Assessment of Belatacept-Mediated Costimulation Blockade Through Evaluation of CD80/86-Receptor Saturation

Authors:
  • CFCatherine Fleener
    Catherine Fleener
  • VLVahideh Lamian
    Vahideh Lamian
  • EKEdward Kulbokas
    Edward Kulbokas
  • PDPatricia M. Davis
    Patricia M. Davis
  • SSSuzanne J. Suchard
    Suzanne J. Suchard
  • MCMark Curran
    Mark Curran
  • FVFlavio Vincenti
    Flavio Vincenti
  • RTRobert Townsend
    Robert Townsend
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Abstract
The selective inhibitor of T-cell costimulation, belatacept, blocks CD28-mediated T-cell activation by binding CD80 and CD86 on antigen-presenting cells. Understanding the extent to which belatacept binds to its targets in patients may enable correlation of belatacept exposure to receptor saturation as a pharmacodynamic measure of costimulation blockade. Flow cytometry-based receptor competition assays were developed to monitor concentration-dependent occupancy of CD80 and CD86 receptors in whole blood and dendritic cell cultures in vitro. Receptor occupancy was correlated with inhibition of mixed leukocyte reactions and clinical validation was obtained by comparing receptor saturation in whole blood from healthy volunteers and in de novo renal transplant recipients participating in studies comparing cyclosporine and belatacept-based immunosuppression. Belatacept saturated CD80 and CD86 receptors in whole blood and dendritic cell cultures, although the belatacept concentrations required for CD86-receptor saturation were approximately 10-fold higher than those required for CD80 saturation (IC50=0.102 μg/mL vs. 0.009 μg/mL). Primary alloresponses were inhibited at the belatacept concentration required for CD86-receptor saturation, but not at the lower concentration needed to saturate CD80. Whole blood from belatacept-treated patients had significantly lower levels of free CD86 receptors versus pretransplant levels, healthy volunteers, or cyclosporine-treated patients. CD86-receptor saturation correlated with belatacept dose/dose frequency and remained consistently more than 80%. These results suggest that belatacept-mediated inhibition of alloresponses involved in transplant rejection correlates with CD86 saturation, indicating that CD86-receptor occupancy may be a valid pharmacodynamic measure of costimulation blockade and provide the first direct clinical evidence that belatacept binds to one of its targets.

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