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Evaluation of [131I]I- and [177Lu]Lu-DTPA-A11 Minibody for Radioimmunotherapy in a Preclinical Model of PSCA-Expressing Prostate Cancer.
- Source :
- Molecular Imaging & Biology; Oct2020, Vol. 22 Issue 5, p1380-1391, 12p
- Publication Year :
- 2020
-
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 ([<superscript>124</superscript>I]I-A11 Mb) or conjugated with deferoxamine (DFO) and labeled with zirconium-89 ([<superscript>89</superscript>Zr]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 [<superscript>131</superscript>I]I-A11 Mb (non-residualizing) and <superscript>177</superscript>Lu chelated using DTPA ([<superscript>177</superscript>Lu]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 [<superscript>131</superscript>I]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 [<superscript>131</superscript>I]I-A11 Mb and [<superscript>177</superscript>Lu]Lu-DTPA-A11 Mb exhibited comparable tumor cell growth inhibition in vitro. In vivo surrogate immunoPET imaging using [<superscript>89</superscript>Zr]Zr-DFO-A11 Mb showed activity retention in liver and kidney up to 72 h, while [<superscript>124</superscript>I]I-A11 Mb cleared from liver, kidney, and blood by 48 h. Based on full biodistribution and dosimetry calculations, administering 37 MBq [<superscript>131</superscript>I]I-A11 Mb was predicted to deliver a favorable dose to the tumor (35 Gy), with a therapeutic index of 22 (tumor:bone marrow). For [<superscript>177</superscript>Lu]Lu-DTPA-A11 Mb, the kidneys would be dose-limiting, and the maximum tolerated activity (7.4 MBq) was not predicted to deliver an effective radiation dose to tumor. Radioimmunotherapy with a single dose of [<superscript>131</superscript>I]I-A11 Mb showed dose-dependent tumor inhibition with minimal off-target toxicity and improved median survival (19 and 24 days, P < 0.001) compared with untreated mice (12 days). Conclusions: These findings show the potential of the anti-PSCA minibody for targeted radioimmunotherapy with minimal toxicity, and the application of immunoPET and dosimetry for personalized treatment. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 15361632
- Volume :
- 22
- Issue :
- 5
- Database :
- Complementary Index
- Journal :
- Molecular Imaging & Biology
- Publication Type :
- Academic Journal
- Accession number :
- 145733586
- Full Text :
- https://doi.org/10.1007/s11307-020-01518-4