Arndt Claudia, Bergmann Ralf, Striese Franziska, Merkel Keresztély, Máthé Domokos, Loureiro Liliana R, Mitwasi Nicola, Kegler Alexandra, Fasslrinner Frederick, González Soto Karla Elizabeth, Neuber Christin, Berndt Nicole, Kovács Noemi, Szöllősi David, Hegedűs Nikolett, Tóth Gyula, Emmermann Jan-Philipp, Harikumar Kuzhuvelil B, Kovacs Tibor, Bachmann Michael, Feldmann Anja
Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, D-01328 Dresden, Germany.
Mildred Scheel Early Career Center, Faculty of Medicine Carl Gustav Carus, TU Dresden, D-01328 Dresden, Germany.
Cancers (Basel). 2022 Apr 14;14(8):1996. doi: 10.3390/cancers14081996.
Due to its overexpression on the surface of prostate cancer (PCa) cells, the prostate stem cell antigen (PSCA) is a potential target for PCa diagnosis and therapy. Here we describe the development and functional characterization of a novel IgG4-based anti-PSCA antibody (Ab) derivative (anti-PSCA IgG4-TM) that is conjugated with the chelator DOTAGA. The anti-PSCA IgG4-TM represents a multimodal immunotheranostic compound that can be used (i) as a target module (TM) for UniCAR T cell-based immunotherapy, (ii) for diagnostic positron emission tomography (PET) imaging, and (iii) targeted alpha therapy. Cross-linkage of UniCAR T cells and PSCA-positive tumor cells via the anti-PSCA IgG4-TM results in efficient tumor cell lysis both in vitro and in vivo. After radiolabeling with Cu, the anti-PSCA IgG4-TM was successfully applied for high contrast PET imaging. In a PCa mouse model, it showed specific accumulation in PSCA-expressing tumors, while no uptake in other organs was observed. Additionally, the DOTAGA-conjugated anti-PSCA IgG4-TM was radiolabeled with Ac and applied for targeted alpha therapy. A single injection of the Ac-labeled anti-PSCA IgG4-TM was able to significantly control tumor growth in experimental mice. Overall, the novel anti-PSCA IgG4-TM represents an attractive first member of a novel group of radio-/immunotheranostics that allows diagnostic imaging, endoradiotherapy, and CAR T cell immunotherapy.
由于前列腺干细胞抗原（PSCA）在前列腺癌（PCa）细胞表面的过度表达，它是PCa诊断和治疗的一个潜在靶点。在此，我们描述了一种新型的基于IgG4的抗PSCA抗体（Ab）衍生物（抗PSCA IgG4-TM）的开发及其功能特性，该衍生物与螯合剂DOTAGA偶联。抗PSCA IgG4-TM是一种多模态免疫诊疗化合物，可用于：（i）作为基于通用嵌合抗原受体（UniCAR）T细胞免疫疗法的靶向模块（TM）；（ii）用于诊断性正电子发射断层扫描（PET）成像；（iii）靶向α治疗。通过抗PSCA IgG4-TM实现UniCAR T细胞与PSCA阳性肿瘤细胞的交联，可在体外和体内有效裂解肿瘤细胞。用铜进行放射性标记后，抗PSCA IgG4-TM成功应用于高对比度PET成像。在PCa小鼠模型中，它在表达PSCA的肿瘤中显示出特异性积聚，而在其他器官中未观察到摄取。此外，用钫（Ac）对与DOTAGA偶联的抗PSCA IgG4-TM进行放射性标记，并应用于靶向α治疗。单次注射Ac标记的抗PSCA IgG4-TM能够显著控制实验小鼠的肿瘤生长。总体而言，新型抗PSCA IgG4-TM代表了一组新型放射/免疫诊疗试剂中有吸引力的首个成员，可实现诊断成像、内放射治疗和CAR T细胞免疫治疗。
