Fetuin a for the treatment or prevention of pathological inflammation

Abstract

This invention relates to fetoglobulin A in a method for treating or preventing pathological inflammation in patients, preferably patients having the following characteristics: serum fetoglobulin A levels are lower than non-pathological serum levels; and / or serum tumor necrosis factor α (TNF-α) levels are higher than the average serum levels in healthy individuals.

Description

Technical Field

[0001] This invention relates to the use of fetuin-A (α2-HS-glycoprotein) in the treatment of inflammation. Therefore, this invention relates to fetuin-A in methods for treating or preventing pathological inflammation in patients, wherein the patient condition preferably has the following characteristics: serum levels of fetuin-A are lower than non-pathological serum levels, and / or serum levels of tumor necrosis factor-α (TNF-α) are higher than the average serum levels in healthy individuals. Background Technology

[0002] Overwhelming immune responses pose serious risks to patients. For example, lipopolysaccharide (LPS) immune responses caused by Gram-negative bacteria can even be fatal. Even low-dose LPS exposure can trigger severe symptoms. Similarly, sepsis and hypoxia can lead to adverse and sometimes uncontrollable immune responses. Therefore, it is desirable to modulate the patient's immune system to maintain it in an ideal balance.

[0003] Inflammation (Latin: inflammatioInflammatory response (INF) is part of a complex biological response of the body to harmful stimuli such as pathogens, damaged cells, or irritants (Ferrero-Miliani L, et al.: Chronic inflammation: importance of NOD2 and NALP3 in interleukin-1beta generation, Clin Exp Immunol 147(2) 2007, 227; Chen, LD et al.: Inflammatory responses and inflammation-associated diseases in organs, Oncotarget Impact J LLC. 9(6), 2017, 7204), and is a protective response involving immune cells, blood vessels, and molecular mediators. The function of inflammation is to eliminate the initial cause of cell damage, clear necrotic cells and tissues resulting from the original damage and inflammatory process, and initiate tissue repair. Its five typical signs are: heat, pain, redness, swelling, and loss of function. Inflammation is a nonspecific response and is therefore considered an innate immune mechanism, as opposed to adaptive immunity, which is specific to each pathogen (Abbas AB, Lichtman AH (2009). Ch.2 Innate Immunity. In Saunders (Elsevier) (ed.). Basic Immunology. Functions and disorders of the immune system (3rd ed.). ISBN 978-1-4160-4688-2). Insufficient inflammation can lead to progressive tissue damage from harmful stimuli such as bacteria, jeopardizing the organism's survival. Conversely, excessive inflammation, presenting as chronic inflammation, is associated with a variety of diseases, such as hay fever, periodontal disease, atherosclerosis, and osteoarthritis.

[0004] Inflammation can be classified as acute or chronic. Acute inflammation is generally understood as the body's initial response to a harmful stimulus, achieved through increased movement of plasma and leukocytes (especially granulocytes) from the blood to damaged tissue. A series of biochemical events promote the spread and maturation of the inflammatory response, involving the local vascular system, the immune system, and various cells within the damaged tissue. Long-term, persistent inflammation is called chronic inflammation, which leads to a progressive change in cell types at the site of inflammation, such as an increase in monocytes, and is characterized by simultaneous tissue destruction and healing during the inflammatory process. In addition, inflammation is also classified as type 1 and type 2 inflammation based on the types of cytokines and helper T cells (Th1 and Th2) involved (Berger A (August 2000). "Th1 and Th2 responses: what are they?". BMJ. 321 (7258): 424).

[0005] Helper T cells (Th cells) interact with a variety of cytokines. There is cross-regulation between type 1 helper T cells (Th1 cells) and type 2 helper T cells (Th2 cells), and vice versa. Th1 cells are known to secrete interferon-γ (IFN-γ) and interleukins (ILs) IL-2, as well as IL-12 (new nomenclature). This may contribute to the dominant cellular immune response. Th1 cells can influence Th2 cells through IFN-γ and IL-12 (new nomenclature). Th2 cells are known to secrete IL-4, IL-5, IL-6, and IL-10, as well as IL-13 (new nomenclature). This may contribute to the dominant humoral immune response. Th2 cells can influence Th1 cells through IL-4 and IL-10 (new nomenclature). In the old nomenclature, Th cells may have been based on clonal T cells; in the new nomenclature, Th cells may have been based on undissociated peripheral blood mononuclear cells (PBMCs).

[0006] Inflammation, especially an overwhelming inflammatory response, can significantly affect the secretion of cytokines, which may be influenced and controlled by other intrinsic components. Extensive evidence suggests that pro-inflammatory cytokines have detrimental effects on the cardiovascular system (Schernthaner C, Lichtenauer M, Wernly B, Paar V, Pistulli R, Rohm I, et al.: Multi-biomarker analysis in patients with acute myocardial infarction. Eur J Clin Invest. 2017; 47(9): 638-48). During inflammation, pro-inflammatory cytokines (such as IL-1β and IL-6) reduce the synthesis of fetoglobulin A in the liver. Fluctuations in the levels of C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), interleukins, S100 protein, metalloproteinases, and angiopoietin can be observed in various body fluids. Because these biomarkers each perform different functions, it is argued that inflammatory bowel disease (IBD) induces multiple responses, which may then influence the levels of different compounds through feedback mechanisms, consumption, or reprioritization of synthesis. Even relatively harmless stimuli that activate the innate immune system can stimulate the release of various pro-inflammatory cytokines (such as TNF), which may damage or even kill the host (Ombrellino M. et al.: Fetuin-A attenuates TNF synthesis and inflammatory response to carrageenan Shock 15 (2001), 181).

[0007] While inflammation is reasonable and beneficial to the body's recovery in many cases, in others an overwhelming inflammatory response is harmful and therefore undesirable. This undesirable and / or harmful inflammation is called pathological inflammation, which can be acute or chronic. Many serious pathological conditions are often associated with pathological inflammation, such as: Parkinson's disease, cirrhosis, ankylosing spondylitis, antiphospholipid antibody syndrome, autoimmune encephalitis, chronic recurrent multifocal osteomyelitis, gout, Henoch-Schoenlein purpura, juvenile dermatomyositis, juvenile idiopathic arthritis, juvenile lupus erythematosus (SLE), juvenile scleroderma, juvenile vasculitis, Kawasaki disease, lupus (systemic lupus erythematosus), and mixed connective tissue disease. Diseases, myositis, poststreptococcal inflammatory syndromes, psoriatic arthritis, reactive arthritis, rheumatoid arthritis, scleroderma, Sjogren's syndrome, spondyloarthritis / spondyloarthropathy, systemic juvenile idiopathic arthritis, undifferentiated / mixed connective tissue disease, uveitis, vasculitis (of various etiologies), inflammatory bowel disease, and / or other related diseases.

[0008] Therefore, mastering the means to regulate inflammation (such as alleviating inflammation to a non-pathological level) is of great significance.

[0009] A variety of anti-inflammatory compounds (also known as anti-inflammatory drugs, anti-inflammatory agents, or anti-inflammatory agents) exist in the existing technology. For example, many nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, ibuprofen, and naproxen, typically inhibit cyclooxygenase (COX). However, many pathological immune conditions do not respond adequately to these compounds, or even show little to no substantial response. Both acquired and inherent resistance exist.

[0010] Furthermore, treatment or prevention with NSAID / COX inhibitors is often insufficient to significantly improve pathological inflammation, especially when this inflammation evolves into chronic pathological inflammation, where NSAIDs / COX inhibitors often cause adverse side effects or lose their efficacy.

[0011] For severe pathological inflammation, patients are often given corticosteroids, such as cortisone. Especially when long-term use is required or it may be the only treatment, patients can suffer severe side effects.

[0012] Therefore, there is still an urgent need for other treatments to treat and / or prevent pathological inflammation in patients.

[0013] Surprisingly, research has found that fetoglobulin A can be used as a preventative and / or therapeutic agent for treating inflammation and related diseases, independent of serum levels. Fetoglobulin A can be used in the treatment or prevention of acute or chronic inflammation, optionally independent of the current level of fetoglobulin A in plasma. Fetoglobulin A has been identified as a highly potent immunomodulator. Surprisingly, fetoglobulin A can be used to treat acute and chronic inflammation. Summary of the Invention

[0014] This invention relates, in one aspect, to fetoglobulin A in a method for treating or preventing pathological inflammation in a patient. In other words, the invention also relates to a method for treating or preventing pathological inflammation in a patient, wherein an adequate amount of fetoglobulin A is administered to the patient. Inflammation can include acute and chronic inflammation. This invention relates to fetoglobulin A in a method for treating or preventing pathological inflammation in a patient, and is independent of the current level of fetoglobulin A in plasma / serum.

[0015] Surprisingly, the study found that fetoglobulin A can treat and / or prevent inflammation, and observed its ability to inhibit pro-inflammatory cytokines. It was also surprisingly found that fetoglobulin A has a positive effect on lipopolysaccharide-induced (LPS-induced) lung injury: repairing lung damage by preventing immune infiltration and restoring lung function by reducing airway resistance. Furthermore, fetoglobulin A also has a positive effect on hypoxia-induced lung injury: repairing lung damage by preventing immune infiltration and alveolar collapse.

[0016] In a preferred embodiment, the patient is characterized by: serum fetoglobulin A levels below non-pathological serum levels, and / or serum tumor necrosis factor α (TNF-α) levels above the average serum levels of healthy individuals.

[0017] This invention relates to fetoglobulin A for a method of treating or preventing pathological inflammation in a patient, the patient being characterized as follows: (a) Serum levels of fetoglobulin A are lower than non-pathological serum levels; and / or (b) Serum levels of tumor necrosis factor-α (TNF-α) were higher than the average serum levels in healthy individuals.

