title: Therapeutic antibody targeting of indoleamine-2,3-dioxygenase (IDO2) inhibits autoimmune arthritis.
abstract: Rheumatoid arthritis (RA) is a debilitating inflammatory autoimmune disease with no known cure. Recently, we identified the immunomodulatory enzyme indoleamine-2,3-dioxygenase 2 (IDO2) as an essential mediator of autoreactive B and T cell responses driving RA. However, therapeutically targeting IDO2 has been challenging given the lack of small molecules that specifically inhibit IDO2 without also affecting the closely related IDO1. In this study, we develop a novel monoclonal antibody (mAb)-based approach to therapeutically target IDO2. Treatment with IDO2-specific mAb alleviated arthritis in two independent preclinical arthritis models, reducing autoreactive T and B cell activation and recapitulating the strong anti-arthritic effect of genetic IDO2 deficiency. Mechanistic investigations identified FcγRIIb as necessary for mAb internalization, allowing targeting of an intracellular antigen traditionally considered inaccessible to mAb therapy. Taken together, our results offer preclinical proof of concept for antibody-mediated targeting of IDO2 as a new therapeutic strategy to treat RA and other autoantibody-mediated diseases.
authors.affiliation: Lankenau Institute for Medical Research, 100 Lancaster Ave., Wynnewood, PA 19096, USA.
authors.forename: Lauren M F
authors.initials: LMF
authors.lastname: Merlo
authors.affiliation: Lankenau Institute for Medical Research, 100 Lancaster Ave., Wynnewood, PA 19096, USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: Grabler
authors.affiliation: Lankenau Institute for Medical Research, 100 Lancaster Ave., Wynnewood, PA 19096, USA.
authors.forename: James B
authors.initials: JB
authors.lastname: DuHadaway
authors.affiliation: Lankenau Institute for Medical Research, 100 Lancaster Ave., Wynnewood, PA 19096, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Pigott
authors.affiliation: Lankenau Institute for Medical Research, 100 Lancaster Ave., Wynnewood, PA 19096, USA.
authors.forename: Kaylend
authors.initials: K
authors.lastname: Manley
authors.affiliation: Lankenau Institute for Medical Research, 100 Lancaster Ave., Wynnewood, PA 19096, USA; Department of Pathology, Anatomy and Cell Biology, Sidney Kimmel Medical College, Thomas Jefferson University, 1025 Walnut St. #100, Philadelphia, PA 19107, USA; Sidney Kimmel Cancer Center, Thomas Jefferson University, 233 S. 10th St. Suite 1050, Philadelphia, PA 19107, USA.
authors.forename: George C
authors.initials: GC
authors.lastname: Prendergast
authors.affiliation: Lankenau Institute for Medical Research, 100 Lancaster Ave., Wynnewood, PA 19096, USA.
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Laury-Kleintop
authors.affiliation: Lankenau Institute for Medical Research, 100 Lancaster Ave., Wynnewood, PA 19096, USA. Electronic address: Mandik-NayakL@mlhs.org.
authors.forename: Laura
authors.initials: L
authors.lastname: Mandik-Nayak
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D001402:B-Lymphocytes / Q000276:immunology; D005260:Female; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D008198:Lymph Nodes / Q000166:cytology; D008297:Male; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000276:immunology; D013640:Tarsal Joints / Q000187:drug effects / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; C499172:Fcgr2b protein, mouse; C586429:IDO2 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D017452:Receptors, IgG
keywords: Antibody therapy; B cells; Experimental arthritis; IDO; Murine model