What question did this study set out to answer?

The aim is to develop a bispecific antibody drug conjugate targeting DLL3 and SEZ6 to improve treatment efficacy in small cell lung cancer.

April 5, 2026

Abstract 1716: AT06 is a bispecific antibody drug conjugate targeting DLL3 and SEZ6 with potent activity in small cell lung cancer (SCLC) models

Puntos clave

The aim is to develop a bispecific antibody drug conjugate targeting DLL3 and SEZ6 to improve treatment efficacy in small cell lung cancer.
Designed a bispecific antibody drug conjugate targeting DLL3 and SEZ6.
Evaluated cytotoxicity and internalization in SCLC cell lines.
Assessed in vivo efficacy in xenograft tumor models with different DLL3 and SEZ6 expression.
Used a proprietary payload and engineered VHH domains for enhanced functionality.
AT06 showed over 99% tumor growth inhibition at a 1 mg/kg dose in a low DLL3/SEZ6-expression model.
Demonstrated potent in vitro activity across various SCLC cell lines.
Exhibited characteristics that address tumor heterogeneity and resistance in broader patient populations.

Resumen

Abstract 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. Citation Format: Bin Zou, Bryan K. Yeung, Nannan Lang. AT06 is a bispecific antibody drug conjugate targeting DLL3 and SEZ6 with potent activity in small cell lung cancer (SCLC) models 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 1716.

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