Strategies to Optimize Pig-to Primate Kidney Xenograft Survival

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With over 100,000 patients now on the waiting list for a kidney transplant, it is obvious that there is a critical shortage of available donor organs. Xenotransplantation represents a promising solution. While pigs are viewed as the optimal non-human source of organs, the potency of the human immune response to pig organs has prevented the clinical application of pig-to-human kidney transplantation. In this application we propose using cutting-edge genetic engineering approaches in combination with novel, clinically relevant immune- suppressants to reduce both the humoral and cellular immune response of nonhuman primates undergoing kidney xenotransplantation as a preclinical model to inform future human trials. With recent advances in genome editing techniques we and others have created novel pig donors with multiple genetic alterations and resultant improvements in xenograft survival. In addition, we have developed and applied strategies to avoid early antibody mediated rejection by using a pre-transplant antibody screen similar to the crossmatch used in clinical transplantation. We further identified CD4+ T cells as a critical subset in xenograft rejection and demonstrated consistent long-term survival in the pig-to-primate kidney transplant model. These results represent a major advance on the road to clinical translation of xenotransplantation. Here we propose to study three major barriers to the clinical translation of xenotransplantation: (1) All long-term xenograft survival has been dependent on antibody blockade of the CD40-CD154 pathway and there is currently no clinically approved reagent. We will evaluate the only two clinically relevant CD40-CD154 pathway antagonists that are in development and have shown efficacy in human patients: a) Iscalimab, a novel anti-CD40 antibody and b) VIB4920, an innovative CD154-targeting protein. Neither of these new reagents has been tested in xenotransplantation previously. (2) We will determine the impact of two novel desensitization treatments as well as transient complement inhibition on early antibody mediated rejection. We will test imlifidase (IdeS, an IgG degrading enzyme recently approved by the FDA for the prevention and treatment of antibody mediated rejection) as well as an innovative desensitization strategy combining costimulation blockade and proteasome inhibition. In addition to addressing early antibody mediated injury we will test a novel complement-directed therapy, tesidolumab, an anti-C5 antibody that is currently being evaluated in clinical trials. We present exciting data using the novel anti-C5 antibody tesidolumab, suggesting that targeted complement inhibition mitigates early antibody rejection. (3) Lastly we will address the important issue of late antibody mediated injury. Given our success we are uniquely positioned to study this important problem. Similar to clinical kidney transplantation, we have new data that late kidney xenograft injury is directly related to the development of anti-SLA class II antibody. We will test the importance of this finding by deleting the genes for SLA class II DQ and DR in the porcine donor tissue and assessing the impact on rejection and protective immunity.