A Phase 1 Study of PAmAb, a Fully Human Monoclonal Antibody against Bacillus anthracis Protective Antigen, in Healthy Volunteers

• Published in: Clinical infectious diseases Vol. 41; no. 1; pp. 12 - 20
• Main Authors: Subramanian, G. Mani, Cronin, Patrick W., Poley, Gerald, Weinstein, Andrea, Stoughton, Susan M., Zhong, John, Ou, Ying, Zmuda, Jonathan F., Osborn, Blaire L., Freimuth, William W.
• Format: Journal Article
• Language: English
• Published: Chicago, IL The University of Chicago Press 01.07.2005; University of Chicago Press; Oxford University Press
• Subjects: Adolescent; Adult; Aged; Anthrax; Anthrax - prevention & control; Antiarythmic agents; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - adverse effects; Antibodies, Monoclonal - pharmacokinetics; Antigens; Antigens, Bacterial - immunology; Bacillus anthracis; Bacillus anthracis - immunology; Bacteria; Bacterial diseases; Biological and medical sciences; Cardiovascular system; Dosage; Dose-Response Relationship, Drug; Female; Human bacterial diseases; Humans; Infectious diseases; Injections, Intramuscular; Injections, Intravenous; Intramuscular injections; Intravenous injections; Major Articles; Male; Medical sciences; Medical treatment; Middle Aged; Miscellaneous; Monoclonal antibodies; Pharmacokinetics; Pharmacology. Drug treatments; Placebos; Quadriceps muscle; Single-Blind Method; Treatment Outcome; Vaccination; Human; Bacillus anthracis; Vastus lateralis muscle; Purine nucleoside; Adenosine; Healthy subject; Monoclonal antibody; Bacillaceae; Antiarrhythmic agent; Infection; Antigen; Prevention; Bacillales; Anthrax; Bacteriosis; Bacteria; Gluteus maximus muscle
• ISSN: 1058-4838; 1537-6591
• DOI: 10.1086/430708

Background. Inhibition of the binding of Bacillus anthracis protective antigen (PA) to its cellular receptor can abrogate the downstream toxin-mediated deleterious effects of the anthrax toxin. A fully human monoclonal antibody against B. anthracis PA, PAmAb, was previously shown to provide a survival advantage in rabbit and monkey models of inhalational anthrax. Methods. A randomized, single-blind, placebo-controlled, dose-escalation study with 105 healthy volunteers was conducted to evaluate the safety, pharmacokinetics, and biological activity of PAmAb. Subjects received PAmAb or placebo as a single intramuscular injection (11 subjects/cohort) or intravenous infusion (10 subjects/cohort). Three intramuscular dose levels (0.3, 1.0, and 3.0 mg/kg) and 5 intravenous dose levels (1.0, 3.0, 10, 20, and 40 mg/kg) were studied. Two separate intramuscular injection sites (gluteus maximus and vastus lateralis) were evaluated in the cohorts (hereafter, the “IM-GM” and “IM-VL” cohorts, respectively). Results. PAmAb was well tolerated, with no dose-limiting adverse events. All adverse events were transient and mild to moderate in incidence and/or severity. The pharmacokinetics of PAmAb were linear within each route and site of administration but were significantly different between the IM-GM and IM-VL cohorts. The mean terminal elimination half-life ranged from 15 to 19 days. The bioavailability of PAmAb is χ50% for IM-GM injection and 71%–85% for IM-VL injection. The biological activity of PAmAb in serum, assessed using a cyclic adenosine monophosphate assay, correlated with serum concentrations. Conclusions. PAmAb is safe, well tolerated, and bioavailable after a single intramuscular or intravenous dose, which supports further clinical development of PAmAb as a novel therapeutic agent for inhalational anthrax.