Skidmore Lillian K, Mills David, Kim Ji Young, Knudsen Nick A, Nelson Jay D, Pal Manoj, Wang Jianing, Gc Kedar, Gray Michael J, Barkho Wisam, Nagaraja Shastri Prathap, Ramprasad Mysore P, Tian Feng, O'Connor Daniel, Buechler Ying J, Zhang Shawn Shao-Hui
Ambrx, Inc., La Jolla, California.
Mol Cancer Ther. 2024 Dec 3;23(12):1842-1853. doi: 10.1158/1535-7163.MCT-23-0927.
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 an mCRPC tumor antigen with overexpression in tumors and low expression in healthy tissues. Using our proprietary technology for incorporating synthetic amino acids into proteins at selected sites, we have developed ARX517, an antibody-drug conjugate 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 noncleavable polyethylene glycol linker and stable oxime conjugation enabled via synthetic amino acid 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 antitumor activity in both enzalutamide-sensitive and -resistant cell line-derived xenograft and patient-derived xenograft models of prostate cancer. Repeat-dose toxicokinetic studies in nonhuman primates demonstrated that 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 I clinical trial (NCT04662580).
转移性去势抵抗性前列腺癌（mCRPC）是一种晚期疾病，患者最终会对标准的雄激素剥夺疗法产生耐药，生存率较低。前列腺特异性膜抗原（PSMA）已被确认为mCRPC肿瘤抗原，在肿瘤中过度表达，而在健康组织中低表达。利用我们专有的在选定位点将合成氨基酸掺入蛋白质的技术，我们开发了ARX517，这是一种抗体药物偶联物，由人源化抗PSMA抗体与微管蛋白抑制剂以2的药物与抗体比率位点特异性偶联而成。与PSMA结合后，ARX517被内化并分解代谢，导致细胞毒性载荷的递送和细胞凋亡。为了尽量减少载荷的过早释放并最大限度地将其递送至肿瘤细胞，ARX517采用了不可裂解的聚乙二醇连接子，并通过合成氨基酸掺入蛋白质实现稳定的肟偶联，以确保其整体稳定性。体外研究表明，ARX517选择性地诱导表达PSMA的肿瘤细胞系的细胞毒性。ARX517在小鼠体内表现出较长的终末半衰期和较高的血清暴露量，并且在恩杂鲁胺敏感和耐药细胞系衍生的异种移植模型以及患者来源的前列腺癌异种移植模型中均具有剂量依赖性抗肿瘤活性。在非人类灵长类动物中进行的重复剂量毒代动力学研究表明，在远远高于小鼠药理学研究中治疗暴露量的情况下，ARX517仍可耐受，这表明其治疗指数较宽。总之，ARX517在多种mCRPC模型中抑制肿瘤生长，在猴子中显示出可耐受的安全性，并且根据临床前暴露数据具有较宽的治疗指数。基于令人鼓舞的临床前数据，ARX517目前正在一项I期临床试验（NCT04662580）中进行评估。
