Chimeric 2C10R4 Anti-CD40 Antibody Therapy is Critical for Long-term Survival of GTKO.hCD46.hTBM Pig-to-primate Cardiac Xenograft

Overview

Journal Nat Commun

Specialty Biology

Date 2016 Apr 6

PMID 27045379

Citations 204

Authors

Muhammad M Mohiuddin

Avneesh K Singh

Philip C Corcoran

Marvin L Thomas III

Tannia Clark

Billeta G Lewis

Robert F Hoyt

Michael Eckhaus

Richard N Pierson Iii

Aaron J Belli

Eckhard Wolf

Nikolai Klymiuk

Carol Phelps

Keith A Reimann

David Ayares

Keith A Horvath

Affiliations

Soon will be listed here.

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.

Citing Articles

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