title: Pharmacokinetics, pharmacodynamics, safety and tolerability of APG101, a CD95-Fc fusion protein, in healthy volunteers and two glioma patients.
abstract: APG101 is a glycosylated fusion protein consisting of the extracellular domain of human CD95 (APO-1/Fas) and the Fc domain of human IgG1. Administration of APG101 blocks the interaction between CD95 and its cognate ligand CD95L, thereby inhibiting various pathways involved in e.g. proliferation, migration, differentiation and apoptosis induction. The safety and tolerability of ascending single doses of intravenously applied APG101 was examined in a randomized, double-blind, placebo-controlled, mono-centre "first in man" dose escalation study in 34 healthy male volunteers. Pharmacokinetics and pharmacodynamics were also assessed. The maximum serum concentration of 460 μg/ml was achieved following 1h infusion of the highest dose of 20 mg/kg. The systemic clearance was low (0.4 to 0.5 ml/hkg). Mean terminal elimination half-life was 12 to 15 days. Two patients suffering from malignant glioma received APG101 intravenously under compassionate use conditions. They received doses ranging from 5mg to 600 mg APG101. No adverse events and no clinical significant changes in laboratory parameters related to APG101 were reported. The presence of anti-drug-antibodies (ADA) was investigated and revealed no detectable levels of ADA. Overall, single ascending doses of APG101 up to 20 mg/kgbody weight (bw) administered as infusion over 1h were considered as safe and well tolerated in healthy volunteers. After the application of multiple doses of 400 mg in two glioma patients, steady state for APG101 seemed to be reached. These results support further clinical evaluation of APG101 at a dose of 400 mg per week in glioblastoma patients.
authors.affiliation: Department of Neurosurgery, SHG-Klinikum Idar-Oberstein, Dr.-Ottmar-Kohler Strasse 2, Idar-Oberstein, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Tuettenberg
authors.forename: Marcel
authors.initials: M
authors.lastname: Seiz
authors.forename: Klaus-Michael
authors.initials: KM
authors.lastname: Debatin
authors.forename: Wiebke
authors.initials: W
authors.lastname: Hollburg
authors.forename: Michael
authors.initials: M
authors.lastname: von Staden
authors.forename: Meinolf
authors.initials: M
authors.lastname: Thiemann
authors.forename: Barbara
authors.initials: B
authors.lastname: Hareng
authors.forename: Harald
authors.initials: H
authors.lastname: Fricke
authors.forename: Claudia
authors.initials: C
authors.lastname: Kunz
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D057176:Compassionate Use Trials; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005910:Glioma / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D007074:Immunoglobulin G / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D007262:Infusions, Intravenous; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D011993:Recombinant Fusion Proteins / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D055815:Young Adult; D019014:fas Receptor / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; C491901:FAS protein, human; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D011993:Recombinant Fusion Proteins; D019014:fas Receptor; C574675:APG101