一种用于新一代癌症治疗的新型pH依赖性T细胞衔接器平台

On-target off-tumor toxicity is a big challenge for the treatment of solid tumors using T cell engager (TCE) therapy because solid tumor associated antigens (TAAs) often expressed in not only tumor tissue but also normal healthy tissues. The acidic tumor microenvironment (TME) is a key characteristic of cancer and is leveraged to develop conditional tumor-selective therapy, which has been demonstrated with effective tumor control alongside manageable adverse events by encouraging preliminary clinical evidence emerged recently. WuXi Biologics has developed an innovative platform to identify pH dependent TAA binders that selectively bind to tumor and spare normal healthy tissues. As a clinically validated target, FolR1 overexpressed on multiple cancers, especially in ovarian and lung cancers, and associated with high-grade tumor progression & poor prognosis. Low expression of FolR1 in normal tissues is restricted to the luminal surface of lung, kidney, intestine, etc. ELAHERE, the approved FolR1 ADC demonstrated great clinical efficacy to FolR1 high patients but is ineffective to FolR1 low patients. FolR1 targeting TCE might be a promising therapy, though currently several TCEs stopped in pre-clinical stage due to on-target-off-tumor effect or lack of efficacy. To address these challenges, WuXi Biologics identified a novel pH-dependent FolR1 binder that binds to tumor at acidic pH over normal tissue at neutral pH, and then discovered a conditional FolR1 TCE which could kill tumor cell specifically by TME triggered activation and turning off at normal tissue, mitigate on-target-off-tumor toxicity and potentially widen therapeutic window and dose to achieve better clinical benefits. As a potential first-in-class conditional FolR1 TCE candidate, WuXi Biologics' FolR1 TCE showed potent binding to FolR1 + tumor cells at acidic pH and very weak binding to FolR1 low cells at neutral pH (representing normal tissue). Designed with fine-tuned CD3 and FolR1 affinity balance, it exhibited efficient in vitro on-tumor cytotoxicity at acidic pH and minimal cytotoxicity on normal tissue at neutral pH, and correlating cytokine levels released by T cells. WuXi Biologics' FolR1 TCE showed dose-dependent and efficient tumor growth inhibition in human ovarian cancer and NSCLC CDX models. In exploratory cynomolgus monkey tox study, WuXi Biologics' FolR1 TCE was well-tolerated up to 1 mg/kg with better safety profile than 16D5, one conventional benchmark FolR1 TCE which showed severe toxicity as low as 15 μg/kg. These findings suggest that WuXi Biologics' FolR1 TCE offers significant therapeutic potential as a next-generation TCE with minimal on-target-off-tumor cytotoxicity and enhanced therapeutic window. The pH dependent design provided an innovative strategy to offer safer and more effective therapeutic overcome for solid cancer patients.