Chimeric 2C10R4 anti-CD40 antibody therapy is critical for long-term survival of GTKO.hCD46.hTBM pig-to-primate cardiac xenograft

TLDR

Preventing xenograft rejection is one of the greatest challenges of transplantation medicine. The study reports reproducible long‑term survival of cardiac xenografts from GTKO.hCD46.hTBM pigs transplanted into baboons. The regimen used induction with anti‑thymocyte globulin and anti‑CD20, followed by maintenance with mycophenolate mofetil and high‑dose anti‑CD40 (2C10R4) antibody. Median graft survival was 298 days and the longest 945 days, exceeding previous benchmarks, and dose reduction of anti‑CD40 after day 100 or one year caused antibody rebound and graft failure, demonstrating that the genetic modifications plus this regimen sustain survival beyond 900 days.

Abstract

Abstract Preventing xenograft rejection is one of the greatest challenges of transplantation medicine. Here, we describe a reproducible, long-term survival of cardiac xenografts from alpha 1-3 galactosyltransferase gene knockout pigs, which express human complement regulatory protein CD46 and human thrombomodulin ( GTKO.hCD46.hTBM ), that were transplanted into baboons. Our immunomodulatory drug regimen includes induction with anti-thymocyte globulin and αCD20 antibody, followed by maintenance with mycophenolate mofetil and an intensively dosed αCD40 (2C10R4) antibody. Median (298 days) and longest (945 days) graft survival in five consecutive recipients using this regimen is significantly prolonged over our recently established survival benchmarks (180 and 500 days, respectively). Remarkably, the reduction of αCD40 antibody dose on day 100 or after 1 year resulted in recrudescence of anti-pig antibody and graft failure. In conclusion, genetic modifications ( GTKO.hCD46.hTBM ) combined with the treatment regimen tested here consistently prevent humoral rejection and systemic coagulation pathway dysregulation, sustaining long-term cardiac xenograft survival beyond 900 days.