Background: Clinical studies with belatacept have shown improved graft function at the cost of increased rates of and more severe early rejection. Blockade of LFA-1 adhesion and signaling using the mouse anti-CD11a antibody, TS-1/22, has been shown to synergize with belatacept in a non-human primate model of pancreatic islet transplant¹. We hypothesized that combining belatacept and TS-1/22 would prolong graft survival in a primate model of renal transplantation.

Methods: Following nephrectomy, size-matched rhesus macaques underwent renal transplantation. MHC disparity was confirmed by 454 pyrosequencing of Class I loci. All recipients received a single dose of methylprednisolone at the time of transplant and belatacept maintenance therapy. Eight animals additionally received induction therapy with tapering doses of TS-1/22 over eight weeks: 3 received a mouse/rhesus IgG1 chimeric, 4 received a mouse/rhesus IgG4 chimeric, and 1 received the fully mouse antibody. Serum creatinine levels were used to monitor graft function. Flow cytometry of peripheral blood cells and CMV PCR were performed weekly. All animals received viral prophylaxis with valganciclovir.

Results: Two animals that did not receive TS-1/22 had graft survival of 44 and 71 days. Three animals receiving chimeric TS-1/22 IgG1 had graft survival of 21, 28, and 35 days. Four animals received chimeric TS-1/22 IgG4 and had graft survival of 30, 34, 34, >267 days. The animal receiving mouse TS-1/22 continues to have normal graft function 28 days post-transplant. Animals receiving TS-1/22, regardless of form, developed peripheral lymphocytosis and blockade of CD11a staining on flow cytometry, consistent with previous experience. All animals receiving TS-1/22 developed subclinical CMV viremia that did not require additional therapy.

Conclusions: We conclude the addition of chimeric TS-1/22 did not synergize with belatacept in our model of renal transplantation, despite evidence of drug effect by cell counts and flow cytometry and contrary to previous results using the mouse antibody in islet transplantation. An evaluation of the mouse antibody is underway. The emergence of subclinical viremia indicates a need for more selective blockade if the LFA-1 pathway should be targeted clinically.

1. Badell IR, et al. J. Clin. Invest. 2010; 120(12):4520–31.

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