A novel fully human anti-CD40 monoclonal antibody, 4D11, for kidney transplantation in cynomolgus monkeys.
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.
Imai
Atsushi
A
First Department of Surgery, Hokkaido University School of Medicine, Sapporo, Japan.
Suzuki
Tomomi
T
Sugitani
Atsushi
A
Itoh
Tomoo
T
Ueki
Shinya
S
Aoyagi
Takeshi
T
Yamashita
Kenichiro
K
Taniguchi
Masahiko
M
Takahashi
Nobuaki
N
Miura
Toru
T
Shimamura
Tsuyoshi
T
Furukawa
Hiroyuki
H
Todo
Satoru
S
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
D000906:Antibodies; D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D007166:Immunosuppressive Agents