Abstract 658: Translational theranostic imaging of lymphoma using radiolabeled αCD19-antibodies

Abstract

Abstract CD19 proved to be an excellent target in B cell leukemia and lymphoma, especially in patients, refractory or not eligible to αCD20 monoclonal antibody (mAb) therapy. With the CD3-CD19 bispecific mAb Blinatumumab and αCD19 chimeric antigen receptor (CAR) T cells, two promising therapeutics have recently found their way into clinical application with impressive results. However, therapy decisions are mainly based on histological CD19 staining at initial diagnosis disregarding tumor heterogeneity and temporal expression alterations. To address these limitations, Theranostic Imaging approaches using radiolabeled antibodies are emerging tools to advance targeted cancer therapies. Positron-Emission-Tomography (PET) enables non-invasive whole-body visualization of specific target expression perfectly suitable for therapy stratification and to monitor response to targeted drugs. Furthermore, by following antibody biodistribution and tumor targeting in vivo over time modes of action and resistance mechanisms can be uncovered. We here report on the generation, preclinical characterization, and clinical evaluation of a radiolabeled αCD19 antibody for Theranostic Imaging of Non-Hodgkin lymphoma (NHL). Fc-optimized αCD19-mAb (4G7SDIE) with enhanced antibody-dependent cell cytotoxicity was manufactured at our university and successfully tested to treat minimal residual disease of childhood acute lymphoblastic leukemia. For Theranostic Imaging, this antibody was chelator conjugated with DOTAGA at an antibody-to-chelator ratio of 1:15. Radiolabeling with Copper-64 (64Cu) yielded radiochemical purity of >90 %. For clinical application, the radioimmunoconjugate was produced in accordance to GMP. In vitro cell labeling studies revealed specific binding to the target cells and immunoreactive fraction was 30 % after radiolabeling. Three different xenograft NHL mouse models were established in CD1 nude mice for in vivo imaging studies. PET/MRI was performed 6 h, 24 h, and 48 h after i.v. injection confirming specific targeting of 64Cu-DOTAGA-αCD19-mAb compared to CD19-negative tumors. Administration of the radioimmunoconjugate was then carried out in four NHL patients based on compassionate use program to evaluate eligibility of CD19-targeted therapy. Cervical, mediastinal, and abdominal lymphoma sites as well as bone marrow infiltration were detected by PET. Limited uptake was observed in some lesions including bulk tumors indicating partly insufficient amount of injected antibody. To our knowledge, we demonstrate for the first time the feasibility of a radiolabeled αCD19-mAb for lymphoma targeting in human. This theranostic approach might serve as a novel tool to predict response to upcoming CD19-targeting therapies including antibody-based or CAR T cell therapies. Further clinical studies will follow to test optimal dose regime and predosing strategies for enhanced tumor targeting. Citation Format: Dominik Sonanini, Johannes Schwenck, Julia Schmitt, Andreas Maurer, Sergios Gatidis, Christian Seitz, Gerald Reischl, Manfred Kneilling, Gundram Jung, Peter Lang, Lothar Kanz, Konstantin Nikolaou, Rupert Handgretinger, Christian la Fougère, Bernd J. Pichler. Translational theranostic imaging of lymphoma using radiolabeled αCD19-antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 658.