Date: Tuesday, June 14, 2016
Session Time: 2:30pm-4:00pm
Presentation Time: 3:30pm-3:42pm
Location: Veterans Auditorium
Background. CD40-CD154 pathway blockade significantly prolongs renal allograft survival in non-human primates (NHPs), and trials of the novel blocking, non-depleting anti-CD40 monoclonal antibody (mAb) CFZ533 in de novo kidney transplantation have been initiated. The exploration of the relationship between CFZ533 blood/serum levels and CD40 pathway inhibition in tissues is a key aspect in the selection of a dose and regimen that would result in complete CD40-CD154 blockade in kidney transplantation.
Aim. To address this question, we made use of in vitro and in vivo data, examining outcomes of CD40 pathway inhibition in the context of receptor occupancy, CFZ533 serum concentration as well as a relevant tissue pharmacodynamic (PD) effect, namely the decreased cellularity of established germinal centers (GC).
Results. Using an in vitro human whole blood assay where we could simultaneously assess CD40 receptor occupancy (RO) and pathway inhibition by CFZ533, we could clearly demonstrate that full RO was required for complete suppression of recombinant CD154 (rCD154)-mediated expression of CD69, CD23 and ICAM1. In vivo (healthy volunteers), full RO on peripheral blood B cells was observed at CFZ533 plasma concentrations ≥1 [mu]g/mL. In contrast, in vivo experiments in NHPs indicated that steady-state serum CFZ533 concentrations ≥38 [mu]g/mL were required for full suppression of germinal centers in mesenteric lymph nodes, almost 40-fold higher than observed for complete peripheral blood RO.
Conclusions. Our results suggest that CFZ533 dose-selection should not rely solely on RO data in peripheral blood, but also on the relationship between serum exposure and a relevant pathway PD effect in tissue. Such an approach would help avoid under-dosing in the clinic; of particular concern in transplantation, where accelerated target-mediated clearance of anti-CD40 mAbs has been observed. Our results have therefore proved crucial in selecting a dose of CFZ533 that would enable us to test the hypothesis of whether full CD40 pathway blockade would prolong allograft survival patients undergoing de novo renal transplantation in the absence of CNIs.
CITATION INFORMATION: Espie P, Munz J, Flandre T, Haraldsson B, Ulrich P, Rush J. Establishing the Relationship Between Receptor Occupancy, Serum Exposure and Pathway Inhibition by the Blocking, Non-Depleting Anti-CD40 Antibody CFZ533 to Inform Dose Selection in Clinical Transplantation. Am J Transplant. 2016;16 (suppl 3).
To cite this abstract in AMA style:Espie P, Munz J, Flandre T, Haraldsson B, Ulrich P, Rush J. Establishing the Relationship Between Receptor Occupancy, Serum Exposure and Pathway Inhibition by the Blocking, Non-Depleting Anti-CD40 Antibody CFZ533 to Inform Dose Selection in Clinical Transplantation. [abstract]. Am J Transplant. 2016; 16 (suppl 3). https://atcmeetingabstracts.com/abstract/establishing-the-relationship-between-receptor-occupancy-serum-exposure-and-pathway-inhibition-by-the-blocking-non-depleting-anti-cd40-antibody-cfz533-to-inform-dose-selection-in-clinical-transplant/. Accessed January 25, 2021.
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