Ex vivo enzymatic treatment converts blood type A donor lungs into universal blood type lungs

• Published in: Science translational medicine 2022-02, Vol.14 (632), p.eabm7190-eabm7190
• Main Authors: Wang, Aizhou, Ribeiro, Rafaela V P, Ali, Aadil, Brambate, Edson, Abdelnour-Berchtold, Etienne, Michaelsen, Vinicius, Zhang, Yu, Rahfeld, Peter, Moon, Haisle, Gokhale, Hemant, Gazzalle, Anajara, Pal, Prodipto, Liu, Mingyao, Waddell, Thomas K, Cserti-Gazdewich, Christine, Tinckam, Kathryn, Kizhakkedathu, Jayachandran N, West, Lori, Keshavjee, Shaf, Withers, Stephen G, Cypel, Marcelo
• Format: Article
• Language: English
• Subjects: ABO system; Antibodies; Blood groups; Enzymes; Epithelial cells; Erythrocytes; Graft rejection; Lung transplantation; Lungs; Perfusion; Toxicity; Transplants & implants
• ISSN: 1946-6234; 1946-6242; 1946-3242
• DOI: 10.1126/scitranslmed.abm7190

Donor organ allocation is dependent on ABO matching, restricting the opportunity for some patients to receive a life-saving transplant. The enzymes FpGalNAc deacetylase and FpGalactosaminidase, used in combination, have been described to effectively convert group A (ABO-A) red blood cells (RBCs) to group O (ABO-O). Here, we study the safety and preclinical efficacy of using these enzymes to remove A antigen (A-Ag) from human donor lungs using ex vivo lung perfusion (EVLP). First, the ability of these enzymes to remove A-Ag in organ perfusate solutions was examined on five human ABO-A1 RBC samples and three human aortae after static incubation. The enzymes removed greater than 99 and 90% A-Ag from RBCs and aortae, respectively, at concentrations as low as 1 μg/ml. Eight ABO-A1 human lungs were then treated by EVLP. Baseline analyses of A-Ag in lungs revealed expression predominantly in the endothelial and epithelial cells. EVLP of lungs with enzyme-containing perfusate removed over 97% of endothelial A-Ag within 4 hours. No treatment-related acute lung toxicity was observed. An ABO-incompatible transplant was then simulated with an ex vivo model of antibody-mediated rejection using ABO-O plasma as the surrogate for the recipient circulation using three donor lungs. The treatment of donor lungs minimized antibody binding, complement deposition, and antibody-mediated injury as compared with control lungs. These results show that depletion of donor lung A-Ag can be achieved with EVLP treatment. This strategy has the potential to expand ABO-incompatible lung transplantation and lead to improvements in fairness of organ allocation.