Evaluation of [ 131 I]I- and [ 177 Lu]Lu-DTPA-A11 Minibody for Radioimmunotherapy in a Preclinical Model of PSCA-Express
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RESEARCH ARTICLE
Evaluation of [131I]I- and [177Lu]Lu-DTPA-A11 Minibody for Radioimmunotherapy in a Preclinical Model of PSCA-Expressing Prostate Cancer Wen-Ting K Tsai,1,4 Kirstin A Zettlitz,1,5 Magnus Dahlbom,2 Robert E Reiter,3 Anna M Wu 1,5 1
Department of Molecular and Medical Pharmacology, Crump Institute for Molecular Imaging, David Geffen School of Medicine, UC Los Angeles, Los Angeles, CA, USA 2 Department of Molecular and Medical Pharmacology, Ahmanson Translational Imaging Division, David Geffen School of Medicine, UC Los Angeles, Los Angeles, CA, USA 3 Department of Urology, David Geffen School of Medicine, UC Los Angeles, Los Angeles, CA, USA 4 Antibody Engineering, Genentech, South San Francisco, CA, USA 5 Department of Molecular Imaging and Therapy, Beckman Research Institute, City of Hope, Duarte, CA, USA
Abstract Purpose: Radioimmunotherapy uses tumor-specific antibodies to deliver therapeutic radionuclides, but hematological toxicity due to the long serum half-life of intact antibodies remains a challenge. We evaluated a smaller antibody fragment, the minibody, with faster kinetics and a potentially improved therapeutic index. Procedures: The anti-prostate stem cell antigen (PSCA) minibody (A11 Mb) was radiolabeled with iodine-124 ([124I]I-A11 Mb) or conjugated with deferoxamine (DFO) and labeled with zirconium-89 ([89Zr]Zr-DFO-A11 Mb) for surrogate immunoPET to profile pharmacokinetics in a human prostate cancer xenograft model. Subsequently, minibodies labeled with two therapeutic beta emitters, directly iodinated [131I]I-A11 Mb (non-residualizing) and 177Lu chelated using DTPA ([177Lu]Lu-DTPA-A11 Mb) (residualizing), were compared for in vitro antigen-specific cytotoxicity. Full biodistribution studies (in 22Rv1-PSCA tumor bearing and hPSCA knock-in mice) were conducted for dosimetry calculations. Finally, the lead candidate [131I]I-A11 Mb was evaluated in a radioimmunotherapy experiment. Escalating single doses (3.7, 11, or 37 MBq) and saline control were administered to 22Rv1-PSCA tumor bearing mice and anti-tumor effects (tumor volume) and toxicity (body weight) were monitored. Results: Minibodies radiolabeled with therapeutic beta emitters [131I]I-A11 Mb and [177Lu]LuDTPA-A11 Mb exhibited comparable tumor cell growth inhibition in vitro. In vivo surrogate immunoPET imaging using [89Zr]Zr-DFO-A11 Mb showed activity retention in liver and kidney up to 72 h, while [124I]I-A11 Mb cleared from liver, kidney, and blood by 48 h. Based on full biodistribution and dosimetry calculations, administering 37 MBq [131I]I-A11 Mb was predicted to deliver a favorable dose to the tumor (35 Gy), with a therapeutic index of 22 (tumor:bone
Electronic supplementary material The online version of this article (https:// doi.org/10.1007/s11307-020-01518-4) contains supplementary material, which is available to authorized users. Correspondence to: Anna Wu; e-mail: [email protected]
Tsai W.-T.K. et al.: Radioimmunotherapy targeting PSCA in prostate cancer
marrow). For [177Lu]Lu-DTPA-A11 Mb, the kidneys would be dose
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