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.
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.
Getman
Kate E
KE
Department of Pharmaceutical Sciences, University at Buffalo, The State University at New York, Buffalo, New York 14260, USA.
Balthasar
Joseph P
JP
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*
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