Abstract 1722: Optimal targeting of heterogeneous tumors using highly developable bispecific antibody drug conjugates based on an improved heterodimerization platform and precisely controlled conjugation of a novel payload

Abstract We describe the construction of bispecific antibody drug conjugates (ADCs) against multiple target combinations that are clinically correlated, and show that bispecific ADCs have the potential for improved efficacy in heterogeneous tumors compared to single targeted ADCs. Although single-target antibody drug conjugates (ADCs) are highly efficacious in numerous tumor indications, many patients still relapse following ADC therapy due to multiple factors, including inefficient tumor delivery, drug resistance, and antigen escape due to tumor heterogeneity. Thus, there is a high need for developing next generation ADCs that can overcome these limitations. Dual targeting using bispecific antibody-drug conjugates (bsADCs) is an approach that can address important issues such as insufficient targeting due to intra-tumoral expression heterogeneity. Bispecific ADCs are currently being investigated in discovery and early clinical pipelines, but challenges still remain such as selecting optimal target combinations, generating high-quality homogeneous ADC compounds, and optimizing the various ADC components to establish an effective therapeutic window. To develop bispecific antibody drug conjugates, we selected target combinations based on bioinformatics and clinical co-expression. Several in-house platforms were leveraged to create a workflow for rapidly generating bispecific ADCs: (1) an efficient heterodimerization platform for rapidly obtaining native IgG bispecific antibodies from parental monoclonal antibodies, (2) a novel hydrophilic TOPO1 inhibitor payload with an enzyme-cleavable linker, and (3) site-specific conjugation to create ADCs with precisely controlled drug-to-antibody ratio (DAR). A series of bispecific antibodies were constructed against rational combinations of co-expressed targets, and highly homogeneous DAR2 ADCs were obtained by conjugating the payload using Abclick® platform. The bsADCs thus created are less prone to CMC and developability liabilities due to their low hydrophobicity and minimal structural deviation from native IgG. Furthermore, the bispecific ADC showed improved anti-tumor activity in vitro and in vivo compared to the parental mono-targeted ADCs. Together, these results highlight a practical path toward the development of ADCs with improved efficacy in heterogeneous tumors. Citation Format: Dongsop Lee, Younggyu Kong, Seong-Hyun Park, Hyeonseok Jin, Aera Lee, Haerynn Chung, Jungwoo Kim, Jinhoon Jung, Haedueok Jung, Yunjung Um, Youngjee Jeong, Su jin Jung, Haneol Kim, Kyoung-Ho Pyo, Hyungseok Choi, Mi-Kyung Kim. Optimal targeting of heterogeneous tumors using highly developable bispecific antibody drug conjugates based on an improved heterodimerization platform and precisely controlled conjugation of a novel payload 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 1722.