Use of the il-6 inhibitor olokizumab for the treatment of progressive fibrotic interstitial lung diseases

Abstract

The invention pertains to the field of pharmacology and medicine, specifically to the use of the IL-6 inhibitor olokizumab for the treatment of progressive fibrotic interstitial lung diseases (ILDs), including idiopathic pulmonary fibrosis, non-specific interstitial pneumonia, lymphocytic interstitial pneumonia, unclassifiable idiopathic interstitial pneumonia, hypersensitivity pneumonitis (allergic alveolitis), sarcoidosis; interstitial pneumonia with autoimmune features; pneumoconioses; pulmonary histiocytosis; interstitial lung disease associated with autoimmune diseases, such as systemic sclerosis; rheumatoid arthritis; systemic lupus erythematosus; polymyositis / dermatomyositis; primary Sjögren's syndrome; mixed connective tissue disease; other systemic connective tissue diseases, as well as polymyalgia rheumatica and giant cell arteritis. This disclosure can be used for the effective therapy of progressive fibrotic ILDs, as polymyalgia rheumatica, and giant cell arteritis expanding the range of medications used to treat these conditions.

Description

USE OF THE IL-6 INHIBITOR OLOKIZUMAB FOR THE TREATMENT OF PROGRESSIVE FIBROTIC INTERSTITIAL LUNG DISEASESFIELDThe invention pertains to the field of pharmacology and medicine, specifically to the use of the IL-6 inhibitor olokizumab for the treatment of progressive fibrotic interstitial lung diseases (ILD), selected from a range including: idiopathic pulmonary fibrosis, non-specific interstitial pneumonia, lymphocytic interstitial pneumonia, unclassifiable idiopathic interstitial pneumonia, hypersensitivity pneumonitis (allergic alveolitis), sarcoidosis; interstitial pneumonia with autoimmune features; pneumoconioses; pulmonary histiocytosis; interstitial lung disease associated with autoimmune diseases, such as systemic sclerosis; rheumatoid arthritis; systemic lupus erythematosus; polymyositis / dermatomyositis; primary Sjogren's syndrome; mixed connective tissue disease; other systemic connective tissue diseases, as well as polymyalgia rheumatica and giant cell arteritis.BACKGROUNDChronic fibrotic ILDs represent a heterogeneous group of diseases with diverse causes, courses, and prognoses. In some patients, fibrotic ILD may have a progressive course characterized by progressive deterioration of lung function, increasing respiratory failure, reduced quality of life, and the risk of premature death. According to modem understanding, ILDs with a progressive phenotype exhibit a high degree of clinical-pathogenetic similarity and can be considered as a single entity. The progressive phenotype is encountered in 100% of cases in idiopathic pulmonary fibrosis (IFF), 25% in hypersensitivity pneumonitis, 30-40% in ILDs associated with systemic sclerosis (SSc) and rheumatoid arthritis (RA), and 50% in sarcoidosis (Olson, A. L., Gifford, A. H., Inase, N., Perez, E. R. F., & Suda, T. (2018). The epidemiology of idiopathic pulmonary fibrosis and interstitial lung diseases at risk of a progressive-fibrosing phenotype. European Respiratory Review, 27(150)). Progressive fibrotic ILDs are characterized by a high risk of exacerbations and disability , with a median survival ranging from 3 to 5 years irrespective of etiology. The overall prevalence of ILDs with a progressive phenotype in Europe is estimated to be around 28-40 cases per 100,000 population.IL-6 plays a crucial role in the pathogenesis of progressive fibrotic ILDs, especially in the early stages of the disease (Pantelidis P, Fanning GC, Wells AU, Welsh KI, Du Bois RM. Analysis of tumor necrosis factor-alpha, lymphotoxin-alpha, tumor necrosis factor receptor II, and interleukin-6 polymorphisms in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2001;163: 1432-1436). Chronic elevation of systemic and alveolar IL-6 levels contributes to excessive collagen synthesis and collagen deposition in the lung extracellular matrix by activating alveolar macrophages with a profibrotic M2 phenotype, enhancing the production of profibrotic cytokines CCL18, TGF- , and IL-17A, stimulating epithelial -mesenchymal transition, leading to activation and proliferation of lung myofibroblasts. Patients with IPF show an increase in systemic IL-6 levels compared to the population without lung diseases, elevated levels of soluble IL-6R in BAL, and an aberrant response of fibroblasts obtained from IPF patients to IL-6 stimulation. Elevated IL-6 levels serve as a prognostic factor for exacerbations and a more severe course of IPF; high systemic IL-6 levels correlate with higher mortality in patients with IPF and ILDs associated with SSc. In connective tissue diseases, patients with lung involvement exhibit higher IL-6 levels compared to patients without pulmonary symptoms (Cardoneanu, A.; Burlui, A.M.; Macovei, L.A.; Bratoiu, L; Richter, P.; Rezus, E. Targeting Systemic Sclerosis from Pathogenic Mechanisms to Clinical Manifestations: Why IL-6? Biomedicines 2022, 10, 318. https: / / doi.org / 10.3390 / biomedicines 10020318).Inhibiting IL-6 is a promising therapeutic approach for the treatment of interstitial lung involvement. Mice with IL-6 knockout showed suppressed development of lung fibrosis in response to bleomycin compared to the wild type. In a mouse model of lung fibrosis induced by chronic bleomycin administration, blocking the trans-signaling pathway of IL-6 using a soluble chimeric protein, gp!30Fc, consisting of the effector subunit gpl30 and the Fc fragment of IgG, resulted in a pronounced anti-inflammatory and antifibrotic effect.Administration of gp!30Fc led to a reduction in the number of all types of inflammatory cells in bronchoalveolar lavage fluid, decreased levels of pro-inflammatory cytokines and inflammatory biomarkers, suppression of soluble collagen production in lung tissue, reduced histological fibrosis scores. In a model of adenosine-mediated lung injury in mice with knockout of the adenosine deaminase gene, neutralizing antibodies to IL-6 reduced histological signs of inflammation, decreased levels