ONM-421，一种pH响应型聚合物-药物偶联物纳米颗粒，将MMAE递送至实体瘤并在小鼠中展现出抗原非依赖性的抗肿瘤疗效

Introduction: Strategies that enable precise tumor delivery of cytotoxic agents such as monomethyl auristatin E (MMAE) and reduce off-tumor toxicity would profoundly improve cancer treatment outcomes. Though antibody-drug conjugates (ADCs) have been approved for several indications, the efficacy of ADCs can be limited by multiple factors including heterogenous antigen expression and target downregulation which restrict effective treatment in many patients. We have developed ON-BOARD™, an ultra-pH sensitive nanoparticle technology, which shields payloads from systemic exposure during circulation but responds to the acidic tumor microenvironment (TME), to deliver therapeutics in an antigen-independent and histology-independent manner. Herein, we report the preclinical characterization of ONM-421, an ON-BOARD™ polymer-drug conjugate covalently linked to MMAE via a protease-cleavable linker, showing favorable tolerability and anti-tumor efficacy in multiple xenograft models. Methods: Properties and storage stability of ONM-421 were characterized by dynamic light scattering and HPLC. Linker cleavage was investigated in vitro while cytotoxicity assays were performed in human cancer cell lines and primary cells (keratinocytes, corneal epithelial cells) with free MMAE and MMAE-ADCs. Efficacy and tolerability of ONM-421 was studied in vivo in multiple human xenograft models, HT-29, HCT-116, and FaDu compared to docetaxel (DTX) and a tissue factor targeting MMAE-ADC tisotumab vedotin (TV). Results: ONM-421 showed stable uniformly distributed size (D h <50nm), <1% free MMAE, and consistent pH-responsiveness over a 6-month ongoing storage stability study. ONM-421 showed >1,000-fold payload protection compared to free MMAE in vitro , while MMAE payload activity was confirmed after cathepsin B enzymatic cleavage from ONM-421. Incubation of ONM-421 in mouse plasma showed improved stability compared to TV as measured by LC-MS and a cancer cell cytotoxicity assay. ONM-421 also showed markedly reduced toxicity compared to free MMAE and TV in human primary corneal epithelial cell and keratinocytes. In repeat-dose studies, ONM-421 demonstrated potent antitumor efficacy in multiple xenograft models in an antigen independent manner with significantly improved tolerability compared to DTX in all models. ONM-421 resulted in 100% tumor free survival in HT-29 and FaDu, and 82% TGI in HCT-116 while TV was only efficacious in TF Hi FaDu (100% tumor free) but not in TF Lo HCT-116 (20% TGI). ONM-421 also showed better tumor inhibition than TV in large established FaDu and HCT-116 xenografts after a single injection. Conclusion: ONM-421 demonstrated potent antigen-independent antitumor efficacy in multiple xenograft tumors with good tolerability in mice. The data justifies further development of ONM-421 towards IND-enabling studies.