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Molecular Imaging and Biology

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01-10-2020 | Prostate Cancer | Research Article

Evaluation of [¹³¹I]I- and [¹⁷⁷Lu]Lu-DTPA-A11 Minibody for Radioimmunotherapy in a Preclinical Model of PSCA-Expressing Prostate Cancer

Authors: Wen-Ting K Tsai, Kirstin A Zettlitz, Magnus Dahlbom, Robert E Reiter, Anna M Wu

Published in: Molecular Imaging and Biology | Issue 5/2020

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 ([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]Lu-DTPA-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 marrow). For [¹⁷⁷Lu]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 [¹³¹I]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.

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Title: Evaluation of [131I]I- and [177Lu]Lu-DTPA-A11 Minibody for Radioimmunotherapy in a Preclinical Model of PSCA-Expressing Prostate Cancer
Authors: Wen-Ting K Tsai
Kirstin A Zettlitz
Magnus Dahlbom
Robert E Reiter
Anna M Wu
Publication date: 01-10-2020
Publisher: Springer International Publishing
Keywords: Prostate Cancer
Radioimmunotherapy
Prostate Cancer
Published in: Molecular Imaging and Biology / Issue 5/2020
Print ISSN: 1536-1632
Electronic ISSN: 1860-2002
DOI: https://doi.org/10.1007/s11307-020-01518-4

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Evaluation of [¹³¹I]I- and [¹⁷⁷Lu]Lu-DTPA-A11 Minibody for Radioimmunotherapy in a Preclinical Model of PSCA-Expressing Prostate Cancer

Abstract

Purpose

Procedures

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Purpose

Procedures

Results

Conclusions

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