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

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 MU lti-epitope T argeting T etravalent A ntibody (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.