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Molecular Imaging and Biology

, Volume 19, Issue 5, pp 656–664 | Cite as

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

  • Kelly D. Orcutt
  • Gregory P. Adams
  • Anna M. Wu
  • Matthew D. Silva
  • Catey Harwell
  • Jack Hoppin
  • Manabu Matsumura
  • Masakatsu Kotsuma
  • Jonathan Greenberg
  • Andrew M. Scott
  • Robert A. Beckman
Research Article

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.

Key words

Receptor occupancy Tumor penetration Antibody imaging Antibody scaffolds Mathematical model Tumor antigen 

Notes

Compliance with Ethical Standards

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.

Supplementary material

11307_2016_1041_MOESM1_ESM.pdf (495 kb)
ESM 1 (PDF 494 kb)

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Copyright information

© World Molecular Imaging Society 2017

Authors and Affiliations

  • Kelly D. Orcutt
    • 1
  • Gregory P. Adams
    • 2
    • 3
  • Anna M. Wu
    • 4
  • Matthew D. Silva
    • 1
  • Catey Harwell
    • 1
  • Jack Hoppin
    • 1
  • Manabu Matsumura
    • 5
  • Masakatsu Kotsuma
    • 5
  • Jonathan Greenberg
    • 6
  • Andrew M. Scott
    • 7
    • 8
    • 9
  • Robert A. Beckman
    • 10
    • 11
    • 12
    • 13
  1. 1.inviCROLLC BostonBostonUSA
  2. 2.Developmental Therapeutics ProgramFox Chase Cancer CenterPhiladelphiaUSA
  3. 3.Viventia BioPhiladelphiaUSA
  4. 4.Department of Molecular and Medical PharmacologyDavid Geffen School of Medicine at UCLALos AngelesUSA
  5. 5.RD Division of Daiichi Sankyo Co., Ltd.TokyoJapan
  6. 6.Daiichi Sankyo Pharmaceutical DevelopmentEdisonUSA
  7. 7.Olivia Newton-John Cancer Research InstituteMelbourneAustralia
  8. 8.Department of Molecular Imaging and TherapyAustin HospitalMelbourneAustralia
  9. 9.La Trobe UniversityMelbourneAustralia
  10. 10.Department of OncologyGeorgetown University Medical CenterWashingtonUSA
  11. 11.Department of Biostatistics, Bioinformatics, and BiomathematicsGeorgetown University Medical CenterWashingtonUSA
  12. 12.Lombardi Comprehensive Cancer CenterGeorgetown University Medical CenterWashingtonUSA
  13. 13.Innovation Center for Biomedical InformaticsGeorgetown University Medical CenterWashingtonUSA

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