KIVU-305的临床前疗效与安全性，一种用于结直肠癌(CRC)的新型CEACAM5靶向抗体偶联药物(ADC)

CEACAM5 (carcinoembryonic antigen-related cell adhesion molecule 5) is a cell-surface glycoprotein highly expressed in CRC, pancreatic ductal adenocarcinoma (PDAC), gastric cancer and non-small cell lung cancer (NSCLC), with minimal expression in normal adult tissues. Elevated CEACAM5 correlates with tumor burden and poor prognosis, making it an attractive ADC target. The first-generation CEACAM5 ADC labetuzumab govitecan demonstrated clinical feasibility but with limited efficacy at tolerable doses, highlighting the opportunity for an improved ADC with more stable linker payload to provide superior clinical benefit.KIVU-305 is a CEACAM5-targeting ADC composed of a humanized monoclonal antibody conjugated to SYNtecan E™ via the GlycoConnect®/ Hydraspace® (GC/HS) site-specific conjugation technology, delivering an exatecan-based topoisomerase I inhibitor payload at an average drug-to-antibody ratio (DAR) of 4. GlycoConnect ® leverages the native Fc glycan for site-specific conjugation, while HydraSpace ® introduces a hydrophilic spacer to reduce aggregation and systemic payload release, resulting in an ADC with improved manufacturability, plasma stability and pharmacokinetic profile to provide a superior therapeutic index. Upon binding CEACAM5, KIVU-305 undergoes efficient internalization and exatecan release to inhibit DNA topoisomerase I, causing DNA damage, cell cycle arrest and apoptosis. Notably, exatecan is more potent than deruxtecan and is a poor substrate for P-glycoprotein (P-gp), which may help overcome common drug resistance mechanisms in patients.In vitro, KIVU-305 demonstrated potent, target-specific cytotoxicity in vitro at low nanomolar concentrations and robust bystander activity resulting in killing of adjacent CEACAM5-negative cells. In vivo, KIVU-305 induced sustained tumor regressions in multiple CEACAM5-positive CRC and PDAC xenograft models, including models resistant to irinotecan. KIVU-305 exhibited high stability in human and cynomolgus plasma with no measurable DAR loss and minimal free payload release over 21 days. Pharmacokinetic studies in cynomolgus monkeys confirmed linker stability with high intact ADC and minimal systemic payload exposure. Tolerability studies in cynomolgus monkeys demonstrated that KIVU-305 was well tolerated with only mild reversible toxicities consistent with the expected profile of a topoisomerase I inhibitor payload. No on-target toxicities were identified, consistent with historical CEACAM5 ADC experience.Collectively, these data support KIVU-305 as a promising CEACAM5-directed ADC with a favorable safety profile that may provide an improved therapeutic index. A Phase I clinical trial in patients with advanced solid tumors is planned for 2026.