INTERLEUKIN-2 ENHANCEMENT OF CYTOTOXICITY BY HUMANIZED MONOCLONAL-ANTIBODY M195 (ANTI-CD33) IN MYELOGENOUS LEUKEMIA

Humanized M195 (HuM195) is a genetically engineered, human IgG1 versio n of the parent M195, a mouse immunoglobulin G2a, anti-CD33 monoclonal antibody which reacts with early myeloid progenitor cells and myeloge nous leukemia cells, In Phase I studies in patients with relapsed and refractory myelogenous leukemia, HuM195 safely targeted to sites of di sease and was nonimmunogenic, HuM195 shows only modest capability of a ntibody-dependent cellular cytotoxicity (ADCC) against target HL60 cel ls and minimal cytolytic activity mediated by human complement, Theref ore, efforts were made to enhance ADCC using cytokines, gamma-Interfer on, granulocyte-macrophage colony-stimulating factor, and granulocyte colony-stimulating factor did not promote neutrophil-mediated ADCC wit h HuM195, However, interleukin-2 (IL-2) showed a range of 2-6-fold inc reases in ADCC against fresh myelogenous leukemia cells and HL60 cells over that seen with HuM195 or low-dose IL-2 alone, ADCC potency was n ot improved further by the use of homodimeric HuM195, Flow cytometry a nd Fc receptor-blocking experiments showed that CD16(+) cells were ess ential for IL-2-enhanced ADCC, As compared to HL60 cells, a multidrug- resistant line of HL60 cells was at least as susceptible to killing by IL-2 or HuM195 or in combination, suggesting that the mechanism of ki lling may be active against cells surviving and resistant to chemother apy, Since these in vitro levels of IL-2 and HuM195 can be safely achi eved in patients, the enhancement of HuM195 ADCC with low-dose IL-2 is a possible strategy that may be used in vivo to eliminate minimal dis ease in future trials of patients with myeloid leukemias.