WO2024232591A1 - Pharmaceutical composition for treating systemic lupus erythematosus comprising pibf1 as active ingredient - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating systemic lupus erythematosus, comprising PIBF1 as an active ingredient, and the therapeutic role of PIBF1 in a lupus mouse model was confirmed. Particularly, it was confirmed that PIBF1 exhibited excellent effects of alleviating and treating lupus disease progression by significantly reducing both anti-dsDNA autoantibodies in serum and a urine albumin/creatinine ratio (uACR), and also had an excellent effect of preventing lupus by reducing B220+ DNT cells, which are known to be increased in a mouse model susceptible to lupus, and thus the PIBF1 is expected to be effectively used as a composition for preventing or treating systemic lupus erythematosus and lupus nephritis.

Description

Pharmaceutical composition for treating systemic lupus erythematosus containing PIBF1 as an active ingredient

The present invention relates to a pharmaceutical composition for preventing or treating systemic lupus erythematosus, comprising PIBF1 as an active ingredient.

This invention claims the benefit of priority from Republic of Korea Patent Application No. 10-2023-0060305, filed May 10, 2023, the entire contents of which are incorporated herein by reference.

Immunity is one of the body's self-protection systems against all foreign macromolecular substances (antigens) that invade or are injected into living tissue. The main component of the immune system is lymphocytes, which are white blood cells that are produced in the bone marrow and circulate in the blood to lymphatic tissues or organs, mainly lymph nodes, spleen, and tonsils. Lymphocytes are cells involved in immune responses, and when stimulated by an appropriate antigen, B cells rapidly proliferate and form clones that produce special antibodies (immunoglobulins) that neutralize the antigen, and the antibodies produced by B cells circulate in body fluids to perform humoral immunity. In addition, T cells are produced in the thymus and move to lymphatic tissue, and are responsible for cell-mediated immunity that directly attacks antigens.

Meanwhile, one of the most important characteristics of all normal organisms is that they do not react harmfully to antigenic substances that constitute the self, while they have the ability to recognize, react, and eliminate non-self antigens. This lack of response of the body to self-antigens is called immunologic unresponsiveness or tolerance. If there is a problem in inducing or maintaining this self-tolerance, an immune response to self-antigens occurs, and this causes an attack on the body's own tissues, resulting in the occurrence of autoimmune diseases.

Systemic lupus erythematosus is an autoimmune disease caused by abnormal effects of various factors such as genetic, environmental, and hormonal factors on the immune system, and its main characteristic is the pathogenesis caused by excessive production of pathogenic autoantibodies. Immunological disorders have various characteristics such as damage to end organs throughout the body, defects in the removal of apoptotic cells, and the production of pathogenic autoantibodies by plasma cells. Among the mechanisms related to immune regulation disorders, serum autoantibodies are considered to play an important role in the progression of the disease. Autoantibodies are deposited in the form of apoptotic cell debris and immune complexes, causing inflammation in target organs including the kidneys.

According to the above mechanism, patients with lupus disease show various immune disorders including skin rash and renal abnormalities, and lupus nephritis, one of the most representative and fatal complications, is observed. The pathophysiology of lupus nephritis includes abnormal immune regulation and renal inflammation that are significantly worsened by autoantibody-related disorders.

Meanwhile, Progesterone-Induced Blocking Factor 1 (PIBF1) is a protein that is induced when exposed to progesterone. PIBF1 is well known to play an important role in maintaining the balance of the immune system during pregnancy, and has the function of regulating the immune action of progesterone. The weight of the full-length form of PIBF1 is 90 kDa and is reported to be involved in cell cycle regulation.

However, the specific therapeutic effect of PIBF1 in preventing or treating systemic lupus erythematosus or lupus nephritis has not yet been reported.

One object of the present invention is to provide a pharmaceutical composition for preventing or treating systemic lupus erythematosus or lupus nephritis, comprising PIBF1 (Progesterone-Induced Blocking Factor 1) as an active ingredient.

