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Molecular Simulation of Receptor Occupancy and Tumor Penetration of an Antibody and Smaller Scaffolds: Application to Molecular Imaging

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Abstract

Purpose

Competitive radiolabeled antibody imaging can determine the unlabeled intact antibody dose that fully blocks target binding but may be confounded by heterogeneous tumor penetration. We evaluated the hypothesis that smaller radiolabeled constructs can be used to more accurately evaluate tumor expressed receptors.

Procedures

The Krogh cylinder distributed model, including bivalent binding and variable intervessel distances, simulated distribution of smaller constructs in the presence of increasing doses of labeled antibody forms.

Results

Smaller constructs <25 kDa accessed binding sites more uniformly at large distances from blood vessels compared with larger constructs and intact antibody. These observations were consistent for different affinity and internalization characteristics of constructs. As predicted, a higher dose of unlabeled intact antibody was required to block binding to these distant receptor sites.

Conclusions

Small radiolabeled constructs provide more accurate information on total receptor expression in tumors and reveal the need for higher antibody doses for target receptor blockade.

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Authors and Affiliations

  1. inviCRO, LLC Boston, 27 Drydock Ave., 7th Floor West, Boston, MA, 02210, USA

    Kelly D. Orcutt, Matthew D. Silva, Catey Harwell & Jack Hoppin

  2. Developmental Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, USA

    Gregory P. Adams

  3. Viventia Bio, 3711 Market Street, Philadelphia, PA, 19104, USA

    Gregory P. Adams

  4. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    Anna M. Wu

  5. RD Division of Daiichi Sankyo Co., Ltd., Tokyo, Japan

    Manabu Matsumura & Masakatsu Kotsuma

  6. Daiichi Sankyo Pharmaceutical Development, Edison, NJ, USA

    Jonathan Greenberg

  7. Olivia Newton-John Cancer Research Institute, Melbourne, Australia

    Andrew M. Scott

  8. Department of Molecular Imaging and Therapy, Austin Hospital, Melbourne, Australia

    Andrew M. Scott

  9. La Trobe University, Melbourne, Australia

    Andrew M. Scott

  10. Department of Oncology, Georgetown University Medical Center, Washington, DC, USA

    Robert A. Beckman

  11. Department of Biostatistics, Bioinformatics, and Biomathematics, Georgetown University Medical Center, Washington, DC, USA

    Robert A. Beckman

  12. Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA

    Robert A. Beckman

  13. Innovation Center for Biomedical Informatics, Georgetown University Medical Center, Washington, DC, USA

    Robert A. Beckman

Authors
  1. Kelly D. Orcutt
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  2. Gregory P. Adams
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  3. Anna M. Wu
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  4. Matthew D. Silva
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  8. Masakatsu Kotsuma
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  9. Jonathan Greenberg
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  10. Andrew M. Scott
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  11. Robert A. Beckman
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Corresponding author

Correspondence to Kelly D. Orcutt.

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Conflict of Interest

KDO and JH are full-time employees and stockholders of inviCRO. MS is a former employee and owns stock in inviCRO. JG is a full-time employee of Daiichi Sankyo, Inc. and owns stock in Daiichi Sankyo. MK is a full-time employee of Daiichi Sankyo. MM is a former employee and owns stock in Daiichi Sankyo. GPA and AMW are consultants to Daiichi Sankyo. GPA is a full-time employee of Viventia Bio. AMS has received funding/research support from Daiichi Sankyo. RAB is a former employee of Daiichi Sankyo and owns stock in Johnson and Johnson. This work was funded in part by Daiichi Sankyo, Inc.

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Orcutt, K.D., Adams, G.P., Wu, A.M. et al. Molecular Simulation of Receptor Occupancy and Tumor Penetration of an Antibody and Smaller Scaffolds: Application to Molecular Imaging. Mol Imaging Biol 19, 656–664 (2017). https://doi.org/10.1007/s11307-016-1041-y

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  • DOI: https://doi.org/10.1007/s11307-016-1041-y

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