of pro-inflammatory cytokines, restoration of lung barrier function, and suppression of collagen expression, fibronectin, reduction of myofibroblast accumulation in the lower airways, and a decrease in the severity of lung fibrosis. It is assumed that the positive effect of pirfenidone, which slows dow n the progression of ILDs in patients with interstitial pneumonia with autoimmune features (IPAF) and progressive fibrotic ILDs, is partially attributed to its anti-inflammatory activity .The most studied and homogeneous variant of ILD with a progressive phenotype in humans is ILD in patients with sy stemic sclerosis (SSc). Clinical trials (CT) in SSc patients have demonstrated that the IL-6 receptor inhibitor tocilizumab can slow down or even halt the progression of ILD. The multicenter international randomized double-blind placebo-controlled Phase 2 CT named faSScinate (Khanna, D., Denton, C.P., Jahreis, A., van Laar, J.M., Fresh, T.M., Anderson, M.E., Baron, M., Chung, L., Fierlbeck, G., Lakshminarayanan, S. and Allanore, Y., 2016. Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a phase 2, randomized, controlled trial. The lancet, 387(10038), pp.2630-2640) included 87 patients with progressive diffuse SSc active within 5 years of the onset of first symptoms other than Raynaud's syndrome. Weekly, 43 patients received subcutaneous tocilizumab 162 mg, and 44 received placebo. Lung involvement was observed in 30 tocilizumab-treated patients and 36 placebo-treated patients. Although the difference between groups in the mean change in skin score did not reach statistical significance (p = 0.0579), tocilizumab led to a significant improvement in lung function. A smaller proportion of patients receiving tocilizumab experienced a decline in FVC compared to placebo at 24 (p = 0.009) and 48 weeks (p = 0.037) of treatment. A significant reduction in absolute FVC values compared to baseline was also observed in the tocilizumab group compared to placebo: -34 ml and -171 ml (p = 0.0368) at 24 weeks, -117 ml and -237 ml (p = 0.099) at 48 weeks, respectively. Additionally, the tocilizumab group showed a decrease in the level of the profibrotic cytokine CCL18 compared to placebo.These findings were confirmed in the multicenter international randomized double-blind placebo-controlled Phase 3 CT named focuSSed (Khanna, D., Lin, C.J., Furst, D.E., Goldin, J., Kim, G., Kuwana, M., Allanore, Y., Matucci-Cerinic, M., Distler, O., Shima, Y. and van Laar, J.M., 2020. Tocilizumab in systemic sclerosis: a randomized, double-blind, placebo-controlled, phase 3 trial. The Lancet Respiratory Medicine, 8(10), pp.963-974). A total of 212 patients with diffuse SSc, disease duration of no more than 60 months from the onset of first symptoms other than Raynaud's, active disease, and signs of active inflammatoiy processes were included. Weekly, 105 patients received subcutaneous tocilizumab 162 mg, and 107 patients received placebo. Lung involvement was observed in 68 patients in each group. Tocilizumab demonstrated an improvement in lung function in patients with ILD comparedto placebo, using various assessments: distribution of changes in FVC, measured as a percentage of predicted, relative to baseline at 48 weeks of treatment (p = 0.002, key secondary endpoint); a reduction in the mean FVC relative to baseline at 24 weeks (-133 ml in the placebo group and -15 ml in the tocilizumab group, p = 0.008) and at 48 weeks (-255 ml in the placebo group and -14 ml in the tocilizumab group, p < 0.0001); the proportion of patients with worsening lung function, defined as a decrease in % predicted FVC by more than 10% at 24 weeks of treatment (25% in the placebo group and 9% in the tocilizumab group). A statistically significant reduction in the prevalence of lung fibrosis at 48 weeks of treatment was also demonstrated using quantitative HRCT assessment. Based on these trial data, tocilizumab has been approved in the U.S. for the treatment of ILD associated with SSc.Although IL-6 inhibitors are widely used in the treatment of RA, evidence of their effectiveness against lung involvement in RA patients is limited to small studies and case reports. Nevertheless, available evidence suggests a satisfactory safety profile and potential effectiveness in stabilizing lung function in patients with RA-ILD. In a systematic review of case reports and post-marketing reports (Cassone, G., Manfredi, A., Vacchi, C., Luppi, F., Coppi, F., Salvarani, C., & Sebastiam, M. (2020). Treatment of rheumatoid arthritis-associated interstitial lung disease: lights and shadows. Journal of Clinical Medicine, 9(4), 1082), the results of tocilizumab use in 41 RA patients with a diagnosis of ILD at the initiation of therapy were summarized. Most patients experienced favorable effects, with improvement or stabilization of ILD progression observed in 17% and 65.8% of patients, respectively. Only 17% of patients showed worsening of lung function and / or radiological findings according to HRCT dataIn a prospective open observational study of tocilizumab use in 34 RA-ILD patients, a statistically significant decrease in matrix metalloproteinase-3 (MMP-3) levels was observed at 2 and 6 months of treatment compared to levels 2 months before treatment initiation, reflecting a reduction in disease activity. The profibrotic biomarker KL-6 significantly decreased at 6 months of tocilizumab use compared to baseline. In 22 patients who underwent repeat HRCT after 1 year of treatment, the radiological picture remained unchanged (N. Otsuji, K. Sugiyama, H. Arifuku, K. Nakano, H. Watanabe, T. Wakayama, K. Koyama, H. Hirata, Y. Fukushima. (2020). Effect of tocilizumab on interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA). 