KIVU-107：一种临床阶段、同类最佳的PTK7抗体偶联药物(ADC)，具有良好的PK和改善的耐受性特征

PTK7 (protein tyrosine kinase 7) is a catalytically inactive receptor tyrosine kinase associated with tumor-initiating cells and overexpressed in multiple solid tumors, including ovarian, endometrial, lung, breast and gastric cancers. Overexpression of PTK7 is associated with poor prognosis, further exemplifying its pivotal role in carcinogenesis. PTK7 has previously been validated as an ADC target but development of first-generation PTK7 ADCs was limited by payload mediated toxicity, suggesting that an ADC with improved linker payload could improve clinical benefit. KIVU-107 is an antibody-drug conjugate (ADC) composed of a humanized IgG1 monoclonal antibody targeting protein tyrosine kinase 7 (PTK7), conjugated to the SYNtecan E™ linker-payload via the GlycoConnect®/ Hydraspace® (GC/HS) site-specific conjugation technology with a drug-to-antibody ratio (DAR) of 4. The GC/HS platform abolishes Fcgamma receptor-mediated effector activity and utilizes a highly polar spacer to reduce hydrophobicity and aggregation, resulting in an exatecan ADC with improved stability to provide a superior pharmacokinetic and safety profile to expand the therapeutic index.KIVU-107 demonstrated rapid internalization and robust target-specific cytotoxicity across high and low-expressing tumor cell lines. The cleavable linker and cell permeable hydrophilic payload conferred potent bystander killing in PTK7-negative cells co-cultured with PTK7-positive cells, addressing tumor heterogeneity. In vivo, a single dose induced complete regression in multiple xenograft models, including patient-derived xenografts (PDXs) resistant to platinum-based chemotherapy and ADCs such as mirvetuximab soravtansine and datopotamab deruxtecan. KIVU-107 also exhibited enhanced efficacy and improved survival when combined with PARP inhibition, standard-of-care in ovarian, breast and prostate cancers, supporting combination strategies. KIVU-107 was highly stable in vitro, with no measurable DAR loss and minimal free payload release over 21 days in human or cynomolgus plasma. Nonclinical pharmacokinetic and safety evaluations in cynomolgus monkeys confirmed the stability of KIVU-107 with high exposure of intact ADC and minimal unconjugated payload levels and demonstrated favorable tolerability, with a highest non-severely toxic dose (HNSTD) of 60 mg/kg. Hematologic effects were mild, transient and reversible, consistent with the expected profile of a topoisomerase I inhibitor payload.Collectively, these data highlight KIVU-107 as a highly stable, next generation DAR4 exatecan ADC with potent anti-tumor activity, bystander effect and broad therapeutic potential. A Phase I clinical trial in patients with advanced solid tumors is ongoing (NCT07229313).