Pc. Caron et al., INTERLEUKIN-2 ENHANCEMENT OF CYTOTOXICITY BY HUMANIZED MONOCLONAL-ANTIBODY M195 (ANTI-CD33) IN MYELOGENOUS LEUKEMIA, Clinical cancer research, 1(1), 1995, pp. 63-70
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.