Abstract 4300: Receptor occupancy and tumor penetration by antibodies, peptides, and antibody fragments: Molecular simulation of imaging assessment

Abstract

Abstract Background: Non-uniform tumor penetration by antibodies may contribute to therapeutic failure. Competition experiments by radiolabeled antibody imaging can guide selection of the antibody dose that fully blocks target binding and thus corresponds to complete therapeutic coverage. However, because antibodies penetrate tumors slowly and non-uniformly, such a competition experiment may reflect only the most accessible sites. A novel approach, termed enhanced competition, has been proposed in which the radiolabeled moiety is smaller and more readily diffusible. In this study, simulations were conducted in order to examine the enhanced competition experiment. Materials and Methods: The Krogh cylinder distributed model was implemented to simulate the distribution of antibody, antibody fragment, affibody, or peptide in the tumor as a function of time and distance from the capillary wall. Simulations explored traditional and enhanced competition experiments, varying parameters including the nature of the small construct, time between administration of unlabeled and radiolabeled compounds, mass dose, affinity, antigen density, and internalization rate. Results were plotted as nanomolar concentration versus time and distance from the capillary wall. In addition, total tumor %ID/g is presented as a function of time and as a function of unlabeled antibody dose. Results: Simulation results showed that small constructs access sites in tumors at distances far from capillaries that are not readily accessible to intact antibodies. Under conditions of high affinity (1-10 nM), high antigen density (150,000 sites/cell), and compound internalization (t1/2 = 13 h), a mass of > 40 μg/kg of peptide or affibody construct required a higher dose of antibody to displace the radioactive signal compared to traditional competition with radiolabeled antibody. However, the difference in imaging signal between sub-saturating and fully displacing antibody doses is expected to be difficult to detect. Conclusions: The phenomenon predicted by the enhanced competition paradigm using small constructs is validated by modeling. Simulated imaging competition experiments indicate that affinity and mass dose levels are critical factors in this approach. High affinity small constructs and enhanced precision of imaging techniques will be required to fully evaluate target occupancy and saturation in vivo. Citation Format: Kelly D. Orcutt, Gregory P. Adams, Anna M. Wu, Matthew Silva, Jack Hoppin, Catey Harwell, Manabu Matsumura, Masakatsu Kotsuma, Daniel Freeman, Archie Tse, Jonathan Greenberg, Andrew Scott, Robert A. Beckman. Receptor occupancy and tumor penetration by antibodies, peptides, and antibody fragments: Molecular simulation of imaging assessment. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4300. doi:10.1158/1538-7445.AM2014-4300