Initial experience with the human anti-human CD154 monoclonal antibody, ABI793, in pig-to-baboon xenotransplantation.
BACKGROUND
ABI793 (ABI) is a human monoclonal antibody (mAb) specific for human CD154. To assess the suitability of ABI for baboon transplantation studies, we carried out in vitro studies to determine ABI's reactivity with baboon cells expressing CD154, performed in vivo pharmacokinetic studies in two baboons, and tested the effect of ABI administration on elicited antibody production in two baboons undergoing either pig hematopoietic progenitor cell (PBPC) or heterotopic heart transplantation.


METHODS
In vitro: Baboon peripheral blood mononuclear cells were activated in vitro to upregulate CD154, and binding of ABI to CD154 was measured by flow cytometry. In vivo: Serum levels of ABI were measured immediately before and 15 min after the intravenous administration of ABI (20 mg/kg) to two baboons over 28 days. Subsequently, ABI (25 mg/kg on days 0, 1, 4 and 7, and then 20 mg/kg every 5 days) was included in the immunosuppressive regimen in two pig-to-baboon transplants (PBPC or heart transplantation).


RESULTS
In vitro: ABI was almost non-reactive to baboon T cells before stimulation, but bound to activated T cells. In vivo: In the pharmacokinetic study, trough levels of ABI (before the next dose) ranged between 190 and 580 microg/ml, and the estimated half-life was 10-15 days. There was no apparent toxicity. Following pig PBPC or heart transplantation, no elicited antibody was detected while ABI was being administered or during several weeks of follow-up.


CONCLUSIONS
ABI functions in baboons, is well-tolerated, and prevents an elicited antibody response to pig antigens.
Knosalla
C
C
Transplantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, Boston, MA 02129, USA.
Ryan
D J J
DJ
Moran
K
K
Gollackner
B
B
Schuler
W
W
Sachs
D H
DH
Awwad
M
M
Schuurman
H-J
HJ
Cooper
D K C
DK
D000818:Animals; D000911:Antibodies, Monoclonal / Q000097:blood / Q000276:immunology* / Q000493:pharmacokinetics; D061067:Antibodies, Monoclonal, Humanized; D023201:CD40 Ligand / Q000097:blood / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D015870:Gene Expression; D016027:Heart Transplantation / Q000276:immunology*; D006412:Hematopoietic Stem Cells / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology; D010215:Papio / Q000276:immunology; D013552:Swine / Q000276:immunology; D014183:Transplantation, Heterologous / Q000276:immunology*
C484673:ABI793 monoclonal antibody; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D023201:CD40 Ligand