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

Muhammad M. Mohiuddin (), Avneesh K. Singh, Philip C. Corcoran, Marvin L. Thomas, Tannia Clark, Billeta G. Lewis, Robert F. Hoyt, Michael Eckhaus, Richard N. Pierson, Aaron J. Belli, Eckhard Wolf, Nikolai Klymiuk, Carol Phelps, Keith A. Reimann, David Ayares and Keith A. Horvath
Additional contact information
Muhammad M. Mohiuddin: Cardiothoracic Surgery Research Program, NHLBI, NIH
Avneesh K. Singh: Cardiothoracic Surgery Research Program, NHLBI, NIH
Philip C. Corcoran: Cardiothoracic Surgery Research Program, NHLBI, NIH
Marvin L. Thomas: ORS, NIH
Tannia Clark: NICHD/NIH
Billeta G. Lewis: ORS, NIH
Robert F. Hoyt: Leidos Biomedical Research, Inc.
Michael Eckhaus: ORS, NIH
Richard N. Pierson: University of Maryland Medical Center
Aaron J. Belli: MassBiologics, University of Massachusetts Medical School
Eckhard Wolf: Ludwig Maximilian University
Nikolai Klymiuk: Ludwig Maximilian University
Carol Phelps: Revivicor Inc.
Keith A. Reimann: MassBiologics, University of Massachusetts Medical School
David Ayares: Revivicor Inc.
Keith A. Horvath: Cardiothoracic Surgery Research Program, NHLBI, NIH

Nature Communications, 2016, vol. 7, issue 1, 1-10

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.

Date: 2016
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DOI: 10.1038/ncomms11138

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