747).Stabilization or even improvement of lung function in patients with RA-ILD using tocilizumab was noted in a multicenter retrospective study conducted by Manfredi A. and colleagues (Manfredi A, Cassone G, Furini F, Gremese E, Venerito V, Atzeni F, Arrigoni E, Della Casa G, Cerri S, Govoni M, Petricca L, lannone F, Salvarani C, Sebastiani M.Tocilizumab therapy in rheumatoid arthritis with interstitial lung disease: a multicenter retrospective study. Intern Med J. 2019 Sep;50(9): 1085-1090. doi: 10.1111 / imj.14670. PMID: 31661185). The study included 28 RA-ILD patients from 6 clinical centers in Italy who received tocilizumab for at least 6 months, with a median observation period of 30 months (6-90 months). The median duration of ILD, confirmed histologically or by HRCT before the initiation of tocilizumab, was 12 months with an interquartile range of 34 months. Radiological patterns of usual interstitial pneumonia (UIP) were observed in 14 patients (50%), non-specific interstitial pneumonia (NSIP) patterns in 13 patients (46.5%), and a combination of lung fibrosis and emphysema in 1 patient (3.5%). Tocilizumab monotherapy was administered to 23 patients (82. 1%), while 5 patients (17.8%) received tocilizumab in combination with methotrexate. Initially, the median % predicted FVC was 99%, and % predicted DLCO was 58.5%. Clinically significant changes in FVC and DLCO were considered deviations >10% from baseline parameters. At the end of the observation period, FVC and DLCO remained stable in 14 patients (56%), improved in 5 patients (20%), and worsened in 6 patients (24%), with most patients (22 out of 25, available for assessment) showing unidirectional changes. HRCT at the end of the observation period showed radiological stability in the majority of patients (25 out of 28), deterioration in 2 patients, and improvement in 1 patient. None of the patients had tocilizumab therapy discontinued due to worsening lung function or the development of infections.Similar results were obtained in a case series of 4 patients (2 male and 2 female) aged 60 to 71 years with varying degrees of RA-associated ILD and high disease activity, previously described by the same authors (Manfredi A, Sebastiani M, Cassone G, Colaci M, Sandri G, Ferri C. Tocilizumab for the treatment of patients with rheumatoid arthritis and interstitial lung diseases: a case series. Clin Exp Rheumatol. 2018 Mar-Apr;36(2):342. Epub 2018 Feb 14. PMID: 29465372). Tocilizumab monotherapy led to a significant reduction in disease activity. In one patient, there was initial progression of ILD, but lung function and the dynamics of interstitial changes stabilized and remained stable for 3 years. The other patients showed no changes in lung symptoms and / or fibrosis extent based on HRCT during the observation period.A clinical case of combined use of nintedanib and sarilumab for the treatment of RA-ILD is also described (Vacchi C, Manfredi A, Cassone G, Salvarani C, Cerri S, Sebastiani M. Combination Therapy with Nintedanib and Sarilumab for the Management of Rheumatoid Arthritis Related Interstitial Lung Disease. Case Rep Med. 2020 Mar 9; 2020:6390749. doi: 10.1155 / 2020 / 6390749. PMID: 32231705; PMCID: PMC7085352). In this case, a 75-year-old male patient initially diagnosed with ILD showed dyspnea on exertion, chronic cough, and velcro crackles in the lower lungs. Pulmonary function testing revealed a sharp decrease in DLCO to 35% with normal % predicted FVC (109%). Surgical lung biopsy confirmed the UIP pattern. The patient was initially treated with nintedanib at a dose of 150 mg twice daily. After a year, RA of moderate activity was diagnosed, and low-dose glucocorticoids (methylprednisolone 4 mg / day) and hydroxychloroquine at a dose of 200 mg twice daily were added to nintedanib therapy (dose reduced to 100 mg twice daily). After 14 months, the patient experienced a flare-up of RA with a significant increase in CRP levels to 21 mg / 1 and ESR to 36 mm / h, and an increase in disease activity to 6.71 according to the DAS28 scale. HRCT revealed suspected progression of lung fibrosis with an increase in fibrosis extent in basal and subpleural areas, increased severity of traction bronchiectasis, and cellular lung changes, but without changes in respiratory symptoms and with minor deterioration in lung function test parameters. Sarilumab, an IL-6 receptor inhibitor, was added to the current therapy. Over 6 months of sarilumab treatment, there was a marked reduction in RA activity and stabilization of FVC and DLCO. Throughout the observation period, combination therapy was well-tolerated, and no new adverse events were noted.Olokizumab is introduced as a new original IL-6 inhibitor, representing a monoclonal antibody that interacts with the cytokine itself rather than its receptors. Given the substantial evidence indicating the crucial role of IL-6 in the pathogenesis of progressive ILDs, the unfavorable prognosis of the disease, the lack of accessible highly effective therapy, and clinical data on the efficacy of anti-IL-6 therapy in ILD variants associated with SSc and other connective tissue diseases, the use of the IL-6 inhibitor olokizumab appears promising for treating patients with progressive fibrotic ILD.As the field of rheumatology continues to progress, it is seeing increased use of biological products to treat immune-inflammatory rheumatic diseases, particularly giant cell arteritis (GCA) and polymyalgia rheumatica (PMR). There is an unmet medical need for effective steroid-sparing drugs for these conditions. Although tocilizumab has been a long-standing medication for GCA, the approval of sarilumab for PMR treatment by the U.S. Food andDrug Administration (FDA) in 2023 marked a significant milestone: it is the first biologic approved specifically for PMR.The clinical trial leading to the approval of sarilumab showed impressive results. The frequency of stable remission was significantly higher in the sarilumab group, and the likelihood of exacerbation after achieving clinical remission was 44% lower compared to the control group. The chance of achieving remission was nearly twice as high, and the cumulative dose of glucocorticoids (GC) was significantly lower in the sarilumab treatment group. It is also important to note that half of remissions achieved with sarilumab were "steroid-free", compared to only 24.1% in the control group.Tocilizumab has long been registered for GCA treatment, currently it is included in several clinical management guidelines, and is widely used in clinical practice. In addition, tocilizumab is considered as an effective off-label treatment option for PMR, supported by evidence from clinical experience and research.On the one hand, given the high comorbidity rate between GCA and PMR (40% to 60% of patients with GCA report symptoms of PMR, and in 15-20% of patients with PMR, an accompanying vasculitis is present or will develop), their common pathogenetic mechanisms involving the IL-6 signaling axis, similar age demographics, and good response to treatment with GC (Tomelleri A., van der Geest K.S.M., Khurshid M.A., Sebastian A., Coath F , et al. Disease stratification in GCA and PMR: state of the art and future perspectives. Nat Rev Rheumatol. 