新型DLL3 x B7H3双特异性ADC在临床前研究中展示出更优的疗效

Background: Small Cell Lung Cancer (SCLC) is a highly aggressive neuroendocrine carcinoma accounting for approximately 15% of all lung cancer diagnoses. It is characterized by rapid proliferation, early metastasis, and a dismal prognosis, with a 5-year survival rate of only 3% for patients with metastatic disease. Research over the past decade has revealed significant molecular heterogeneity in SCLC, leading to a classification into four major subtypes based on distinct transcriptional signatures: there are defined by the expression of specific transcription factors-ASCL1 high (SCLC-A), NEUROD1 high (SCLC-N), and POU2F3 high (SCLC-P)-and the fourth, SCLC-I, is characterized by low expression of these three factors. Notably, the SCLC-P subtype has been associated with inferior outcomes following chemo-immunotherapy, suggesting it may represent a more treatment-resistant variant. This high heterogeneity is likely a key driver of therapeutic resistance. DLL3, an inhibitory ligand of the Notch pathway, is overexpressed in up to 85% of SCLC tumors and varies significantly across SCLC subtypes, while its expression is negligible in normal tissues. B7H3, a type I transmembrane protein belonging to the B7 immune checkpoint family, is another promising target. It is expressed at low levels in normal tissues but is highly and homogeneously overexpressed across all SCLC subtypes, as well as in other solid tumors. Methods: To address tumor heterogeneity in SCLC and improve responses for treatment-resistant patients-particularly those with the SCLC-P subtype-we pursued a rational design of a bispecific antibody-drug conjugate (ADC) targeting both DLL3 and B7H3. We engineered a diverse library of bispecific antibodies with varying sequence combinations and structural formats, which were then conjugated to diverse linker-topoisomerase 1 inhibitor (Top1i) payloads. Through a systematic screening campaign involving comprehensive in vitro and in vivo evaluations, we successfully identified a superior lead bispecific ADC candidate. Results: The lead bispecific antibody exhibited potent cellular internalization in vitro, while the bispecific ADC demonstrated concentration-dependent and target-specific cytotoxicity in antigen-positive cells. In vivo, across multiple patient-derived xenograft (PDX) models, the lead bispecific ADC exhibited robust and sustained antitumor activity, outperforming both clinical-stage monospecific ADC benchmarks and its parental monospecific ADC. Notably, in refractory SCLC-P PDX models, it maintained superior efficacy compared to clinical monospecific ADC benchmarks. These results support a synergistic mechanism of action conferred by the bispecific ADC. Conclusions: In conclusion, the next-generation bispecific ADC holds great potential to overcome SCLC heterogeneity and improve outcomes for treatment-resistant patients.