SGN-33, Lintuzumab, Demonstrates Anti-Leukemic Activity in Preclinical Models of AML.

SGN-33 is a humanized IgG1 antibody with signaling properties that also mediates effector functions including Antibody-Dependent Cellular Cytotoxicity (ADCC). SGN-33 targets CD33, a sialoadhesion family member expressed on acute myeloid leukemia (AML) cells, eliciting complete remissions in some AML patients. In the laboratory, SGN-33 mediates natural killer (NK) cell lysis of both multi-drug resistant (MDR- positive) and MDR-negative AML cell lines. Additionally, SGN-33 significantly increases survival in SCID mouse disseminated models of MDR-negative and MDR- positive AML. Immunomodulatory compounds such as thalidomide and its analog, lenalidomide (Revlimid®), have been shown to enhance NK cell function and anti-cancer activity. In particular, Revlimid in combination with rituximab demonstrated greater tumor cell killing compared to the antibody alone. Given these reports, we investigated whether thalidomide or lenalidomide would enhance the anti-tumor effects of SGN-33. In vitro, lenalidomide augmented NK function in a dose-dependent fashion, manifested as significant increases in perforin expression. Thalidomide and lenalidomide enhanced ADCC activity (% maximal specific lysis) while having no significant effects on tumor cell levels of CD33. In vivo, treatment of SCID mice with lenalidomide resulted in a 2-fold increase in the absolute numbers of lymphocytes (including NK cells). In vivo studies evaluating the efficacy of the combination of SGN-33 and lenalidomide in SCID mouse models of AML are in progress. In summary, our studies demonstrate the anti-leukemic activity of SGN-33 against MDR-positive AML cell lines, suggesting that this unconjugated anti-CD33 antibody may yield benefit in clinical settings where other therapies fail due to the MDR phenotype of the tumor cells. Additionally, agents augmenting immunologic effector function might provide clinical benefit in combination with SGN-33. The combination of SGN-33 and lenalidomide is now being evaluated in a clinical trial.