The final obstacle to successful pre‐clinical xenotransplantation?

Abstract

Survival of non-human primates (NHPs) with life-supporting kidneys 1-4 or hearts 5 extends for many months. Attention has now turned towards phase transition to the first clinical trials. Ideally, the genetically engineered pig used as the source of the organs in the pre-clinical studies should be the same as that planned for the first clinical trials. Unfortunately, this will be difficult, and maybe impossible, because of differences in antibody binding to pig cells between humans and Old World NHPs. 6,7

Solid organ xenotransplantation at the interface between research and clinical development: Regulatory aspects

“…The scientific community has published requirements on efficacy data to support a clinical trial application, that is, for porcine islets 68 and cornea 69 in recent years, and already in 2000 for a porcine heart 70 . It should be realized in this discussion that studies in animal species have their limitations to translation to the human species; some examples are the complications in long‐term survival of a porcine islet product in diabetic monkeys 71 and incompatibility between non‐human primates and humans regarding expression of some carbohydrate xeno‐antigens 72 . Regulatory agencies do not prescribe which animal models including species combinations need to be used; most often, pivotal transplantation experiments are conducted in a life‐supporting situation, for example, for a kidney in animals after bilaterally nephrectomy.…”

Xenotransplantation literature update for September – October 2020

“…Yamamoto et al comment on relevance of antibody binding in humans and primates with regard to the production of natural antibodies directed at novel xenoantigens. The T‐cell proliferative response to α1,3‐galactosyltransferase gene knockout (GTKO) pig peripheral blood mononuclear cells (PBMCs) is reduced when compared to wild‐type pig PBMCs, while the deletion of expression of all three glycans does not further reduce the proliferative response 3 . However, baboons and old‐world monkeys contain antibodies that bind to RBCs from TKO pigs 4 due to the hypothetical fourth xenoantigen.…”

“…However, baboons and old‐world monkeys contain antibodies that bind to RBCs from TKO pigs 4 due to the hypothetical fourth xenoantigen. Therefore, kidneys and hearts from TKO pigs would not show antibody‐mediated injury when transplanted into humans while the T‐cell response suppressed by blockade of CD40‐CD154 co‐stimulation pathway, while binding of baboon natural antibodies to donor pig (CMAH deleted) activates the complement cascade and results in high serum cytotoxicity irrespective to the binding potential 3‐9 . The authors point out that post‐transplant production of antibody toward the fourth xenoantigen is likely to result in chronic antibody‐mediated rejection.…”

“…The authors point out that post‐transplant production of antibody toward the fourth xenoantigen is likely to result in chronic antibody‐mediated rejection. The obstacle of the fourth antigen may be overcome experimentally either when the xenoantigen is absent in case of additional gene editing, ex‐vivo perfusion of TKO organs with human blood to absorb antibody, or through further investigation by transplantation into brain‐dead human or New world monkey recipients 3 …”

The problem of the “4th xenoantigen” after pig organ transplantation in non‐human primates may be overcome by expression of human “protective” proteins

“…2-4 Therefore, successful pig heart or kidney transplantation in baboons may be more problematic than in a clinical trial. 4 The expression of one or more human complement-regulatory proteins, for example, CD46 and CD55, reduced early graft failure in GTKO pig-to-baboon transplant models. 5,6 However, it is unclear whether expression of additional human transgenes will suppress complement-dependent cytotoxicity (CDC) of TKO pig cells.…”