2023; 19(7): 446-459. doi: 10. 1038 / S41584-023-00976-8), they are often considered closely related conditions requiring similar treatment strategies, mainly involving a use of steroid-sparing drugs. On the other hand, drugs targeting the IL-6 axis could potentially be effective for these conditions.Therefore, an IL-6 inhibitor olokizumab is gaining significant attention as an alternative treatment option to sarilumab or tocilizumab. It was used off-label in real clinical practice when patients with GCA or PMR urgently needed steroid-sparing drugs, while methotrexate therapy was contraindicated or ineffective.IL-6, a pleiotropic pro-inflammatory cytokine, plays a critical role in the pathogenesis of RA and other immunoinflammatory rheumatic diseases. IL-6 inhibitors demonstrate strong anti-inflammatory activity, that are important in treating diseases associated with an acute phase inflammatory response, such as GCA and PMR.SUMMARYThis summary is provided to introduce a selection of concepts in a simplified form that are further described below in the Detailed Description. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used as an aid in determining the scope of the claimed subject matter.In certain aspects the present invention provides for the use of the IL-6 inhibitor olokizumab for the treatment of progressive fibrotic interstitial lung diseases, as well as polymyalgia rheumatica and giant cell arteritis. The progressive fibrotic interstitial lung disease may be idiopathic pulmonary fibrosis, non-specific interstitial pneumonia, lymphocytic interstitial pneumonia, unclassifiable idiopathic interstitial pneumonia, hypersensitivity pneumonitis (allergic alveolitis), sarcoidosis; interstitial pneumonia with autoimmune features; pneumoconioses; pulmonary histiocytosis; interstitial lung disease associated with autoimmune diseases, such as systemic sclerosis; rheumatoid arthritis; systemic lupus erythematosus; polymyositis / dermatomyositis; primary Sjogren's syndrome; mixed connective tissue disease; or other systemic connective tissue diseases.In further aspects the present invention provides for a method for treating progressive fibrotic interstitial lung diseases, comprising administering the IL-6 inhibitor olokizumab to a subject in need of such treatment at a dose of 64 mg subcutaneously once every 4 weeks. The progressive fibrotic interstitial lung disease may be idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia, lymphocytic interstitial pneumonia, unclassifiable idiopathic interstitial pneumonia, hypersensitivity pneumonitis (allergic alveolitis), sarcoidosis; interstitial pneumonia with autoimmune features; pneumoconioses; pulmonary histiocytosis; interstitial lung disease associated with autoimmune diseases, such as systemic sclerosis; rheumatoid arthritis; systemic lupus erythematosus; polymyositis / dermatomyositis; primary Sjogren's syndrome; mixed connective tissue disease; or other systemic connective tissue diseases.In further aspects the present invention provides for a method for treating of polymyalgia rheumatica and giant cell arteritis involving administration of olokizumab at a dose of 64 mg subcutaneously once every 2 weeks or once every 4 weeks to a subject in need of such treatment.BRIEF DESCRIPTION OF THE DRAWINGSFigure 1 shows influence of olokizumab (CDP6038) on the phosphorylation intensity of STAT3 induced by incubating human whole blood cells with IL-6: Phosphorylated STAT-3 signal (vertical axis) is the level of STAT-3 phosphorylation; [IL-6]: Log g / mL (horizontal axis) is the logarithm of IL-6 concentration, lg(g / ml); [CDP6038]: log g / mL is the logarithm of investigated CDP6038 concentration, lg(g / ml); n = 3 indicates that samples were performed in triplicates; • 0 - data for samples without the addition of CDP6038; o -8.00 -sample with the addition of CDP6038 at a concentration of 10A-8 g / ml; ■ -7.52 - sample with the addition of CDP6038 at a concentration of 10A-7.52 g / ml; □ -7.00 - sample with the addition of CDP6038 at a concentration of 10A-7 g / ml; ▲ -6.52 - sample with the addition of CDP6038 at a concentration of 10A-6.52 g / ml; A -6.00 - sample with the addition of CDP6038 at a concentration of 10A-6 g / ml.DETAILED DESCRIPTIONThe present teachings are aimed at evaluating the pharmacological activity of olokizumab against progressive fibrotic interstitial lung diseases, as well as polymyalgia rheumatica and giant cell arteritis. The technical result of the teachings lies in the effectiveness of treating patients with progressive fibrotic ILDs, as well as polymyalgia rheumatica and giant cell arteritis, using IL-6 inhibitor olokizumab therapy, expanding the range of drugs for treating the mentioned disease.The present teachings are further detailed in the examples provided below. These examples are for illustrative purposes and do not imply any limitation on the scope of the future claims.Example 1. The ability of olokizumab (CDP6038) to block IL-6 signaling by activating the transcription factor STAT3.Experimental data obtained during the study are presented in the graphs:Fig. 1 shows the dependence of the intensity of the optical signal reflecting the level of STAT3 (Signal Transducer and Activator of Transcription 3) phosphorylation on the concentration of IL-6 in the presence of various