AT06 is a bispecific antibody drug conjugate targeting DLL3 and SEZ6 with potent activity in small cell lung cancer (SCLC) models

Small cell lung cancer (SCLC) and other high-grade neuroendocrine neoplasms (NENs) are therapeutically challenging malignancies with limited treatment options. For patients with extensive-stage SCLC the median survival is 6 to 12 months with current treatment options making it the most aggressive type of pulmonary tumor. Delta-like ligand 3 (DLL3) and seizure-related homolog 6 (SEZ6) are selectively expressed in SCLC, neuroendocrine carcinomas, and glioblastomas with minimal expression on normal adult tissues, making them attractive targets for antibody-drug conjugates (ADC ) therapy. While DLL3 and SEZ6 single-target ADCs have shown clinical benefit, tumor heterogeneity and antigen downregulation may limit their long term efficacy. Moreover, as much as 88% of all SCLC patients display DLL3 and SEZ6 co-expression making bispecific ADCs a promising approach for improving efficacy and broadening patient coverage. Our approach utilizes a 2+2 VHH format fused to a human Fc region and engineered to bind both SEZ6 and DLL3 antigens. VHH domains were optimized for improved affinity, internalization, and developability over the parental VHH and conjugated to a proprietary topoisomerase I inhibitor payload with strong bystander effect, high DAR homogeneity, and a hydrophilic enzyme-cleavable linker. In vitro cytotoxicity, internalization efficiency, and target-dependent activity were evaluated across a panel of SCLC cell lines. In vivo efficacy was assessed in xenograft tumor models with varying SEZ6 and DLL3 expression profiles. In a low DLL3/SEZ6-expression model of SCLC (NCI-H82), AT06 displayed strong and durable tumor growth inhibition (>99%) at a 1 mg/kg dose. These data reflect a promising dual-targeting bispecific ADC therapeutic with the potential to address tumor heterogeneity and resistance mechanisms across a broader range of patients.