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An Analysis of Isoclonal Antibody Formats Suggests a Role for Measuring PD-L1 with Low Molecular Weight PET Radiotracers

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Abstract

Purpose

The swell of new and diverse radiotracers to predict or monitor tumor response to cancer immunotherapies invites the opportunity for comparative studies to identify optimal platforms. To probe the significance of antibody format on image quality for PD-L1 imaging, we developed and studied the biodistribution of a library of antibodies based on the anti-PD-L1 IgG1 clone C4.

Procedure

A C4 minibody and scFv were cloned, expressed, and characterized. The antibodies were functionalized with desferrioxamine and radiolabeled with Zr-89 to enable a rigorous comparison with prior data collected using 89Zr-labeled C4 IgG1. The biodistribution of the radiotracers was evaluated in C57Bl6/J or nu/nu mice bearing B16F10 or H1975 tumors, respectively, which are models that represent high and low tumor autonomous PD-L1 expression.

Results

The tumor uptake of the 89Zr-C4 minibody was higher than 89Zr-C4 scFv and equivalent to previous data collected using 89Zr-C4 IgG1. However, the peak tumors to normal tissue ratios were generally higher for 89Zr-C4 scFv compared with 89Zr-C4 minibody and 89Zr-IgG1. Moreover, an exploratory study showed that the rapid clearance of 89Zr-C4 scFv enabled detection of endogenous PD-L1 on a genetically engineered and orthotopic model of hepatocellular carcinoma.

Conclusion

In summary, these data support the use of low molecular weight constructs for PD-L1 imaging, especially for tumor types that manifest in abdominal organs that are obstructed by the clearance of high molecular weight radioligands.

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Funding

M.J.E. was supported by an American Cancer Society Research Scholar Grant (130635-RSG-17-005-01-CCE) and the National Institute Biomedical Imaging and Bioengineering (R01EB025207). L.F. was supported by a Prostate Cancer Foundation Challenge Grant and the National Cancer Institute (R01CA223484, U01CA233100, and U01CA244452). C.S.C. was supported by the National Cancer Institute (P41CA196276). D.R. was supported by the National Cancer Institute (R35CA242986). Small animal PET/CT studies were performed on the instrument supported by National Institutes of Health grant S10RR023051. Research from UCSF reported in this publication was supported in part by the National Cancer Institute of the National Institutes of Health under Award Number P30CA082103. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Research from Singapore Immunology Network in this publication was supported by the Category 3 Industrial Alignment Fund (IAF 311007) awarded by the Biomedical Research Council of A*STAR.

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Author notes

  1. Junnian Wei and Yung-hua Wang contributed equally to this work.

Authors and Affiliations

  1. Department of Radiology and Biomedical Imaging, University of California San Francisco, 505 Parnassus Ave, San Francisco, CA, 94143, USA

    Junnian Wei, Yung-hua Wang, Robert R. Flavell, Henry F. VanBrocklin, Youngho Seo & Michael J. Evans

  2. Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove Immunos #03-06, Biopolis, Singapore, 138648, Singapore

    Chia Yin Lee & Cheng-I Wang

  3. Imagerie Moleculaire In Vivo, INSERM, CEA, Univ. Paris Sud, CNRS, Universite Paris Saclay, CEA-Service Hospitalier Frederic Joliot, 94100, Orsay, France

    Charles Truillet

  4. Department of Medicine, University of California San Francisco, 513 Parnassus Ave, San Francisco, CA, 94143, USA

    David Y. Oh & Lawrence Fong

  5. Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, 505 Parnassus Ave, San Francisco, CA, 94143, USA

    David Y. Oh, Davide Ruggero, Robert R. Flavell, Henry F. VanBrocklin, Youngho Seo, Charles S. Craik, Lawrence Fong & Michael J. Evans

  6. Department of Urology, University of California San Francisco, 505 Parnassus Ave, San Francisco, CA, 94143, USA

    Yichen Xu & Davide Ruggero

  7. Department of Pharmaceutical Chemistry, University of California San Francisco, 505 Parnassus Ave, San Francisco, CA, 94143, USA

    Charles S. Craik & Michael J. Evans

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  1. Junnian Wei
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  2. Yung-hua Wang
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Correspondence to Michael J. Evans.

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Wei, J., Wang, Yh., Lee, C.Y. et al. An Analysis of Isoclonal Antibody Formats Suggests a Role for Measuring PD-L1 with Low Molecular Weight PET Radiotracers. Mol Imaging Biol 22, 1553–1561 (2020). https://doi.org/10.1007/s11307-020-01527-3

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  • DOI: https://doi.org/10.1007/s11307-020-01527-3

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