concentrations of olokizumab (laboratory code CDP6038). The graph demonstrates that increasing the concentration of olokizumab 100 times from 10'8 to 10'6 mg / ml dose-dependently suppressed STAT3 phosphorylation in the test cell system.The ability of olokizumab (CDP6038) to block IL-6 signaling by activating the transcription factor STAT3 was studied in a specialized test system using human whole blood. STAT3 is a key intracellular mediator of the IL-6 receptor complex activation. This protein is a critically important transcription factor in the JAK-STAT signaling pathway, playing a significant role in the pathogenesis of lung fibrosis. After activation of the signaling complex, phosphorylated STAT3 dimerizes and translocates into the nucleus, where it binds to DNA and regulates the transcription of genes associated with proliferation, apoptosis, angiogenesis, and immune response.STAT3 contributes to the proliferation and activation of fibroblasts, key cells involved in the synthesis of the extracellular matrix and lung tissue fibrosis. This leads to thickening and densification of lung tissue, reducing its functionality. STAT3 is involved in regulating the production and release of inflammatory cytokines and chemokines. These molecules enhance the inflammatory process, which is one of the factors contributing to the development and progression of fibrosis. STAT3 may contribute to epithelial-mesenchymal transition (EMT), a process in which epithelial cells acquire mesenchymal properties, including increased migratory ability and production of extracellular matrix. This also contributes to fibrosis and tissue remodeling. Activation of STAT3 contributes to tissue remodeling, which can exacerbate fibrotic changes in the lungs.In the experiment, mixtures of IL-6 and olokizumab (CDP6038) at various concentrations were prepared, incubated for 20 minutes, and then added to whole blood samples and incubated for 20 minutes at 37°C. The amount of phosphorylated STAT3 was measured, and graphs were constructed showing its dependence on IL-6 concentration at different concentrations of CDP6038 in the sample. Based on the obtained graphs showing the dependence of STAT3 phosphorylation concentration on IL-6 at different concentrations of CDP6038, the researchers calculated the affinity value of CDP6038, which was 10-7 19 g / ml,equivalent to 65 ng / ml (434 pmol / 1). The researchers concluded that when administering CDP6038 at a dose < 2 pg / kg, ligand (IL-6) saturation would be less than 50%.Example 2. Evaluation of the anti-inflammatory activity of olokizumab.The anti-inflammatory activity of olokizumab was assessed in an experiment conducted on rhesus macaques. The study examined the ability of antibodies with the laboratory code 24O.gl (corresponding to olokizumab) to suppress the development of collagen Il-induced arthritis. Thirty female monkeys were used, to which bovine collagen II in Freund's complete adjuvant was administered to model arthritis. One day before collagen immunization, 240. l was intravenously administered at a dose of 1 or 20 mg / kg, followed by weekly administration for 11 weeks. The positive control group received antibodies to the human IL-6 receptor (KC-1) instead of 24O.gl, and the carrier control group received a phosphate-buffered saline.The results of the study were as follows. The 240. gl antibodies at a dose of 20 mg / kg significantly slowed down the development of joint swelling starting from the third week after the start of administration. Control antibodies KC-1 at a dose of 20 mg / kg also prevented joint swelling but in significantly fewer cases compared to 240. gl. Radiographs showed that both antibodies comparably reduced the severity of joint damage.Histopathological examination of the organs of animals receiving 240. gl at a dose of 20 mg / kg revealed rare cases of high-degree histopathological changes, manifested in cartilage degeneration, granulation tissue morphogenesis, cartilage resorption, and osteogenesis. Similarly rare histopathological changes were observed in animals receiving KC-1 at a dose of 20 mg / kg, characterized by fibrosis, granulation tissue morphogenesis, and osteogenesis. The general condition index did not show statistically significant changes in animals receiving antibodies compared to the indicators of animals from the carrier control group. Biochemical analysis of blood revealed a significant decrease (compared to the indicators of animals from the earner control group) in the levels of C-reactive protein and haptoglobin in animals receiving antibodies KC-1 or 240. gl at doses of 20 mg / kg. No toxicologically significant changes were observed in animals receiving the tested antibodies.Example 3. Clinical case of olokizumab use in a patient with interstitial lung involvement associated with systemic sclerosis.A 39-year-old male patient diagnosed with diffuse systemic sclerosis presented with subacute activity, involving skin (pitting, dense edema of hands), lungs (history ofnonspecific interstitial pneumonia), gastrointestinal tract (esophageal dyskinesia), joints (non-erosive polyarthritis), and vessels (Raynaud's three-phase syndrome), with an activity score of 1. The disease had been progressing for 5 years, and due to lung involvement, rapidly progressing extensive skin lesions, and an unfavorable prognosis indicated by the immunologic subtype of the disease (Scl-70 3+), biological therapy initiation was warranted. Treatment: olokizumab (Artlegia) 64 mg every 4 weeks subcutaneously. After 5 months of olokizumab administration, no adverse events were observed. The treatment's positive effects included a reduction in dense hand edema, decreased arthralgia, and a reduction in lung involvement based on computed tomography.Example 4. Clinical case of olokizumab use in a patient with interstitial lung involvement associated with systemic sclerosis resistant to standard therapy.A 60-year-old male diagnosed with diffuse systemic sclerosis had a disease duration of over 30 years. Despite immunosuppressive therapy, the disease progressed with increasing