PO.ET08.01 · 实验与分子治疗
CD46靶向的双模态α粒子及细胞毒载荷负载抗体用于增强转移性去势抵抗性前列腺癌的治疗
CD46-targeted dual-modality alpha-particle and cytotoxic payload-loaded antibody for enhanced treatment of metastatic castration-resistant prostate cancer
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摘要 Abstract
中文摘要
背景：CD46是一个经验证的治疗靶点，在前列腺癌中广泛表达，包括转移性去势抵抗性以及PSMA低表达或神经内分泌亚型。靶向CD46的YS5抗体支持两种互补的治疗平台：一种CD46导向的抗体-药物偶联物（YS5-MMAE），以及一种递送α发射体锕-225的放射免疫偶联物（225Ac-YS5）。每种单一疗法均可诱导肿瘤消退，但剂量递增会增加全身毒性，凸显了联合方法的必要性。
方法：评估了两种联合策略：（1）YS5-MMAE与225Ac-Macropa-PEG4-YS5联合给药，以及（2）一种双标记构建体225Ac-Macropa-PEG4-YS5-MMAE，将两种载荷整合于单一支架上。双构建体通过将MMAE偶联至YS5、连接Macropa-PEG4螯合剂并用225Ac进行放射标记而合成。确认了放化纯度、抗原结合和体外稳定性。在22Rv1前列腺癌细胞中评估体外细胞毒性，并在荷22Rv1肿瘤小鼠（每组n = 9）中测试体内疗效，小鼠接受生理盐水、YS5-MMAE（1.8 mg/kg）、225Ac-YS5（0.125 µCi）、二者联合或双标记构建体。
结果：在体外，联合治疗诱导的细胞毒性大于任一单一疗法，表明存在协同相互作用。在体内，生理盐水组中位生存期为24天，YS5-MMAE组为30天，225Ac-YS5组为66天。YS5-MMAE与225Ac-Macropa-PEG4-YS5联合给药使生存期延长至80天以上，肿瘤进展延迟。相比之下，双标记构建体使生存期超过90天，伴随持久的肿瘤消退和极小的肾脏或血液学毒性。联合治疗和双模态治疗与单药治疗相比均表现出增强的治疗疗效。
结论：同时对CD46进行α粒子和细胞毒靶向可产生协同效应，在减少剂量限制性毒性的同时改善肿瘤控制。双标记构建体代表了一种下一代放射治疗诊断学平台，结合了靶向α治疗和细胞毒载荷递送，为晚期前列腺癌治疗提供了增强的效力、安全性和转化潜力。
查看英文原文 English abstract
Background: CD46 is a validated therapeutic target broadly expressed in prostate cancer, including metastatic castration-resistant and PSMA-low or neuroendocrine subtypes. The CD46-targeting YS5 antibody supports two complementary therapeutic platforms: a CD46-directed antibody-drug conjugate (YS5-MMAE) and a radioimmunoconjugate delivering the alpha-emitter actinium-225 ( 225 Ac-YS5). Each monotherapy induces tumor regression, yet dose escalation increases systemic toxicity, underscoring the need for a combined approach.
Methods: Two combination strategies were evaluated: (1) co-administration of YS5-MMAE with 225 Ac-Macropa-PEG4-YS5, and (2) a dual-labeled construct, 225 Ac-Macropa-PEG4-YS5-MMAE, integrating both payloads on a single scaffold. The dual construct was synthesized by conjugating MMAE to YS5, attaching the Macropa-PEG4 chelator, and radiolabeling with 225 Ac. Radiochemical purity, antigen binding, and in vitro stability were confirmed. In vitro cytotoxicity was assessed in 22Rv1 prostate cancer cells, and in vivo efficacy was tested in 22Rv1 tumor-bearing mice (n = 9 per group) receiving saline, YS5-MMAE (1.8 mg/kg), 225 Ac-YS5 (0.125 µCi), their combination, or the dual-labeled construct.
Results: In vitro, combination therapy induced greater cytotoxicity than either monotherapy, indicating synergistic interaction. In vivo, median survival was 24 days for saline, 30 for YS5-MMAE, and 66 for 225 Ac-YS5. Co-administration of YS5-MMAE and 225 Ac-Macropa-PEG4-YS5 extended survival beyond 80 days, with delayed tumor progression. In contrast, the dual-labeled construct achieved survival exceeding 90 days, accompanied by durable tumor regression and minimal renal or hematologic toxicity. Both combination and dual-modality therapies exhibited enhanced therapeutic efficacy compared to single-agent treatments.
Conclusion: Simultaneous alpha-particle and cytotoxic targeting of CD46 produces synergistic effects, improving tumor control while reducing dose-limiting toxicity. The dual-labeled construct represents a next-generation radiotheranostic platform combining targeted alpha therapy and cytotoxic payload delivery, offering enhanced potency, safety, and translational potential for advanced prostate cancer therapy.
利益披露 Disclosure
A. Bidkar, None..
S. Bidlingmaier, None..
A. Wadhwa, None..
K. Bobba, None..
S. Naik, None..
C. Xue, None..
A. Raveendran, None..
M. Basak, None..
J. Chou, None..
R. Aggarwal, None..
H. VanBrocklin, None..
Y. Seo, None..
B. Liu, None..
R. Flavell, None.