title: Pharmacokinetic effects of 4C9, an anti-FcRn antibody, in rats: implications for the use of FcRn inhibitors for the treatment of humoral autoimmune and alloimmune conditions.
abstract: FcRn protects immune gamma globulin (IgG) from intracellular catabolism, and thereby contributes to the long plasma half-life associated with this class of antibody. The present study tested the hypothesis that 4C9, an anti-FcRn antibody, would increase the in vivo systemic clearance of a model antibody, anti-methotrexate IgG (AMI), in rats. Hybridomas secreting 4C9 and AMI were grown in serum free medium, and monoclonal 4C9 and AMI were purified via protein-G chromatography. Rats were instrumented with jugular vein cannulas 2-3 days prior to investigation, and 4C9 was administered intravenously at doses of 3, 15, and 60 mg/kg. AMI was then administered 4, 24, and 48 h after administration of 4C9. Blood samples were collected and assayed to determine AMI concentrations. The anti-FcRn antibody, 4C9, increased AMI systemic clearance in a dose-dependent manner (from 0.99+/-0.14 mg/h/kg in control animals to 1.27+/-0.05, 1.73+/-0.50, and 1.97+/-0.49 mL/h/kg in animals treated with 3, 15, and 60 mg/kg 4C9; p<0.05). These data were well-captured with an indirect-effect pharmacokinetic-pharmacodynamic model. The effect of 4C9 was found to be transient; no significant effects on AMI systemic clearance were observed when pre-treatment time was increased to 24 or 48 h. As such, the data demonstrate that 4C9, a monoclonal anti-FcRn antibody, induces a transient, dose-dependent increase in the elimination of IgG. The results suggest that FcRn inhibitors may have utility in the treatment of antibody-mediated autoimmune and alloimmune conditions.
authors.affiliation: Department of Pharmaceutical Sciences, University at Buffalo, The State University at New York, Buffalo, New York 14260, USA.
authors.forename: Kate E
authors.initials: KE
authors.lastname: Getman
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Balthasar
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000917:Antibody Formation / Q000276:immunology; D000964:Antimetabolites, Antineoplastic / Q000276:immunology; D019540:Area Under Curve; D001327:Autoimmune Diseases / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G / Q000276:immunology / Q000302:isolation & purification; D008727:Methotrexate / Q000276:immunology; D051379:Mice; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley; D011961:Receptors, Fc / Q000037:antagonists & inhibitors* / Q000276:immunology*
chemical_list: C502491:4C9 antibody, rat; D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D000964:Antimetabolites, Antineoplastic; D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G; D011961:Receptors, Fc; C100688:Fc receptor, neonatal; D008727:Methotrexate