Preclinical characterization of IPN60300, a first-in-class ITGA2 antibody-drug conjugate for cancer therapy

Background: Integrin alpha-2 (ITGA2), a component of the heterodimeric transmembrane receptor integrin alpha2/beta1, plays a key role in cell adhesion and transduction. Although ITGA2 is expressed at low levels across normal tissues, it is notably overexpressed in various solid tumors, including pancreatic, gastric and colorectal, where it contributes to tumor progression via extracellular matrix signaling and epithelial-mesenchymal transition. We report the development of IPN60300, a novel antibody-drug conjugate (ADC) targeting ITGA2, designed to specifically deliver exatecan, a potent topoisomerase I inhibitor, to ITGA2 expressing cancer cells. IPN60300 consists of a humanized Fc mutated monoclonal antibody site-specifically conjugated to exatecan via a cathepsin-cleavable linker, with a drug-to-antibody ratio of 8. Methods: The pharmacological characteristics of IPN60300 were assessed through comprehensive in vitro and in vivo studies including analysis in ITGA2-expressing cell lines, cell-derived xenograft models, and cynomolgus monkey, chosen for its homology with human ITGA2. Results: IPN60300 demonstrated a specific and high-affinity binding to ITGA2, efficient internalization into tumor cells, and intracellular release of exatecan, resulting in potent cytotoxicity in ITGA2-positive cell lines. The engineered Fc region of the antibody decreased FcgammaRI binding, reducing off-target toxicity while maintaining FcRn interaction. In tumor-bearing mice, IPN60300 exhibited plasma stability and led to significant exatecan accumulation in xenograft tumors, resulting in high, dose-dependent anti-tumor activity in models of cholangiocarcinoma, pancreatic ductal adenocarcinoma, gastric, and colorectal cancers. Toxicology studies in cynomolgus monkeys revealed favorable tolerability and pharmacokinetic characteristics supporting an acceptable therapeutic index. Conclusion: These preclinical findings support IPN60300 as a promising first-in-class ITGA2-targeting ADC, combining potent anti-tumor efficacy with a favorable safety profile. IPN60300 holds potential to improve clinical outcomes for patients with ITGA2-expressing malignancies and is advancing to First-in-Human clinical trial (NCT07213817).