HWK-007的临床前评估：一种采用新型生物偶联及连接子-载荷技术的新一代PTK7靶向ADC

Protein tyrosine kinase-7 (PTK7) is a catalytically-inactive receptor tyrosine kinase that promotes tumor progression through the Wnt/planar cell polarity (PCP), phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), mitogen-activated protein kinase (MAPK), and vascular endothelial growth factor (VEGF) pathways. Overexpression of PTK7 contributes to metastasis, chemoresistance, and poor clinical outcomes in multiple tumor types. PTK7 is overexpressed in up to 70% of solid tumors, including-but not limited to-lung, ovarian, and endometrial cancers, and has low expression in normal cells, making it an attractive target for an antibody-drug conjugate (ADC). Results from early clinical trials of cofetuzumab pelidotin, a PTK7-targeted, auristatin-based ADC, showed promising signs of clinical activity. HWK-007 is a next-generation, PTK7-targeting ADC that comprises an Fc effector-attenuated IgG1 antibody conjugated to the DNA topoisomerase I inhibitor CPT116, with a drug-to-antibody ratio of 6. HWK-007 incorporates novel bioconjugation (carbon bridge cysteine re-pairing) and advanced linker-payload technologies, designed to maximize intracellular delivery while minimizing systemic exposure of free payload. The mechanism of action of HWK-007 was investigated in preclinical models of cancer. Results showed that HWK-007 bound specifically to cells expressing PTK7, was internalized through receptor-mediated endocytosis into lysosomes, and induced DNA damage resulting in loss of cell viability. Potent antitumor activity was demonstrated in multiple xenograft tumor models, with durable tumor regression observed with as low a dosage as 1 mg/kg single dose; this antitumor activity was superior to that of cofetuzumab pelidotin at equivalent doses. HWK-007 showed a notable bystander killing effect in vitro , suggesting the ability to elicit activity against heterogeneous tumors. HWK-007 demonstrated a favorable pharmacokinetic profile in non-human primates (NHP), with an extended half-life and very low levels of free payload observed (0.0067% of the AUC). Repeat-dose toxicology studies in NHP determined a highest non-severely toxic dose (HNSTD) of 60 mg/kg. Combined with preclinical efficacy results, these data suggest a therapeutic index that is suitable for testing in humans. In summary, HWK-007 is a highly potent and selective, next-generation, PTK7-targeted ADC. A phase I dose-escalation study is planned to evaluate HWK-007 in patients with advanced solid tumors.