title: A novel fully human anti-CD40 monoclonal antibody, 4D11, for kidney transplantation in cynomolgus monkeys.
abstract: BACKGROUND
  CD40-CD154 pathway blockade by anti-CD154 monoclonal antibodies (mAbs) significantly prolongs allograft survival in nonhuman primates. However, thromboembolic complications have prevented clinical application. Thus, blockade of the counter molecule by a novel fully human anti-CD40 mAb, 4D11, is an attractive alternative.
  
  
  METHODS
  Kidney transplantations were performed between outbred cynomolgus monkeys (stimulation index >3 in a mixed lymphocyte reaction). The animals were divided into five groups: nontreatment control (Group 1, n=3), 10-week treatment with either 10 mg/kg (Group 2, n=3), 20 mg/kg (Group 3, n=3), or 40 mg/kg (Group 4, n=1), and 4-week treatment (Group 5, n=1 each) with 10 mg/kg, 20 mg/kg, or 40 mg/kg followed by monthly administration. Graft survival, biochemistry, complete blood counts, lymphocyte phenotypes, blood drug levels, antidonor and antidrug antibodies, and renal histology were examined.
  
  
  RESULTS
  Survival (days) was as follows: Group 1 (5, 6, 7), Group 2 (150, 108, 108), Group 3 (84, 108, 379), Group 4 (147), and Group 5 (147, 102, 112). Two animals in Group 3 with normal graft function were killed upon development of hydronephrosis and cerebral infarction. B lymphocytes fell to one-third of the preoperative value at 4 weeks after transplantation in all animals. Antidonor antibodies developed in most of the animals after stopping drug treatment or at the time of death. No animals except for one formed anti-4D11 antibody.
  
  
  CONCLUSIONS
  4D11 appears to be a promising agent for antirejection treatment in clinical organ transplantation.
authors.affiliation: First Department of Surgery, Hokkaido University School of Medicine, Sapporo, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Imai
authors.forename: Tomomi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sugitani
authors.forename: Tomoo
authors.initials: T
authors.lastname: Itoh
authors.forename: Shinya
authors.initials: S
authors.lastname: Ueki
authors.forename: Takeshi
authors.initials: T
authors.lastname: Aoyagi
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Yamashita
authors.forename: Masahiko
authors.initials: M
authors.lastname: Taniguchi
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Takahashi
authors.forename: Toru
authors.initials: T
authors.lastname: Miura
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Shimamura
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Furukawa
authors.forename: Satoru
authors.initials: S
authors.lastname: Todo
mesh_terms: D000818:Animals; D000906:Antibodies / Q000097:blood; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019013:CD40 Antigens / Q000037:antagonists & inhibitors*; D006084:Graft Rejection / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D007165:Immunosuppression Therapy / Q000379:methods*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007668:Kidney / Q000473:pathology; D016030:Kidney Transplantation / Q000473:pathology; D019520:Living Donors; D008252:Macaca fascicularis
chemical_list: D000906:Antibodies; D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D007166:Immunosuppressive Agents