Anti-CD28 Antibody and Belatacept Exert Differential Effects on Mechanisms of Renal Allograft Rejection

Abstract

Belatacept is a biologic that targets CD80/86 and prevents its interaction with CD28 and its alternative ligand, cytotoxic T lymphocyte antigen 4 (CTLA-4). Clinical experience in kidney transplantation has revealed a high incidence of rejection with belatacept, especially with intensive regimens, suggesting that blocking CTLA-4 is deleterious. We performed a head to head assessment of FR104 (n=5), a selective pegylated Fab' antibody fragment antagonist of CD28 that does not block the CTLA-4 pathway, and belatacept (n=5) in kidney allotransplantation in baboons. The biologics were supplemented with an initial 1-month treatment with low-dose tacrolimus. In cases of acute rejection, animals also received steroids. In the belatacept group, four of five recipients developed severe, steroid-resistant acute cellular rejection, whereas FR104-treated animals did not. Assessment of regulatory T cell-specific demethylated region methylation status in 1-month biopsy samples revealed a nonsignificant trend for higher regulatory T cell frequencies in FR104-treated animals. Transcriptional analysis did not reveal significant differences in Th17 cytokines but did reveal higher levels of IL-21, the main cytokine secreted by CD4 T follicular helper (Tfh) cells, in belatacept-treated animals. In vitro, FR104 controlled the proliferative response of human preexisting Tfh cells more efficiently than belatacept. In mice, selective CD28 blockade also controlled Tfh memory cell responses to KLH stimulation more efficiently than CD80/86 blockade. Our data reveal that selective CD28 blockade and belatacept exert different effects on mechanisms of renal allograft rejection, particularly at the level of Tfh cell stimulation.

Selective blockade of CD28 on human T cells facilitates regulation of alloimmune responses

“…Conversely, Poirier and colleagues have shown that selective blockade of CD28 costimulation promotes Treg suppression in a nonhuman primate model (37). Ville and colleagues have also shown that FR104 prevents acute rejection, in contrast to CTLA4-Ig, by controlling CD4 T cell follicular helper cells in a nonhuman primate model (38). In a separate mouse study, Zhang and colleagues have shown that selective CD28 blockade using a Table 2.…”

Costimulation Blockade in Autoimmunity and Transplantation: The CD28 Pathway

“…Both compounds seem to be devoid of the activating properties seen with TGN1412 and are highly effective in preclinical models of transplantation and autoimmunity, presumably because they preserve coinhibitory signals transmitted through CTLA-4 (76–79). Importantly, selective CD28 blockade better preserves Treg functionality and better inhibits pathogenic memory T cell responses in transplantation relative to CTLA-4–Ig (76, 80– 82). Although there have been other promising compounds that target various costimulatory pathways (e.g., anti-CD154, anti-CD40, anti–LFA-1, LFA-3–Ig, anti-OX40L), none are used in patients.…”

Mechanisms of Mixed Chimerism-Based Transplant Tolerance

“…Moreover, human Tregs fail to up-regulate CD40L upon activation, in contrast to conventional CD4+ T cells [85]. Also of interest, blocking anti-CD28 antibody treatment was associated with an increased Treg frequency in large animal models [86], and was extremely potent in preventing alloantibody development by blocking follicular T-helper cell activation [87], while preserving CTLA-4 dependent T follicular regulatory T cell function [88]. …”