Monotherapy with the novel human anti-CD154 monoclonal antibody ABI793 in rhesus monkey renal transplantation model.
BACKGROUND
This study assesses the safety and efficacy of the novel human anti-human CD154 monoclonal antibody ABI793 in rhesus monkeys.


METHODS
Outbred rhesus monkeys were used for renal transplantation from major histocompatibility complex-mismatched donors. Seven recipients were treated with ABI793, and six untreated recipients were used as controls. Graft function was monitored by urine output, serum creatinine, and renal biopsy. Phenotypic analysis of peripheral blood lymphocytes and mixed lymphocyte reaction were performed before transplantation and periodically after transplantation. Anti-donor major histocompatibility complex class I antibody levels were measured at the time of sacrifice.


RESULTS
Monkeys in the treated group demonstrated prolonged graft survival compared with controls. One monkey was sacrificed because of a urine leak on postoperative day 13. Three monkeys were sacrificed because of acute rejection (days 44, 149, and 158). Two monkeys were sacrificed because of chronic active rejection (days 154 and 221). One monkey was sacrificed on day 139 without rejection to observe the effects of ABI793 in the absence of rejection. There were no obvious clinical side effects of ABI793, but microscopic thromboembolic changes were observed in two monkeys. Lymphocyte subsets remained unaltered in all monkeys. Mixed lymphocyte reaction showed nonspecific suppression 6 weeks after transplantation. The monkeys with chronic active rejection showed relatively strong alloantibody responses.


CONCLUSIONS
ABI793 induces prolonged renal allograft survival in rhesus monkeys. Nevertheless, thromboembolic complications may occur and chronic allograft nephropathy may develop after anti-CD154 treatment is discontinued.
Kanmaz
Turan
T
Department of Surgery, University of Wisconsin, Madison, Wisconsin 53792, USA.
Fechner
John J H
JJ
Torrealba
Jose
J
Kim
Hyoung Tae
HT
Dong
Yinchen
Y
Oberley
Terry D
TD
Schultz
Jacqueline M
JM
Bloom
Debra D
DD
Katayama
Masaaki
M
Dar
Wasim
W
Markovits
Judit
J
Schuler
Walter
W
Hu
Huaizhong
H
Hamawy
Majed M
MM
Knechtle
Stuart J
SJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D023201:CD40 Ligand / Q000276:immunology* / Q000627:therapeutic use*; D003404:Creatinine / Q000097:blood; D004231:Diuresis; D006085:Graft Survival / Q000187:drug effects*; D006650:Histocompatibility Testing; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000276:immunology / Q000473:pathology / Q000502:physiology*; D007959:Lymphocyte Culture Test, Mixed; D008253:Macaca mulatta; D013997:Time Factors; D014184:Transplantation, Homologous
C484673:ABI793 monoclonal antibody; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007166:Immunosuppressive Agents; D023201:CD40 Ligand; D003404:Creatinine