Efficacy and safety of ABI793, a novel human anti-human CD154 monoclonal antibody, in cynomolgus monkey renal allotransplantation.
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.
Schuler
Walter
W
Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland. walter.schuler@pharma.novartis.com
Bigaud
Marc
M
Brinkmann
Volker
V
Di Padova
Franco
F
Geisse
Sabine
S
Gram
Hermann
H
Hungerford
Valerie
V
Kleuser
Beate
B
Kristofic
Colette
C
Menninger
Klaus
K
Tees
Reet
R
Wieczorek
Grazyna
G
Wilt
Corinne
C
Wioland
Catherine
C
Zurini
Mauro
M
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
D000911:Antibodies, Monoclonal; D000939:Epitopes; D023201:CD40 Ligand