Another object of the present invention is to provide a food composition for preventing or improving systemic lupus erythematosus or lupus nephritis, containing PIBF1 as an active ingredient.

Another object of the present invention is to provide a kit for preventing or treating systemic lupus erythematosus or lupus nephritis, comprising a composition comprising PIBF1 as an active ingredient and an instruction manual.

Another object of the present invention is to provide a method for characterizing responders to a therapeutic agent for treating systemic lupus erythematosus or lupus nephritis, comprising the following steps:

(S1) a step of measuring the level of CXCL10 (C-X-C motif chemokine ligand 10) in a blood sample isolated from a subject; and

(S2) If the level of CXCL10 measured in the above step (S1) is increased compared to the control group, a step of determining the responder to a treatment for systemic lupus erythematosus or lupus nephritis;

A method wherein the above treatment comprises PIBF1 as an active ingredient.

Another object of the present invention is to provide a composition for assessing a patient with systemic lupus erythematosus or lupus nephritis in need of administration of the composition, comprising as an active ingredient an agent for measuring the level of CXCL10 in blood isolated from a subject.

However, the technical problems to be achieved by the present invention are not limited to the problems mentioned above, and other problems not mentioned can be clearly understood by a person having ordinary skill in the technical field to which the present invention belongs from the description below.

The present invention provides a pharmaceutical composition for preventing or treating systemic lupus erythematosus or lupus nephritis, comprising PIBF1 (Progesterone-Induced Blocking Factor 1) as an active ingredient.

In one embodiment of the present invention, the PIBF1 may be encoded by a nucleic acid sequence represented by SEQ ID NO: 1, but is not limited thereto.

In one embodiment of the present invention, the composition may be administered by any one method selected from the group consisting of intraperitoneal administration, intravenous administration, and oral administration, but is not limited thereto.

In one embodiment of the present invention, the composition may be administered twice a week at 20 to 30 μg, but is not limited thereto.

In one embodiment of the present invention, the composition may be characterized by, but is not limited to, one or more of the following:

Decreased anti-dsDNA autoantibodies in serum;

Decreased urine albumin creatinine ratio (uACR); and

Increase in marginal zone B cells (MZ B cells) and regulatory B cells.

The present invention provides a food composition for preventing or improving systemic lupus erythematosus or lupus nephritis, comprising PIBF1 as an active ingredient.

In one embodiment of the present invention, the food may be a health functional food, but is not limited thereto.

The present invention provides a kit for preventing or treating systemic lupus erythematosus or lupus nephritis, comprising a composition comprising PIBF1 as an active ingredient and an instruction manual.

The present invention provides a method for characterizing a responder to a therapeutic agent for treating systemic lupus erythematosus or lupus nephritis, comprising the following steps:

(S1) a step of measuring the level of CXCL10 in a blood sample isolated from a subject; and

(S2) If the level of CXCL10 measured in the above step (S1) is increased compared to the control group, a step of determining the responder to a treatment for systemic lupus erythematosus or lupus nephritis;

A method wherein the above treatment comprises PIBF1 as an active ingredient.

The present invention provides a composition for assessing a patient with systemic lupus erythematosus or lupus nephritis in need of administration of the composition, comprising as an active ingredient an agent for measuring the level of CXCL10 in blood isolated from a subject.

In addition, the present invention provides a use of PIBF1 (Progesterone-Induced Blocking Factor 1) or a composition containing it as an active ingredient for preventing, improving, or treating systemic lupus erythematosus or lupus nephritis.

In addition, the present invention provides a use for manufacturing a preparation for preventing, improving or treating systemic lupus erythematosus or lupus nephritis using PIBF1 (Progesterone-Induced Blocking Factor 1) or a composition containing it as an active ingredient.

In addition, the present invention provides a method for preventing or treating systemic lupus erythematosus or lupus nephritis, comprising a step of administering PIBF1 (Progesterone-Induced Blocking Factor 1) or a composition containing it as an active ingredient to a subject in need thereof.

