SCR-A014, a novel bispecific ADC targeting B7H3 and DLL3 for SCLC therapy, exhibits potent anti-tumor efficacy

Background: Small cell lung cancer (SCLC) is a most aggressive lung neuroendocrine tumor, accounting for approximately 15% of all lung cancers. Delta-like ligand 3 (DLL3) is an inhibitory Notch ligand that is highly expressed in SCLC and other neuroendocrine tumors but minimally expressed in normal tissues. B7H3, also known as CD276, is a type I transmembrane protein belonging to the B7 family that includes immune checkpoint molecules such as PD-L1, B7-1, and B7-2. DLL3 and B7H3 are highly overexpressed in small cell lung cancer (SCLC) tumor tissues, with limited presence in normal tissues, making them attractive therapeutic targets. Both B7H3 and DLL3 target shows a high positivity rate (>80%) in SCLC patient samples. However, the expression levels of DLL3 and B7H3 are not high, most samples are at a 1+ level. Moreover, B7H3 exhibits relatively slow internalization, whereas DLL3 demonstrates rapid internalization. Based on these complementary characteristics, we propose a dual-antibody drug conjugate strategy targeting both B7H3 and DLL3. This innovative approach aims to enhance antitumor efficacy. Methods & Results: We developed a novel B7H3 x DLL3 targeted bispecific antibody-drug conjugate (ADC) called SCR-A014, which is comprised of B7H3/DLL3 bispecific antibody conjugated with topoisomerase 1 inhibitor (CPT116). SCR-A014 specifically bind B7H3 and DLL3 with high affinity, and showed enhanced internalization and binding capacity compared to parental monoclonal antibody ADC separately in the B7H3/DLL3 co-expressing cell line. SCR-A014 induced tumor cell lysis in various tumor cell lines, and showed remarkable anti-tumor efficacy in several CDX models in a dose dependent manner. SCR-A014 exhibits significantly stronger anti-tumor activity than their parental monoclonal-ADC or clinical ADC in B7H3+DLL3+ double positive tumor cells. SCR-A014 also have very good stability and favorable developability. Conclusion: These findings suggest that SCR-A014 is a potential first-in-class bispecific ADC and may offer a novel therapeutic strategy for SCLC cancers positive for B7H3 and DLL3.