Alemtuzumab activity and CD52 expression in human CD52 transgenic mice

4133 Alemtuzumab (Campath) is a recombinant humanized IgG1 monoclonal antibody directed against the 28 kD cell surface glycoprotein CD52. CD52 is expressed on the surface of several cell types including normal and malignant B and T lymphocytes as well as on NK cells, and macrophages. Currently, Campath is approved for the treatment of B-cell chronic lymphocytic leukemia (B-CLL). The exact mechanisms by which Campath mediates its biological effect in vivo are not clearly defined. To explore this issue, a transgenic mouse was created that expresses human CD52 under the control of the endogenous CD52 promoter. In these mice, human CD52 is expressed on B-cells and T-cells and to a lesser extent on NK-cells of peripheral blood, lymph nodes, and spleen as determined by FACS analysis. Preliminary immunohistochemical staining indicates that human CD52 is expressed in lymphoid organs such as spleen and inguinal lymph nodes. Pharmacokinetic experiments revealed that Campath displays a half-life of approximately one and a half days in these mice. Treatment with a single i.p. dose of Campath resulted in a transient increase in the circulating levels of TNF-α, IFN-γ and IL-6 within four hours following administration. Campath depleted CD4+ and CD8+ T-cells, CD19+ B-cells as well as NK cells in a dose- and time-dependent manner in the peripheral blood and reduced these same cell populations in the lymphoid organs of the transgenic mice. Following lymphocyte depletion with a single dose of Campath, B-cells appear to recover to the level of untreated controls prior to T-cells. Taken together, these data suggest that the human CD52 transgenic mouse may serve as a promising animal model to investigate in vivo efficacy and the mechanism of action of Campath.