Despite therapeutic advances, the poor prognoses for
acute myeloid leukemia (AML) and intermediate and high-risk
myelodysplastic syndromes (MDS) point to the need for better treatment options. AML and MDS cells express the myeloid marker CD33, making it amenable to CD33-targeted
therapy.
Lintuzumab (SGN-33), a humanized monoclonal anti-CD33 antibody undergoing clinical evaluation, induced meaningful responses in a Phase 1 clinical trial and demonstrated anti-leukemic activity in preclinical models. Recently, it was reported that
5-azacytidine (Vidaza™) prolonged the overall survival of a group of high risk MDS and AML patients. To determine whether the combination of
lintuzumab and
5-azacytidine would be beneficial, a mouse xenograft model of disseminated AML was used to evaluate the combination. There was a significant reduction in
tumor burden and an increase in overall survival in mice treated with
lintuzumab and
5-azacytidine. The effects were greater than that obtained with either agent alone. As the in vivo anti-leukemic activity of
lintuzumab was dependent upon the presence of mouse effector cells including macrophages and neutrophils, in vitro effector function assays were used to assess the impact of
5-azacytidine on
lintuzumab activity. The results show that
5-azacytidine significantly enhanced the ability of
lintuzumab to promote
tumor cell killing through antibody-dependent cellular cytotoxicity (ADCC) and phagocytic (ADCP) activities. These results suggest that
lintuzumab and
5-azacytidine act in concert to promote
tumor cell killing. Additionally, these findings provide the rationale to evaluate this combination in the clinic.