A novel bispecific RDC+ADC theranostic approach to overcome trastuzumab deruxtecan resistance and tumor heterogeneity.

e15150 Background: Resistance to single-antigen HER2-targeted ADCs, such as trastuzumab deruxtecan and trastuzumab emtansine, poses a significant challenge in HER2-positive cancers, often due to tumor heterogeneity and antigen expression downregulation. To address this unmet medical need, we developed RB02 and B836, first-in-class bispecific radionuclide drug conjugates (RDC) and ADCs leveraging the proprietary Nanolattix Biolattix technology platform. RB02-RDC and B836-ADC are engineered to target both HER2 and Tissue Factor (TF), an attractive therapeutic target overexpressed in various tumor types. Methods: The therapeutic potential of B836 was evaluated through in vitro binding and internalization assays. In vivo efficacy was assessed in comparison to trastuzumab deruxtecan. Safety and toxicokinetic studies for B836-ADC were conducted in cynomolgus monkeys. The theranostic potential of RB02-177Lu was evaluated using SPECT/CT imaging in animal models and xenograft tumor models to monitor tumor accumulation, spatial and timing dynamic distribution, and clearance. Results: In vitro experiments demonstrated that B836 achieved significantly enhanced cancer cell binding and internalization compared to single-target ADCs. In vivo studies of B836 showed superior anti-tumor efficacy over trastuzumab deruxtecan. In safety studies, no systemic toxicity was detected for B836-ADC at doses up to 5 mg/kg in cynomolgus monkeys. SPECT/CT imaging analysis revealed the specific spatial and timing dynamic distribution of RB02-177Lu after i.v. injection. RB02-177Lu demonstrated rapid and specific tumor accumulation with retention over 7 days and non-target clearance by 4 hours post-injection. Conclusions: These collective findings support the continued clinical development of RB02-RDC + B836-ADC as a promising bispecific RDC+ADC theranostic and synergistic drug combination approach in oncology.