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Abstract Background: Folate Receptor alpha (FRα) is a validated cancer target that is prevalently expressed in multiple cancers with high unmet need, including ovarian cancer and other gynecological cancers, NSCLC, endometrial cancer and TNBC. Due to FRα’s favorable expression profile, multiple antibody-drug conjugates (ADCs) are being explored in this setting. Here we present the preclinical characterization of a new anti-FRα ADC, ZW191. ZW191 is a bystander active antibody drug conjugate (ADC) comprised of a humanized IgG1 antibody conjugated to a novel camptothecin-based topoisomerase 1 inhibitor (TOPO1i) payload, ZD06519, via a maleimidocaproyl (MC) anchor and a glycyl glycyl phenylalanyl glycyl (GGFG) -aminomethyl (AM) cleavable linker at a drug-to-antibody ratio (DAR) of 8. ZW191 is projected to undergo IND submission in 2024. Materials and Methods: The novel antibody and drug-linker components of ZW191 were generated, characterized, and optimally integrated. The apparent binding affinity and cellular internalization of the ZW191 antibody were determined in FRα-expressing cells. Tumor spheroid cancer cell cultures were utilized to determine ZW191’s degree of tissue penetration and its cytotoxicity. The bystander activity of ZW191 was assessed using antigen positive and negative co-culture experiments. The anti-tumor activity of ZW191 was evaluated in a panel of ovarian cancer, NSCLC, endometrial cancer and TNBC patient-derived xenografts (PDX) spanning a range of FRα expression. ZW191 was evaluated in toxicology and pharmacokinetic (PK) studies performed in non-human primates (NHP). Results: The antibody component of ZW191 features a favorable binding profile with strong binding to FRα, and drives superior tumor spheroid penetration, cellular internalization, and payload delivery compared to FRα targeted antibodies used in multiple other ADCs. ZW191 demonstrates potent activity in FRα expressing cell cultures and effective bystander activity. In a panel of PDX models representing a range of FRα expression, ZW191 demonstrates compelling anti-tumor activity across ovarian and endometrial cancers, NSCLC and TNBC. ZW191 demonstrates an encouraging tolerability profile in NHP, with favorable PK. The promising efficacy, tolerability, and PK support the potential of ZW191 as a novel therapeutic agent that may help address unmet need in patients with high and low FRα expressing cancers. Citation Format: Sam Lawn, Andrea Hernandez Rojas, Raffaele Colombo, Jodi Wong, Kaylee Wu, Vincent Fung, Manuel Lasalle, Mark E. Petersen, Lemlem Degefie, Araba Sagoe-Wagner, Dunja Urosev, Luying Yang, Ambroise Wu, Catrina Kim, Amos Chua, Kurt Stahl, Geoffrey C. Winters, John C. Fann, Jamie Rich, Stuart Barnscher. ZW191 - a FRα-targeting antibody drug conjugate with strong preclinical activity across multiple FRα-expressing indications abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 1862.
Lawn et al. (Fri,) studied this question.