Effects on an α-Gal-PEG conjugate, NEX1285, on survival of CD46 transgenic heterotopic cardiac xenografts in baboons
Anti-Gal antibodies play a central role in the hyperacute (HAR) and vascular rejection of pig to primate xenografts. Without therapy to block anti-Gal antibodies, transgenic pig organs can generally suppress HAR but succumb to vascular rejection that appears to correlate with a strong induction of anti-Gal antibody. Previous pig to baboon transplants (n = 9) without anti-Gal therapy using transgenic pig hearts and a Cyclophosphamide (CyP), Cyclosporin (CsA) and steroid immunosuppression regime had a median organ survival of 4.5 days (range: 0.5-23 days) compared to 0.035 days for non-transgenic pig hearts. In this study baboons (n = 9) received 6 infusions of NEX1285 (50 mg/kg) at three day intervals prior to transplant and daily infusion after transplant along with immunosuppression with CyP, CsA and steroids. The median organ survival after NEX1285 treatment was 16 days (range: 8-40 days). Five of the baboons died with functioning grafts one each from exsangination resulting from a pulled line, a strangulated bowel, a left atrium tear and two animals from sepsis. Rejection in the remaining animals was characterized by edema, thrombosis and ischemia. Infusion of NEX1285 produced over 90% reduction in serum anti-Gal antibodies prior to transplant, however, the grafts generally exhibited antibody binding without complement deposition in 30 min post transplant biopsies. Post explant serum from surviving animals exhibited little induction of anti-Gal antibodies but anti-non-Gal antibodies, detected by endothelial cell ELISA, was present in the serum from one animal. Antibody eluted from the grafts contained less anti-Gal specificity, exhibited reduced cytotoxicity and a higher prevalence of non-Gal cytotoxicity compared to organs without NEX1285. Infusion of NEX1285 significantly prolonged organ survival and reduced the level of anti-Gal antibody induction normally seen during a xenograft.