SGN-CD33A in Combination with Cytarabine or Hypomethylating Agents Demonstrates Enhanced Anti-Leukemic Activity in Preclinical Models of AML
Authors: Sutherland May S.K. , Yu Changpu , Anderson Martha , Emmerton Kim , Zeng Weiping , O'Meara Megan M. , Kennedy Dana A. , Ryan Maureen C. , Benjamin Dennis R. 
Published: October 2019

Long-term survival rates for acute myeloid leukemia (AML) patients remain poor, highlighting the need for further treatment options. AML cells express the myeloid marker CD33, making them amenable to CD33-targeted therapy. SGN-CD33A is a novel anti-CD33 antibody-drug conjugate (ADC) composed of a humanized antibody conjugated to a highly potent DNA-binding pyrrolobenzodiazepine (PBD) dimer drug via a protease-cleavable dipeptide linker. An engineered cysteine on each heavy chain attaching the PBD dimer to the antibody allows uniform drug loading of approximately two PBD dimers per antibody. Upon binding to CD33 on the cell surface, SGN-CD33A is internalized, the linker is cleaved by proteases in the lysosomes, and the released drug forms DNA crosslinks, resulting in cell death.

SGN-CD33A is active as a single agent against a broad panel of primary AML samples and in preclinical models of AML that are characteristically resistant to chemotherapy (multi-drug-resistant, MDR-positive) (Sutherland et al. Blood 2013). In the present study, we tested the activity of SGN-CD33A in cytotoxicity assays in combination with therapies commonly used in the treatment of myeloid malignancies including cytarabine (Ara-C) and the hypomethylating agents, 5-azacytidine (vidaza) or 5-aza-2-deoxcytidine (decitabine). Significant synergism in tumor cell killing, as assessed by the Chou-Talalaly Combination Index (CI), was observed when MDR-positive AML cell lines, KG-1 and TF1-a, were treated simultaneously with the combination of SGN-CD33A and Ara-C (CI < 0.7) or SGN-CD33A and a hypomethylating agent (CI < 0.7).

Consistent with these observations, mouse xenograft experiments were conducted with AML cell lines, and demonstrated improved antitumor activity with the combinations compared to either agent alone. In the subcutaneous MDR-positive TF1-a model of AML, a single low dose of SGN-CD33A (30 mcg/kg) in combination with Ara-C significantly reduced tumor burden compared to either agent alone or to the nonbinding control ADC groups (p< 0.0001). Significant reductions in tumor growth were also observed in subcutaneous MDR-positive TF1-a or KG-1 murine models of AML treated with SGN-CD33A in combination with hypomethylating agents. Whereas a single low dose of SGN-CD33A or the hypomethylating agents decitabine or vidaza delayed tumor growth, the combination delivered greater antitumor activity than the individual agents alone. These findings demonstrate that SGN-CD33A can be combined with therapies that are commonly used in treating myeloid malignancies to deliver significantly improved antitumor activity in preclinical drug-resistant models of AML.

Disclosures

Sutherland: Seattle Genetics: Employment, Equity Ownership. Yu:Seattle Genetics: Employment, Equity Ownership. Anderson:Seattle Genetics: Employment, Equity Ownership. Emmerton:Seattle Genetics: Employment, Equity Ownership. Zeng:Seattle Genetics: Employment, Equity Ownership. O'Meara:Seattle Genetics, Inc.: Employment, Equity Ownership. Kennedy:Seattle Genetics, Inc.: Employment, Equity Ownership. Ryan:Seattle Genetics: Employment, Equity Ownership. Benjamin:Seattle Genetics: Employment, Equity Ownership.