[0018] Another aspect of the present invention relates to fetoglobulin A for a method of treating or preventing pathological inflammation in a patient, the patient being characterized as follows: (a) Serum levels of fetoglobulin A were lower than non-pathological serum levels; and (b) Serum levels of tumor necrosis factor-α (TNF-α) were higher than the average serum levels in healthy individuals.

[0019] In the context of this invention, "fetoprotein A" may be interpreted in the broadest sense known in the art. The terms "fetoprotein-A", "α2-HS glycoprotein", "α2-HS glycoprotein", "AHSG", "Ahsg", "α2-HS", "A2HS", "AHS" and "HSGA" are used interchangeably.

[0020] Tumor necrosis factor α (TNF-α) can also be referred to as "TNF", "TNF-α", "TNF α", "tumor necrosis factor", "cachexin", "diffusion", DIF, TNFA, TNFSF2, or TNLG1F. TNF-α can be understood as both an adipokine and a cytokine. TNF-α can exist in both soluble and transmembrane forms. Preferably, in the context of this invention, TNF-α refers to the soluble form of TNF-α, which is soluble in the patient's serum. When measuring plasma levels, all forms of TNF-α, including potentially glycosylated forms, should be considered.

[0021] If a patient receives TNF-α treatment, TNF-α also includes its recombinant form.

[0022] Alternatively or further, patients are characterized by higher levels of TNF-α in their lung tissue than the average level in healthy individuals.

[0023] In addition, optionally, the patients are characterized by serum interferon-α (IFN-α) levels higher than the average serum levels in healthy individuals.

[0024] Interferon-α (IFN-α) can also be called "interferon α" (IUPAC standard nomenclature), "IFN-α", "leukocyte interferon", "type I interferon" or "human leukocyte interferon α (HuIFN-α-Le)".

[0025] IFN-α can be any of its isoforms, such as IFNA1, IFNA2, IFNA4, IFNA5, IFNA6, IFNA7, IFNA8, IFNA10, IFNA13, IFNA14, IFNA16, IFNA17, and / or IFNA21, or a mixture of two or more, or even all, of the above isoforms. When considering plasma levels, the total amount of all IFN-α is taken into account, i.e., the sum of the amounts of all isoforms. When measuring plasma levels, all IFN-α, including potential glycosylated forms, are considered.

[0026] If the patient is receiving IFN-α treatment, IFN-α also includes its recombinant forms, including interferon α-1, as well as artificially modified variants of IFN-α (e.g., polyethylene glycol-modified IFN-α, such as polyethylene glycol-modified interferon α-2a and / or polyethylene glycol-modified interferon α-2b). For artificially modified variants, only the peptide content is considered.

[0027] It should be understood that, in this document, fetoglobulin A and any other components (such as other optional anti-inflammatory compounds) encompass their pharmaceutically acceptable salts. Such pharmaceutically acceptable salts may include, for example, counterions: sodium, potassium, chloride, ammonium, sulfate, acetate, phosphate, etc.

[0028] Fetoprotein A is well known to those skilled in the art. Fetoprotein A can originate from any species. Preferably, fetoprotein A is mammalian or bovine fetoprotein A. More preferably, fetoprotein A is human, mouse, rat, or bovine fetoprotein A. More preferably, fetoprotein A is human fetoprotein A.

[0029] Fetoglobulin A as used herein is applicable to medical / therapeutic scenarios. Fetoglobulin A can be (but is not necessarily) isolated fetoglobulin A. It can optionally be isolated according to the method described in European Patent Application No. EP 23173323.9. Fetoglobulin A is also commercially available. It can be obtained by separation and purification from blood or blood components (such as plasma), or by genetic engineering methods (such as heterologous expression). In a preferred embodiment, fetoglobulin A can be isolated from human plasma. In some scenarios, this helps to achieve optimal biocompatibility. This can provide optimal biocompatibility. Due to the wide variation in the composition of plasma components, various purification methods can be used to extract fetoglobulin A from human biological fluids to efficiently and fully utilize existing resources. For example, fetoglobulin A can be isolated from human plasma Cohn fraction IV, such as using chromatography. Similarly, recombinant sources can also be used.

[0030] In this document, "isolation" is used in the broadest sense interchangeably with "purification," i.e., increasing the content of isolated fetoglobulin A in the composition. It is not required that the product be pure. However, preferably, the product of this method contains at least 25% (w / w) of fetoglobulin A based on the total protein weight. More preferably, the product of this method contains at least 50% (w / w), even more preferably at least 70% (w / w), even more preferably at least 80% (w / w), and particularly at least 90% (w / w) of fetoglobulin A based on the total protein weight.

[0031] Fetuin A has a variety of functions in the body. Besides acting as a bone-stabilizing protein, fetuin A is known to participate in many other functions, such as regulating immune responses during inflammation. Fetuin A is a heterodimeric plasma glycoprotein consisting of a 282-amino acid A chain and a 27-amino acid B chain linked by a single intermolecular disulfide bond. Fetuin A can bind to a large number of receptors and exhibits diverse physiological and pathological functions. Fetuin A is involved in calcium metabolism, osteogenic processes, and the regulation of the insulin signaling pathway. Furthermore, it also functions as an inhibitor of ectopic calcification, a protease inhibitor, an inflammatory mediator, an anti-inflammatory cofactor, an atherogenic factor, and an adipogenic factor. Studies have also confirmed that fetuin A plays an important role in the pathogenesis of various diseases (Abede EC et al.: The structure, biosynthesis, and biological roles of fetuin-A: A review. Front Cell Dev Biol, 2022).

[0032] Fetuin A is a negative acute-phase protein that has both pro-inflammatory and anti-inflammatory effects on the immune system (Wang H., Sama AE (2012): Anti-inflammatory role of fetuin-A in injury and infection. Curr Mol Med 12(5): 625-633). Under certain conditions, in vitro and in vivo experiments have shown that it has an inhibitory effect on the secretion of interleukin (IL) and tumor necrosis factor (TNF) (Dziegielewska KM, Andersen N. A., Saunders NR (1998): Modification of macrophage response tolipopolysaccharide by fetuin. Immunol Lett 60(1): 31-35; Ombrellino M., Wang H., Yang H., Zhang M., Vishnubhakat J., Frazier A., ​​Scher LA, Friedman SG, Tracey KJ (2001): Fetuin, a negative acute phase protein, attenuates TNF synthesis and the innate inflammatory response to carrageenan. Shock 15(3): 181-185). Fetuin-A also plays a role in regulating inflammatory responses during severe inflammatory events such as sepsis (Wang H., Sama AE (2012): Anti-inflammatory role of fetuin-A in injury and infection. Curr Mol Med 12(5): 625-633). Hennige et al. (2008) also reported the pro-inflammatory effects of fetuin-A in mouse experiments and in vitro experiments using the human mononuclear cell line THP-1 derived from acute monocytic leukemia. Fetuin-A may be associated with atherosclerosis. Studies have shown that fetuin-A can perform multiple immune functions, including regulating macrophage-related lipopolysaccharide-induced opsonization and regulating TNF-α and transforming growth factor β (TGF-β) levels. Decreased levels of fetuin-A in circulating blood limit the activity of various anti-inflammatory mediators, thereby exacerbating inflammatory responses.Fetuin A is also one of the inhibitors of soft tissue and vascular system calcification (Cakir, H. et al.: Lower Serum Fetuin-A Levels are Associated with a Higher Ten-Year Mortality Risk in Patients with ST-Elevation Myocardial Infarction Arq BrasCardiol, 11, 2022, 14).

[0033] Surprisingly, based on experimental findings, research has confirmed that fetoglobulin A can be used as a beneficial antagonist in type 1 inflammation. Proliferating helper T cells develop into effector T cells, which further differentiate into two main cell subtypes: Th1 and Th2 cells (also known as type 1 and type 2 helper T cells, respectively). Th1 helper cells induce enhanced cell-mediated immune responses (primarily mediated by macrophages and cytotoxic T cells), typically targeting intracellular bacteria and protozoa. These responses can be triggered by the polarizing cytokine IL-12, whose effector cytokines are IFN-γ and IL-2. The main effector cells of Th1 immunity include macrophages, CD8+ T cells, IgG+ B cells, and IFN-γ+CD4+ T cells. Key transcription factors for Th1 may include STAT4 and T-bet. IFN-γ secreted by CD4+ T cells can activate macrophages, enabling them to engulf and digest intracellular bacteria and protozoa. In addition, IFN-γ can activate inducible nitric oxide synthase (iNOS), producing nitric oxide free radicals that directly kill bacteria and protozoa within cells. When Th1 cells are overactivated against their own antigens, it can lead to type IV or delayed-type hypersensitivity reactions. Tuberculin reaction and type 1 diabetes are both autoimmune diseases of this type (Zhu J, Paul WE (September 2008). "CD4 Tcells: fates, functions, and faults". Blood. 112 (5): 1557. doi:10.1182 / blood-2008-05-078154).

[0034] Fetoprotein A inhibits IFN-γ synthesis and simultaneously inhibits transmembrane peptidase (merpins). Therefore, fetoprotein A is the optimal treatment for type 1 inflammation. It is particularly beneficial for adult multisystem inflammatory syndrome (MIS-A). MIS is a rare but serious syndrome initially identified in children and adolescents infected with SARS-CoV-2 (the virus that causes COVID-19) (MIS-C). Similar to children, adults who have been infected with SARS-CoV-2 may also develop MIS (MIS-A) within days to weeks after infection with COVID-19. MIS-A is a syndrome involving inflammation in various internal and external sites of the body, such as the heart, gastrointestinal tract, skin, or brain. The incidence of MIS-A is lower than that of MIS-C. Compared to MIS-C, MIS-A is also more difficult to distinguish from acute COVID-19 infection. However, like children with MIS-C, adults with MIS-A appear to recover rapidly from the most dangerous heart-related complications.

[0035] In this paper, in the context of serum levels, “non-pathological” can be understood as: the serum levels of the corresponding compound are considered healthy in the art, preferably in a medical context.

