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Theranostics 2018; 8(21):5903-5914. doi:10.7150/thno.27679 This issue Cite

Research Paper

Dual-Modality ImmunoPET/Fluorescence Imaging of Prostate Cancer with an Anti-PSCA Cys-Minibody

Wenting K Tsai¹, Kirstin A Zettlitz¹, Richard Tavaré^1,2, Naoko Kobayashi³, Robert E Reiter³, Anna M Wu^1,4✉

1. Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, UC Los Angeles
2. Current address: Regeneron Pharmaceuticals, Inc., Tarrytown, New York
3. Department of Urology, David Geffen School of Medicine, UC Los Angeles
4. Current address: Department of Molecular Imaging and Therapy, Beckman Research Institute, City of Hope, Duarte

✉ Corresponding author: Anna M Wu, Department of Molecular Imaging and Therapy, Beckman Research Institute, City of Hope, 1500 E. Duarte Rd. Duarte, CA 91010, USA. Tel: 1 (626) 218-8051; email: awuorg

Abstract

Inadequate diagnostic methods for prostate cancer lead to over- and undertreatment, and the inability to intraoperatively visualize positive margins may limit the success of surgical resection. Prostate cancer visualization could be improved by combining the complementary modalities of immuno-positron emission tomography (immunoPET) for preoperative disease detection, and fluorescence imaging-guided surgery (FIGS) for real-time intraoperative tumor margin identification. Here, we report on the evaluation of dual-labeled humanized anti-prostate stem cell antigen (PSCA) cys-minibody (A11 cMb) for immunoPET/fluorescence imaging in subcutaneous and orthotopic prostate cancer models.

Methods: A11 cMb was site-specifically conjugated with the near-infrared fluorophore Cy5.5 and radiolabeled with ¹²⁴I or ⁸⁹Zr. ¹²⁴I-A11 cMb-Cy5.5 was used for successive immunoPET/fluorescence imaging of prostate cancer xenografts expressing high or moderate levels of PSCA (22Rv1-PSCA and PC3-PSCA). ⁸⁹Zr-A11 cMb-Cy5.5 dual-modality imaging was evaluated in an orthotopic model. Ex vivo biodistribution at 24 h was used to confirm the uptake values, and tumors were visualized by post-mortem fluorescence imaging.

Results: A11 cMb-Cy5.5 retained low nanomolar affinity for PSCA-positive cells. Conjugation conditions were established (dye-to-protein ratio of 0.7:1) that did not affect the biodistribution, pharmacokinetics, or clearance of A11 cMb. ImmunoPET using dual-labeled ¹²⁴I-A11 cMb-Cy5.5 showed specific targeting to both 22Rv1-PSCA and PC3-PSCA s.c. xenografts in nude mice. Ex vivo biodistribution confirmed specific uptake to PSCA-expressing tumors with 22Rv1-PSCA:22Rv1 and PC3-PSCA:PC3 ratios of 13:1 and 5.6:1, respectively. Consistent with the immunoPET, fluorescence imaging showed a strong signal from both 22Rv1-PSCA and PC3-PSCA tumors compared with non-PSCA expressing tumors. In an orthotopic model, ⁸⁹Zr-A11 cMb-Cy5.5 immunoPET was able to detect intraprostatically implanted 22Rv1-PSCA cells. Importantly, fluorescence imaging clearly distinguished the prostate tumor from surrounding seminal vesicles.

Conclusion: Dual-labeled A11 cMb specifically visualized PSCA-positive tumor by successive immunoPET/fluorescence, which can potentially be translated for preoperative whole-body prostate cancer detection and intraoperative surgical guidance in patients.

Keywords: immunoPET, fluorescence, prostate cancer, antibody fragment, molecular imaging

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