severity of microcirculatory disturbances. Recunent, non-healing digital ulcers, along with complaints of fever, respiratory disturbances, gastrointestinal issues, and joint manifestations, emerged after a prolonged stable period. On examination, skin thickening was noted in the upper and lower extremities, face, and abdomen (modified Rodnan skin score (mRSS) 22). Laboratory analyses indicated active inflammation and severe anemia. High-resolution chest CT revealed subpleural interstitial changes in both lungs, pericardial effusion, pleural effusions, and intrathoracic lymphadenopathy. Despite 6 months of therapy withmy cophenolate mofetil (MMF) at a dose of 720 mg / day, prednisolone at a dose of 10 mg / day, colchicine at a dose of 0.5 mg / day, combined with anticoagulants and antihypertensive therapy, normalization of body temperature, reduced chest pain, resolution of arthritis, and healing of digital ulcers were observed. However, dyspnea, dysphagia, and dyspeptic symptoms remained unchanged, and echocardiography revealed an increase in systolic pulmonary artery pressure to 55-60 mmHg. Treatment: Due to persistent respiratory disturbances, interstitial lung changes, polyserositis, and increasing disease activity with attempts to reduce prednisolone below 5 mg / day, the decision was made to initiate olokizumab (Artlegia) therapy at a dose of 64 mg subcutaneously every 4 weeks.During the treatment, there was progressive reduction in dyspnea and skin thickening, relief of chest pain and joint stiffness. Six months after starting olokizumab, mRSS decreased to 15, digital ulcers on the right lower limb healed, calculated systolic pulmonary arterypressure decreased to 35 mmHg, and the severity of subpleural interstitial changes significantly reduced in terms of volume and density. Complete regression of pleural and pericardial effusion and reduction in the size of intrathoracic lymph nodes were observed. Laboratory analyses demonstrated an increase in hemoglobin levels and normalization of erythrocyte sedimentation rate. After 8 months of treatment, it was possible to discontinue glucocorticoid therapy without signs of disease exacerbation. Olokizumab administration led to significant improvement in lung function, regression of pericarditis, reduction in skin symptoms, and relief of joint syndrome. The therapy with olokizumab was well tolerated, and no adverse events were identified during the entire observation period.Example 5: Assessment of the Efficacy and Safety of Olokizumab. Phase III Clinical Trials in Rheumatoid Arthritis (RA) with Moderate to High Disease Activity.The primary objective of these studies was to evaluate the efficacy and safety of olokizumab at a dose of 64 mg administered every 4 weeks or every 2 weeks as subcutaneous injections in patients with RA exhibiting moderate to high disease activity and inadequate response to methotrexate (MTX) or TNF inhibitors.Brief Study Protocol Overview:Double-blind, randomized, placebo-controlled clinical trial CL04041022 in parallel groups to assess the efficacy and safety of olokizumab in patients with moderate to high activity RA insufficiently controlled by MTX.Double-blind, randomized, placebo, and active-controlled clinical trial CL04041023 in parallel groups to evaluate the efficacy and safety of olokizumab in patients with moderate to high activity' RA insufficiently controlled by MTX.Double-blind, randomized, placebo-controlled clinical trial CL04041023 in parallel groups to assess the efficacy and safety of olokizumab in patients with moderate to high activity RA with inadequate response to tumor necrosis factor-alpha inhibitors (TNFi).Study Design:The study included male and female patients over 18 years old with RA of moderate or high disease activity insufficiently controlled by MTX or TNFi. Patients with RA-ILD were allowed to participate. Background therapy included MTX at a dose of 15-25 mg per week (or >10 mg / week if intolerance to higher doses was documented) for at least 12 weeks before screening, with a stable dose maintained for at least 6 weeks before screening and throughout the study. For patients not responding to treatment within 14 weeks, adjunctive therapy with sulfasalazine or hydroxychloroquine was provided in addition to the investigational drugs.The intention-to-treat (ITT) population, comprising all patients randomized to receive any of the investigational drugs, was the primary population for efficacy assessment. Patients who prematurely discontinued treatment or withdrew from the study were considered as not deriving clinical benefit from the treatment in the efficacy analysis. Sensitivity analyses were conducted to assess the impact of dropout or treatment discontinuation on efficacy measures using various methods of missing data imputation.The primary efficacy endpoint was the proportion of patients responding to treatment based on ACR20 criteria at 12 weeks from the start of therapy. Secondary endpoints included the proportion of patients responding based on ACR50 criteria, the proportion achieving low disease activity (DAS28(CRP) <3.2), the proportion achieving remission (Clinical Disease Activity Index (CD Al) < 2.8), and the change in mean Health Assessment Questionnaire Disability Index (HAQ-DI) score from baseline. Additional assessments included patient-reported outcomes (PRO) using validated questionnaires in a language familiar to the patient. Respiratory function was evaluated through physical examination, vital signs (respiratory rate), and the number of exacerbations during the treatment period.Treatment Arms Investigated:Olokizumab 64 mg every 4 weeks for 24 weeks: 782 patients (6 patients with RA-ILD).Olokizumab 64 mg every 2 weeks for 24 weeks: 745 patients (8 patients with RA-ILD).Adalimumab 40 mg every 2 weeks for 24 weeks: 462 patients (3 patients with RA-ILD).Placebo every 2 weeks for 24 weeks: 455 patients (6 patients with RA-ILD).Results:The results for all efficacy and safety criteria evaluated in this study indicate a satisfactory safety profile, good tolerability, and high efficacy of olokizumab