enhance the bystander activity of ADCs, which is the ability of ADCs to generate cell-permeable catabolites that can diffuse into and kill proximal cancer cells with little or no target expression. With the goal of improving the potency of anti-FRα ADC in solid tumors with heterogeneous FRα expression, we constructed the M9346A-NL-DM. M9346A-NL-DM is a conjugate of the tubulin-disrupting maytansinoid (DM), linked via a novel linker to M9346A, a humanized antibody that binds FRα with high affinity. After cellular uptake and catabolism of the ADC, the new linker undergoes lysosomal cleavage followed by self-immolation to generate free DM that can readily penetrate neighboring cancer cells. Correspondingly, M9346A-NL-DM showed enhanced bystander cytotoxic activity against proximal antigen-negative cells in vitro. In the xenograft tumor models in vivo, M9346A-NL-DM demonstrated enhanced efficacy against tumors with heterogeneous expression of FRα. Interestingly, M9346A-NL-DM also showed improved antitumor activity against a tumor model with homogeneous expression of FRα, possibly due to better tumor penetration of the cell-permeable catabolite. In summary, M9346A-NL-DM is a novel ADC with enhanced bystander activity and antitumor activity that can target tumors with heterogeneous expression of FRα. Citation Format: Qifeng Qiu, Rui Wu, Leanne Lanieri, Erin Maloney, Anna Skaletskaya, Shan Jin, Lintao Wang, Olga Ab, Joe Ponte, Yulius Setiady, Wayne Widdison, Thomas Keating, Ravi Chari, Richard Gregory, Erica Hong. Bystander activity and in vivo efficacy of a folate receptor α (FRα)-targeting antibody-drug conjugate with a novel peptide linker [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 71. doi:10.1158/1538-7445.AM2017-71
Published Version
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