title: Clinical safety and pharmacological profile of the HLA-DR antibody 1D09C3 in patients with B cell chronic lymphocytic leukemia and lymphoma: results from a phase I study.
abstract: 1D09C3 is a human monoclonal IgG4-type antibody against human leukocyte antigen-DR (HLA-DR) which has demonstrated pro-apoptotic activity against lymphoid tumors in vitro and in vivo. We report results from a phase I dose-escalation study which aimed to identify tolerated dosing, and the pharmacokinetic and pharmacodynamic profile of 1D09C3. Fourteen patients with relapsed/refractory B cell type leukemia/lymphoma were treated and followed after up to 4 weekly infusions of 1D09C3, administered in 6 dose levels at 0.25-8 mg/kg/day. Treatment was tolerated well with mostly mild side effects. The most common grade III-IV toxicities were hematological events observed in 4 patients. In one patient, treated at 8.0 mg/kg/day, a dose limiting toxicity occurred, identified as an invasive catheter-related infection. Adverse events resolved completely without long-term sequelae. 1D09C3 reduced peripheral blood B cells and monocytes by a median of 73-81 % in all patients, with a nadir reached 30-60 min after infusion and sustained for <96 h. Granulocytes and natural killer cells predominantly increased with variable time courses. Pharmacokinetic assessments showed detectable drug concentrations at doses 4-8 mg/kg/day and a terminal half-life of 0.7-7.9 h. Effective saturation of HLA-DR on peripheral blood B cells/monocytes was achieved, varying consistently with available serum concentrations and the cell-reducing activity of 1D09C3. In summary, 1D09C3 could be administered safely in patients with advanced B cell malignancies. Pharmacodynamic studies demonstrated a strong dose dependent but transient reduction of peripheral blood B cells and monocytes, consistent with a short drug serum availability.
authors.affiliation: Department of Internal Medicine I, Center of Integrated Oncology Cologne Bonn, University of Cologne, Kerpener Str. 62, 50937, Cologne, Germany. carmen.schweighofer@uk-koeln.de
authors.forename: Carmen D
authors.initials: CD
authors.lastname: Schweighofer
authors.forename: Armin
authors.initials: A
authors.lastname: Tuchscherer
authors.forename: Sabine
authors.initials: S
authors.lastname: Sperka
authors.forename: Thorsten
authors.initials: T
authors.lastname: Meyer
authors.forename: Benno
authors.initials: B
authors.lastname: Rattel
authors.forename: Sandra
authors.initials: S
authors.lastname: Stein
authors.forename: Semra
authors.initials: S
authors.lastname: Ismail
authors.forename: Thomas
authors.initials: T
authors.lastname: Elter
authors.forename: Peter
authors.initials: P
authors.lastname: Staib
authors.forename: Marcel
authors.initials: M
authors.lastname: Reiser
authors.forename: Michael
authors.initials: M
authors.lastname: Hallek
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects* / Q000276:immunology / Q000493:pharmacokinetics; D061067:Antibodies, Monoclonal, Humanized; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006098:Granulocytes / Q000187:drug effects / Q000276:immunology; D006684:HLA-DR Antigens / Q000276:immunology*; D006207:Half-Life; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000276:immunology*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000276:immunology
chemical_list: C528511:1D09C3 monoclonal antibody; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D006684:HLA-DR Antigens