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[89Zr]A2cDb Immuno-PET of Prostate Cancer in a Human Prostate Stem Cell Antigen Knock-in (hPSCA KI) Syngeneic Model

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Abstract

Purpose

A great challenge in the diagnosis and treatment of prostate cancer is distinguishing between indolent or local disease and aggressive or metastatic disease. Antibody-based positron emission tomography (immuno-PET) as a cancer-specific imaging modality could improve diagnosis of primary disease, aid the detection of metastases to regional lymph nodes as well as to distant sites (e.g., bone), and monitor response to therapy.

Procedure

In search for a more physiologically relevant disease model, a human prostate stem cell antigen knock-in (hPSCA KI) mouse model was generated. The use of a syngeneic prostate cancer cell line transduced to express human PSCA (RM-9-hPSCA) enabled the evaluation of anti-PSCA immuno-PET in immunocompetent mice and in the context of normal tissue expression of PSCA. Two PSCA-specific humanized antibody fragments, A11 minibody and A2 cys-diabody, were radiolabeled with positron emitters iodine-124 and zirconium-89, respectively ([124I]A11 Mb and [89Zr]A2cDb), and used for immuno-PET in wild-type, hPSCA KI and tumor-bearing mice.

Results

The hPSCA KI mice express PSCA at low levels in the normal prostate, bladder and stomach, reproducing the expression pattern seen in humans. [124I]A11 Mb immuno-PET detected increased levels of PSCA expression in the stomach, and because I-124 is non-residualizing, very little activity was seen in organs of clearance (liver, kidney, spleen). However, due to the longer half-life of the 80 kDa protein, blood activity (and thus urine activity) at 20 h postinjection remains high. The smaller 50 kDa [89Zr]A2cDb cleared faster, resulting in lower blood and background activity, despite the use of a residualizing radiometal. Importantly, [89Zr]A2cDb immuno-PET showed antigen-specific targeting of PSCA-expressing tumors and minimal nonspecific uptake in PSCA-negative controls.

Conclusion

Tracer biodistribution was not significantly impacted by normal tissue expression of PSCA. [89Zr]A2cDb immuno-PET yielded high tumor-to-blood ratio at early time points. Rapid renal clearance of the 50 kDa tracer resulted in an unobstructed view of the pelvic region at 20 h postinjection that would allow the detection of cancer in the prostate.

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Acknowledgments

We thank Chau Tran, Jean Kimi Wang, and Johnny Guan for their technical assistance. We thank Dr. Saul Priceman for providing cell lines RM-9 and RM-9-hPSCA.

Funding

This work was supported by NIH grant R01 CA174294 and Department of Defense IDEA Award W81XWH-15-1-0725. Small-animal imaging and pathology core services were supported by the Jonsson Comprehensive Cancer Center (JCCC) P30 CA016042.

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Author notes

  1. Kirstin A. Zettlitz & Anna M. Wu

    Present address: Molecular Imaging and Therapy, Beckman Research Institute, City of Hope, 1500 E. Duarte Rd, Duarte, CA, 91010, USA

  2. Scott M. Knowles

    Present address: University of Washington/Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N-D5-100, Seattle, WA, 98109, USA

Authors and Affiliations

  1. Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA

    Kirstin A. Zettlitz, Wen-Ting K. Tsai, Scott M. Knowles, Felix B. Salazar & Anna M. Wu

  2. David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA

    Kirstin A. Zettlitz, Wen-Ting K. Tsai, Scott M. Knowles, Felix B. Salazar, Naoko Kobayashi, Robert E. Reiter & Anna M. Wu

  3. Department of Urology, University of California Los Angeles, Los Angeles, CA, USA

    Naoko Kobayashi & Robert E. Reiter

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  1. Kirstin A. Zettlitz
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Corresponding author

Correspondence to Kirstin A. Zettlitz.

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Conflict of Interest

AM Wu holds ownership interest in and is a consultant/advisory board member for ImaginAb, Inc. AM Wu and RE Reiter are members of the JCCC. All other authors declare that they have no conflict of interest.

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All applicable institutional and/or national guidelines for the care and use of animals were followed. This article does not contain studies with human participants.

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Zettlitz, K.A., Tsai, WT.K., Knowles, S.M. et al. [89Zr]A2cDb Immuno-PET of Prostate Cancer in a Human Prostate Stem Cell Antigen Knock-in (hPSCA KI) Syngeneic Model. Mol Imaging Biol 22, 367–376 (2020). https://doi.org/10.1007/s11307-019-01386-7

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  • DOI: https://doi.org/10.1007/s11307-019-01386-7

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