Merlo Lauren M F, Grabler Samantha, DuHadaway James B, Pigott Elizabeth, Manley Kaylend, Prendergast George C, Laury-Kleintop Lisa D, Mandik-Nayak Laura
Lankenau Institute for Medical Research, 100 Lancaster Ave., Wynnewood, PA 19096, USA.
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.
Clin Immunol. 2017 Jun;179:8-16. doi: 10.1016/j.clim.2017.01.016. Epub 2017 Feb 20.
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.
类风湿性关节炎（RA）是一种使人衰弱的炎症性自身免疫疾病，目前尚无治愈方法。最近，我们确定免疫调节酶吲哚胺-2,3-双加氧酶2（IDO2）是驱动RA的自身反应性B细胞和T细胞反应的关键介质。然而，鉴于缺乏能特异性抑制IDO2而不影响密切相关的IDO1的小分子，靶向IDO2进行治疗一直具有挑战性。在本研究中，我们开发了一种基于新型单克隆抗体（mAb）的方法来靶向治疗IDO2。用IDO2特异性mAb治疗可缓解两种独立的临床前关节炎模型中的关节炎，减少自身反应性T细胞和B细胞的活化，并重现基因IDO2缺陷的强大抗关节炎作用。机制研究确定FcγRIIb是mAb内化所必需的，从而能够靶向传统上认为mAb疗法无法触及的细胞内抗原。综上所述，我们的结果为抗体介导的靶向IDO2作为治疗RA和其他自身抗体介导疾病的新治疗策略提供了临床前概念验证。