in patients with RA of moderate to high disease activity, including those with RA-ILD.Example 6: Treatment of PMR using induction therapy with olokizumabAn 81 -year-old male, under long-term clinical observation for various cardiovascular diseases, was hospitalized due to intense pain. His bilateral pain in the shoulder and pelvic girdle, neck, lower back, persistent inflammatory pain and joint stiffness that barely subsided throughout the day, and high laboratory activity (C-reactive protein (CRP) 39.6 mg / 1), normal rheumatoid factor (RF) levels, and the absence of peripheral arthritis led to a diagnosis of PMR. There was no evidence of secondary PMR. The disease activity was very high, however, standard treatment was avoided because of multiple risk factors for glucocorticoid (GC) therapy: the patient had identified acute stomach ulcers in the stage of incomplete scarring, type 2 diabetes, and severe cardiovascular diseases like ischemic heart disease, postinfarction cardiosclerosis, aortocoronary bypass, and atrial fibrillation.Therefore, while there was a need to treat PMR (chronic pain syndrome and laboratory activity were unfavorable prognosis factors), it was inadvisable to use standard doses of GCs due to the risk of therapy complications. A compromise was reached by prescribing a reduced dose of prednisolone (7.5 mg / day, less than the currently recommended doses) while simultaneously beginning treatment with olokizumab. The first two subcutaneous injections were administered with a 7-day interval for faster remission achievement. Despite a swift normalization of CRP (within 4 days), a stable clinical improvement was only achieved after 1-2 weeks, leading to a gradual reduction of the GC dose.There were no complications from the GC therapy, and after one month, a reduction of clinical symptoms of PMR was observed. Treatment with olokizumab 64 mg subcutaneously was continued with administrations every 2 weeks, later changed to every 4 weeks administrations. After 6 months of therapy, the patient independently stopped treatment with olokizumab, and then treatment with GC was discontinued. Consequently, PMR remission was achieved, no relapses were observed, and the patient is not currently receiving immunosuppressive therapy.Example 7: Steroid-sparing due to using olokizumab in the late stages of treatmentThe following two patients are best described together due to similarity in diagnoses, gender, ages, comparability of medical histories, and similar goals of treatment with olokizumab. The women, 81 and 83 years old, were managed at the E.M. Tareev Clinic (Moscow, Russia). More than ten years ago, they were diagnosed with GCA with PMR according to actual criteria. While patients presented primarily GCA manifestations at the onset of the disease, later the PMR symptoms became predominant, with the absence ofcranial features. The management involved long-term therapy with low doses of corticosteroids, resulting in various complications. In addition, synthetic steroid-sparing drugs showed no significant effectiveness, as an occurrence of the multifactorial pain syndrome. Also noted was the low laboratory activity, represented primarily by fluctuations in CRP levels from normal to 2 upper limit of normal (ULN), and clinical activity, presented by inflammatory pain in the shoulder and pelvic girdle, the intensity of pain decreased with increasing dosage of GCs.Complications of GC therapy included diabetes, steroid skin lesions, osteopenia or osteoporosis with vertebral compression fractures, drug-induced Cushing's syndrome, and widespread atherosclerosis. The pain syndrome developed in the context of primary disease, as well as severe osteoarthritis, degenerative changes in the spine, polyneuropathy associated with diabetes, and central sensitization associated with chronic long-term pain.At the time of consultation, one patient had CRP within normal range, the other had increased up to 1.5xULN, and both patients had pain associated with PMR. Thus, the objectives of prescnbing olokizumab in this case were to normalize CRP (in one patient), as well as to reduce pain and achieve steroid-sparing effects. The patients were treated with olokizumab for several months. After the very first injection of the drug, CRP in the patient with the increased CRP level returned to normal; there was also an improvement in terms of the pain syndrome, reducing pain from 80-100 to 30-40 mm on VAS. The GC dose was reduced from 5 to 2.5 mg / day of prednisolone in the first patient and from 5 to 3.75 mg / day in the second (without worsening condition, which was previously impossible).Thus, the treatment objectives were achieved: inflammatory activity was normalized, pain was reduced, and the GC dose was lowered. Importantly, the clinical response required a longer duration of treatment and only became evident after several months. The reduction in GC dose was limited not by disease activity but by the development of steroid dependency as a result of many years of GC treatment.Example 8: Treatment of PMR exacerbation using olokizumab without GCsA 59-year-old woman presented with significant pain and stiffness in the shoulder girdle, along with elevated acute phase parameters in the blood. She was examined in her hometown of Ufa, where a diagnosis of PMR was confirmed. She was treated with methylprednisolone at a starting dose of 12 mg / day, which had a complete effect and was subsequently reduced until it was completely discontinued, leading to a relapse that required the resumption of methylprednisolone therapy at a dose of 6 mg / day. This resulted in clinical and laboratory' effect and gradual discontinuation of therapy. Another PMR exacerbation occurred, characterized by stiffness and pain in the shoulder and pelvic girdle, and an increase in CRP up to 2.5xULN. NSAID intake was initiated with a short-term effect, and she sought a second opinion due to her unwillingness to restart GCs. It was decided to treat her with subcutaneous olokizumab 64 mg every 2 weeks. After one month of this treatment, a decrease in pain and the need