Introduction: Effective T cell activation and effector function requires (1) cognate antigen recognition (2) appropriate costimulation and (3) successful cytokine signaling. Recently approved strategies to prolong kidney allograft survival and improve unwanted side effects have focused on the blockade of the CD28-CD80/86 costimulatory pathway with the high-affinity CTLA-4-Ig fusion protein belatacept. Unfortunately, wide-spread acceptance has been hindered by increased rates and grades of rejection. CD122, the β-chain shared by both the IL-2 and IL-15 receptors, is expressed on CD4 and CD8 T cells as well as NK cells. Antibody targeting CD122 will block signals from IL-2 and IL-15, thereby inhibiting both naïve and memory T cell responses. Here we assess the efficacy and safety of the anti-CD122 antibody alone and in combination with CTLA4-Ig/belatacept in both murine and non-human primate models of transplantation.

Methods: Fully MHC mismatched mice (Balb/c->B6) underwent skin grafts and were treated with costimulation blockade (CTLA-4-Ig /anti-CD154) +/- anti-CD122. Rhesus macaques underwent bilateral nephrectomy and life-sustaining renal transplantation using a kidney from an MHC-mismatched donor. Animals were treated with belatacept monotherapy, anti-CD122 monotherapy, or anti-CD122 + belatacept. Weekly serum chemistries assessed graft function post-transplant. Rejection was defined as serum creatinine >5mg/dL or BUN >100mg/dL on two consecutive measurements.

Results/Conclusions: Combined CD122 and costimulation blockade significantly prolonged skin graft survival over costimulation or CD122 blockade alone (MST of 70 days, 26 days and 13 days respectively n=10/gp). Next we evaluated the impact of anti-CD122 therapy in a non-human primate model of renal transplantation. Similar to the murine model, CD122 blockade synergized with costimulation blockade to prolong kidney allograft survival (>91, >84 and >35 days) compared to CD122 blockade alone (7 & 7 days) or Belatacept alone (MST 29 days, n=5). CD122 is up regulated on subsets of effector (CD45RA-CCR7-) and memory (CD45RA-CCR7+) T Cells and NK Cells in NHPs. Taken together, these data suggest that combined costimulatory and cytokine blockade using anti-CD122 and belatacept is a promising strategy to induce long-term graft survival.

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