[0036] In this article, serum fetoglobulin A levels are lower than non-pathological serum levels, which can refer to any degree of reduction.

[0037] In a preferred embodiment, the serum level of fetoglobulin A is reduced by at least 1 wt%, preferably by at least 5 wt%, more preferably by at least 10 wt%, and particularly preferably by at least 20 wt% or at least 50 wt%, relative to the lowest serum level considered non-pathological (i.e., the normal range for healthy patients).

[0038] According to existing scientific literature, the serum level of non-pathological minimum fetoglobulin A can be as low as 300 µg / mL.

[0039] According to existing scientific literature, the serum level of fetoglobulin A is considered to be within the healthy range, ranging from 300 to 1000 µg / mL. For example, Abebe et al. (Frontiers in Cell and Developmental Biology, 2022, DOI 10.3389 / fcell.2022.945287) indicated that the normal range for serum fetoglobulin A levels is 300 to 1000 µg / mL. Li et al. (PLoS One, 2011, 6(2):e16945) also confirmed this normal range.

[0040] This is consistent with other existing literature. Manolakis et al. (World Journal of Gastroenterology, 2017, 23(3):437-446) taught that the normal range for serum fetoprotein A levels is approximately 710 µg / mL. Minas et al. (Journal of Chronic Obstructive Pulmonary Disease, 2013, 10:28-34) taught that the serum fetoprotein A level in the control group was approximately 487 µg / mL. These values ​​are all within the range considered non-pathological, i.e., within the healthy range. For example, the study by Zissimopoulos et al. (Hel J Nucl Med., 2015, 18, Suppl 1:147) showed that serum levels in patients with coronary heart disease were far below normal levels (below 140 mg / mL).

[0041] In this document, a serum level of tumor necrosis factor α (TNF-α) higher than the average serum level in healthy individuals can refer to any degree of elevation. In a preferred embodiment, the serum TNF-α level is elevated by at least 1 wt%, preferably by at least 5 wt%, more preferably by at least 10 wt%, particularly preferably by at least 20 wt%, or by at least 50 wt%, or by at least 75 wt%, or by at least 2 times (by weight), or by at least 3 times (by weight), relative to the average serum level in healthy individuals.

[0042] According to reports, the average serum level in healthy patients is in the range of approximately 75 pg / mL (Damas et al., Critical Care Medicine, 1989, 17(10):975-978).

[0043] In this document, serum levels of interferon-α (IFN-α) higher than the average serum levels found in healthy individuals can refer to any degree of elevation. In a preferred embodiment, the serum IFN-α level is elevated by at least 1 wt%, preferably at least 5 wt%, more preferably at least 10 wt%, particularly preferably at least 20 wt%, or at least 50 wt%, or at least 75 wt%, or at least 2 times (by weight), or at least 3 times (by weight), relative to the average serum levels found in healthy individuals.

[0044] The average serum level found in healthy individuals can be considered to be in the range of approximately 42 pg / mL. Contoli et al. (Frontiers in Immunology, 2021, 12:1-10, Article 648004) taught that the level in healthy patients ranged from 24 to 87 pg / mL, with an average of approximately 42 pg / mL.

[0045] In the context of this invention, the term "patient" may be understood in its broadest sense as a subject receiving a dose of fetoglobulin A, whether human or animal, and regardless of whether they exhibit clinical symptoms. Preferably, the patient is a human patient.

[0046] Fetoprotein A (optionally, as part of the pharmaceutical composition) may be administered to the patient in any manner.

[0047] In a preferred embodiment, fetoglobulin A (optionally, as part of a pharmaceutical composition) is administered via the respiratory tract, preferably via intranasal administration; or by injection, preferably via intravenous (iv), intraperitoneal (ip), intradermal (id), arterial (ia), intramuscular (im), and / or subcutaneous (sc); it may also be administered topically or orally (also known as oral administration, po).

[0048] In a preferred embodiment, fetoglobulin A (optionally, as part of a pharmaceutical composition) is administered via the respiratory tract, particularly intranasally. This can be achieved by any means, such as administering an aerosol containing droplets of fetoglobulin A to the patient.

[0049] Fetoglobulin A (optionally, as part of the pharmaceutical composition) can also be injected into tissues or blood vessels via syringe or infusion line. Alternatively, it can be administered via intraperitoneal injection, or by oral, intranasal, topical, or subcutaneous route. Exemplarily, fetoglobulin A can be administered intravenously (iv), intraperitoneally (ip), intradermally (id), intra-arterially (ia), intramuscularly (im), and / or subcutaneously (sc). Alternatively, fetoglobulin A can be taken orally, for example, in the form of powders, tablets, pills, capsules, chewable capsules, syrups, oral solutions, gels, liquids, or ointments. Alternatively, fetoglobulin A can be taken nasally (e.g., as a spray or aerosol), percutaneously (e.g., as a cream, spray, ointment, and / or via a patch), and / or by inhalation (e.g., as an inhaled aerosol or spray). It should be understood that fetoglobulin A can be administered locally or systemically.

[0050] "Preventive treatment" can be understood in its broadest sense as the prophylactic administration of fetoglobulin A (optionally, as part of a pharmaceutical composition) to patients who are at risk of developing pathological inflammation, regardless of whether they have clinical symptoms.

[0051] "Treatment of patients" can be understood in its broadest sense as the administration of fetoglobulin A (optionally, as part of a pharmaceutical composition) to patients with pathological inflammation, regardless of whether they have clinical symptoms.

[0052] Inflammation can occur in almost any tissue of a patient's body. In principle, fetoglobulin A can be used to treat inflammation in any tissue. In a preferred embodiment, pathological inflammation includes inflammation of the lung tissue, particularly related to respiratory failure.

[0053] In a preferred embodiment, the pathological inflammation is associated with hypoxia. In a preferred embodiment, the pathological inflammation is associated with pulmonary hypoxia.

[0054] In a preferred embodiment, the inflammation is induced by lipopolysaccharide (LPS). Optionally, LPS may be derived from one or more Gram-negative bacteria. In a preferred embodiment, the pathological inflammation is induced by LPS and is at least partially located in the lungs. In a preferred embodiment, the pathological inflammation is associated with pneumonia.

[0055] In a preferred embodiment, the pathological inflammation is chronic pathological inflammation. Chronic inflammation is generally considered to be slow, prolonged inflammation. Chronic pathological inflammation typically lasts at least two weeks. In a preferred embodiment, the chronic pathological inflammation lasts at least one month, at least six months, or at least one year.

[0056] In a preferred embodiment, the pathological inflammation is in a late stage of inflammation. Therefore, known methods may not be able to adequately induce downregulation mechanisms to terminate inflammation. In a preferred embodiment, the chronic pathological inflammation has persisted for at least one month, at least six months, or at least one year from the onset of inflammation to the initiation of treatment.

[0057] Pathological inflammation may or may not be related to fetoprotein A deficiency. In the presence of fetoprotein A deficiency, it may not be related to the cause of inflammation. Patients with acute or chronic inflammation may be treated or prevented using pharmaceutical compositions containing fetoprotein A.

[0058] In a preferred embodiment, the patient is repeatedly administered fetoglobulin A for at least one month, at least two months, or at least three months.

[0059] In a preferred embodiment, the patient suffers from chronic pathological inflammation and is repeatedly administered fetoglobulin A for at least one month, at least two months, or at least three months.

[0060] The above administration can be performed according to any route of administration. Fetoprotein A can be administered to patients once daily, once weekly, once every two weeks, once every three weeks, once monthly, once every two months, or less than once every two months.

[0061] In a preferred embodiment, fetoglobulin A is repeatedly administered to the patient at a frequency not exceeding once a week for a period of at least one month, at least two months, or at least three months.

[0062] In a preferred embodiment, fetoglobulin A is repeatedly administered to the patient by injection, with each injection ranging from 1 to 1000 µg / kg body weight.

[0063] In a preferred embodiment, the patient is injected no more than once a week for a period of at least one month, at least two months, or at least three months.

[0064] In a preferred embodiment, fetoglobulin A is repeatedly administered to the patient via injection, with each injection ranging from 1 to 1000 µg / kg body weight. The frequency of injections is no more than once every two weeks, and the treatment lasts for at least three months. In another preferred embodiment, the pathological inflammation is acute pathological inflammation.

[0065] In this case, optionally, a bolus dose of fetoglobulin A may be administered to the patient. The preferred route of administration is injection, such as by syringe bolus or intravenous infusion. Acute pathological inflammation may be, for example, sepsis or related to sepsis.

[0066] The preventive or therapeutic methods of the present invention are particularly beneficial to patients suffering from inflammation who do not respond to treatment with other anti-inflammatory drugs or other anti-inflammatory agents.

[0067] In a preferred embodiment, the patient is unresponsive to cyclooxygenase (COX) inhibitors, particularly to nonsteroidal anti-inflammatory drugs (NSAIDs); or the patient has contraindications to COX inhibitors.

[0068] In a preferred embodiment, the patient has the following characteristics: (a) No response to existing anti-inflammatory drugs; (b) The patient’s blood fetoglobulin A level is below normal, above normal, or within the normal range.

[0069] In another preferred embodiment, the patient has the following characteristics: (a) No response or weak response to existing anti-inflammatory drugs; (b) The patient’s blood fetoglobulin A level is below normal, above normal, or within the normal range.

[0070] In this article, the term "no therapeutic response" can be understood as: the effective response to a compound does not reach the level of therapeutic efficacy.

[0071] Preferably, the anti-inflammatory compound that does not respond to treatment cannot reduce one or more inflammatory biomarkers at the treatment site to a reasonable level. Preferably, when applied to the treatment site at a therapeutically reasonable dose (preferably according to the instructions for use) relative to the level before treatment with the anti-inflammatory compound, it cannot reduce one or more inflammatory biomarkers by at least 10%, at least 25%, or at least 50%.

