HEC-922：一款靶向CDH17阳性肿瘤的CDH17-4-1BB双特异性抗体，显示出强效抗肿瘤活性

HEC-922 is a novel bispecific agonistic antibody targeting Cadherin-17(CDH17) and the immune agonistic receptor 4-1BB for the treatment of CDH17-positive tumors, particularly gastrointestinal tumors. CDH17 is a tumor associated antigen highly expressed in various tumors, including colorectal cancer, gastric cancer, and neuroendocrine tumors. Activating monoclonal antibodies against 4-1BB have shown clinical efficacy but was limited by systemic toxicity. The design of HEC-922 enables CDH17-dependent agonism of 4-1BB in the presence of CDH17 positive tumor cells, enabling tumor specific T cell activation while minimizing systemic immune toxicity. A high affinity nanobody against CDH17 and a nanobody against 4-1BB were identified for the construction of HEC- 922 containing an ADCC-silenced Fc. HEC-922 shows potent co-binding to both CDH17 and 4-1BB targets and is cross-reactive to the Rhesus macaque. In an assay using 4-1BB high expression 293 cells with NFkB-luciferase reporter, HEC-922 mediated 4-1BB activation in the presence of CDH17 positive cells but not CDH17 negative cells. HEC-922 demonstrated effective tumor growth inhibition in xenograft models of CDH17 positive tumor lines, restored the function of immune cells, reduced the proportion of exhausted T cells, and achieved a sustained and potent anti-tumor effect. Initial drug feasibility and toxicity studies results of HEC-922 were favorable. Overall result demonstrated that HEC- 922 is a promising candidate for CDH17 positive cancer immunotherapy.HEC-921, another bispecific antibody developed on the same 4-1BB platform with Ly6G6D as the targeted tumor antigen, has completed Dose Range Finding (DRF) study in cynomolgus monkeys, with a no-observed-adverse-effect level (NOAEL) of 100 mg/kg, validating the safety of the 4-1BB platform.