整合素α-2(ITGA2)是一种新型且非常适合的抗体药物偶联物(ADC)靶点

Background: IPN60300 is a novel, potential first-in-class ADC targeting ITGA2, a subunit of the heterodimeric transmembrane receptor integrin alpha2/beta1 involved in cell adhesion and signal transduction. The ADC is designed to deliver exatecan, a potent topoisomerase I inhibitor, to ITGA2-expressing cancer cells. Here, we present a summary of newly generated and publicly available data indicating that the expression pattern of ITGA2 is well-suited for an ADC target. ITGA2 shows low expression in normal tissue and marked overexpression in various solid tumors, in particular gastrointestinal malignancies, where ITGA2 is known to contribute to tumor progression via extracellular matrix signaling and epithelial-mesenchymal transition. Furthermore, we confirm that IPN60300 activity in preclinical models is dependent on ITGA2 expression. Methods: ITGA2 RNA and protein expression data were extracted from public databases (GEPIA 2, cProSite) and published literature. Additional expression data were generated through immunohistochemical analysis on human tissue microarrays (TMAs). Target-dependent anti-cancer activity was assessed in preclinical models with differential ITGA2 expression. Results: ITGA2 is expressed ubiquitously at low levels in normal tissue, but is restricted to few cell types, in particular epithelial cells. In contrast, ITGA2 is overexpressed in several cancers, in particular in gastrointestinal tract tumors. Both transcriptomics and proteomics data demonstrate a strong differential expression of ITGA2 between tumor and normal tissue, with high overexpression in cholangiocarcinoma, pancreatic, colorectal, esophageal and stomach cancers, among other indications. Published literature further supports that in many cancer patient samples, ITGA2 is highly expressed in tumor cells. In addition, we confirm this expression pattern on TMAs, and show that overall, >90% of gastrointestinal tumor samples present ITGA2 expression, with a majority displaying medium-to-high expression levels. In preclinical studies, IPN60300 showed potent in vitro ITGA2-dependent cytotoxicity in cells overexpressing ITGA2 compared to the parental cell line. Consistently, in vivo, IPN60300 demonstrated strong anti-tumor activity in mice bearing ITGA2-expressing tumors, whereas no efficacy was observed in mice with ITGA2 knockout tumors. Conclusion: The ITGA2 expression pattern makes it a well-suited ADC target, and IPN60300 efficacy in preclinical models is dependent on ITGA2 expression. These findings support IPN60300 as a promising first-in-class ADC for individuals harboring ITGA2-expressing tumors. IPN60300 is advancing to a First-in-Human clinical trial (NCT07213817).