Abstract LB193: A novel DLL3-B7H3 bispecific dual-payload ADC, KHN928, demonstrates potent antitumor efficacy in small cell lung cancer

Abstract Delta-like ligand 3 (DLL3) is a target with high tumor specificity overexpressed in neuroendocrine cancers such as small cell lung cancer (SCLC), yet its expression level is often limited. While the immunoregulatory transmembrane protein B7-H3 (B7-homologue 3) is broadly and highly expressed across multiple malignancies including SCLC, but demonstrates lower tumor specificity due to its presence on various normal blood cells. Although antibody-drug conjugates (ADCs) targeting either DLL3 or B7-H3 alone have shown encouraging clinical efficacy in SCLC clinical study but with unsustainable benifit. A dual-targeting strategy with dual-payloas was employed to address this issue. Here, we present KHN928, a bispecific dual-payload ADC designed to co-target DLL3 and B7-H3 for the treatment of SCLC. KHN928 combines a DLL3-targeting nanobody with a humanized B7-H3 antibody, site-specifically conjugated via cysteine and glycosite coupling to two distinct payloads: a topoisomerase I inhibitor (exatecan) and an RNA polymerase II inhibitor (triptolide). The molecule is engineered with high affinity for DLL3 and moderate affinity for B7-H3 to drive selective tumor accumulation while avoiding off-target exposure. KHN928 exhibits a homogeneous drug-to-antibody ratio (DAR) of ∼7. 6 (3. 8 per target), high SEC purity, uniform particle size, and favorable thermal stability. KHN928 concurrently disrupts RNA synthesis (via triptolide) and induces DNA double-strand breaks (via exatecan). Notably, neither payload is associated with interstitial lung disease (ILD). The dual TAA-targeting of bispecific antibody demonstrates enhanced binding avidity, and promotes superior internalization across multiple SCLC cell lines, with binding confirmed to be specific to DLL3 and B7-H3. KHN928 showed stronger cytotoxic activity compared to the monospecific, mono-payload ADC I-DXd in vitro. KHN928 achieved profound tumor growth inhibition (TGI up to 99. 8%) and significantly prolonged survival in aggressive metastatic SHP-77 and NCI-H82 SCLC models, which the efficacy was limited to parental monospecific ADCs and I-DXd analog. Furthermore, in patient-derived xenograft (PDX) models with varying expression levels of B7-H3 and DLL3, KHN928 exhibited broader and stronger antitumor activity than monospecific ADCs, including in I-DXd resistant PDX model, underscoring its ability to overcome both target- and payload-mediated resistance. A non-GLP toxicity study in cynomolgus monkeys indicated a favorable safety profile with a highest non-severely toxic dose (HNSTD) of 40 mg/kg. In summary, the DLL3 Χ B7-H3 bispecific dual-payload ADC KHN928 exhibits superior and broad-spectrum antitumor efficacy, robust activity against resistant tumors, and an acceptable preclinical safety profile, highlighting its strong therapeutic potential for SCLC. Citation Format: Lu Qi, Gang Lei, Pengfei Ren, Dan Zhang, Menglong Guan, Shijun Yin, Xinzou Fan, Jianglin Tang, Zhengping Li, Yanhua Xu, Xiao Ke, Yonghao Zhao. A novel DLL3-B7H3 bispecific dual-payload ADC, KHN928, demonstrates potent antitumor efficacy in small cell lung cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr LB193.