Abstract C016: Model-optimized bispecific antibodies improve antibody-drug conjugate localization to tumors

Abstract Background: Antibody-drug conjugates (ADCs) provide a mechanism to target chemotherapeutic payloads to tumors based on antibodies targeted against tumor-associated proteins. Despite this, ADC efficacy remains constrained by toxicity, some of which is driven by ADC binding to non-tumor tissues expressing the ADC’s target. For example, anti-HER2 ADCs have been shown to induce serious cardiac toxicity related to HER2 expression in the heart and glembatumumab vedotin is thought to cause severe rash due to expression of its target, gpNMB, in the skin. Improving the differential localization of ADCs to tumors compared to non-tumor tissue could improve the therapeutic window of these drugs. Methods: To evaluate the ability of dual targeting to improve target-mediated on-tumor versus off-tumor localization of ADCs, we developed a mechanistic pharmacokinetic/ receptor occupancy model accounting for antibody affinity and avidity. This model predicts on-tumor and off-tumor target binding for ADCs as a function of ADC pharmacokinetics, target properties, and binding affinity. Results: Bispecific antibodies can improve ADC localization to the tumor compared to healthy target-expressing tissues – and therefore therapeutic window – if the affinities for the two targets are properly optimized. A bispecific ADC’s extent of differential localization is a function of the bispecific antibody’s on- and off-rates for binding to both targets. As four parameters require optimization, this is best performed using a computational model, as we have developed here. The improvements ADC localization are robust to differences in the expression density of the two targets of about two orders of magnitude. Conclusions: Bispecific antibodies with model-optimized affinities for two tumor-associated antigens are predicted to improve the ratio of target-mediated on-tumor to off-tumor ADC engagement compared to single-target ADCs. This concept may be more broadly applicable to antibody-based therapeutics. Citation Format: Madison Stoddard, Lin Yuan, Sheetal Panday, Humphrey Gardner, Timothy Wyant, Arijit Chakravarty. Model-optimized bispecific antibodies improve antibody-drug conjugate localization to tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C016.