Abstract 6758: MUlti-epitope Targeting Tetravalent Antibody (MUTTA™) platform for developing NexGen ADCs with an improved therapeutic window

Abstract Antibody-drug conjugates (ADCs) are a class of targeted chemotherapeutic precision medicines that became available to oncology clinical practice in 2000. In the 25 years since, >450 ADCs have progressed into the clinic, of which only 15 ADCs have been approved by the FDA, while >130 have been discontinued or are inactive. The high failure rate (∼90%) of ADCs in the clinic is often associated with factors such as low tumor antigen copy number, heterogenous expression of tumor targets in solid tumor cancers, target antigen escape, poor internalization, efficacy-limiting off-target toxicity, and developability risks. Aarvik Therapeutics has developed a novel MUlti-epitope Targeting Tetravalent Antibody (MUTTA™ ) platform to engineer NextGen ADCs with multifunctional properties to tackle difficult-to-treat solid tumor cancers. The MUTTA™ ADC platform is designed to overcome many of the limitations described above and to broaden the therapeutic window of ADCs. MUTTA™ ADCs apply an OR-gate approach and can address therapeutic limitations such as antigen escape seen with monospecific ADCs in the treatment of solid tumors. We focused initially on developing tetravalent antibody formats with optimal manufacturing properties by screening several tetravalent antibody formats using few hundred constructs and successfully identified MUTTA™ formats specifically suitable for the ADC drug development. To develop and validate the MUTTA™ platform and to test its utility to generate multifunctional therapeutic antibodies, we initially applied this technology to well-validated tumor targets such as Her2 and EGFR for which clinically proven function-blocking antibodies (e.g., trastuzumab, pertuzumab, cetuximab) are available. We successfully engineered a MUTTA™ antibody with 4 different antibody functionalities (4-in-1) and demonstrated functional synergy in blocking-ERK phosphorylation in a trastuzumab-resistant cancer cell line. We demonstrated that multi-target MUTTA™ antibodies display superior internalization over single-target antibodies. In addition, MUTTA™ ADCs exhibited superior cellular potency compared to single-target ADCs and exhibited normal IgG-like pharmacokinetic properties. We further applied the MUTTA™ platform to several solid tumors such as Breast, Colon, Lung, Ovarian, Prostate and Pancreas by first identifying complementary tumor antigens based on co-expression profiles in these solid tumor cancers and then engineering optimally-designed multi-target MUTTA™ ADCs based on this analysis. We will present data that demonstrate in vitro and in vivo validation of multi-target MUTTA™ ADCs and their improved therapeutic window compared to single-target ADCs, as well as the broad applicability of the MUTTA™ platform across several tumor antigens. Citation Format: Sunil Bhakta, Jiang Liu, Levi Blazer, Jarrett Adams, Vasu Jammalamadaka, Anbalagan Jaganathan, Shane Miersch, Viswanatham Katta, Anay Limaye, Ying-Ping Jiang, Vidya S. Jonnalagadda, Reva Raghupathi, Pradeep Fernandes, Sean Givens, Paul Polakis, Sachdev S. Sidhu, Jagath R. Junutula, . MUlti-epitope Targeting Tetravalent Antibody (MUTTA™) platform for developing NexGen ADCs with an improved therapeutic window [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 6758.