title: Targeted alpha-particle immunotherapy for acute myeloid leukemia.
abstract: Because alpha-particles have a shorter range and a higher linear energy transfer (LET) compared with beta-particles, targeted alpha-particle immunotherapy offers the potential for more efficient tumor cell killing while sparing surrounding normal cells. To date, clinical studies of alpha-particle immunotherapy for acute myeloid leukemia (AML) have focused on the myeloid cell surface antigen CD33 as a target using the humanized monoclonal antibody lintuzumab. An initial phase I study demonstrated the safety, feasibility, and antileukemic effects of bismuth-213 ((213)Bi)-labeled lintuzumab. In a subsequent study, (213)Bi-lintuzumab produced remissions in some patients with AML after partial cytoreduction with cytarabine, suggesting the utility of targeted alpha-particle therapy for small-volume disease. The widespread use of (213)Bi, however, is limited by its short half-life. Therefore, a second-generation construct containing actinium-225 ((225)Ac), a radiometal that generates four alpha-particle emissions, was developed. A phase I trial demonstrated that (225)Ac-lintuzumab is safe at doses of 3 μCi/kg or less and has antileukemic activity across all dose levels studied. Fractionated-dose (225)Ac-lintuzumab in combination with low-dose cytarabine (LDAC) is now under investigation for the management of older patients with untreated AML in a multicenter trial. Preclinical studies using (213)Bi- and astatine-211 ((211)At)-labeled anti-CD45 antibodies have shown that alpha-particle immunotherapy may be useful as part conditioning before hematopoietic cell transplantation. The use of novel pretargeting strategies may further improve target-to-normal organ dose ratios.
authors.affiliation: From the Division of Hematology/Oncology, Department of Medicine, Columbia University Medical Center; the New York-Presbyterian Hospital, and the Herbert Irving Comprehensive Cancer Center, New York, NY.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Jurcic
authors.affiliation: From the Division of Hematology/Oncology, Department of Medicine, Columbia University Medical Center; the New York-Presbyterian Hospital, and the Herbert Irving Comprehensive Cancer Center, New York, NY.
authors.forename: Todd L
authors.initials: TL
authors.lastname: Rosenblat
mesh_terms: D000512:Alpha Particles / Q000627:therapeutic use*; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D001729:Bismuth / Q000627:therapeutic use; D002986:Clinical Trials as Topic / Q000379:methods; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use*; D015470:Leukemia, Myeloid, Acute / Q000532:radiotherapy*; D058990:Molecular Targeted Therapy / Q000379:methods; D016499:Radioimmunotherapy / Q000379:methods*; D011868:Radioisotopes / Q000627:therapeutic use
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018796:Immunoconjugates; D011868:Radioisotopes; D001729:Bismuth; C477390:lintuzumab