B836: A novel bispecific antibody-drug conjugate (ADC) as a clinical candidate to overcome trastuzumab deruxtecan resistance

Resistance to single-antigen HER2-targeted ADCs, such as Enhertu (trastuzumab deruxtecan, DS-8201) and Kadcyla (trastuzumab emtansine, T-DM1), poses a significant challenge in HER2-positive cancers, often due to tumor heterogeneity and antigen downregulation. To address this unmet medical need, we developed B836, a first-in-class bispecific ADC leveraging the Nanolattix Biolattix technology platform. B836 is engineered to target both HER2 and Tissue Factor (TF). TF is an attractive therapeutic target and is overexpressed in various tumor types. Results from 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 Enhertu, particularly in animal models characterized by low HER2 expression, suggesting its potential for overcoming primary or acquired resistance mechanisms. GLP safety and toxicokinetic (TK) studies were conducted in cynomolgus monkeys. No drug-related ocular toxicity or abnormalities in body temperature, blood pressure, or electrocardiogram (ECG) were observed. Furthermore, no systemic toxicity was detected at doses up to 5 mg/kg. These collective findings support the continued clinical development of B836, promising therapeutic potential in oncology.