title: SGN-CD33A: a novel CD33-targeting antibody-drug conjugate using a pyrrolobenzodiazepine dimer is active in models of drug-resistant AML.
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 patients with AML, but efficacy is limited by heterogeneous drug conjugation, linker instability, and a high incidence of multidrug 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 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 pyrrolobenzodiazepine 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, antileukemic activity is observed with SGN-CD33A in AML models with the multidrug-resistant 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.
authors.affiliation: Department of Research & Translational Medicine, Seattle Genetics Inc., Bothell, WA 98021, USA. msutherland@seagen.com
authors.forename: May S
authors.initials: MS
authors.lastname: Kung Sutherland
authors.forename: Roland B
authors.initials: RB
authors.lastname: Walter
authors.forename: Scott C
authors.initials: SC
authors.lastname: Jeffrey
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Burke
authors.forename: Changpu
authors.initials: C
authors.lastname: Yu
authors.forename: Heather
authors.initials: H
authors.lastname: Kostner
authors.forename: Ivan
authors.initials: I
authors.lastname: Stone
authors.forename: Maureen C
authors.initials: MC
authors.lastname: Ryan
authors.forename: Django
authors.initials: D
authors.lastname: Sussman
authors.forename: Robert P
authors.initials: RP
authors.lastname: Lyon
authors.forename: Weiping
authors.initials: W
authors.lastname: Zeng
authors.forename: Kimberly H
authors.initials: KH
authors.lastname: Harrington
authors.forename: Kerry
authors.initials: K
authors.lastname: Klussman
authors.forename: Lori
authors.initials: L
authors.lastname: Westendorf
authors.forename: David
authors.initials: D
authors.lastname: Meyer
authors.forename: Irwin D
authors.initials: ID
authors.lastname: Bernstein
authors.forename: Peter D
authors.initials: PD
authors.lastname: Senter
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Benjamin
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Drachman
authors.forename: Julie A
authors.initials: JA
authors.lastname: McEarchern
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000737:chemistry*; D017209:Apoptosis; D001569:Benzodiazepines / Q000737:chemistry*; D002453:Cell Cycle; D003432:Cross-Linking Reagents / Q000737:chemistry / Q000494:pharmacology; D003545:Cysteine / Q000235:genetics; D019281:Dimerization; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D057809:HEK293 Cells; D018922:HL-60 Cells; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D063268:Sialic Acid Binding Ig-like Lectin 3 / Q000737:chemistry*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D003432:Cross-Linking Reagents; D018796:Immunoconjugates; D063268:Sialic Acid Binding Ig-like Lectin 3; D001569:Benzodiazepines; D003545:Cysteine; C477390:lintuzumab