Alemtuzumab is a humanized monoclonal antibody against CD52, an antigen found on 
the surface of normal and malignant lymphocytes. It is approved for the 
treatment of B-cell chronic lymphocytic leukaemia and is undergoing Phase III 
clinical trials for the treatment of multiple sclerosis. The exact mechanism by 
which alemtuzumab mediates its biological effects in vivo is not clearly defined 
and mechanism of action studies have been hampered by the lack of 
cross-reactivity between human and mouse CD52. To address this issue, a 
transgenic mouse expressing human CD52 (hCD52) was created. Transgenic mice did 
not display any phenotypic abnormalities and were able to mount normal immune 
responses. The tissue distribution of hCD52 and the level of expression by 
various immune cell populations were comparable to those seen in humans. 
Treatment with alemtuzumab replicated the transient increase in serum cytokines 
and depletion of peripheral blood lymphocytes observed in humans. Lymphocyte 
depletion was not as profound in lymphoid organs, providing a possible 
explanation for the relatively low incidence of infection in alemtuzumab-treated 
patients. Interestingly, both lymphocyte depletion and cytokine induction by 
alemtuzumab were largely independent of complement and appeared to be mediated 
by neutrophils and natural killer cells because removal of these populations 
with antibodies to Gr-1 or asialo-GM-1, respectively, strongly inhibited the 
activity of alemtuzumab whereas removal of complement by treatment with cobra 
venom factor had no impact. The hCD52 transgenic mouse appears to be a useful 
model and has provided evidence for the previously uncharacterized involvement 
of neutrophils in the activity of alemtuzumab.