In addition, the present invention provides a use for characterizing responders to a therapeutic agent for treating systemic lupus erythematosus or lupus nephritis, comprising PIBF1 (Progesterone-Induced Blocking Factor 1) or a composition containing the same as an active ingredient.

In addition, the present invention provides a preparation for measuring the level of CXCL10 in blood isolated from a subject or a composition containing the preparation as an active ingredient for use in the diagnosis of a patient with systemic lupus erythematosus or lupus nephritis.

In addition, the present invention provides a method for assessing a patient with systemic lupus erythematosus or lupus nephritis, comprising a step of measuring the level of CXCL10 in blood isolated from a subject using a preparation for measuring the level of CXCL10 in blood isolated from a subject or a composition comprising the preparation as an active ingredient.

A pharmaceutical composition containing PIBF1 as an active ingredient for preventing or treating systemic lupus erythematosus confirmed the therapeutic role of PIBF1 in a lupus nephritis-like mouse model. Specifically, PIBF1 showed excellent lupus disease progression alleviation and treatment effects by significantly reducing both serum anti-dsDNA autoantibodies and urine albumin creatinine ratio (uACR), and also showed excellent lupus prevention effects by reducing B220+ DNT cells known to increase in a lupus-prone mouse model. Therefore, it is expected to be usefully utilized as a composition for preventing or treating systemic lupus erythematosus and lupus nephritis.

Figure 1 is a schematic diagram showing the experimental design of the lupus mouse model of the present invention.

Figure 2 is a graph showing the decrease in hormone levels in a group of mice that underwent ovariectomy.

Figure 3 is a graph showing the effect of increasing the concentration of lupus-related autoantibodies according to PIBF1 treatment.

Figure 4 is a graph showing the effect of reducing the urine albumin/creatinine ratio according to PIBF1 treatment.

Figure 5a is a photograph showing the results of staining the kidney of a mouse with H&E, MT, and PAS after PIBF1 treatment.

Figures 5b and 5c are graphs showing the effect of PIBF1 treatment on reducing renal disease activity and chronicity score.

Figures 6a to 6f are graphs showing the changes in the proportion of CD4-CD8- double negative T cells (DNT cells), B220+ DNT cells, follicular helper T cells (Tfh cells), regulatory B cells (B reg cells), MZ B cells, and CD22- B cells, respectively, according to PIBF1 treatment.

Figure 7 is a graph showing the inhibitory effect of reducing pro-inflammatory cytokines according to PIBF1 treatment.

Figure 8 is a graph showing the CXCL10 inhibitory effect according to PIBF1 treatment and the resulting treatment effect on systemic lupus erythematosus and lupus nephritis.

The present invention provides a pharmaceutical composition for preventing or treating systemic lupus erythematosus or lupus nephritis, comprising PIBF1 (Progesterone-Induced Blocking Factor 1) as an active ingredient.

Hormone binding induces a conformational change in the steroid receptor, allowing DNA binding and gene induction, leading to protein synthesis. Progesterone-induced blocking factor (PIBF) is one of the progesterone-regulated genes, and the resulting protein is responsible for the immunomodulatory effects of progesterone.

The PIBF1 gene encodes a 90-kDa PIBF1 protein, which is the source of several smaller isoforms and is a transcribed mRNA containing 18 exons. The full-length PIBF and smaller isoforms have distinct functions: the 90-kDa form is associated with the nucleus and may be a component of pericentromeric satellites, whereas the smaller form is localized to the cytoplasm. The former plays a role in cell cycle regulation, whereas the smaller isoform is secreted and can bind to glycosylphosphatidylinositol (GPI)-anchored PIBF receptors.

In the present invention, PIBF1 may be a recombinant protein in which FC is bound to PIBF for drug optimization such as half-life extension and stabilization, and may be recombined with not only FC but also albumin, albumin binding protein, IgG, PEGylation, etc., but is not limited thereto.

Additionally, in the present invention, the PIBF1 protein may be described as PIBF1, and both words may be used interchangeably.

