Anti-C5 Antibody Tesidolumab Reduces Early Antibody Mediated Rejection And Prolongs Survival In Renal Xenotransplantation
*Andrew B Adams1, *Brendan P Lovasik1, *David A Faber1, *Cynthia Breeden1, *Jose L Estrada2, *Luz M Reyes2, *Rodrigo M Vianna2, *Matthew F Tector3, Alfred J Tector2
1Emory School of Medicine, Atlanta, GA;2University of Miami School of Medicine, Miami, FL;3Makana Therapeutics, Minneapolis, MN
Objective: Pig-to-primate renal xenotransplantation is plagued by early antibody mediated graft loss which precludes clinical application of renal xenotransplantation. We evaluated whether temporary complement inhibition with anti-C5 antibody Tesidolumab could minimize the impact of early antibody mediated rejection in rhesus monkeys receiving pig kidneys receiving costimulatory blockade-based immunosuppression.
Methods: Double (Gal and Sda) and triple xenoantigen (Gal, Sda, and SLA I) pigs were created using CRISPR/Cas. Kidneys from DKO and TKO pigs were transplanted into rhesus monkeys that had the least reactive crossmatches. Recipients received anti-C5 antibody weekly for 70 days, and T cell depletion, anti-CD154, mycophenolic acid, and steroids as baseline immunosuppression (n = 7). Control recipients did not receive anti-C5 therapy (n = 10).
Results: Temporary anti-C5 therapy reduced early graft loss secondary to antibody mediated rejection and improved graft survival (p <0.01, figure). Deleting class I MHC (SLA I) in donor pigs did not ameliorate early antibody mediated rejection (table). Anti-C5 therapy did not allow for the use of tacrolimus instead of anti-CD154 (table), prolonging survival to a maximum of 62 days.
Conclusions: C5 inhibition allows for prolonged renal xenotransplant survival using costimulation blockade-based immunosuppression, suggesting clinical translation is feasible.
| Donor kidney genetics | Number of Transplants | Anti-C5 yes or no | Baseline Immunosuppression | Survival (Days) |
| Gal/β4GalNT2 KO | 6 | n | Anti-CD154 | 5, 6, 6, 35, 100, 435 |
| Gal/β4GalNT2 KO | 4 | y | Anti-CD154 | 8, 70, >452, >466 |
| Gal/β4GalNT2/SLA I KO | 4 | n | Anti-CD154 | 6, 7, 11, 95 |
| Gal/β4GalNT2/SLA I KO | 3 | y | Anti-CD154 | 43*, 205, >326 |
| Gal/β4GalNT2 KO | 4 | y | Tacrolimus | 16, 21, 23, 62 |
*Censored for weight loss
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