Introduction. Xenotransplantation may alleviate the organ shortage, yet experimental renal xenotransplantation has met limited success. T cell-mediated damage remains a critical problem. Our group has demonstrated that a domain antibody targeting CD28 (CD28dAb) prolongs survival in a primate (NHP) kidney transplant model, so we compared belatacept (directed against donor porcine and recipient NHP APCs) vs CD28dAb (directed at recipient NHP T cells) in pig-to-NHP xenotransplantation.

Methods. Labeled belatacept was incubated with PBMCs from humans, NHPs, and pigs. Belatacept or CD28dAb were put into mixed lymphocyte reactions (MLRs) to assess impacts on proliferation and effector function of xenostimulated NHP cells. NHPs with low titers of antibodies against donor transgenic α-1,3-galactosyltransferase knockout, human decay-accelerating factor pigs underwent renal xenotransplant with either CD28dAb (n=3) or belatacept (n=3).

Results. There was a lower frequency of porcine cells bound by belatacept compared to human/NHP cells; significantly less belatacept was bound to porcine cells (p=.021). In MLRs, CD28dAb prevented T cell proliferation and effector function significantly better than belatacept (p=.003, .024). CD28dAb therapy significantly prolonged xenograft survival better than belatacept (MST 72 vs 21, p=.025).Conclusions. Belatacept is less effective at binding donor porcine APCs than human/NHP APCs. CD28dAb is more effective at preventing proliferation and effector function of xenostimulated NHP T cells. These in vitro differences had a biologic difference when translated to a pig-to-NHP xenotransplantation model, as CD28dAb significantly prolonged xenograft survival vs belatacept.

CITATION INFORMATION: Kim S, Higginbotham L, Mathews D, Breeden C, Stephenson A, Larsen C, Ford M, Tector J, Adams A. CD28 Directed Immunotherapy Is More Potent Than Belatacept in a Nonhuman Primate Xenotransplant Model. Am J Transplant. 2017;17 (suppl 3).

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