Abstract 2660: AV-P138-ADC (ARR-002), a novel MUC16/NaPi2b dual-target tetravalent ADC, for the treatment of ovarian and endometrial cancers

Abstract Antibody-drug conjugates (ADCs) are a class of precision medicines available to oncology clinical practice since 2000. To date, only 15 single-target ADCs (out of >450 entering clinical development) have been approved by the FDA. Dual-target ADCs aim to overcome challenges underlying the high failure rate of single-target ADCs in the clinic including limited internalization, low payload delivery, and heterogeneous target expression in tumors. We designed AV-P138-ADC (also known as ARR-002), a first-in-class, Mucin-16 (MUC16) and sodium-dependent phosphate transport protein 2b (NaPi2b) dual-target, tetravalent (2+2 format) ADC, with site-specific conjugation to vcMMAE at a DAR of 4. Both these cell surface antigens are expressed in ovarian and endometrial cancers with limited expression in normal tissues, making them ideal co-targets. AV-P138-ADC utilizes Aarvik Therapeutics’ proprietary MUlti-epitope Targeting Tetravalent Antibody (MUTTA™) platform to engineer multivalent antibodies with precise conjugation sites to improve targeting and broaden the ADC therapeutic window, especially in tumors with heterogeneous target expression. Characterization of AV-P138-ADC showed it effectively bound MUC16 and NaPi2b individually, engaged both targets simultaneously, and enhanced internalization compared to the single-target antibody controls. Robust in vitro activity was maintained in OVCAR-3 cells with moderately high expression of both MUC16 and NaPi2b, as well as OVCAR-3 variant cells enriched for either MUC16 or NaPi2b only. AV-P138-ADC also exhibited better cytotoxicity compared to the combination of the site-specifically-conjugated single-target ADCs, a bivalent (1+1 format) bispecific MUC16/NaPi2b ADC, and a MUC16 DAR2 clinical comparator surrogate. Superior in vivo efficacy compared to single-target ADCs was further confirmed in the OVCAR-3 xenograft model. AV-P138-ADC also exhibited a PK profile resembling a typical IgG antibody and high conjugation stability. It demonstrated a favorable tolerability profile in cynomolgus monkeys, consisting of reversible hematologic findings at a higher maximum tolerated single dose compared with random-conjugated vcMMAE ADCs, suggesting a wider therapeutic window. In conclusion, AV-P138-ADC is a novel, site-specifically-conjugated, dual-target tetravalent ADC that may overcome the limitations of conventional single-target or bivalent (1+1 format) bispecific ADCs to potentially provide a safer and more effective treatment option for a broad spectrum of ovarian and endometrial cancer patients. Aarvik Therapeutics and ArriVent BioPharma collaborated on the pre-clinical development of AV-P138-ADC. ArriVent subsequently exercised an option for an exclusive global license to the molecule, now known as ARR-002. Citation Format: Sunil Bhakta, Levi Blazer, Cristina Abrahams, Jiang Liu, Coen Kuijl, Jarrett Adams, Marcin Kowanetz, Luna Musib, Amy Kim, Wanda Kwan, Viswanatham Katta, Vidya S. Jonnalagadda, Reva Raghupathi, Paul Polakis, Stuart Lutzker, Sachdev S. Sidhu, Jagath Reddy Junutula. AV-P138-ADC (ARR-002), a novel MUC16/NaPi2b dual-target tetravalent ADC, for the treatment of ovarian and endometrial cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2660.