HWK-206的临床前评估：一种采用新型生物偶联及连接子-载荷技术的新一代双互补位SEZ6靶向ADC

Seizure-related 6 homolog (SEZ6) is a cell-surface transmembrane protein that plays a role in neuronal development. SEZ6 expression is highly elevated in neuroendocrine (NE) tumors, including, but not limited to, small cell lung cancer (SCLC), brain or central nervous system cancers, and NE tumors of prostate and bladder origin, and has limited expression in normal tissues. In SCLC, SEZ6 expression is correlated with worse survival outcomes. Single-epitope, SEZ6-directed antibody-drug conjugates (ADCs), such as ABBV-706, have shown initial promise in SCLC and NE neoplasms, but with some potential challenges attributed to side effects associated with these agents. HWK-206 is a next-generation ADC that utilizes a biparatopic antibody (bpAb) approach to target SEZ6, with an Fc effector-attenuated IgG1 antibody conjugated to the novel DNA topoisomerase I inhibitor, CPT116. HWK-206 was designed using novel bioconjugation (carbon bridge cysteine re-pairing) and advanced linker-payload technologies to maximize intracellular delivery while minimizing systemic exposure of free payload. The mechanism of action of the HWK-206 bpAb was investigated in preclinical SCLC models. Results showed that the HWK-206 bpAb bound to SEZ6 with higher affinity than the parental antibodies or that reported previously for ABBV-706. HWK-206 induced DNA damage and loss of SCLC tumor cell viability. Furthermore, the HWK-206 bpAb demonstrated superior binding, receptor-mediated internalization, and reduction in viability of SCLC tumor cells expressing varying levels of SEZ6, compared with the parental antibodies and historical benchmarks. Potent antitumor activity was observed in various SCLC xenograft tumor models, with tumor regression observed at single doses as low as 2 mg/kg. HWK-206 demonstrated a bystander killing effect in vitro , suggesting the ability to elicit activity against heterogeneous tumors. The pharmacokinetic (PK) and safety profiles of HWK-206 were evaluated in nonclinical toxicology studies. HWK-206 demonstrated a favorable PK profile and was well tolerated. In summary, HWK-206 is a highly potent and selective next-generation, biparatopic, SEZ6-targeted ADC that warrants further investigation. A planned phase I dose-escalation study will investigate HWK-206 in patients with advanced solid tumors.