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

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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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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Key words

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