Effects of humanized monoclonal antibody to rhesus CD11a in rhesus monkey cardiac allograft recipients

Introduction. Leukocyte function-associated antigen-1 (LFA-1, CD11a) monocl onal antibody (mAb) affects many leukocyte functions without cell depletion . We hypothesized that the use of a humanized, antirhesus modified LFA-1 mA b (H2C12) in rhesus monkeys would cause: (1) prolonged heart allograft surv ival, (2) inhibition of primary but not secondary antibody responses, and ( 3) minimal drug toxicity, Methods and 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 inoc ulated with GP120 protein antigen on day -28 and -1 and grafted with hetero topic abdominal hearts (day 0), Do nor-recipient pairs were equally MLR mis matched (4329.8+/-1124.1 CPM controls vs. 7289.0+/-1926.5 treated, P=NS), M ean heart allograft survival as evaluated by daily abdominal palpation was significantly prolonged in high dose recipients (23.0+/-2.6, n=4) vesus con trols (8.2+/-1.3, n=5, P<0.02, Mann-Whitney U test), H2C12 treatment did no t 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 postopera tive Con A or MLR and did not prevent mAb clearance due to the rhesus-antih uman antibody response. The addition of mycophenolate mofitil prevented rhe sus-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 showin g that monotherapy with anti-leukocyte function-associated antigen-1 mAb pr olonged survival of MLR mismatched allogenic cardiac grafts in primates.