[0072] In this invention, the term "anti-inflammatory compound" can be broadly understood to mean any compound with clinical efficacy for the prevention or treatment of inflammation. In a preferred embodiment, the anti-inflammatory compound is selected from the group consisting of: (a) Nonsteroidal anti-inflammatory drugs (NSAIDs), preferably: salicylates (e.g., acetylsalicylic acid, difluorobenzylsalicylic acid, salicylic acid, disalicylate); propionic acid derivatives (e.g., ibuprofen, dextrobuprofen, naproxen, fenprofen, ketoprofen, dextroketoprofen, flurbiprofen, oxapazine, loxoprofen, pelumizine, zaltoprofen, fenbuprofen, tiprofen); acetic acid derivatives (e.g., indomethacin, acimetidine, tometidine, sulindac, etodoxacin, ketoprofen, diclofenac, fenclofenac, aceclofenac, bromofenac, fentiazine, nabumetone); enolates (xylene) (e.g., piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, itoxicam, phenylbutazone); anthranilic acid derivatives (fenamic acid derivatives, such as mefenamic acid, meclofenamic acid, flufenamic acid, tofenamic acid, etofenadate); selective COX-2 inhibitors (coxib derivatives, such as celecoxib, rofecoxib, vardicoxib, parecoxib, phenicoxib (registered with the Australian Therapeutic Goods Administration has been deregistered), etofocoxib, fenicoxib); sulfonamide derivatives (e.g., nimesulide), chlornisin, levofloxacin, H-harpagide; (a non-steroidal anti-inflammatory drug (NSAID), preferably a salicylate (eg, acetylsalicylic acid), dolobid, salicylic acid, disalcid), a propionic acid derivative (eg,ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen,flurbiprofen, oxaprozin, loxoprofen, pelubiprofen, zaltoprofen, fenbufen,tiaprofenic acid), an acetic acid derivative (eg, indomethacin, acemetacin,tolmetin, sulindac, etodolac, ketorolac, diclofenac, fenclofenac,aceclofenac, bromfenac, fentiazac, nabumetone), an enolic acid (oxicam)derivative (eg, piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam,isoxicam, phenylbutazone), an anthranilic acid derivatives (fenamates)), mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid,etofenamate, a selective COX-2 inhibitor (Coxib) (eg, celecoxib, rofecoxib,valdecoxib, parecoxib, lumiracoxib TGA canceled registration, etoricoxib, firocoxib), a sulfonanilide (eg, nimesulide), clonixin, licofelone, or H-harpagide). (b) Antileukotriene drugs, preferably ablukast, iralukast, masilukast, montelukast, pobilukast, pranlukast, tipelukast, tomelukast, verlukast, zafirlukast, or zileuton; (c) Immunoselective anti-inflammatory derivatives (ImSAID), preferably antibodies that can bind to at least one pro-inflammatory factor and inactivate the factor, such as anti-TNF-α antibodies, or antibodies that can bind to at least one pro-inflammatory factor receptor and inactivate the receptor; (d) Corticosteroids, preferably cortisol, cortisone, or aldosterone, with cortisone being particularly preferred; (e) The anti-inflammatory compound is different from those in (a) to (d), preferably eugenol, eucalyptol, menthone, or menthol.

[0073] It should be understood that two or more of the above compounds can be used in combination. It should also be understood that not all compounds are suitable for all routes of administration. For example, menthol is typically used only topically and not for systemic administration.

[0074] In this document, inflammatory biomarkers are well known to those skilled in the art. Exemplarily, inflammatory biomarkers are selected from the following group: (a) One or more interleukins, particularly interleukin-1 (IL-1), interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-8 (IL-8), and / or interleukin-18 (IL-18); (b) Tumor necrosis factor α (TNF-α); (c) C-reactive protein (CRP); (d) One or more eicosanoids, particularly one or more prostaglandins (PGs) and / or one or more leukotrienes; (e) A combination of two or more of the above markers.

[0075] In this article, inflammation is typically accompanied by elevated levels of one or more of the aforementioned inflammatory biomarkers. In this article, "elevated" means, for example, a biomarker level that is at least 10%, at least 25%, or at least 50% higher than that of a homologous tissue sample from a healthy individual of the same species.

[0076] For example, a treatment-unresponsive COX inhibitor cannot reduce the level of target prostaglandins at the treatment site to a reasonable level; preferably, when administered at a therapeutically appropriate dose to the treatment site (preferably according to the instructions for use), it cannot reduce the level of target prostaglandins at the treatment site by at least 10%, at least 25%, or at least 50% compared to the level before treatment with the COX inhibitor. A treatment-unresponsive NSAID cannot reduce the pain level to a identifiable degree. Similarly, a treatment-unresponsive NSAID cannot reduce the pain level to a tolerable level.

[0077] In a preferred embodiment, the patient does not respond to anti-inflammatory drugs other than corticosteroids.

[0078] Pathological inflammation can have any molecular etiology and may be associated with any inflammatory biomarkers or other compounds. Surprisingly, fetoglobulin A has been found to be an inhibitor of membrane-penetrating peptidases (meprins), particularly meprinase α and β. Therefore, fetoglobulin A could be used to treat and prevent pathological inflammation associated with elevated levels of meprinase α and / or meprinase β in the site of inflammation and / or in the patient's systemic plasma.

[0079] In a preferred embodiment, pathological inflammation is associated with elevated levels of transmembrane peptidase α and / or transmembrane peptidase β at the site of inflammation and / or in the patient's systemic plasma.

[0080] In this document, "membrane-penetrating peptidase" is understood in the broadest sense known in the art. A membrane-penetrating peptidase can be membrane-penetrating peptidase A (EC 3.4.24.18, also known as: endopeptidase 2, membrane-penetrating peptidase α, membrane-penetrating peptidase, N-benzoyl-L-tyrosyl-p-aminobenzoic acid hydrolase, PABA-peptide hydrolase, PPH). A membrane-penetrating peptidase is a metalloproteinase. A membrane-penetrating peptidase can be membrane-penetrating peptidase α, membrane-penetrating peptidase β, or a mixture thereof.

[0081] Since Erwin Sterchi and Jidith Bond discovered a metalloproteinase derived from kidney tissue in the early 1980s, this enzyme has been commonly referred to as "meprins" and has received considerable attention from the scientific community due to its various physiological functions (Beynon, RJ, Shannon, JD and Bond, JS 1981. Purification and characterization of a metallo-endoproteinase from mouse kidney. Biochem. J.199, 591–598; Sterchi, EE, Green, JR and Lentze, MJ 1982. Non-pancreatic hydrolysis of N-benzoyl-L-tyrosyl-p-aminobenzoic acid (PABA-peptide) in the human small intestine. ClinSci. 62, 557–560). Transmembrane peptidases α and β are encoded by two different genes located on different chromosomes (Gorbea, CM, Marchand, P., Jiang, W., Copeland, NG, Gilbert, DJ, Jenkins, NAa, Bond, JS 1993 Cloning, expression, and chromosomal localization of the mouse meprin β subunit. J.Biol.Chem. 268, 21035–21043; Jiang, W., Sadler, PM, Jenkins, NA, Gilbert, DJ, Copeland, NG and Bond, JS (1993) Tissue-specific expression and chromosomal localization of the α subunit of mouse meprin AJBiol.Chem. 268, 10380–10385).Transmembrane peptidases α and β belong to the zinc-dependent metalloproteinases of the astacin family and the metzicin superfamily (Stocker, W. and Zwilling, R. (1995) Astacin. Methods Enzymol. 248, 305–325). Therefore, they are phylogenetically associated with matrix metalloproteinases (MMPs) and ADAMs. These highly glycosylated, complex, multi-domain meprins are expressed as zymogens. Functional activation of meprins is achieved by removing the N-terminal propeptide via substrate-specific serine proteases (Kruse, MN, Becker, C., Lottaz, D., Kohler, D., Yiallouros, I., Krell, HW, Sterchi, EE and Stocker, W. 2004 Human meprin α and β homo-oligomers: cleavage of basement membrane proteins and sensitivity to metalloprotease inhibitors. Biochem. J. 378, 383–389; Becker, C., Kruse, MN, Slotty, KA, Kohler, D., Harris, JR, Rosmann, S., Sterchi, EE and Stocker, W. 2003 Differences in the activation mechanism between the α and β subunits of human meprin. Biol-Chem. 384, 825–831). Once activated, meprins can perform a variety of functions.Both enzymes function as C-terminal and N-terminal procollagenases, promoting collagen maturation and assembly (Biasin V, Marsh LM, Egemnazarov B, Wilhelm J, Ghanim B et.al. 2014. Meprin β, a novel mediator of vascular remodelling underlying pulmonary hypertension. J.Pathol. May;233(1):7-17; Prox J, Arnold P, Becker-Pauly C.2015 Meprin α and meprin β:Procollagen proteinases in health and disease. MatrixBiol. 2015 May-Jul;44-46:7-13). Chronic inflammatory bowel disease (IBD), such as Crohn's disease (CD) and ulcerative colitis (UC), is a chronic inflammation of the gastrointestinal tract characterized by diffuse leukocyte infiltration of the intestinal mucosa and dysregulation of the mucosal immune system (Neuman, MG 2007 Immune dysfunction in inflammatory bowel disease. Transl.Res.149, 173–186).Genetic analysis studies show that IBD is associated with meprins (Banerjee, S., Oneda, B., Yap, LM, Jewell, DP, Matters, GL, Fitzpatrick, LR, Seibold, F., Sterchi, EE, Ahmad, T., Lottaz, D. and Bond, JS 2009 MEP1A allele for meprin A metalloprotease is a susceptibility gene for inflammatory bowel disease. MucosalImmunol. 2,220–231; Banerjee, S., Jin, G., Bradley, SG, Matters, GL, Gailey, RD, Crisman, JM, Bond, JS 2011 Balance of meprin A and B in mice affects the progression of experimental inflammatory bowel disease. Am.J.Physiol.Gastroinstest. LiverPhysiol. 300, G273–G282). Experimental data clearly demonstrate that meprins regulate the immune environment by processing and activating pro-inflammatory cytokines (such as interleukins IL-1β and IL-18), transforming growth factor α (TGF-α), and tumor necrosis factor α (TNF-α), thereby promoting inflammation (Jefferson, T., auf dem Keller, U., Bellac, C., Metz, VV, Broder, C., Hedrich, J., Ohler, A., Maier, W., Magdolen, V., Sterchi, E. et al. 2012...).

