Certain features that make an antigen a good candidate for antibody therapy have been defined. CD52 is a 21- to 28-kd nonmodulating cell surface glycosylphosphatidylinositol-linked glycoprotein that is abundantly expressed (up to 5 x 10(5) molecules per cell) on most normal and malignant lymphocytes and monocytes. Its functions are unknown. CD52 is an excellent target for complement-mediated lysis and antibody-dependent cellular cytotoxicity. A series of rat and genetically reshaped human CD52 antibodies has been assessed for the ability to deplete lymphocytes in vivo to induce immunosuppression and for the treatment of lymphoid malignancies. CD52 antibodies that activate both complement and antibody-dependent cellular cytotoxicity consistently deplete lymphocytes from blood, spleen, and bone marrow but are less effective against lymph node disease or extranodal masses. CD52 antibodies provide effective therapy for chronic leukemias, such as T-cell prolymphocytic leukemia and some subtypes of B-cell chronic lymphocytic leukemia, that may be resistant to conventional chemotherapy. For example, most patients with T-cell prolymphocytic leukemia, including those with large tumor burdens and high peripheral white blood cell counts, will enter complete remission using the antibody CAMPATH-1H without any evidence of tumor lysis. In contrast, in chronic lymphocytic leukemia, CD52 antibodies may be more effective in the setting of minimal residual disease and may allow harvesting of uncontaminated stem cells. Further experiments to enhance the activity of CD52 antibodies in sites refractory to antibody alone are currently being undertaken.