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

2017-10

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

Antibody imaging

Antibody scaffolds

Mathematical model

Receptor occupancy

Tumor antigen

Tumor penetration

Journal Article

0000-0002-6656-295X

10.1007/s11307-016-1041-y

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 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. 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.

link

Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging 2017; 19(5): 656-664

Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging