title: Efficacy and safety of ABI793, a novel human anti-human CD154 monoclonal antibody, in cynomolgus monkey renal allotransplantation.
abstract: BACKGROUND
  Anti-CD154 monoclonal antibodies (mAbs) cause long-term graft survival in preclinical allotransplantation experiments. This is the first report on the efficacy and safety of ABI793, a novel human anti-human CD154 mAb, in Cynomolgus renal transplant recipients.
  
  
  METHODS
  ABI793 (human immunoglobulin-G1:kappa) was derived from a hybridoma generated after immunization of human immunoglobulin transgenic mice (HuMAb-Mouse, Medarex Inc., Annandale, NJ). Cynomolgus monkey recipients of major histocompatibility complex-mismatched, life-supporting renal allografts were treated repeatedly with intravenous ABI793 for a 3-month period posttransplantation. Graft function was monitored by serum creatinine, and rejection was confirmed histologically.
  
  
  RESULTS
  ABI793 binds to human, Cynomolgus and Rhesus monkey CD154; it inhibits dose dependently in vitro CD154:CD40 binding and human mixed lymphocyte reaction. ABI793 is comparable to the mouse anti-human CD154 mAbs 5c8 and 24-31 with respect to affinity, inhibitory capacity, and species specificity; however, ABI793 binds to a different CD154 epitope. With 20 mg/kg of ABI793, five of nine recipients showed substantially prolonged graft survival after cessation of treatment, whereas four of nine recipients were killed because of high serum creatinine while still receiving treatment. ABI793 treatment was associated with episodes of severe acute tubular necrosis (which was unrelated to rejection and responded to fluid and diuretic treatment) and a decrease in platelet numbers. Chronic and acute thromboembolic vascular lesions with hemorrhages were observed in the lung and brain of two allograft recipients. None of these side effects were observed in animals that underwent autotransplantation, thus excluding direct toxicity of ABI793.
  
  
  CONCLUSIONS
  ABI793 treatment effectively prevents graft rejection in Cynomolgus monkeys. Evidence for rare thromboembolic events, as also previously observed with different anti-human CD154 mAbs, suggests that thromboembolic complications may be a class effect of anti-CD154 mAbs, unrelated to their epitope specificity.
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland. walter.schuler@pharma.novartis.com
authors.forename: Walter
authors.initials: W
authors.lastname: Schuler
authors.forename: Marc
authors.initials: M
authors.lastname: Bigaud
authors.forename: Volker
authors.initials: V
authors.lastname: Brinkmann
authors.forename: Franco
authors.initials: F
authors.lastname: Di Padova
authors.forename: Sabine
authors.initials: S
authors.lastname: Geisse
authors.forename: Hermann
authors.initials: H
authors.lastname: Gram
authors.forename: Valerie
authors.initials: V
authors.lastname: Hungerford
authors.forename: Beate
authors.initials: B
authors.lastname: Kleuser
authors.forename: Colette
authors.initials: C
authors.lastname: Kristofic
authors.forename: Klaus
authors.initials: K
authors.lastname: Menninger
authors.forename: Reet
authors.initials: R
authors.lastname: Tees
authors.forename: Grazyna
authors.initials: G
authors.lastname: Wieczorek
authors.forename: Corinne
authors.initials: C
authors.lastname: Wilt
authors.forename: Catherine
authors.initials: C
authors.lastname: Wioland
authors.forename: Mauro
authors.initials: M
authors.lastname: Zurini
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000918:Antibody Specificity; D023201:CD40 Ligand / Q000276:immunology*; D002460:Cell Line; D000939:Epitopes / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology* / Q000517:prevention & control*; D006085:Graft Survival / Q000276:immunology; D006801:Humans; D007668:Kidney / Q000166:cytology; D016030:Kidney Transplantation / Q000276:immunology*; D008252:Macaca fascicularis; D051379:Mice; D008822:Mice, Transgenic; D014182:Transplantation, Autologous; D014184:Transplantation, Homologous
chemical_list: D000911:Antibodies, Monoclonal; D000939:Epitopes; D023201:CD40 Ligand