[0082] Substrate degradation studies of meprin metalloproteinases revealed an unexpected proteolytic association between meprin β and ADAM10 (Cell. Mol. Life. Sci.; McGovern, DP, Gardet, A., Torkvist, L., Goyette, P., Essers, J., Taylor, KD, Neale, BM, Ong, RT, Lagace, C., Li, C. et al. 2010 Genome-wide association identifies multiple ulcerativecolitis susceptibility loci. Nat. Genet. 42, 332–337; Herzog, C., Haun, RS, Kaushal, V., Mayeux, PR, Shah, SV and Kaushal, GP 2009 Meprin A and meprin α generate biologically functional IL-1β from pro-IL-1β. Biochem. Biophys. Res. Commun. 379, 904–908; Herzog, C., Kaushal, GP and Haun, RS2005 Generation of biologically active interleukin-1β by meprin B. Cytokine 31, 394–403). Further studies have shown that meprin β mediates intestinal leukocyte infiltration, a function consistent with its ability to cleave adhesion molecules and extracellular matrix components.(Crisman, J. M., Zhang, B., Norman, L.P. andBond, J.S. 2004 Deletion of the mouse meprin β metalloprotease genediminishes the ability of leukocytes to disseminate through extracellularmatrix. J.Immunol. 172, 4510–4519;Kruse, M. N., Becker, C., Lottaz, D.,Kohler, D., Yiallouros, I., Krell, H.W., Sterchi, EE., Stocker, W. 2004 Humanmeprin α and β homo-oligomers: cleavage of basement membrane proteins andsensitivity to metalloprotease inhibitors. Biochem.J. 378, 383–389;Ambort,D., Brellier, F., Becker-Pauly, C., Stocker, W., Andrejevic-Blant, S.,Chiquet, M., Sterchi, E.E. 2009 Specific processing of tenascin-C by themetalloprotease meprin beta neutralizes its inhibition of cell spreading.MatrixBiol. 29, 31–42;Oneda, B., Lods, N., Lottaz, D., Becker-Pauly, C.,Stocker, W., Pippin, J., Huguenin, M., Ambort, D., Marti, H.P., Sterchi, E.E.2008 Metalloprotease meprin β in rat kidney: glomerular localization anddifferential expression in glomerulonephritis. PloS ONE 3,e2278)。

[0083] In vivo studies have shown that mice in the absence of meprin-α are protected, while mice with normal meprin-α levels suffer from acute renal failure (Mathew, R., Futterweit, S., Valderrama, E., Tarectecan, AA, Bylander, JE, Bond, JS, Trachtman, H. 2005 Meprin-α inchronic diabetic nephropathy: interaction with the renin-angiotensin axis. Am. J. Physiol. Renal Physiol. 289, F911–F921; DeGuzman, JB, Speiser, PW and Trachtman, H. 2004 Urinary meprin-α: a potential marker of diabetic nephropathy. J. Pediatr. Endocrinol. Metab. 17, 1663–1666; Trachtman, H., Valderrama, E., Dietrich, JM and Bond, JS 1995 The role of meprin A in the pathogenesis of acute renal failure. Biochem. Biophys. Res. Commun. 208, 498–505. Studies have found that during ischemia / reperfusion (IR) injury and cisplatin-induced acute kidney injury (AKI) in rodents, meprin α and meprin β redistribute from the apical brush border membrane of the proximal tubule to the basement membrane of the basal tubule, thereby triggering IR that leads to inflammatory initiation and rapid tissue damage.(Oneda, B., Lods, N., Lottaz, D., Becker-Pauly, C., Stocker, W., Pippin, J., Huguenin, M., Ambort, D., Marti, H.P. andSterchi, E.E. 2008 Metalloprotease meprin β in rat kidney: glomerularlocalization and differential expression in glomerulonephritis. PloS ONE 3,e2278;Bylander, J., Li, Q., Ramesh, G., Zhang, B., Reeves, W.B. and Bond,J.S. 2008 Targeted disruption of the meprin metalloproteinase β gene protectsagainst renal ischemia-reperfusion injury in mice.Am.J.Physiol.Renal.Physiol. 294, F480–F490;Herzog, C., Seth, R., Shah, S.V.and Kaushal, G.P. 2007 Role of meprin A in renal tubular epithelial cellinjury. KidneyInt. 71, 1009–1018;Schrier, R.W., Wang, W., Poole, B. andMitra, A. 2004 Acute renal failure: definitions, diagnosis, pathogenesis, andtherapy. J.Clin.Invest. 114, 5–14)。

[0084] To restore the normal physiological function of tissues or organs, activated meprins must be neutralized; otherwise, the aforementioned harmful effects may occur. Jana Hedrich and colleagues have demonstrated that fetuin-A is an endogenous biological inhibitor of meprin α and β (Hedrich J, Lottaz D, Meyer K, Yiallouros I, Jahnen-Dechent W, Stöcker W, Becker-Pauly C. Fetuin-A and cystatin C are endogenous inhibitors of human meprin metalloproteases. Biochemistry. 2010 Oct 5;49(39):8599-607). The inhibition constant (Ki) of fetuin-A on meprin α is 4.2 x 10⁻⁶. -5 M, while the Ki value for meprin-β is 1.5 x 10 -6 M. In addition, computer simulations of protein-protein interactions have revealed the interaction mechanism between meprins and fetuin A (Dholey Y, Chaudhuri A, Sen Chakraborty S, An integrated in silicoapproach to understand protein-protein interactions: human meprin-β withfetuin-AJBiomol.Struct.Dyn. 2020 Apr;38(7):2080-2092).

[0085] Another hypothesis suggests a close relationship between TNF-α, activated and secreted by meprin, and fetuin A. The fetuin A gene contains a TNF-α binding site; therefore, the binding of TNF-α to the fetuin A gene reduces the expression level of fetuin A. (Manolakis AC, Christodoulidis G, Kapsoritakis AN, Georgoulias P, Tiaka EK, Oikonomou K, Valotassiou VJ, Potamianos SP, α2-Heremans-schmidglycoprotein (fetuin A) downregulation and its utility in inflammatory boweldisease. World J Gastroenterol. 2017 Jan 21;23(3):437-446).

[0086] This invention relates to a proven mechanism for controlling the expression of pro-inflammatory cytokines (such as TNF-α and other factors) through meprin α and β regulators, thereby controlling inflammation and related diseases. This invention demonstrates that fetoglobulin A is a natural biological inhibitor of meprin α and β, capable of preventing or suppressing inflammation. Fetoglobulin A is an immunomodulator (factor).

[0087] During infection and inflammation, meprin proteins are activated, which in turn promotes the production of TNF-α. Maintaining TNF-α levels within a reasonable range is crucial; otherwise, it can lead to harmful effects such as tissue damage and necrosis.

[0088] Meprin can regulate the expression of pro-inflammatory cytokines (tumor necrosis factor-α (TNF-α) and other factors). TNF-α, as one of the pro-inflammatory cytokines, plays a major role in inflammation. It is generally necessary to control the level of TNF-α within a reasonable range, otherwise it will exhibit detrimental effects such as tissue damage, adverse apoptosis, and / or necrosis. Therefore, in a preferred embodiment, the present invention may include controlling the expression of pro-inflammatory cytokines (TNF-α and other factors). This can be achieved by controlling the expression of meprin α and / or β regulators through fetoglobulin A. The present invention demonstrates that fetoglobulin A is a natural biological inhibitor of meprin α and β, and therefore can prevent or inhibit inflammation. Fetoglobulin A is thought to downregulate the production of TNF-α by directly regulating one or more meprin proteins. During infection and inflammation, meprin proteins may be activated, thereby promoting the production of TNF-α.

[0089] In a preferred embodiment, the pathological inflammation is associated with Parkinson's disease, cirrhosis, ankylosing spondylitis, antiphospholipid syndrome, autoimmune encephalitis, chronic relapsing multifocal osteomyelitis, gout, allergic purpura, juvenile dermatomyositis, juvenile idiopathic arthritis, juvenile systemic lupus erythematosus (SLE), juvenile scleroderma, juvenile vasculitis, Kawasaki disease, lupus (systemic lupus erythematosus), mixed connective tissue disease, myositis, post-streptococcal inflammatory syndrome, psoriatic arthritis, reactive arthritis, rheumatoid arthritis, scleroderma, Sjögren's syndrome, spondyloarthritis / spondyloarthropathy, systemic juvenile idiopathic arthritis, undifferentiated / mixed connective tissue disease, uveitis, vasculitis of various etiologies, inflammatory bowel disease, and / or one or more other related diseases.

[0090] Therefore, the present invention also relates to methods of using fetoglobulin A (or pharmaceutical compositions containing the substance) to treat or prevent patients suffering from Parkinson's disease, cirrhosis, ankylosing spondylitis, antiphospholipid antibody syndrome, autoimmune encephalitis, chronic relapsing multifocal osteomyelitis, gout, allergic purpura, juvenile dermatomyositis, juvenile idiopathic arthritis, juvenile systemic lupus erythematosus (SLE), juvenile scleroderma, juvenile vasculitis, Kawasaki disease, lupus (systemic lupus erythematosus), mixed connective tissue disease, myositis, post-streptococcal inflammatory syndrome, psoriatic arthritis, reactive arthritis, rheumatoid arthritis, scleroderma, Sjögren's syndrome, spondyloarthritis / spondyloarthropathy, systemic juvenile idiopathic arthritis, undifferentiated / mixed connective tissue disease, uveitis, vasculitis of various etiologies, inflammatory bowel disease, and / or other related diseases.

