Kelly D Orcutt1, Gregory P Adams2,3, Anna M Wu4, Matthew D Silva5, Catey Harwell5, Jack Hoppin5, Manabu Matsumura6, Masakatsu Kotsuma6, Jonathan Greenberg7, Andrew M Scott8,9,10, Robert A Beckman11,12,13,14. 1. inviCRO, LLC Boston, 27 Drydock Ave., 7th Floor West, Boston, MA, 02210, USA. orcutt@invicro.com. 2. Developmental Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, USA. 3. Viventia Bio, 3711 Market Street, Philadelphia, PA, 19104, USA. 4. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. 5. inviCRO, LLC Boston, 27 Drydock Ave., 7th Floor West, Boston, MA, 02210, USA. 6. RD Division of Daiichi Sankyo Co., Ltd., Tokyo, Japan. 7. Daiichi Sankyo Pharmaceutical Development, Edison, NJ, USA. 8. Olivia Newton-John Cancer Research Institute, Melbourne, Australia. 9. Department of Molecular Imaging and Therapy, Austin Hospital, Melbourne, Australia. 10. La Trobe University, Melbourne, Australia. 11. Department of Oncology, Georgetown University Medical Center, Washington, DC, USA. 12. Department of Biostatistics, Bioinformatics, and Biomathematics, Georgetown University Medical Center, Washington, DC, USA. 13. Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA. 14. Innovation Center for Biomedical Informatics, Georgetown University Medical Center, Washington, DC, USA.
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.
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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