转移性去势抵抗性前列腺癌 (mCRPC) 是一种晚期疾病，患者最终无法接受标准的雄激素剥夺治疗，并且生存率很低。前列腺特异性膜抗原 (PSMA) 已被验证为 mCRPC 肿瘤抗原，在肿瘤中过度表达，在健康组织中低表达。利用我们在选定位点将合成氨基酸 (SAA) 整合到蛋白质中的专有技术，我们开发了 ARX517，这是一种抗体药物偶联物 (ADC)，由人源化抗 PSMA 抗体与微管蛋白抑制剂位点特异性偶联组成。药物与抗体的比率为 2。结合 PSMA 后，ARX517 被内化和分解代谢，导致细胞毒性有效负载递送和细胞凋亡。为了最大限度地减少过早的有效负载释放并最大限度地向肿瘤细胞输送，ARX517 采用不可切割的 PEG 连接体和通过 SAA 蛋白掺入实现的稳定肟缀合，以确保其整体稳定性。体外研究表明，ARX517 选择性诱导表达 PSMA 的肿瘤细胞系的细胞毒性。 ARX517 在小鼠中表现出长的终末半衰期和高血清暴露，并且在恩杂鲁胺敏感和耐药的 CDX 和 PDX 前列腺癌模型中表现出剂量依赖性抗肿瘤活性。非人类灵长类动物的重复剂量毒代动力学研究表明，在小鼠药理学研究中，ARX517 在远高于治疗暴露的暴露量下具有耐受性，表明其具有广泛的治疗指数。总之，ARX517 在多种 mCRPC 模型中抑制肿瘤生长，在猴子中表现出可耐受的安全性，并且基于临床前暴露数据具有广泛的治疗指数。基于令人鼓舞的临床前数据，ARX517 目前正在 1 期临床试验中进行评估 ([NCT04662580])。

Metastatic castration-resistant prostate cancer (mCRPC) is an advanced disease in which patients ultimately fail standard of care androgen-deprivation therapies and exhibit poor survival rates. The prostate-specific membrane antigen (PSMA) has been validated as a mCRPC tumor antigen with over-expression in tumors and low expression in healthy tissues. Using our proprietary technology for incorporating synthetic amino acids (SAAs) into proteins at selected sites, we have developed ARX517, an antibody drug conjugate (ADC) which is composed of a humanized anti-PSMA antibody site-specifically conjugated to a tubulin inhibitor at a drug-to-antibody ratio of 2. After binding PSMA, ARX517 is internalized and catabolized, leading to cytotoxic payload delivery and apoptosis. To minimize premature payload release and maximize delivery to tumor cells, ARX517 employs a non-cleavable PEG linker and stable oxime conjugation enabled via SAA protein incorporation to ensure its overall stability. In vitro studies demonstrate that ARX517 selectively induces cytotoxicity of PSMA-expressing tumor cell lines. ARX517 exhibited a long terminal half-life and high serum exposure in mice, and dose-dependent anti-tumor activity in both enzalutamide-sensitive and -resistant CDX and PDX prostate cancer models. Repeat dose toxicokinetic studies in non-human primates demonstrated ARX517 was tolerated at exposures well above therapeutic exposures in mouse pharmacology studies, indicating a wide therapeutic index. In summary, ARX517 inhibited tumor growth in diverse mCRPC models, demonstrated a tolerable safety profile in monkeys, and had a wide therapeutic index based on preclinical exposure data. Based on the encouraging preclinical data, ARX517 is currently being evaluated in a Phase 1 clinical trial ([NCT04662580]).