title: Rational development of LEA29Y (belatacept), a high-affinity variant of CTLA4-Ig with potent immunosuppressive properties.
abstract: 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.
authors.affiliation: Emory Transplant Center, Department of Surgery, School of Medicine, Emory University Atlanta, Georgia, USA. clarsen@emoryhealthcare.org
authors.forename: Christian P
authors.initials: CP
authors.lastname: Larsen
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Pearson
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Adams
authors.forename: Paul
authors.initials: P
authors.lastname: Tso
authors.forename: Nozomu
authors.initials: N
authors.lastname: Shirasugi
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Strobert
authors.forename: Dan
authors.initials: D
authors.lastname: Anderson
authors.forename: Shannon
authors.initials: S
authors.lastname: Cowan
authors.forename: Karen
authors.initials: K
authors.lastname: Price
authors.forename: Joseph
authors.initials: J
authors.lastname: Naemura
authors.forename: John
authors.initials: J
authors.lastname: Emswiler
authors.forename: JoAnne
authors.initials: J
authors.lastname: Greene
authors.forename: Lori Ann
authors.initials: LA
authors.lastname: Turk
authors.forename: Jurgen
authors.initials: J
authors.lastname: Bajorath
authors.forename: Robert
authors.initials: R
authors.lastname: Townsend
authors.forename: David
authors.initials: D
authors.lastname: Hagerty
authors.forename: Peter S
authors.initials: PS
authors.lastname: Linsley
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Peach
mesh_terms: 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
chemical_list: 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