title: In Vitro and In Vivo Efficacy of a Novel CD33-Targeted Thorium-227 Conjugate for the Treatment of Acute Myeloid Leukemia.
abstract: The clinical efficacy of the first approved alpha pharmaceutical, Xofigo (radium-223 dichloride,223RaCl2), has stimulated significant interest in the development of new alpha-particle emitting drugs in oncology. Unlike radium-223 (223Ra), the parent radionuclide thorium-227 (227Th) is able to form highly stable chelator complexes and is therefore amenable to targeted radioimmunotherapy. We describe the preparation and use of a CD33-targeted thorium-227 conjugate (CD33-TTC), which binds to the sialic acid receptor CD33 for the treatment of acute myeloid leukemia (AML). A chelator was conjugated to the CD33-targeting antibody lintuzumab via amide bonds, enabling radiolabeling with the alpha-emitter227Th. The CD33-TTC induced in vitro cytotoxicity on CD33-positive cells, independent of multiple drug resistance (MDR) phenotype. After exposure to CD33-TTC, cells accumulated DNA double-strand breaks and were arrested in the G2phase of the cell cycle. In vivo, the CD33-TTC demonstrated antitumor activity in a subcutaneous xenograft mouse model using HL-60 cells at a single dose regimen. Dose-dependent significant survival benefit was further demonstrated in a disseminated mouse tumor model after single dose injection or administered as a fractionated dose. The data presented support the further development of the CD33-TTC as a novel alpha pharmaceutical for the treatment of AML. Mol Cancer Ther; 15(10); 2422-31. ©2016 AACR.
authors.affiliation: Thorium Conjugate Research, Bayer AS, Oslo, Norway. urs.hagemann@bayer.com.
authors.forename: Urs B
authors.initials: UB
authors.lastname: Hagemann
authors.affiliation: Thorium Conjugate Research, Bayer AS, Oslo, Norway.
authors.forename: Katrine
authors.initials: K
authors.lastname: Wickstroem
authors.affiliation: Thorium Conjugate Research, Bayer AS, Oslo, Norway.
authors.forename: Ellen
authors.initials: E
authors.lastname: Wang
authors.affiliation: Thorium Conjugate Research, Bayer AS, Oslo, Norway.
authors.forename: Adam O
authors.initials: AO
authors.lastname: Shea
authors.affiliation: Thorium Conjugate Research, Bayer AS, Oslo, Norway.
authors.forename: Kristine
authors.initials: K
authors.lastname: Sponheim
authors.affiliation: Thorium Conjugate Research, Bayer AS, Oslo, Norway.
authors.forename: Jenny
authors.initials: J
authors.lastname: Karlsson
authors.affiliation: Thorium Conjugate Research, Bayer AS, Oslo, Norway.
authors.forename: Roger M
authors.initials: RM
authors.lastname: Bjerke
authors.affiliation: Thorium Conjugate Research, Bayer AS, Oslo, Norway.
authors.forename: Olav B
authors.initials: OB
authors.lastname: Ryan
authors.affiliation: Thorium Conjugate Research, Bayer AS, Oslo, Norway.
authors.forename: Alan S
authors.initials: AS
authors.lastname: Cuthbertson
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry / Q000494:pharmacology*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D051379:Mice; D016499:Radioimmunotherapy; D063268:Sialic Acid Binding Ig-like Lectin 3 / Q000037:antagonists & inhibitors*; D016019:Survival Analysis; D013910:Thorium / Q000737:chemistry; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D018796:Immunoconjugates; D063268:Sialic Acid Binding Ig-like Lectin 3; D013910:Thorium