title: Targeted alpha particle immunotherapy for myeloid leukemia.
abstract: Unlike beta particle-emitting isotopes, alpha emitters can selectively kill individual cancer cells with a single atomic decay. HuM195, a humanized anti-CD33 monoclonal antibody, specifically targets myeloid leukemia cells and has activity against minimal disease. When labeled with the beta-emitters (131)I and (90)Y, HuM195 can eliminate large leukemic burdens in patients, but it produces prolonged myelosuppression requiring hematopoietic stem cell transplantation at high doses. To enhance the potency of native HuM195 yet avoid the nonspecific cytotoxicity of beta-emitting constructs, the alpha-emitting isotope (213)Bi was conjugated to HuM195. Eighteen patients with relapsed and refractory acute myelogenous leukemia or chronic myelomonocytic leukemia were treated with 10.36 to 37.0 MBq/kg (213)Bi-HuM195. No significant extramedullary toxicity was seen. All 17 evaluable patients developed myelosuppression, with a median time to recovery of 22 days. Nearly all the (213)Bi-HuM195 rapidly localized to and was retained in areas of leukemic involvement, including the bone marrow, liver, and spleen. Absorbed dose ratios between these sites and the whole body were 1000-fold greater than those seen with beta-emitting constructs in this antigen system and patient population. Fourteen (93%) of 15 evaluable patients had reductions in circulating blasts, and 14 (78%) of 18 patients had reductions in the percentage of bone marrow blasts. This study demonstrates the safety, feasibility, and antileukemic effects of (213)Bi-HuM195, and it is the first proof-of-concept for systemic targeted alpha particle immunotherapy in humans.
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center and Weill Medical College of Cornell University, New York, NY 10021, USA. jurcicj@mskcc.org
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Jurcic
authors.forename: Steven M
authors.initials: SM
authors.lastname: Larson
authors.forename: George
authors.initials: G
authors.lastname: Sgouros
authors.forename: Michael R
authors.initials: MR
authors.lastname: McDevitt
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Finn
authors.forename: Chaitanya R
authors.initials: CR
authors.lastname: Divgi
authors.forename: Ase M
authors.initials: AM
authors.lastname: Ballangrud
authors.forename: Klaus A
authors.initials: KA
authors.lastname: Hamacher
authors.forename: Dangshe
authors.initials: D
authors.lastname: Ma
authors.forename: John L
authors.initials: JL
authors.lastname: Humm
authors.forename: Martin W
authors.initials: MW
authors.lastname: Brechbiel
authors.forename: Roger
authors.initials: R
authors.lastname: Molinet
authors.forename: David A
authors.initials: DA
authors.lastname: Scheinberg
mesh_terms: D000512:Alpha Particles / Q000009:adverse effects / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics; D018952:Antigens, CD34 / Q000276:immunology; D001729:Bismuth / Q000008:administration & dosage / Q000627:therapeutic use; D001752:Blast Crisis / Q000473:pathology / Q000532:radiotherapy; D006801:Humans; D000922:Immunotoxins / Q000627:therapeutic use*; D015470:Leukemia, Myeloid, Acute / Q000473:pathology / Q000532:radiotherapy*; D015477:Leukemia, Myelomonocytic, Chronic / Q000473:pathology / Q000532:radiotherapy*; D007970:Leukopenia / Q000209:etiology; D011868:Radioisotopes / Q000008:administration & dosage / Q000627:therapeutic use
chemical_list: D000911:Antibodies, Monoclonal; D018952:Antigens, CD34; D000922:Immunotoxins; D011868:Radioisotopes; D001729:Bismuth