[0091] In a preferred embodiment, the pathological inflammation (preferably chronic pathological inflammation) is associated with at least one of the following diseases: (a) Chronic neurological disorders, particularly those caused by Parkinson's disease, multiple sclerosis, and neurocognitive impairments caused by prions, such as Creutzfeldt-Jakob disease, variant Creutzfeldt-Jakob disease, or other forms of cavernous encephalitis; (b) Rheumatoid diseases and / or inflammatory arthritis, particularly those selected from juvenile dermatomyositis, juvenile idiopathic arthritis, gout, scleroderma (e.g., juvenile scleroderma), vasculitis (e.g., juvenile vasculitis), rheumatoid arthritis, psoriatic arthritis (e.g., psoriatic arthritis), spondyloarthritis / spondyloarthropathy, adult-onset Still's disease, scleroderma, and juvenile idiopathic arthritis; (c) Chronic inflammatory diseases of the gastrointestinal tract, particularly Crohn's disease, ulcerative colitis, and inflammatory bowel disease (IBD); and / or (d) Autoimmune and / or autoinflammatory diseases, particularly those selected from ankylosing spondylitis, antiphospholipid syndrome, autoimmune encephalitis, chronic relapsing multifocal osteomyelitis, Henoch-Schoenlein purpura, juvenile lupus erythematosus, lupus (such as juvenile and / or systemic lupus erythematosus, e.g., systemic lupus erythematosus), mixed connective tissue diseases, and Sjögren's syndrome; and / or (e) Other inflammatory diseases, selected from Kawasaki disease, myositis, post-streptococcal inflammatory syndrome, reactive arthritis, systemic juvenile idiopathic arthritis, cirrhosis, undifferentiated / mixed connective tissue disease, and uveitis.

[0092] Therefore, the present invention also relates to the use of fetoglobulin A (or a pharmaceutical composition containing the substance) in methods for treating or preventing patients suffering from one or more of the aforementioned diseases.

[0093] The prevention or treatment of this invention is not limited to compensating for a deficiency of fetoprotein A. Similarly, patients with non-pathological or even elevated levels of fetoprotein A may also benefit from the administration of fetoprotein A.

[0094] In a preferred embodiment, a predetermined dose of fetoglobulin A is administered to the patient, the dose being independent of the patient's current level of fetoglobulin A in their plasma.

[0095] Therefore, it is not necessary to measure fetoglobulin A levels beforehand. Understandably, serum levels can also be measured in blood, serum, or other blood components.

[0096] The dose of fetoglobulin A administered may be substantially equal or different in each injection. In a preferred embodiment, fetoglobulin A is administered at least two, at least three, or at least five times in substantially equal doses.

[0097] It should be understood that the term "substantially equal" means that there is no significant deviation between them. Preferably, the term "substantially equal" can be understood as the deviation between them not exceeding 10%.

[0098] In a preferred embodiment, the patient has the following characteristics: (a) Serum fetoglobulin A levels are below 300 µg / mL, preferably below 290 µg / mL, more preferably below 250 µg / mL, and particularly preferably below 200 µg / mL; and / or (b) Serum TNF-α levels are above 42 pg / mL, preferably above 75 pg / mL, more preferably above 90 pg / mL, and even more preferably above 100 pg / mL, or above 110 pg / mL, or above 130 pg / mL, or above 150 pg / mL, or above 170 pg / mL.

[0099] Therefore, fetoprotein A can be used to treat patients diagnosed with fetoprotein A deficiency. Further, or alternatively, fetoprotein A can also be used to treat patients diagnosed with TNF-α excess.

[0100] Optionally, these patients may also be diagnosed with IFN-α overdose, and / or overdose of one or more other (pro-)inflammatory mediators or biomarkers.

[0101] Alternatively or further, the patient is characterized by: an increase of at least 1 wt% in TNF-α levels in the lung tissue relative to the average lung tissue level found in healthy individuals, preferably at least 5 wt%, more preferably at least 10 wt%, particularly preferably at least 20 wt%, 50 wt%, 75 wt%, or 2 times (by weight) or 3 times (by weight).

[0102] Alternatively or further, the patient is characterized by: INF-α blood levels above 42 pg / mL, preferably above 43 pg / mL, more preferably above 45 pg / mL, and even more preferably above 50 pg / mL, 60 pg / mL, 70 pg / mL, 80 pg / mL or 90 pg / mL.

[0103] The fetoglobulin A used herein may be part of a composition with one or more other pharmaceutically acceptable ingredients. Preferably, such compositions are also suitable for medical / therapeutic applications. For example, such compositions may contain one or more solvents, one or more other ingredients present in blood, one or more peptides, one or more pharmaceutically acceptable salts, and / or other pharmaceutically acceptable ingredients.

[0104] In a preferred embodiment, fetoglobulin A is part of a composition along with one or more other pharmaceutically acceptable ingredients. In one embodiment, the composition may include one or more additional ingredients, such as a liquid carrier (e.g., a buffer). Optionally, the composition may be a pharmaceutical composition. Furthermore, the present invention includes pharmaceutical compositions comprising a protein formulation containing fetoglobulin A as described above and at least one pharmaceutically acceptable carrier for the treatment or prevention of a patient suffering from fetoglobulin A deficiency.

[0105] In a preferred embodiment, fetoglobulin A constitutes part of a pharmaceutical composition comprising fetoglobulin A and at least one pharmaceutically acceptable carrier.

[0106] Accordingly, the present invention also relates to a pharmaceutical composition for a method of treating or preventing pathological inflammation in a patient, the pharmaceutical composition comprising fetoglobulin A and at least one pharmaceutically acceptable carrier.

[0107] In other words, the present invention also relates to a method for treating or preventing pathological inflammation in a patient, wherein a sufficient amount of a pharmaceutical composition comprising fetoglobulin A and at least one pharmaceutically acceptable carrier is administered to the patient.

[0108] It should be understood that the implementation methods and definitions described above for the use of fetoglobulin A, with necessary modifications, are also applicable to the use of the pharmaceutical composition.

[0109] In this document, the terms "pharmaceutical composition" and "pharmaceutical formulation" are used interchangeably. In the broadest sense, the terms "pharmaceuticalally acceptable carrier," "pharmaceuticalally acceptable excipient," and "carrier" and "excipient" are used interchangeably to refer to any substance that supports or at least does not impede the pharmaceutical acceptance of fetoglobulin A. Such pharmaceutical compositions may be ready-to-use and are preferably liquid formulations, particularly injectable formulations.

[0110] In a preferred embodiment, fetoglobulin A is part of an injectable pharmaceutical composition.

[0111] The pharmaceutical composition may also be a unit-dose formulation. Therefore, the present invention also relates to unit-dose formulations of the pharmaceutical compositions that can be used in the therapeutic or preventative settings of the present invention. Exemplarily, the present invention may relate to single-dose containers or multi-dose dosage forms.

[0112] For example, a pharmaceutically acceptable carrier may be selected from the following list: aqueous buffer, saline, water, dimethyl sulfoxide (DMSO), ethanol, vegetable oil, paraffin oil, or a combination of two or more of these. Furthermore, the pharmaceutically acceptable carrier may optionally contain one or more detergents, one or more foaming agents (e.g., sodium lauryl sulfate (SLS), sodium dodecyl sulfate (SDS)), one or more colorants (e.g., food coloring), one or more vitamins, one or more salts (e.g., sodium, potassium, calcium, zinc salts), one or more humectants (e.g., sorbitol, glycerin, mannitol, propylene glycol, polydextrose), one or more enzymes, one or more preservatives (e.g., benzoic acid, methylparaben), one or more antioxidants, one or more herbal and plant extracts, one or more stabilizers, one or more chelating agents (e.g., ethylenediaminetetraacetic acid (EDTA), and / or one or more uptake mediators (e.g., polyethyleneimine (PEI), cell-penetrating peptides, protein transduction domains (PTDs), antimicrobial peptides, etc.).

[0113] The present invention also relates to unit-dose formulations of pharmaceutical compositions that can be used in the therapeutic or preventative settings of the present invention. Exemplarily, the present invention may relate to single-dose containers or multi-dose dosage forms.

[0114] The compositions of this invention are also suitable for medical / therapeutic applications. This invention also relates to uses as a medicine.

[0115] Optionally, one or more additional anti-inflammatory compounds are administered to the patient. In a preferred embodiment, one or more corticosteroids are also administered to the patient. Such corticosteroids can be any corticosteroid with anti-inflammatory activity. In a preferred embodiment, cortisone is also administered to the patient. Optionally, one or more nonsteroidal anti-inflammatory drugs (NSAIDs) may also be administered to the patient.

[0116] The use of the term "also applied" throughout this invention does not necessarily mean that the compound is applied in the same composition as fetoglobulin A.

[0117] Additional anti-inflammatory compounds may be administered before, simultaneously with, or after the administration of fetoglobulin A. In a preferred embodiment, the additional anti-inflammatory compound is administered such that the additional anti-inflammatory compound reaches a therapeutically effective concentration at the same time as fetoglobulin A. In a preferred embodiment, the additional anti-inflammatory compound is administered no more than one week before, on the same day as, or no more than one week after the administration of fetoglobulin A. In a preferred embodiment, the additional anti-inflammatory compound is administered no more than one day before, on the same day as, or no more than one day after the administration of fetoglobulin A. In a preferred embodiment, the additional anti-inflammatory compound is administered no more than one hour before or no more than one hour after the administration of fetoglobulin A.

[0118] Other anti-inflammatory compounds can be administered via the same or different routes as fetoglobulin A. For example, it is also possible to administer one active ingredient systemically while another is administered topically (e.g., topical application).

