title: Fc-Silent Anti-CD154 Domain Antibody Effectively Prevents Nonhuman Primate Renal Allograft Rejection.
abstract: The advent of costimulation blockade provides the prospect for targeted therapy with improved graft survival in transplant patients. Perhaps the most effective costimulation blockade in experimental models is the use of reagents to block the CD40/CD154 pathway. Unfortunately, successful clinical translation of anti-CD154 therapy has not been achieved. In an attempt to develop an agent that is as effective as previous CD154 blocking antibodies but lacks the risk of thromboembolism, we evaluated the efficacy and safety of a novel anti-human CD154 domain antibody (dAb, BMS-986004). The anti-CD154 dAb effectively blocked CD40-CD154 interactions but lacked crystallizable fragment (Fc) binding activity and resultant platelet activation. In a nonhuman primate kidney transplant model, anti-CD154 dAb was safe and efficacious, significantly prolonging allograft survival without evidence of thromboembolism (Median survival time 103 days). The combination of anti-CD154 dAb and conventional immunosuppression synergized to effectively control allograft rejection (Median survival time 397 days). Furthermore, anti-CD154 dAb treatment increased the frequency of CD4+CD25+Foxp3+regulatory T cells. This study demonstrates that the use of a novel anti-CD154 dAb that lacks Fc binding activity is safe without evidence of thromboembolism and is equally as potent as previous anti-CD154 agents at prolonging renal allograft survival in a nonhuman primate preclinical model.
authors.affiliation: Emory Transplant Center, Department of Surgery, School of Medicine, Emory University, Atlanta, GA.
authors.forename: S C
authors.initials: SC
authors.lastname: Kim
authors.affiliation: Emory Transplant Center, Department of Surgery, School of Medicine, Emory University, Atlanta, GA.
authors.forename: W
authors.initials: W
authors.lastname: Wakwe
authors.affiliation: Emory Transplant Center, Department of Surgery, School of Medicine, Emory University, Atlanta, GA.
authors.forename: L B
authors.initials: LB
authors.lastname: Higginbotham
authors.affiliation: Emory Transplant Center, Department of Surgery, School of Medicine, Emory University, Atlanta, GA.
authors.forename: D V
authors.initials: DV
authors.lastname: Mathews
authors.affiliation: Emory Transplant Center, Department of Surgery, School of Medicine, Emory University, Atlanta, GA.
authors.forename: C P
authors.initials: CP
authors.lastname: Breeden
authors.affiliation: Emory Transplant Center, Department of Surgery, School of Medicine, Emory University, Atlanta, GA.
authors.forename: A C
authors.initials: AC
authors.lastname: Stephenson
authors.affiliation: Yerkes National Primate Research Center, School of Medicine, Emory University, Atlanta, GA.
authors.forename: J
authors.initials: J
authors.lastname: Jenkins
authors.affiliation: Yerkes National Primate Research Center, School of Medicine, Emory University, Atlanta, GA.
authors.forename: E
authors.initials: E
authors.lastname: Strobert
authors.affiliation: Bristol Myers-Squibb Pharmaceutical Research Institute, Princeton, NJ.
authors.forename: K
authors.initials: K
authors.lastname: Price
authors.affiliation: Bristol Myers-Squibb Pharmaceutical Research Institute, Princeton, NJ.
authors.forename: L
authors.initials: L
authors.lastname: Price
authors.affiliation: Bristol Myers-Squibb Pharmaceutical Research Institute, Princeton, NJ.
authors.forename: R
authors.initials: R
authors.lastname: Kuhn
authors.affiliation: Bristol Myers-Squibb Pharmaceutical Research Institute, Princeton, NJ.
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.affiliation: Bristol Myers-Squibb Pharmaceutical Research Institute, Princeton, NJ.
authors.forename: A
authors.initials: A
authors.lastname: Yamniuk
authors.affiliation: Bristol Myers-Squibb Pharmaceutical Research Institute, Princeton, NJ.
authors.forename: S
authors.initials: S
authors.lastname: Suchard
authors.affiliation: Emory Transplant Center, Department of Surgery, School of Medicine, Emory University, Atlanta, GA.
authors.forename: A B
authors.initials: AB
authors.lastname: Farris
authors.affiliation: Emory Transplant Center, Department of Surgery, School of Medicine, Emory University, Atlanta, GA.
authors.forename: T C
authors.initials: TC
authors.lastname: Pearson
authors.affiliation: Emory Transplant Center, Department of Surgery, School of Medicine, Emory University, Atlanta, GA.
authors.forename: C P
authors.initials: CP
authors.lastname: Larsen
authors.affiliation: Emory Transplant Center, Department of Surgery, School of Medicine, Emory University, Atlanta, GA.
authors.forename: M L
authors.initials: ML
authors.lastname: Ford
authors.affiliation: Bristol Myers-Squibb Pharmaceutical Research Institute, Princeton, NJ.
authors.forename: A
authors.initials: A
authors.lastname: Suri
authors.affiliation: Bristol Myers-Squibb Pharmaceutical Research Institute, Princeton, NJ.
authors.forename: S
authors.initials: S
authors.lastname: Nadler
authors.affiliation: Emory Transplant Center, Department of Surgery, School of Medicine, Emory University, Atlanta, GA.
authors.forename: A B
authors.initials: AB
authors.lastname: Adams
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D023201:CD40 Ligand / Q000276:immunology*; D005919:Glomerular Filtration Rate; D006084:Graft Rejection / Q000209:etiology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology*; D007074:Immunoglobulin G / Q000276:immunology*; D007677:Kidney Function Tests; D016030:Kidney Transplantation / Q000009:adverse effects*; D011323:Primates; D012307:Risk Factors; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014181:Transplantation Immunology
chemical_list: D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D023201:CD40 Ligand
keywords: animal models: nonhuman primate; basic (laboratory) research/science; costimulation; fusion proteins and monoclonal antibodies: costimulation molecule specific; immunosuppressant; immunosuppression/immune modulation; rejection: T cell mediated (TCMR); translational research/science