Effects of humanized monoclonal antibody to rhesus CD11a in rhesus monkey cardiac allograft recipients.
BACKGROUND
Leukocyte function-associated antigen-1 (LFA-1, CD11a) monoclonal antibody (mAb) affects many leukocyte functions without cell depletion. We hypothesized that the use of a humanized, anti-rhesus modified LFA-1 mAb (H2C12) in rhesus monkeys would cause: (1) prolonged heart allograft survival, (2) inhibition of primary but not secondary antibody responses, and (3) minimal drug toxicity.


RESULTS
Control (n=5) and H2C12-treated (n=7) (8-20 mg/kg i.v. on day -1 followed by 10 mg/kg/day) adult male rhesus recipients were inoculated with GP120 protein antigen on day -28 and -1 and grafted with heterotopic abdominal hearts (day 0). Donor-recipient pairs were equally MLR mismatched (4329.8+/-1124.1 CPM controls vs. 7289.0+/-1926.5 treated, P=NS). Mean heart allograft survival as evaluated by daily abdominal palpation was significantly prolonged in high dose recipients (23.0+/-2.6, n=4) vesus controls (8.2+/-1.3, n=5, P<0.02, Mann-Whitney U test). H2C12 treatment did not produce signs of cytokine release or toxicity, was nondepleting, but down-modulated PBL CD11a expression to 43.4+/-3.6% (n=4) of control levels (n=5) at day 7 as demonstrated by flow cytometry. It had no effect on postoperative Con A or MLR and did not prevent mAb clearance due to the rhesus-antihuman antibody response. The addition of mycophenolate mofitil prevented rhesus-antihuman antibody response with therapeutic H2C12 levels seen for >35 days.


CONCLUSIONS
The use of this mAb to block CD11a had the benefit of being a well tolerated, highly targeted therapy. These are the first results showing that monotherapy with anti-leukocyte function-associated antigen-1 mAb prolonged survival of MLR mismatched allogenic cardiac grafts in primates.
Poston
R S
RS
Transplantation Immunology, Department of Cardiothoracic Surgery, Stanford University School of Medicine, CA 94305-5247, USA.
Robbins
R C
RC
Chan
B
B
Simms
P
P
Presta
L
L
Jardieu
P
P
Morris
R E
RE
D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006085:Graft Survival / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D006650:Histocompatibility Testing; D006801:Humans; D007165:Immunosuppression Therapy / Q000379:methods; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D018655:Lymphocyte Count; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology*; D008253:Macaca mulatta; D008297:Male; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use; D015428:Myocardial Reperfusion Injury; D013997:Time Factors; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D007166:Immunosuppressive Agents; D016169:Lymphocyte Function-Associated Antigen-1; C114320:anti-LFA-1 monoclonal antibody; D009173:Mycophenolic Acid