[0119] In a preferred embodiment, fetoglobulin A is administered together with another anti-inflammatory compound, and both are combined in the same pharmaceutical composition.

[0120] Therefore, another aspect of the present invention relates to a pharmaceutical composition comprising: (A) Fetoprotein A; (B) One or more other anti-inflammatory compounds; and (C) One or more pharmaceutically acceptable carriers.

[0121] It should be understood that the implementation methods and definitions described above for the use of fetoglobulin A are also applicable to pharmaceutical compositions after necessary modifications.

[0122] It should also be understood that pharmaceutical compositions comprising (A) fetoglobulin A; (B) one or more additional anti-inflammatory compounds; and (C) one or more pharmaceutically acceptable carriers may be used in methods of treating or preventing pathological inflammation in patients.

[0123] For pharmaceutical compositions, the additional anti-inflammatory compounds differ from fetal protein A. In the context of this invention, additional anti-inflammatory compounds may be as defined above.

[0124] In another preferred embodiment, cortisone is not administered to the patient, and in particular, no corticosteroids are administered. In this case, in a preferred embodiment, fetoglobulin A may be the only active ingredient administered to the patient.

[0125] The following examples and accompanying drawings are intended to provide illustrative embodiments of the invention described and claimed herein. These examples are not intended to limit the scope of the subject matter of the invention. The following drawings, examples, and claims further illustrate the invention. Attached Figure Description

[0126] Figure 1 This figure illustrates the effect of fetoglobulin A on airway resistance in LPS-induced pulmonary dysfunction. In this figure, diamonds represent untreated control mice; squares represent mice treated with LPS (tracheal administration, solvent-based, 1 mg / kg); triangles represent mice treated with LPS (tracheal administration, 1 mg / kg) + prophylactic fetoglobulin A (intranasal administration, 1 mg / kg); and crosses represent mice treated with LPS (tracheal administration, 1 mg / kg) + therapeutic fetoglobulin A (intranasal administration, 1 mg / kg). The baseline percentage of airway resistance (%resistance) was set based on assessments using phosphate-buffered saline (PBS) aerosol, with a baseline value of 100%. In this figure, asterisks ( () indicates p<0.01 compared to the control group; double cross indicates p<0.01 compared to mice treated with LPS (administered intratracheally, solvent-based, dose 1 mg / kg).

[0127] Figure 2 The effect of fetoglobulin A on cytokine levels in LPS-induced lung dysfunction is shown. The cytokines include (A) tumor necrosis factor-α (TNF-α, pg / 100 µg total lung tissue lysate), (B) interleukin-6 (IL-6, pg / 15 µg total lung tissue lysate), (C) interleukin-17 (IL-17, U / 100 µg total lung tissue lysate), and (D) interleukin-13 (IL-13, pg / 5 µg total lung tissue lysate). Ctrl: Control group mice (untreated); LPS+Veh: Mice treated with LPS (tracheal administration, solvent-based, 1 mg / kg); LPS+Pro: Mice treated with LPS (tracheal administration, 1 mg / kg) + prophylactic fetoglobulin A (intranasal administration, 1 mg / kg); LPS+Ther: Mice treated with LPS (tracheal administration, 1 mg / kg) + therapeutic fetoglobulin A (intranasal administration, 1 mg / kg).

[0128] Figure 3The effects of fetoglobulin A on LPS-induced lung dysfunction at the tissue level are shown in (A) control mice (untreated), (B) mice treated with LPS (tracheal administration, solvent-based, 1 mg / kg), (C) mice treated with LPS (tracheal administration, 1 mg / kg) + prophylactic fetoglobulin A (intranasal administration, 1 mg / kg), and (D) mice treated with LPS (tracheal administration, 1 mg / kg) + therapeutic fetoglobulin A (intranasal administration, 1 mg / kg). In this figure, "A" represents alveoli and "V" represents blood vessels. The arrows in (B) indicate increased inflammation in the lung parenchyma, and the arrows in (D) indicate decreased inflammation in the lung parenchyma.

[0129] Figure 4 The effect of fetoglobulin A on hypoxic stress is illustrated. This figure shows the results of Western blot analysis of the hypoxia stress biomarkers (A) hypoxia-inducible factor α (HIF-α) and (C) nuclear factor E2-related factor 2 (Nrf2). Furthermore, the levels of (B) HIF-α and (D) Nrf2, determined by optical density ratio, are also shown. The subjects included untreated mice (control group), mice treated with CoCl2 (80 mg / kg via drinking water) (CoCl2 treatment group), and mice treated with CoCl2 (80 mg / kg via drinking water) + fetoglobulin A (1 mg / kg via intranasal administration) (CoCl2 + fetoglobulin A treatment group).

[0130] Figure 5 This study illustrates the effect of fetoglobulin A on cytokine levels under hypoxic stress. Cytokines included (A) tumor necrosis factor-α (TNF-α, pg / 100 µg total lung tissue lysate), (B) interleukin-17 (IL-17, pg / 100 µg total lung tissue lysate), (C) interleukin-6 (IL-6, U / 5 µg total lung tissue lysate), and (D) interleukin-13 (IL-13, pg / 5 µg total lung tissue lysate). Test subjects included untreated mice (control group), mice treated with CoCl2 (drinking water, 80 mg / kg) (CoCl2 treatment group), and mice treated with CoCl2 (drinking water, 80 mg / kg) + fetoglobulin A (intranasal administration, 1 mg / kg) (CoCl2 + fetoglobulin A treatment group).

[0131] Figure 6The effects of fetoglobulin A on tissue levels under hypoxic stress are shown in (A) untreated mice (control group), (B) mice treated with CoCl2 (80 mg / kg via drinking water) (CoCl2 treatment group), and (C) mice treated with CoCl2 (80 mg / kg via drinking water) + fetoglobulin A (1 mg / kg via intranasal administration) (CoCl2 + fetoglobulin A treatment group). In (B), arrow 1 indicates increased peribronchial space inflammation, and arrow 2 indicates alveolar collapse. In (C), the arrows indicate reduced inflammation after treatment with fetoglobulin A. Detailed Implementation

[0132] Example 1: The role of fetoglobulin A in a mouse model of lipopolysaccharide-induced (LPS-induced) acute lung injury.

[0133] Materials and Methods Experimental animals: Healthy male C57BL / 6 mice aged 6-7 weeks. It is reasonable to assume that their serum levels were within the normal range at the start of the experiment.

[0134] Reagents and kits: Mouse TNF-α DuoSet ELISA Kit (Supplier Code: DY410-05) Mouse IL-6 DuoSet ELISA Kit (Supplier Code: DY406-05) Mouse IL-17 DuoSet ELISA Kit (Supplier Code: DY421) Mouse IL-13 DuoSet ELISA Kit (Supplier Code: DY413) Experimental Grouping: Before the experiment, animals were housed in the animal facility for 7 days to acclimatize. All mice used in the experiment were randomly assigned to four groups: control group, LPS solvent group, LPS + prophylactic fetoglobulin A treatment group (administered 1 mg / kg fetoglobulin A once daily for two consecutive days before LPS stimulation), and LPS + therapeutic fetoglobulin A treatment group (administered 1 mg / kg fetoglobulin A on the first day after LPS stimulation). On day 4, all animals underwent pulmonary function (airway hyperresponsiveness / airway resistance) testing using a ventilator. A brief description of the research protocol is shown below.

[0135] Study groups (5 mice per group (n = 5)) Group 1: Control group (untreated mice) Group 2: LPS (administered intratracheally, dose 1 mg / kg) Group 3: LPS (administered via trachea, dose 1 mg / kg) + prophylactic fetoglobulin A (administered via nasal route, dose 1 mg / kg) Group 4: LPS (administered via trachea, dose 1 mg / kg) + Therapeutic fetoglobulin A (administered via nasal route, dose 1 mg / kg) Table 1. Research Protocol for LPS Study

[0136] Airway hyperresponsiveness (AHR) testing Airway hyperresponsiveness (AHR) in anesthetized animals was assessed using an invasive airway mechanics device with a ventilator (FlexiVent, SciReq, Canada). The device utilizes a mouse ventilator to measure respiratory mechanics, and the entire process is computer-controlled. In short, mice were anesthetized with xylazine and thiopental. These mice were then tracheotomized and intubated, with the tube subsequently connected to the FlexiVent's Y-tube. PBS / different concentrations of methacholine were then nebulized using an ultrasonic nebulizer. The device calculated various parameters, such as airway resistance, lung compliance, and lung elasticity, with and without methacholine stimulation. Methacholine, as a non-specific airway constrictor, is commonly used to assess lung function. Generally, diseased mice exhibit respiratory distress even at low concentrations of methacholine compared to healthy mice. Airway resistance was measured by progressively increasing the concentration of methacholine (Mch). Results were expressed as a baseline of 100% for PBS aerosol dosage, with the dosage of methacholine increased accordingly. Therefore, mice with impaired lung function exhibited high airway resistance even at lower concentrations of methacholine.

[0137] Lung injury and inflammation assessment To assess LPS-induced lung injury, animals were euthanized by cervical dislocation. After euthanasia, lung tissue was collected and divided into two parts: one for histological examination and the other for assessment of inflammatory cytokines. In this study, various pro-inflammatory cytokines were assessed according to the user manual of the specific ELISA kit (as shown in Table 3 below). For histopathological evaluation, periodic acid-Schiff (PAS) staining and hematoxylin and eosin (H&E) staining were used.

[0138] Consistent with what is known in the art, serum levels of fetoglobulin A are considered to be reduced below non-pathological serum levels due to the administration of LPS; while serum levels of tumor necrosis factor α (TNF-α) are considered to be above average serum levels due to the presence of inflammation.

