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SGN-CD33A: a novel CD33-targeting antibody-drug conjugate utilizing a pyrrolobenzodiazepine dimer is active in models of drug-resistant AML

May S. Kung Sutherland, Roland B. Walter, Scott C. Jeffrey, Patrick J. Burke, Changpu Yu, Heather Kostner, Ivan Stone, Maureen C. Ryan, Django Sussman, Robert P. Lyon, Weiping Zeng, Kimberly H. Harrington, Kerry Klussman, Lori Westendorf, David Meyer, Irwin D. Bernstein, Peter D. Senter, Dennis R. Benjamin, Jonathan G. Drachman and Julie A. McEarchern

Key points

  • Preclinical development and characterization of a novel ADC, SGN-CD33A, an anti-CD33 mAb conjugated to a potent DNA cross-linking cytotoxin

  • SGN-CD33A is highly active in a broad panel of preclinical AML models and in contrast to GO, is active despite MDR or poor-risk cytogenetics

Abstract

Outcomes in acute myeloid leukemia (AML) remain unsatisfactory, and novel treatments are urgently needed. One strategy explores antibodies and their drug conjugates, particularly those targeting CD33. Emerging data with gemtuzumab ozogamicin (GO) demonstrate target validity and activity in some AML patients, but efficacy is limited by heterogeneous drug conjugation, linker instability, and a high incidence of multi-drug resistance. We describe here the development of SGN-CD33A, a humanized anti-CD33 antibody with engineered cysteines, conjugated to a highly potent, synthetic DNA cross-linking pyrrolobenzodiazepine (PBD) dimer via a protease-cleavable linker. The use of engineered cysteine residues at the sites of drug linker attachment results in a drug loading of approximately 2 PBD dimers per antibody. In preclinical testing, SGN-CD33A is more potent than GO against a panel of AML cell lines and primary AML cells in vitro and in xenotransplantation studies in mice. Unlike GO, anti-leukemic activity is observed with SGN-CD33A in AML models with the multi-drug resistant (MDR) phenotype. Mechanistic studies indicate that the cytotoxic effects of SGN-CD33A involve DNA damage with ensuing cell cycle arrest and apoptotic cell death. Together, these data suggest that SGN-CD33A has CD33-directed antitumor activity and support clinical testing of this novel therapeutic in patients with AML.

  • Submitted March 19, 2013.
  • Accepted June 2, 2013.