Preclinical Studies of PG70 LEAPS Peptide Vaccines for Rheumatoid Arthritis

描述（由申请人提供）：目前，fda批准的用于治疗类风湿性关节炎（RA）的药物主要侧重于通过疼痛管理、一般免疫抑制或拮抗细胞因子（如TNF-α）来缓解症状。尽管生物疗法最近取得了进展，但这些疗法并不能解决潜在的自身免疫性疾病。配体表位抗原呈递系统（L.E.A.P.S.）偶联物是一种肽疫苗平台，旨在以抗原特异性方式调节免疫反应。LEAPS由两种肽组分组成，一种是免疫细胞结合配体（ICBL），另一种是与感染性或自身免疫性疾病有关的肽（表位）。ICBLs包括来自人ß-2微球蛋白的肽J，具有th1极化活性，以及来自人MHC II类ß链的肽derG（或G）具有Th2极化活性。在患有胶原诱导关节炎（CIA）（一种th17介导的疾病）的小鼠中，j -胶原肽偶联物通过抑制促炎细胞因子和增加保护细胞因子来降低疾病的严重程度。迄今为止，没有derG缀合物显示出保护活性。在本研究中，我们假设L.E.A.P.S.疫苗在另一种RA小鼠模型——软骨蛋白多糖（PG）诱导的关节炎（PGIA）中调节免疫反应，达到保护状态。PGIA模型的一个优点是，根据诱导途径，分别是腹腔（i.p）或皮下（s.c），它是Th1或Th17细胞因子依赖性关节炎。使用

DESCRIPTION (provided by applicant): Currently, FDA-licensed pharmaceuticals used to treat rheumatoid arthritis (RA) focus largely on alleviation of symptoms, either through pain management, general immunosuppression, or by antagonizing cytokines such as TNF-α. Despite recent advances in biologic therapies, these treatments do not address the underlying autoimmune condition. Ligand epitope antigen presentation system (L.E.A.P.S.") conjugates are a peptide vaccine platform designed to modulate the immune response in an antigen-specific manner. LEAPS are composed of two peptide components, an immune cell binding ligand (ICBL) and a peptide (epitope) implicated in an infectious or autoimmune disease. The ICBLs include peptide J from human ß-2 microglobulin, with Th1-polarizing activity, and peptide derG (or G) from human MHC class II ß chain with Th2 polarizing activity. In mice with collagen-induced arthritis (CIA), a Th17-mediated disease, a J-collagen peptide conjugate reduced disease severity by suppressing pro-inflammatory cytokines and increasing protective cytokines. To date, no derG conjugates have shown protective activity. In the present proposal, we hypothesize that L.E.A.P.S. vaccine modulates the immune response towards a protective condition in a second mouse model of RA, cartilage proteoglycan (PG) induced arthritis (PGIA). An advantage of the PGIA model is that it is either a Th1 or Th17 cytokine dependent arthritis based on the route of induction, intraperitoneal (i.p.) or subcutaneous (s.c.), respectively. Using the dominant arthritogenic epitope PG70 (ATEGRVRVNSAYQDK) of the G1 domain of PG, conjugated to J or derG, preliminary studies in the i.p. PGIA model demonstrate that the derG-PG70 conjugate inhibits ongoing arthritis by shifting the balance from a Th1 to a Th2/Treg response. Based on studies in CIA, we expect that the J-PG70 conjugate will modulate pathogenic Th17 responses in s.c.-induced PGIA toward protective Th1 responses. Efficacy will be assessed by measuring arthritis index, histopathological examination of peripheral joints, antibody production, T cell proliferation, and cytokine responses. In Aim 1, we will compare the LEAPS-PG70 peptide conjugates and subunit peptides for therapeutic efficacy in both the i.p. and s.c. PGIA models. In Aim 2, we will examine the mechanism of action focusing on binding to (and effects on) T cells and dendritic cells for the two conjugates using cells from naive PG-TCR-transgenic and PG-immunized (i.p. or s.c.) wild type mice. After success in phase I SBIR, we will advance the L.E.A.P.S vaccine to a phase II SBIR, with the initial goal of further characterizing the mechanisms by which LEAPS peptides act on immune cells from mice and humans, and with the ultimate goal of optimizing the vaccine for the treatment of RA.