[0139] in conclusion like Figure 1 As shown, both prophylactic and therapeutic doses of fetoglobulin A significantly reduced LPS-induced lung dysfunction compared to animals treated with LPS solvent. Figure 2 As can be seen, all the tested pro-inflammatory cytokines (TNF-α, IL-6, IL-13, and IL-17) were also significantly reduced. Histopathological examination clearly showed that the lungs of LPS-treated animals exhibited parenchymal inflammation dominated by neutrophil infiltration; while in both fetoglobulin A treatment groups, parenchymal inflammation was significantly reduced (see...). Figure 3 ).

[0140] Experimental results demonstrate that fetoglobulin A plays a positive role in LPS-induced lung injury: it repairs lung damage by preventing immune cell infiltration, restores lung function by reducing airway resistance, and attenuates the release of pro-inflammatory cytokines. Therefore, this confirms that fetoglobulin A can be used to treat inflammatory diseases.

[0141] Example 2: The role of fetoglobulin A in a hypoxic mouse model Materials and Methods Experimental animals: 6-7 week old male C57BL / 6 mice.

[0142] Reagents and kits: Mouse TNF-α DuoSet ELISA Kit (Supplier Code: DY410-05) Mouse IL-6 DuoSet ELISA Kit (Supplier Code: DY406-05) Mouse IL-17 DuoSet ELISA Kit (Supplier Code: DY421) Mouse IL-13 DuoSet ELISA Kit (Supplier Code: DY413) HIF1a antibody (28b) (Supplier code: sc-13515) Recombinant anti-HIF-1α antibody (supplier code: ab179483) Anti-Nrf2 antibody (supplier code: ab31163) Experimental Grouping: Before the experiment, animals were housed in the animal facility for 7 days to acclimatize. All animals used in the experiment were randomly assigned to three groups: a control group of untreated mice, a cobalt chloride (CoCl2) solvent group (ingesting CoCl2 via drinking water throughout the study), and a CoCl2 + therapeutic fetoglobulin A treatment group (administered fetoglobulin A at a dose of 1 mg / kg on days 8, 10, and 12 after CoCl2 stimulation). On day 14, all animals underwent pulmonary function (airway hyperresponsiveness / airway resistance) testing using a ventilator and were euthanized. A brief description of the study protocol is shown below.

[0143] Research Group Group 1: Control group (untreated mice, n = 2) Group 2: CoCl2 group (obtained via drinking water, dose 80 mg / kg, n = 3) Group 3: CoCl2 (taken via drinking water, dose 80 mg / kg) + fetoglobulin A (administered intranasally, dose 1 mg / kg) group (n = 3) Table 2. Research scheme for CoCl2 study

[0144] Airway hyperresponsiveness (AHR) testing and assessment of lung injury and inflammation were performed as described in Example 1 above. Western blot analysis was performed using conventional methods recognized in the art. (See the list of reagents and kits in Example 2 above).

[0145] Consistent with what is known in the art, serum levels of fetoglobulin A are considered to be reduced below non-pathological serum levels due to the administration of LPS; while serum levels of tumor necrosis factor α (TNF-α) are considered to be above average serum levels due to the presence of inflammation.

[0146] result Western blot analysis of hypoxia stress-related proteins HIF-α and Nrf2 showed that these two proteins were significantly upregulated in the CoCl2 group, confirming the presence of hypoxic stress. Treatment with fetoglobulin A significantly reduced the levels of these proteins. Figure 4 As shown. Figure 5 As shown, after treatment with fetoprotein A, all the pro-inflammatory cytokines (TNF-α, IL-6, IL-13 and IL-17) detected were also significantly reduced.

[0147] Histopathological examination clearly showed peribronchial inflammation and alveolar collapse in the lungs of animals treated with CoCl2; however, these pathological conditions improved after treatment with fetoglobulin A (see...). Figure 6 ).

[0148] The results indicate that fetoglobulin A plays a positive role in hypoxia-induced lung injury by repairing it by preventing immune cell infiltration and alveolar collapse. Furthermore, it was observed to attenuate pro-inflammatory cytokines, similar to the effects seen in the LPS model. Therefore, this model also confirms that fetoglobulin A can be used to treat and / or prevent inflammation.

Claims

1. Fetoglobulin A for use in treating or preventing pathological inflammation in a patient, said patient having the following characteristics: (a) Serum levels of fetoglobulin A were lower than non-pathological serum levels; and (b) Serum levels of tumor necrosis factor-α (TNF-α) were higher than the average serum levels in healthy individuals.

2. The fetoglobulin A of the method for treating or preventing pathological inflammation in a patient according to claim 1, characterized in that, The fetoglobulin A is administered via the respiratory tract, preferably via intranasal administration; or by injection, preferably via intravenous (iv), intraperitoneal (ip), intradermal (id), arterial (ia), intramuscular (im), and / or subcutaneous (sc); or by local administration; or by oral administration.

3. The fetoglobulin A of the method for treating or preventing pathological inflammation in a patient according to claim 1 or 2, characterized in that, The pathological inflammation includes inflammation of the lung tissue, particularly that is associated with respiratory insufficiency.

4. The fetoglobulin A of the method for treating or preventing pathological inflammation in a patient according to any one of claims 1 to 3, characterized in that, The pathological inflammation is associated with hypoxia.

5. The fetoglobulin A of the method for treating or preventing pathological inflammation in a patient according to any one of claims 1 to 4, characterized in that, The inflammation is induced by lipopolysaccharide (LPS) and / or associated with pneumonia.

6. The fetoglobulin A of the method for treating or preventing pathological inflammation in a patient according to any one of claims 1 to 5, characterized in that, The pathological inflammation is chronic pathological inflammation; preferably, the chronic pathological inflammation lasts for at least one month, at least six months, or at least one year; preferably, the patient is repeatedly administered fetoglobulin A for at least one month, at least two months, or at least three months.

7. Fetoglobulin A in the method for treating or preventing pathological inflammation in a patient according to any one of claims 1 to 6, characterized in that, Fetoprotein A is administered to patients repeatedly via injection, with each injection ranging from 1 to 1000 µg / kg body weight.

8. The fetoglobulin A of the method for treating or preventing pathological inflammation in a patient according to any one of claims 1 to 7, characterized in that, The pathological inflammation mentioned is acute pathological inflammation.

9. The fetoglobulin A of the method for treating or preventing pathological inflammation in a patient according to any one of claims 1 to 8, characterized in that, The patient is unresponsive to cyclooxygenase (COX) inhibitors, particularly to nonsteroidal anti-inflammatory drugs (NSAIDs); or the patient has contraindications to COX inhibitors; particularly the patient is unresponsive to anti-inflammatory drugs other than corticosteroids.

10. Fetoglobulin A of the method for treating or preventing pathological inflammation in a patient according to any one of claims 1 to 9, characterized in that, The pathological inflammation is associated with elevated levels of membrane-penetrating peptidase α (meprinα) and / or membrane-penetrating peptidase β (meprinβ) at the site of inflammation and / or in the patient's systemic plasma.

11. The fetoglobulin A of the method for treating or preventing pathological inflammation in a patient according to any one of claims 1 to 10, characterized in that, The pathological inflammation, preferably chronic pathological inflammation, is associated with at least one of the following diseases: (a) Chronic neurological disorders, particularly selected from Parkinson's disease, multiple sclerosis, and neurocognitive impairments caused by prions, such as Creutzfeldt-Jakob disease, variant Creutzfeldt-Jakob disease, or other forms of cavernous encephalitis; (b) Rheumatoid diseases and / or inflammatory arthritis, particularly selected from juvenile dermatomyositis, gout, scleroderma such as juvenile scleroderma, vasculitis such as juvenile vasculitis, rheumatoid arthritis, psoriatic arthritis such as psoriatic arthritis, spondyloarthritis / spondyloarthropathy, adult Still's disease, scleroderma, and juvenile idiopathic arthritis. (c) Chronic inflammatory diseases of the gastrointestinal tract, particularly Crohn's disease, ulcerative colitis, and inflammatory bowel disease; and / or (d) Autoimmune and / or autoinflammatory diseases, particularly selected from ankylosing spondylitis, antiphospholipid syndrome, autoimmune encephalitis, chronic relapsing multifocal osteomyelitis, allergic purpura, juvenile lupus, lupus such as juvenile and / or systemic lupus, such as lupus erythematosus, mixed connective tissue disease, and Sjögren's syndrome; and / or (e) Other inflammatory diseases, selected from Kawasaki disease, myositis, post-streptococcal inflammatory syndrome, reactive arthritis, systemic juvenile idiopathic arthritis, cirrhosis, undifferentiated / mixed connective tissue disease, and uveitis.

12. The fetoglobulin A of the method for treating or preventing pathological inflammation in a patient according to any one of claims 1 to 11, characterized in that, The patient is given a predetermined dose of fetoglobulin A, which is independent of the current plasma fetoglobulin A level; in particular, fetoglobulin A is administered at least twice, at least three times, or at least five times at substantially equal doses.

13. The fetoglobulin A of the method for treating or preventing pathological inflammation in a patient according to any one of claims 1 to 12, characterized in that, The patient has the following characteristics: (a) Serum fetoglobulin A levels are below 300 µg / mL, preferably below 290 µg / mL, more preferably below 250 µg / mL, and particularly below 200 µg / mL; and / or (b) Serum TNF-α levels above 42 pg / mL, preferably above 75 pg / mL, more preferably above 90 pg / mL, and even more preferably above 100 pg / mL, or above 110 pg / mL, or above 130 pg / mL, or above 150 pg / mL, or above 170 pg / mL.

14. The fetoglobulin A of the method for treating or preventing pathological inflammation in a patient according to any one of claims 1 to 13, characterized in that, One or more corticosteroids, particularly cortisone, were also administered to the patient.

15. The fetoglobulin A of the method for treating or preventing pathological inflammation in a patient according to any one of claims 1 to 14, characterized in that, The fetoglobulin A constitutes part of a pharmaceutical composition comprising fetoglobulin A and at least one pharmaceutically acceptable carrier; in particular, the fetoglobulin A constitutes part of an injectable pharmaceutical composition.

Images