Sonanini Dominik, Schwenck Johannes, Blaess Simone, Schmitt Julia, Maurer Andreas, Ehrlichmann Walter, Ritter Malte, Skokowa Julia, Kneilling Manfred, Jung Gundram, Fend Falko, Krost Simon, Seitz Christian M, Lang Peter, Reischl Gerald, Handgretinger Rupert, Fougère Christian la, Pichler Bernd J
Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, University of Tübingen, Röntgenweg 13, 72076, Tübingen, Germany.
Department of Medical Oncology and Pneumology, University Hospital Tübingen, University of Tübingen, Tübingen, Germany.
Biomark Res. 2024 May 12;12(1):50. doi: 10.1186/s40364-024-00595-9.
Cell- and antibody-based CD19-directed therapies have demonstrated great potential for treating B-cell non-Hodgkin lymphoma (B-NHL). However, all these approaches suffer from limited response rates and considerable toxicity. Until now, therapy decisions have been routinely based on histopathological CD19 staining of a single lesion at initial diagnosis or relapse, disregarding heterogeneity and temporal alterations in antigen expression. To visualize in vivo CD19 expression noninvasively, we radiolabeled anti-human CD19 monoclonal antibodies with copper-64 (Cu-αCD19) for positron emission tomography (CD19-immunoPET). Cu-αCD19 specifically bound to subcutaneous Daudi xenograft mouse models in vivo. Importantly, Cu-αCD19 did not affect the anti-lymphoma cytotoxicity of CD19 CAR-T cells in vitro. Following our preclinical validation, Cu-αCD19 was injected into four patients with follicular lymphoma, diffuse large B-cell lymphoma or mantle zone lymphoma. We observed varying Cu-αCD19 PET uptake patterns at different lymphoma sites, both within and among patients, correlating with ex vivo immunohistochemical CD19 expression. Moreover, one patient exhibited enhanced uptake in the spleen compared to that in patients with prior B-cell-depleting therapy, indicating that Cu-αCD19 is applicable for identifying B-cell-rich organs. In conclusion, we demonstrated the specific targeting and visualization of CD19 B-NHL in mice and humans by CD19-immunoPET. The intra- and interindividual heterogeneous Cu-αCD19 uptake patterns of lymphoma lesions indicate variability in CD19 expression, suggesting the potential of CD19-immunoPET as a novel tool to guide CD19-directed therapies.
基于细胞和抗体的CD19定向疗法已显示出治疗B细胞非霍奇金淋巴瘤（B-NHL）的巨大潜力。然而，所有这些方法都存在缓解率有限和毒性较大的问题。到目前为止，治疗决策通常基于初诊或复发时单个病灶的组织病理学CD19染色，而忽略了抗原表达的异质性和时间变化。为了在体内无创可视化CD19表达，我们用铜-64（Cu-αCD19）对抗人CD19单克隆抗体进行放射性标记，用于正电子发射断层扫描（CD19免疫PET）。Cu-αCD19在体内特异性结合皮下Daudi异种移植小鼠模型。重要的是，Cu-αCD19在体外不影响CD19嵌合抗原受体T细胞（CD19 CAR-T细胞）的抗淋巴瘤细胞毒性。经过临床前验证后，将Cu-αCD19注入4例滤泡性淋巴瘤、弥漫性大B细胞淋巴瘤或套细胞淋巴瘤患者体内。我们观察到不同淋巴瘤部位在患者体内和患者之间存在不同的Cu-αCD19 PET摄取模式，这与体外免疫组化CD19表达相关。此外，与先前接受过B细胞清除治疗的患者相比，1例患者脾脏摄取增强，表明Cu-αCD19适用于识别富含B细胞的器官。总之，我们通过CD19免疫PET证明了在小鼠和人类中对CD19 B-NHL的特异性靶向和可视化。淋巴瘤病灶的个体内和个体间Cu-αCD19摄取模式的异质性表明CD19表达存在变异性，提示CD19免疫PET作为指导CD19定向治疗的新工具具有潜力。
