Rational development of LEA29Y (belatacept), a high-affinity variant of CTLA4-Ig with potent immunosuppressive properties.
Current success in organ transplantation is dependent upon the use of calcineurin-inhibitor-based immunosuppressive regimens. Unfortunately, current immunotherapy targets molecules with ubiquitous expression resulting in devastating non-immune side effects. T-cell costimulation has been identified as a new potential immunosuppressive target. The best characterized pathway includes CD28, its homologue CTLA4 and their ligands CD80 and CD86. While an immunoglobulin fusion protein construct of CTLA4 suppressed rejection in rodents, it lacked efficacy in primate transplant models. In an attempt to increase the biologic potency of the parent molecule a novel, modified version of CTLA4-Ig, LEA29Y (belatacept), was constructed. Two amino acid substitutions (L104E and A29Y) gave rise to slower dissociation rates for both CD86 and CD80. The increased avidity resulted in a 10-fold increase in potency in vitro and significant prolongation of renal allograft survival in a pre-clinical primate model. The use of immunoselective biologics may provide effective maintenance immunosuppression while avoiding the collateral toxicities associated with conventional immunsuppressants.
Larsen
Christian P
CP
Emory Transplant Center, Department of Surgery, School of Medicine, Emory University Atlanta, Georgia, USA. clarsen@emoryhealthcare.org
Pearson
Thomas C
TC
Adams
Andrew B
AB
Tso
Paul
P
Shirasugi
Nozomu
N
Strobert
Elizabeth
E
Anderson
Dan
D
Cowan
Shannon
S
Price
Karen
K
Naemura
Joseph
J
Emswiler
John
J
Greene
JoAnne
J
Turk
Lori Ann
LA
Bajorath
Jurgen
J
Townsend
Robert
R
Hagerty
David
D
Linsley
Peter S
PS
Peach
Robert J
RJ
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D051940:B7-2 Antigen; D018106:CD28 Antigens / Q000276:immunology; D016466:CHO Cells; D060908:CTLA-4 Antigen; D049109:Cell Proliferation / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D018796:Immunoconjugates / Q000235:genetics / Q000276:immunology*; D007700:Kinetics; D008562:Membrane Glycoproteins / Q000276:immunology; D015202:Protein Engineering; D013601:T-Lymphocytes / Q000187:drug effects
D015703:Antigens, CD; D000943:Antigens, Differentiation; D051940:B7-2 Antigen; D018106:CD28 Antigens; C497964:CD86 protein, human; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D018796:Immunoconjugates; D008562:Membrane Glycoproteins; D000069594:Abatacept