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Title: Molecular Simulation of Receptor Occupancy and Tumor Penetration of an Antibody and Smaller Scaffolds: Application to Molecular Imaging.
Austin Authors: Orcutt, Kelly D;Adams, Gregory P;Wu, Anna M;Silva, Matthew D;Harwell, Catey;Hoppin, Jack;Matsumura, Manabu;Kotsuma, Masakatsu;Greenberg, Jonathan;Scott, Andrew M ;Beckman, Robert A
Affiliation: inviCRO, LLC Boston, Boston, MA, USA
Developmental Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, USA
Viventia Bio, Philadelphia, PA, USA
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
RD Division of Daiichi Sankyo Co., Ltd., Tokyo, Japan
Daiichi Sankyo Pharmaceutical Development, Edison, NJ, USA
Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
Department of Molecular Imaging and Therapy, Austin Health, Heidelberg, Victoria, Australia
La Trobe University, Melbourne, Australia
Department of Oncology, Georgetown University Medical Center, Washington, DC, USA
Department of Biostatistics, Bioinformatics, and Biomathematics, Georgetown University Medical Center, Washington, DC, USA
Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
Innovation Center for Biomedical Informatics, Georgetown University Medical Center, Washington, DC, USA
Issue Date: Oct-2017
Publication information: Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging 2017; 19(5): 656-664
Abstract: 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. 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. Smaller constructs <25┬ákDa 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. 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.
DOI: 10.1007/s11307-016-1041-y
ORCID: 0000-0002-6656-295X
PubMed URL: 28213834
Type: Journal Article
Subjects: Antibody imaging
Antibody scaffolds
Mathematical model
Receptor occupancy
Tumor antigen
Tumor penetration
Appears in Collections:Journal articles

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