Purpose: Initially, prostate cancer responds to hormone therapy but eventually resistance develops. Beta emitter-based PSMA (prostate-specific membrane antigen)-targeted radionuclide therapy is approved for the treatment of metastatic castration-resistant prostate cancer. Here we introduce a targeted alpha therapy (TAT) consisting of the PSMA antibody pelgifatamab covalently linked to a macropa chelator and labeled with actinium-225 and compare its efficacy and tolerability with other TATs. Experimental Design: The in vitro characteristics and in vivo biodistribution, antitumor efficacy, and tolerability of 225Ac-macropa-pelgifatamab (225Ac-pelgi) and other TATs were investigated in cell line- and patient-derived prostate cancer xenograft models. The antitumor efficacy of 225Ac-pelgi was also investigated in combination with the androgen receptor inhibitor darolutamide. Results: Actinium-225-labeling of 225Ac-pelgi was efficient already at room temperature. Potent in vitro cytotoxicity was seen in PSMA-expressing (LNCaP, MDA-PCa-2b, and C4-2) but not in PSMA-negative (PC-3 and DU-145) cell lines. High tumor accumulation was seen for both 225Ac-pelgi and 225Ac-DOTA-pelgi in the MDA-PCa-2b xenograft model. In the C4-2 xenograft model, 225Ac-pelgi showed enhanced antitumor efficacy with a T/Cvolume (treatment/control) ratio of 0.10 compared with 225Ac-DOTA-pelgi, 225Ac-DOTA-J591, and 227Th-HOPO-pelgifatamab (227Th-pelgi) (all at 300 kBq/kg) with T/Cvolume ratios of 0.37, 0.39, and 0.33, respectively. 225Ac-pelgi was less myelosuppressive than 227Th-pelgi. 225Ac-pelgi showed dose-dependent treatment efficacy in the patient-derived KuCaP-1 model and strong combination potential with darolutamide in both cell line- (22Rv1) and patient-derived (ST1273) xenograft models. Conclusions: These results provide a strong rationale to investigate 225Ac-pelgi in patients with prostate cancer. A clinical phase 1 study has been initiated (NCT06052306).

中文翻译：

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PSMA 靶向锕-225 缀合物 (225Ac-macropa-pelgifatamab) 的临床前疗效 - 前列腺癌的靶向 α 疗法

目的：最初，前列腺癌对激素治疗有反应，但最终会产生耐药性。基于 Beta 发射体的 PSMA（前列腺特异性膜抗原）靶向放射性核素疗法被批准用于治疗转移性去势抵抗性前列腺癌。在这里，我们介绍了一种靶向α疗法（TAT），该疗法由与macropa螯合剂共价连接并用actinium-225标记的PSMA抗体pelgifatamab组成，并将其与其他TAT的疗效和耐受性进行比较。实验设计：在细胞系和患者来源的前列腺癌异种移植模型中研究了 225Ac-macropa-pelgifatamab (225Ac-pelgi) 和其他 TAT 的体外特性和体内生物分布、抗肿瘤功效和耐受性。还研究了 225Ac-pelgi 与雄激素受体抑制剂达洛鲁胺联合使用的抗肿瘤功效。结果：225Ac-pelgi 的 Actinium-225 标记在室温下已经是有效的。在表达 PSMA（LNCaP、MDA-PCa-2b 和 C4-2）的细胞系中观察到有效的体外细胞毒性，但在 PSMA 阴性（PC-3 和 DU-145）细胞系中观察不到。在 MDA-PCa-2b 异种移植模型中，225Ac-pelgi 和 225Ac-DOTA-pelgi 均观察到高肿瘤积累。在 C4-2 异种移植模型中，与 225Ac-DOTA-pelgi、225Ac-DOTA-J591 和 227Th-HOPO-pelgifatamab (227Th -pelgi）（均为 300 kBq/kg），T/C 体积比分别为 0.37、0.39 和 0.33。 225Ac-pelgi 的骨髓抑制作用低于 227Th-pelgi。 225Ac-pelgi 在患者来源的 KuCaP-1 模型中显示出剂量依赖性治疗功效，并且在细胞系 (22Rv1) 和患者来源的 (ST1273) 异种移植模型中与 darolutamide 具有强大的联合潜力。结论：这些结果为研究前列腺癌患者的 225Ac-pelgi 提供了强有力的依据。临床 1 期研究已启动 (NCT06052306)。