for NSAIDs was noted, along with normalization of CRP and ESR levels. After two months, laboratory parameters remained normal. Due to significant pain relief, the patient has stopped taking painkillers; the therapy has been continued.Example 9: The control of GCA laboratory activityThe following two patients share common diagnoses (isolated GCA), ineffectiveness of MTX, and the need to reduce inflammatory' activity (including CRP level normalization) to eliminate the risks of clinical exacerbation of GCA.The patients, a 67-year-old woman and a 75-year-old man, were diagnosed with GCA approximately six months before the decision to prescribe olokizumab. Both patients had ocular involvement (transient ischemic optic neuropathy in one patient and partial atrophy of the optic nerve in the other), and the GCA diagnosis was verified by duplex scanning of the temporal arteries. The male patient also had PMR manifestations at disease onset, but this did not affect the treatment approach. A reduction in prednisolone dosage to 10 mg / day in the male patient and 20 mg / day in the female patient resulted in an exacerbation of the disease presented as increased CRP levels. The use of MTX in maximal tolerable doses (15 mg / week in the woman and 20 mg / week in the man) did not reduce disease activity. Therefore, in both cases, although there were no clinical signs of GCA exacerbation, and the patienf s condition was satisfactory, the elevated CRP indicated a high risk of recurrent ocular lesion potentially resulting in development of blindness. Furthermore, while the man could continue prednisolone treatment at 10 mg / day, albeit undesirable in the long term, for the women a treatment with prednisolone at 20 mg / day carried a high risk of multiple complications of steroid therapy.Given these factors, a decision was made to start treatment with olokizumab at a dose of 64 mg subcutaneously every 2 weeks. After the first injection, a stable normalization of CRP occurred, which allowed for the reduction of the daily GC dosage within a month. Over five months, both patients were able to gradually reduce and discontinue prednisolone,maintaining a stable condition without exacerbations. The patients continued monotherapy with olokizumab. The man developed moderate leukopenia during olokizumab therapy, which led to the discontinuation of MTX and subsequently , the administration of olokizumab was adjusted to a dose of 64 mg subcutaneously every 4 weeks without any clinical or laboratory manifestations of the disease.In conclusion, clinical data on the effectiveness of anti-IL-6 therapy in SSD-ILD and other connective tissue diseases, and the clinical examples provided, confirm that the use of olokizumab is effective for treating patients with progressive fibrosing interstitial lung diseases.Olokizumab demonstrated high efficacy in steroid-sparing in cases of inability7 to reduce the dose of GCs in PMR and GCA; in achieving remission in cases of persistent clinical or laboratory activity in long-lasting PMR, and also in treating PMR relapses without the use of GCs; in achieving remission in cases of persistent laboratory activity in GCA. Moreover, its use at the start of treatment (induction of remission) proved effective as an additional component of therapy when it's impossible to prescribe GCs in full dosage. It's particularly important to emphasize the safety and good tolerability of the conducted treatment. Based on clinical data, the subjective tolerability of olokizumab injections was good for all patients.All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference.While specific embodiments of the subject matter have been discussed, the above specification is illustrative and not restrictive. Many variations will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations 

Claims

 1. An IL-6 inhibitor olokizumab for use in the treatment of progressive fibrotic interstitial lung diseases, as well as polymyalgia rheumatica and giant cell arteritis. 2. The IL-6 inhibitor olokizumab for use according to claim 1, wherein the progressive fibrotic interstitial lung disease is selected from a group including idiopathic pulmonary fibrosis, non-specific interstitial pneumonia, lymphocytic interstitial pneumonia, unclassifiable idiopathic interstitial pneumonia, hypersensitivity pneumonitis (allergic alveolitis), sarcoidosis; interstitial pneumonia with autoimmune features; pneumoconioses; pulmonary histiocytosis; interstitial lung disease associated with autoimmune diseases, such as systemic sclerosis; rheumatoid arthritis; systemic lupus erythematosus; polymyositis / dermatomyositis; primary Sjogren's syndrome; mixed connective tissue disease; other systemic connective tissue diseases. 3. The IL-6 inhibitor olokizumab for use in treating progressive fibrotic interstitial lung diseases according to claim 1, comprising administering the IL-6 inhibitor olokizumab to a subject in need of such treatment at a dose of 64 mg subcutaneously once every 4 weeks. 4. The IL-6 inhibitor olokizumab for use according to claim 3, wherein the progressive fibrotic interstitial lung disease is selected from a group including idiopathic pulmonary fibrosis, non-specific interstitial pneumonia, lymphocytic interstitial pneumonia, unclassifiable idiopathic interstitial pneumonia, hypersensitivity pneumonitis (allergic alveolitis), sarcoidosis; interstitial pneumonia with autoimmune features; pneumoconioses; pulmonary histiocytosis; interstitial lung disease associated with autoimmune diseases, such as systemic sclerosis; rheumatoid arthritis; systemic lupus erythematosus; polymyositis / dermatomyositis; primary Sjogren's syndrome; mixed connective tissue disease; other systemic connective tissue diseases. 5. The IL-6 inhibitor olokizumab for use in treating of polymyalgia rheumatica and giant cell arteritis according to claim 1, comprising administration of the IL-6 inhibitor olokizumab at a dose of 64 mg subcutaneously once every 2 weeks or once every 4 weeks to a subject in need of such treatment.

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