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Hetero-bivalent agents targeting FAP and PSMA

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

A Correction to this article was published on 31 August 2022

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Abstract

Purpose

We developed a theranostic radiopharmaceutical that engages two key cell surface proteases, fibroblast activation protein alpha (FAP) and prostate-specific membrane antigen (PSMA), each frequently overexpressed within the tumor microenvironment (TME). The latter is also expressed in most prostate tumor epithelium. To engage a broader spectrum of cancers for imaging and therapy, we conjugated small-molecule FAP and PSMA-targeting moieties using an optimized linker to provide 64Cu-labeled compounds.

Methods

We synthesized FP-L1 and FP-L2 using two linker constructs attaching the FAP and PSMA-binding pharmacophores. We determined in vitro inhibition constants (Ki) for FAP and PSMA. Cell uptake assays and flow cytometry were conducted in human glioma (U87), melanoma (SK-MEL-24), prostate cancer (PSMA + PC3 PIP and PSMA − PC3 flu), and clear cell renal cell carcinoma lines (PSMA + /PSMA − 786-O). Quantitative positron emission tomography/computed tomography (PET/CT) and tissue biodistribution studies were performed using U87, SK-MEL-24, PSMA + PC3 PIP, and PSMA + 786-O experimental xenograft models and the KPC genetically engineered mouse model of pancreatic cancer.

Results

64Cu-FP-L1 and 64Cu-FP-L2 were produced in high radiochemical yields (> 98%) and molar activities (> 19 MBq/nmol). Ki values were in the nanomolar range for both FAP and PSMA. PET imaging and biodistribution studies revealed high and specific targeting of 64Cu-FP-L1 and 64Cu-FP-L2 for FAP and PSMA. 64Cu-FP-L1 displayed more favorable pharmacokinetics than 64Cu-FP-L2. In the U87 tumor model at 2 h post-injection, tumor uptake of 64Cu-FP-L1 (10.83 ± 1.02%ID/g) was comparable to 64Cu-FAPI-04 (9.53 ± 2.55%ID/g). 64Cu-FP-L1 demonstrated high retention 5.34 ± 0.29%ID/g at 48 h in U87 tumor. Additionally, 64Cu-FP-L1 showed high retention in PSMA + PC3 PIP tumor (12.06 ± 0.78%ID/g at 2 h and 10.51 ± 1.82%ID/g at 24 h).

Conclusions

64Cu-FP-L1 demonstrated high and specific tumor targeting of FAP and PSMA. This compound should enable imaging of lesions expressing FAP, PSMA, or both on the tumor cell surface or within the TME. FP-L1 can readily be converted into a theranostic for the management of heterogeneous tumors.

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Funding

We thank Precision Molecular Inc., the Emerson Collective Cancer Research Fund, W81XWH2110920, EB024495, and CA184228 for financial support.

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Authors and Affiliations

  1. Russell H. Morgan Department of Radiology and Radiological Science, Baltimore, MD, USA

    Srikanth Boinapally, Alla Lisok, Gabriela Lofland, Il Minn, Yu Yan, Zirui Jiang, Min Jay Shin, Vanessa F. Merino, Martin G. Pomper & Sangeeta Ray Banerjee

  2. Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA

    Lei Zheng, Martin G. Pomper & Sangeeta Ray Banerjee

  3. Department of Molecular and Comparative Pathobiology, Baltimore, MD, USA

    Cory Brayton

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Contributions

Sangeeta Ray Banerjee and Martin G. Pomper contributed to the study’s conception and design. Material preparation (Srikanth Boinapally and Sangeeta Ray Banerjee), data collection, and analysis were performed by Srikanth Boinapally, Ala Lisok, Gabriela Lofland, Il Minn, Yu Yan, Zirui Jiang, Min Jay Shin, Vanessa Merino, Cory Brayton, and Sangeeta Ray Banerjee. Sangeeta Ray Banerjee wrote the first draft of the manuscript, and all authors commented on previous versions. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Martin G. Pomper or Sangeeta Ray Banerjee.

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All animal studies complied with the regulations of the Johns Hopkins University animal care and use committee.

Competing interests

Under a license agreement with Johns Hopkins University. S.B., I.M., M.G.P., and S.R.B. are entitled to royalty distributions related to the technology described in the study discussed in this publication. This arrangement has been reviewed and approved by Johns Hopkins University following its conflict-of-interest policies.

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Boinapally, S., Lisok, A., Lofland, G. et al. Hetero-bivalent agents targeting FAP and PSMA. Eur J Nucl Med Mol Imaging 49, 4369–4381 (2022). https://doi.org/10.1007/s00259-022-05933-3

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  • DOI: https://doi.org/10.1007/s00259-022-05933-3

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