Anti-ICAM-1 monoclonal antibody R6.5 (Enlimomab) promotes activation of neutrophils in whole blood

R6.5 (BIRR-1, Enlimomab), a murine IgG2a mAb to the human ICAM-1, inhibits leukocyte adhesion to the vascular endothelium, thereby; decreasing leukocy te extravasation and inflammatory tissue injury. In initial clinical trials , R6.5 proved to be beneficial in reducing both disease activity in refract ory rheumatoid arthritis and the incidence of acute rejection after kidney and liver allograft transplantations. However, adverse effects such as feve r, leukopenia, or cutaneous reactions were not infrequent, We studied the e ffects of R6.5 on neutrophil function in whole blood samples ex vivo, Surpr isingly, at the concentrations achieved in clinical trials, R6.5 activated neutrophilic granulocytes, as indicated by a significant increase in expres sion of the adhesion molecule beta(2)-integrin CD11b, a concurrent decrease in L-selectin expression, and an enhancement of the oxidative burst activi ty, Neutrophil activation was not exerted by an anti-ICAM-1 mAb of the IgG1 isotype, by isotype-matched, irrelevant anti-2-phenyloxazolone mAb, or by F(ab')(2) fragments of R6.5, Neutrophil activation was completely inhibited by soluble complement receptor type 1. We conclude that in whole blood, R6 .5 activates resting neutrophils in a complement-dependent manner. This fin ding can explain, at least in part, the side effects associated with R6.5 t herapy.