Neonatal Fc receptor blockade by Fc engineering ameliorates arthritis in a murine model.

Abstract

Multiple autoimmune diseases are characterized by the involvement of autoreactive Abs in pathogenesis. Problems associated with existing therapeutics such as the delivery of intravenous immunoglobulin have led to interest in developing alternative approaches using recombinant or synthetic methods. Toward this aim, in the current study, we demonstrate that the use of Fc-engineered Abs (Abs that enhance IgG degradation [Abdegs]) to block neonatal FcR (FcRn) through high-affinity, Fc region binding is an effective strategy for the treatment of Ab-mediated disease. Specifically, Abdegs can be used at low, single doses to treat disease in the K/B×N serum transfer model of arthritis using BALB/c mice as recipients. Similar therapeutic effects are induced by 25- to 50-fold higher doses of i.v. Ig. Importantly, we show that FcRn blockade is a primary contributing factor toward the observed reduction in disease severity. The levels of albumin, which is also recycled by FcRn, are not affected by Abdeg delivery. Consequently, Abdegs do not alter FcRn expression levels or subcellular trafficking behavior. The engineering of Ab Fc regions to generate potent FcRn blockers therefore holds promise for the therapy of Ab-mediated autoimmunity.

• Authors: Dipesh A Patel, Alberto Puig-Canto, Dilip Kumar Challa, Héctor Perez Montoyo, Raimund J Ober, E Sally Ward
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 187 Issue 2 Pg. 1015-22 (Jul 15 2011) ISSN: 1550-6606 [Electronic] United States
• PMID: 21690327 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Antibodies, Blocking
• Histocompatibility Antigens Class I
• Immunoglobulin Fc Fragments
• Immunoglobulin G
• Receptors, Antigen, T-Cell, alpha-beta
• Receptors, Fc
• Recombinant Proteins
• T cell receptor Vbeta6, human
• Glucose-6-Phosphate Isomerase
• Fc receptor, neonatal

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (metabolism, therapeutic use)
• Antibodies, Blocking (genetics, metabolism, therapeutic use)
• Antibody Affinity (genetics)
• Arthritis, Experimental (immunology, pathology, therapy)
• Glucose-6-Phosphate Isomerase (immunology)
• Histocompatibility Antigens Class I (metabolism)
• Humans
• Immunoglobulin Fc Fragments (genetics, metabolism, therapeutic use)
• Immunoglobulin G (genetics, metabolism, therapeutic use)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred NOD
• Mice, Transgenic
• Protein Engineering (methods)
• Receptors, Antigen, T-Cell, alpha-beta (genetics, immunology, metabolism)
• Receptors, Fc (antagonists & inhibitors, deficiency, metabolism)
• Recombinant Proteins (chemical synthesis, metabolism, therapeutic use)
• Severity of Illness Index