Phase I Clinical Trial with a Novel Altered Peptide Ligand Derived from Human Heat-Shock Protein 60 for Treatment of Rheumatoid Arthritis: Safety, Pharmacokinetics and Preliminary Therapeutic Effects (jctr)

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CIGB 814 is an Altered Peptide Ligand (APL) from a CD4+ T-cell epitope of human heat shock protein 60 (HSP60), an auto-antigen involved in the pathogenesis of rheumatoid arthritis (RA). It induced mechanisms associated with restoration of peripheral tolerance in preclinical studies. This clinical trial was conducted to assess safety and pharmacokinetics (PK) of CIGB-814 in patients with RA. 20 patients with moderated active RA were included in an open label trial. Sequential dose-escalation of 1, 2.5 and 5 mg of CIGB-814 was studied. Consecutive groups of six, five and nine patients received a subcutaneous dose weekly of the peptide during the first month and one dose monthly during the next five months. Clinical response in patients was evaluated according to the American College of Rheumatology (ACR) and Disease Activity Score in 28 joints (DAS 28) criteria. Function and health-related quality of life, quantification of proinflammatory cytokines and radiographic changes in patients by magnetic resonance imaging (MRI) were also assessed. Result: The treatment was well tolerated at all doses. Only mild events were observed. PK study showed that CIGB-814 reached the maximum concentration in plasma in 30 min and was cleared mostly after 4 h. CIGB-814 reduced disease activity and MRI score in patients. This effect was less marked with the dose of 5 mg. Five and eleven out of 18 patients achieved ACR 50 and ACR 70 respectively at the end of the treatment. In addition, patients showed decreases of DAS28 scores, during treatment and at the end of the follow-up. This therapy improved function and health-related quality of life of patients. CIGB-814 significantly decreased interleukin (IL)-17 in patients treated with 2.5 mg. Therapy with 1 mg and 2.5 mg of CIGB-814 led to significant reduction of interferon gamma (IFN-γ). Phase I concluded showing safety of CIGB-814. The PK profile revealed that peptide is cleared from plasma very rapidly. Results indicated preliminary evidences of clinical efficacy and support further clinical investigation of this peptide for treatment of RA.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by persistent inflammatory synovitis leading to various degrees of cartilage destruction, bone erosion, and finally deformity and loss of joint function. Although the etiology of RA is not totally understood, many studies have shown that T lymphocytes, macrophages, and proliferating synovial cells play a major role in the pathogenesis of this disease. Methotrexate (MTX) is the standard therapy for RA, but despite the introduction of other disease-modifying anti-rheumatic drug (DMARD), only a fraction of RA cases achieved a complete remission. Improved understanding of RA pathogenesis led to the development of several classes of biologic treatments. Нese therapies are an alternative for patients not responding to MTX or other DMARDs and constitute the best addition to the anti-rheumatic arsenal. Biologic agents are drugs targeting specific inflammatory cells, cellular interactions and cytokines that mediate RA-related tissue damage. Such treatments are designed to reduce signs and symptoms of RA and slow disease progression. However, many patients have inadequate response to such therapies. Drugs already approved by regulatory agencies remain insuٹcient for 40-50% of patients with RA. In this context, other approaches need to be evaluated intensively, one of which is the induction of peripheral tolerance by antigenspecific therapy. Нis approach is aimed at eliminating T-cell clones that have escaped to the control mechanisms of peripheral tolerance. Нe central role of T cells in the pathogenesis of RA is well established. TH17 cell subset has been implicated in development and perpetuation of RA by secretion of pro-inflammatory cytokines such as: IL-17 and IL-21 which have pathogenic roles in this disease. Нe potentialities of altered peptide ligands (APLs) as inductors of peripheral tolerance in experimental models have been reported by several authors. APLs are similar to native epitopes but with one or several substitutions in the essential contact positions with TCell Receptor (TCR) or MHC class II molecules, modifying the cascade of necessary events for activation of T cells. Нese peptides can down-regulate the response of auto-reactive T cells by diوٴerent mechanisms for controlling autoimmune diseases. Нe selection of a specific auto-antigen for designing APLs is an essential point in this approach. HSP60 has been used in the induction of tolerance in autoimmune arthritis. We previously predicted a novel CD4+ T cell epitope from human HSP60 using bioinformatics tools. In particular, one amino acid residue of the wild-type peptide was substituted for increasing its aٹnity to HLA class II molecules related to RA. According to preceding results, this APL (called previously APL-1 and here CIGB-814) increases the frequency of regulatory T cells (Treg) and their suppressive capacity against antigen responding eوٴector CD4+ T cells from RA patients. In addition, this peptide inhibits significantly IL-17 levels produced by eوٴector CD4+ T cells from peripheral blood mononuclear cells (PBMCs) of RA patients. Furthermore, CIGB-814 reduced the course of adjuvant induced arthritis (AA) in Lewis rats. Likewise, CIGB-814 eٹciently inhibits collagen induced arthritis (CIA) in DBA/1 mice, associated with a decrease of tumor necrosis factor α (TNF-α) levels. CIA is accompanied by a robust T- and B-cell response to type II collagen. Нis animal model has been widely used for testing new potential therapeutic agents for treatment of human RA. CIGB-814 inhibits eٹciently the course of arthritis in CIA, similar to MTX, which is the current standard treatment for RA. Нis fact suggests the therapeutic potential of CIGB-814 as a first-line therapeutic candidate for RA. Нe primary intention of this study was to evaluate the safety of diوٴerent doses during 28 weeks as well as determination of the PK profile of CIGB-814 in RA patients. In addition, this study explores the therapeutic potentials of this peptide.

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