title: Chimeric 2C10R4 anti-CD40 antibody therapy is critical for long-term survival of GTKO.hCD46.hTBM pig-to-primate cardiac xenograft.
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.
authors.affiliation: Cardiothoracic Surgery Research Program, NHLBI, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Muhammad M
authors.initials: MM
authors.lastname: Mohiuddin
authors.affiliation: Cardiothoracic Surgery Research Program, NHLBI, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Avneesh K
authors.initials: AK
authors.lastname: Singh
authors.affiliation: Cardiothoracic Surgery Research Program, NHLBI, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Philip C
authors.initials: PC
authors.lastname: Corcoran
authors.affiliation: Division of Veterinary Resources, ORS, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Marvin L
authors.initials: ML
authors.lastname: Thomas Iii
authors.affiliation: NICHD/NIH, Bethesda, Maryland 20892, USA.
authors.forename: Tannia
authors.initials: T
authors.lastname: Clark
authors.affiliation: Division of Veterinary Resources, ORS, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Billeta G
authors.initials: BG
authors.lastname: Lewis
authors.affiliation: Leidos Biomedical Research, Inc., Bethesda, Maryland 20892, USA.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Hoyt
authors.affiliation: Division of Veterinary Resources, ORS, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Eckhaus
authors.affiliation: University of Maryland Medical Center, Baltimore, Maryland 20201, USA.
authors.forename: Richard N
authors.initials: RN
authors.lastname: Pierson Iii
authors.affiliation: MassBiologics, University of Massachusetts Medical School, Boston, Massachusetts 02126, USA.
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Belli
authors.affiliation: Ludwig Maximilian University, Munich 81377, Germany.
authors.forename: Eckhard
authors.initials: E
authors.lastname: Wolf
authors.affiliation: Ludwig Maximilian University, Munich 81377, Germany.
authors.forename: Nikolai
authors.initials: N
authors.lastname: Klymiuk
authors.affiliation: Revivicor Inc., Blacksburg, Virginia 24060, USA.
authors.forename: Carol
authors.initials: C
authors.lastname: Phelps
authors.affiliation: MassBiologics, University of Massachusetts Medical School, Boston, Massachusetts 02126, USA.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Reimann
authors.affiliation: Revivicor Inc., Blacksburg, Virginia 24060, USA.
authors.forename: David
authors.initials: D
authors.lastname: Ayares
authors.affiliation: Cardiothoracic Surgery Research Program, NHLBI, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Horvath
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000906:Antibodies / Q000494:pharmacology*; D000961:Antilymphocyte Serum / Q000494:pharmacology; D019013:CD40 Antigens / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D005260:Female; D005700:Galactosyltransferases / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D015870:Gene Expression; D006085:Graft Survival / Q000187:drug effects*; D016027:Heart Transplantation; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D007167:Immunotherapy / Q000379:methods*; D008297:Male; D051916:Membrane Cofactor Protein / Q000235:genetics / Q000276:immunology; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D010215:Papio; D000069283:Rituximab / Q000494:pharmacology; D013552:Swine; D018180:Thrombomodulin / Q000235:genetics / Q000276:immunology; D019076:Transgenes; D014183:Transplantation, Heterologous
chemical_list: D000906:Antibodies; D000961:Antilymphocyte Serum; D019013:CD40 Antigens; C497857:CD46 protein, human; D007155:Immunologic Factors; D051916:Membrane Cofactor Protein; C546931:THBD protein, human; D018180:Thrombomodulin; D000069283:Rituximab; D005700:Galactosyltransferases; C530267:alpha-1,3-galactosyltransferase 1, porcine; D009173:Mycophenolic Acid