Worldwide First Successful Long-term Survival after Orthotopic Cardiac Xenotransplantation of Multitransgenic Pig Hearts into Baboons Using a CD40mAb or CD40L Costimulation Blockade

Objectives: In our orthotopic cardiac xenotransplantation (OHXTx) pig-to-baboon model with GalT-KO/hCD46/hTM transgenic donor pigs we used a non-toxic immunosuppression (IS) based on CD40mAb co-stimulation blockade in group G1 and in a group G2 a new PAsylated, nonthrombogenic CD40L-Ab. The procedure of PASylation prolongs plasma half-life to several days. Primary aims were to achieve a constant preclinical long-term survival in a life-supporting cardiac xenotransplantation model and to prevent perioperative cardiac xenograft dysfunction (PCXD).

Methods: OHXTx according to the technique of Lower and Shumway were performed in 9 baboons with transgenic pig hearts. The new IS consisted of a recombinant mouse-rhesus chimeric CD40 (clone 2C10R4) antibody in G1 (n = 6) or a PAsylated Fab-CD40L antibody (XL-protein/Wacker-Chemie) in G2 (n = 3) combined with ATG, rituximab, MMF (no tacrolimus or cyclosporine!) and cortisone.

Results: Survival in G1 with CD40mAb were 3, 1, 30, 1, 1** and 27 day(s) with 2 cases of PCXD. Using CD40L-Ab in G2 PCXD was observed in 1 case and the recipients survived 1, 18 and 40 days. Cardiac ischemic time ranged from 112–128 minute. Cause of death mostly were renal and hepatic failure, one died of a neurological deficit**, another after hematothorax, but no hyperacute or delayed xenograft rejection occurred. After several weeks a pig donor organ (over)growth was found. All long-term surviving baboons were in good general conditions until to the last days. Mean survival in G1 (CD40Ab) was 10.5 ± 4.90 days and in G2 (Fab-CD40L) 19.7 ± 7.84 days and without PCXD and brain damage** 20 ± 6.55 days in G1 and 29 ± 7.78 days in G2. In a preliminary modified group (unpublished data und matter of a patent) one baboon with CD40L-Ab survived 50 days and another baboon (B67 with CD40Ab) reached and was successfully terminated at the endpoint of study on day 90!

Conclusion: Thus co-stimulation blockade with CD40L antibody tended to prolong survival time after orthotopic cardiac xenotransplantation, but with yet incomplete groups statistically not significant. Survival in this important life-supporting orthotopic model was significantly prolonged with a less toxic IS and better quality of life. This is an important step forward, milestone and progress on the way to a long-term survival of 2–3 months, which is necessary for clinical cardiac xenotransplantation. This aim was now first time worldwide reached with our last 90-days surviving baboon B67.

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