title: A Phase 1 study of the safety, pharmacokinetics and anti-leukemic activity of the anti-CD123 monoclonal antibody CSL360 in relapsed, refractory or high-risk acute myeloid leukemia.
abstract: Acute myeloid leukemia (AML) blasts express high levels of interlekin-3 (IL-3) receptor-α (CD123). CSL360 is a recombinant, chimeric immunoglobulin G1 (IgG1), anti-CD123 monoclonal antibody (MoAb) that neutralizes IL-3 and demonstrates anti-leukemic activity in vitro. This phase 1 study assessed safety, pharmacokinetics and bioactivity of weekly intravenous CSL360 for 12 weeks in 40 patients with advanced AML across five dose levels (0.1-10.0 mg/kg). Other than mild infusion reactions, CSL360 was well tolerated. The maximal tolerated dose was not reached. The half-life was 4.9 days, and the area under the curve (AUC) and maximum concentration (Cmax) increased proportionally with dose. Doses ≥ 3.0 mg/kg resulted in complete saturation and down-regulation of CD123 and abolition of ex vivo proliferative responsiveness to IL-3, indicating adequate blockade of IL-3 signaling. Two patients responded, with one remaining in complete remission after 17 doses. CSL360 bound CD123 specifically, but did not induce anti-leukemic activity in most patients. While safe, MoAb blockade of CD123 function is insufficient as a therapeutic strategy.
authors.affiliation: Department of Clinical Haematology and BMT Service, The Royal Melbourne Hospital , Melbourne , Australia.
authors.forename: Simon Z
authors.initials: SZ
authors.lastname: He
authors.forename: Samantha
authors.initials: S
authors.lastname: Busfield
authors.forename: David S
authors.initials: DS
authors.lastname: Ritchie
authors.forename: Mark S
authors.initials: MS
authors.lastname: Hertzberg
authors.forename: Simon
authors.initials: S
authors.lastname: Durrant
authors.forename: Ian D
authors.initials: ID
authors.lastname: Lewis
authors.forename: Paula
authors.initials: P
authors.lastname: Marlton
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: McLachlan
authors.forename: Ian
authors.initials: I
authors.lastname: Kerridge
authors.forename: Kenneth F
authors.initials: KF
authors.lastname: Bradstock
authors.forename: Glen
authors.initials: G
authors.lastname: Kennedy
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Boyd
authors.forename: Trina M
authors.initials: TM
authors.lastname: Yeadon
authors.forename: Angel F
authors.initials: AF
authors.lastname: Lopez
authors.forename: Hayley S
authors.initials: HS
authors.lastname: Ramshaw
authors.forename: Harry
authors.initials: H
authors.lastname: Iland
authors.forename: Simone
authors.initials: S
authors.lastname: Bamford
authors.forename: Megan
authors.initials: M
authors.lastname: Barnden
authors.forename: Mark
authors.initials: M
authors.lastname: DeWitte
authors.forename: Russell
authors.initials: R
authors.lastname: Basser
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Roberts
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007377:Interleukin-3 / Q000378:metabolism; D053650:Interleukin-3 Receptor alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C000606072:CSL360; D007377:Interleukin-3; D053650:Interleukin-3 Receptor alpha Subunit
keywords: Acute myeloid leukemia (AML); immunotherapy; interleukin-3 (IL-3) receptor-α (CD123); leukemic stem cell (LSC)