需要新的疗法来延长转移性去势抵抗性前列腺癌（mCRPC）的生存期。前列腺特异性膜抗原 (PSMA) 是一种在 PC 中过度表达的细胞表面抗原，提供了一个经过验证的靶点。这项剂量递增研究调查了 225Ac-J591、用 α 发射体锕-225 放射性标记的抗 PSMA 单克隆抗体 J591 的安全性、有效性、最大耐受剂量 (MTD) 和推荐的 II 期剂量 (RP2D)。 -为了进行临床前研究，我们招募了对标准治疗方案（包括雄激素受体途径抑制剂，并且已接受或被认为不适合紫杉烷化疗）难治或拒绝的进展性 mCRPC 患者。没有对 PSMA 进行选择。患者以七个剂量递增水平之一接受单剂量 225Ac-J591，然后以最高剂量进行扩展。剂量递增队列的主要终点是确定剂量限制毒性 (DLT) 和 RP2D。放射化学和动物研究是有利的。 32 名患者接受了加速剂量递增设计中的 225Ac-J591（22 名患者接受剂量递增，10 名患者接受扩展）。一名患者（22 人中的 1 人；4.5%）在队列 6 中经历了 DLT（80 KBq/kg），但在队列 7 中没有经历过 DLT；未达到 MTD，RP2D 为最高剂量水平（93.3 KBq/kg）。大多数高级不良事件（AE）是血液学的，与所施用的放射性有明显的关系。非血液学 AE 通常为低级别。观察到前列腺特异性抗原 (PSA) 下降和循环肿瘤细胞 (CTC) 控制：46.9% 的人在任何时候 PSA 下降至少 50%（34.4% 确认 PSA 反应），其中 13 人出现方案定义的 CTC 计数反应22 (59.1%)。 据我们所知，这是首次在 32 名接受过治疗的进行性 mCRPC 患者中进行单剂量 225Ac-J591 的人体 I 期剂量递增试验，显示了安全性和初步疗效信号。进一步调查正在进行中。

Novel therapies are needed to extend survival in metastatic castration-resistant prostate cancer (mCRPC). Prostate-specific membrane antigen (PSMA), a cell surface antigen overexpressed in PC, provides a validated target. This dose-escalation study investigated the safety, efficacy, maximum tolerated dose (MTD), and recommended phase II dose (RP2D) for 225Ac-J591, anti-PSMA monoclonal antibody J591 radiolabeled with the alpha emitter actinium-225.Following investigational new drug-enabling preclinical studies, we enrolled patients with progressive mCRPC that was refractory to or who refused standard treatment options (including androgen receptor pathway inhibitor and had received or been deemed ineligible for taxane chemotherapy). No selection for PSMA was performed. Patients received a single dose of 225Ac-J591 at one of seven dose-escalation levels followed by expansion at the highest dose. Primary end point of dose-escalation cohort was determination of dose-limiting toxicity (DLT) and RP2D.Radiochemistry and animal studies were favorable. Thirty-two patients received 225Ac-J591 in an accelerated dose-escalation design (22 in dose escalation, 10 in expansion). One patient (1 of 22; 4.5%) experienced DLT in cohort 6 (80 KBq/kg) but none in cohort 7; MTD was not reached, and RP2D was the highest dose level (93.3 KBq/kg). The majority of high-grade adverse events (AEs) were hematologic with an apparent relationship with administered radioactivity. Nonhematologic AEs were generally of low grade. Prostate-specific antigen (PSA) declines and circulating tumor cell (CTC) control were observed: 46.9% had at least 50% PSA decline at any time (34.4% confirmed PSA response), and protocol-defined CTC count response occurred in 13 of 22 (59.1%).To our knowledge, this is the first-in-human phase I dose-escalation trial of a single dose of 225Ac-J591 in 32 patients with pretreated progressive mCRPC demonstrated safety and preliminary efficacy signals. Further investigation is underway.