*Purpose: Sensitized transplant recipients represent a challenge due to the presence of donor-specific antibodies (DSA), which increase the risk of antibody-mediated rejection. Complement inhibition has been shown to protect the graft against DSA; however, strategies target classical pathway activation, or terminal effectors such as C5b-9. We hypothesized that targeting C3 at the time of transplant can prevent both direct antibody mediated damage, and abrogate immune responses.

*Methods: Eleven (11) rhesus macaques were sensitized to maximally MHC mismatched donors by two sequential skin transplants. Primates subsequently received kidney allografts from their skin donors without prior desensitization therapy. All primates received induction therapy with rhesus specific anti-thymocyte globulin (rhATG) and maintenance immunosuppression with tacrolimus, mycophenolate mofetil and prednisone. A subset of 6 primates was additionally treated with the C3 complement inhibitor Compstatin for 14 days after kidney transplantation.

*Results: No difference in preformed DSA levels was observed prior to kidney transplantation between groups (mean MFI 909 vs. 1019, p=0.64). The addition of Compstatin significantly prolonged the median graft survival from 4 days in the control group to 15.5 days (p=0.028, Figure 1a), with reduced antibody-mediated injury on protocol kidney biopsies. The longest graft survival was 48 days. While all primates showed a significant increase in DSA after transplant, Compstatin enabled primates to maintain kidney function for up to 1 month beyond the last day of administration (POD14) in the presence of high serum DSA level (Figure 1b). Compstatin did not significantly alter T cell depletion by rhATG. However, we observed a significantly lower frequency of Ki67+ proliferating T cells (34.2% vs. 14.9%, p=0.004) and CD69+ activated T cells (25.7% vs. 16.4%, p=0.01) in the Compstatin group immediately post-transplant.

*Conclusions: Compstatin treatment significantly prolonged graft survival in a sensitized NHP kidney allotransplantation model, and protected the graft against acute antibody mediated injury in spite of high serum DSA levels. Under Compstatin, T cell activation and proliferation were decreased, suggesting an immunomodulatory effect of this therapy.

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