OBI-904，一种基于聚糖的位点特异性Nectin-4靶向ADC，在非临床研究中表现出强效持久的抗肿瘤活性、改善的PK特征并克服EV耐药

Nectin-4 is a type I transmembrane adhesion molecule with low expression in normal tissues but is highly overexpressed in multiple cancers. Its expression is associated with tumor proliferation, metastasis, and poor prognosis, making it a clinically validated target for ADC development. Although Padcev (enfortumab vedotin, EV) has demonstrated meaningful clinical benefit, safety concerns, suboptimal dosing schedules, and emerging resistance underscore the need for next-generation Nectin-4-targeted ADCs. OBI-904 is a Nectin-4-targeted ADC conjugated with the topoisomerase I inhibitor Exatecan (DAR 8) via glycan conjugation platform and dual-action enzymatic technology, designed to provide homogenous DAR, improve ADC stability, and optimal payload delivery. In vitro linker-payload stability was evaluated in human serum albumin by LC-MS. Pharmacokinetics (PK) were assessed in serum and tumor using HNSCC xenograft models. Antitumor activity was tested in CDX models of HNSCC, CRC, TNBC, prostate cancer, cholangiocarcinoma, and in PDX models of cervical and sarcoma, as well as in an EV-resistant bladder CDX model, with Padcev and ETx-22 as benchmarks. GLP toxicology studies were conducted in cynomolgus monkeys at 5, 15, and 30 mg/kg Q2W for three doses (Days 1, 15, 29), followed by a six-week recovery period. OBI-904, the glycan conjugated ADC, maintained a 100% DAR in serum albumin, longer half-life, overcoming the instability associated with conventional cysteine-based linkers. OBI-904 exhibited improved pharmacokinetics and slow release of payload in tumor cells for prolonged anti-tumor responses. In vivo, OBI-904 demonstrated potent antitumor activity across multiple models, including CDX models of HNSCC, CRC, TNBC as well as PDX models of cervical and sarcoma, showing antitumor effect independent of Nectin-4 expression levels. Durable responses were observed in prostate (high Nectin-4) and cholangiocarcinoma (low Nectin-4) CDX models. Notably, OBI-904 effectively overcame EV-resistant bladder cancer, highlighting its potential to address acquired resistance. In the GLP toxicology studies, a highest non-severely toxic dose (HNSTD) of 30 mg/kg was determined in non-human primates with favorable toxicology findings. OBI-904, a next-generation Nectin-4-targeted ADC with optimized stability and payload delivery, demonstrated potent antitumor activity across multiple models, including EV-resistant tumors, independent of Nectin-4 expression. Favorable pharmacokinetics and toxicology support its further clinical development as a promising therapy for Nectin-4-expressing cancers.