Additionally, the PIBF1 protein may have a molecular weight of 25 to 45 kDa, preferably a molecular weight of 30 to 40 kDa, and more preferably a molecular weight of 35 kDa.

In the present invention, PIBF1 is a recombinant protein and may be a full 35 kDa secretory form. “TTGGCCGCGTCGGCCGCTAGC” in sequence number 1 of the present invention and “Leu Ala Ala Ser Ala Ala Ser” in sequence number 2 may mean a linker between the full 35 kDa PIBF and the Fc tag. The PIBF1 recombinant protein of the present invention may have improved stability due to attachment of an Fc tag, thereby further increasing the efficacy in preventing or treating systemic lupus erythematosus or lupus nephritis, but is not limited thereto.

In one embodiment of the present invention, the PIBF1 may be encoded by a nucleic acid sequence represented by SEQ ID NO: 1, but is not limited thereto.

Additionally, the PIBF1 protein may be encoded by a nucleic acid sequence represented by SEQ ID NO: 1, may include an amino acid sequence represented by SEQ ID NO: 2, or may be represented by SEQ ID NO: 2, but is not limited thereto.

Additionally, the terms “percent identity,” “sequence identity,” “percent similarity,” “sequence similarity,” “percentage sequence identity,” and the like, as used herein with respect to amino acid sequences and/or nucleic acid sequences in the present invention, may refer to, but are not limited to, a measure determined by comparing the degree of similarity of two sequences based on alignment of the sequences that maximizes the similarity between aligned amino acid residues or nucleotides and is a function of the number of identical or similar residues or nucleotides, the total number of residues or nucleotides, and the presence and length of gaps in the sequence alignment.

Portions of a polynucleotide or polypeptide sequence may include additions or deletions (i.e., gaps) compared to a reference sequence (which does not include additions or deletions) for optimal alignment of the two sequences. The percentage is calculated by determining the number of positions at which the same nucleic acid base or amino acid residue appears in both sequences to yield the number of matching positions, dividing the number of matching positions by the total number of positions in the comparison window, and multiplying the result by 100 to yield the percent sequence identity.

The term “identical” or percent “identity” in relation to two or more nucleic acid or polypeptide sequences refers to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues or nucleotides that are the same (i.e., about 60% identity, preferably 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher identity, when compared and aligned for maximum correspondence over a comparison window or represented region) as measured using the BLAST or BLAST 2.0 sequence comparison algorithms using the default parameters described below, or by manual alignment and visual inspection (see, e.g., the NCBI website at http:/www.ncbi.nlm.nih.gov/BLAST/, etc.). These sequences are then said to be “substantially identical.”

This definition also refers to, or can be applied to, complementation of a test sequence. The definition also includes sequences having deletions and/or additions as well as substitutions. As described below, preferred algorithms can account for gaps, etc. Preferably, the identity exists over a region that is at least about 25 amino acids or nucleotides in length, or more preferably over a region that is 50 to 100 amino acids or nucleotides in length.

An amino acid or nucleotide base “position” is indicated by a number that sequentially identifies each amino acid (or nucleotide base) in the reference sequence based on its position relative to the N-terminus (or 5’-end). Because of deletions, insertions, truncations, fusions, etc. that must be considered when determining optimal alignment, the number of amino acid residues in a test sequence, as determined simply by counting from the N-terminus, will not necessarily be the same as the number of corresponding positions in the reference sequence. For example, if a variant has a deletion relative to the aligned reference sequence, there will be no amino acid in the variant corresponding to the position in the reference sequence at the deletion site. If there is an insertion in the aligned reference sequence, the insertion will not correspond to an amino acid position numbered in the reference sequence. In the case of a truncation or fusion, there may be a stretch of amino acids in either the reference or aligned sequence that does not correspond to any amino acid in the corresponding sequence.

The terms “numbered with respect to” or “corresponding to” when used in reference to the numbering of a given amino acid or polynucleotide sequence refers to the numbering of residues in a reference sequence specified when the given amino acid or polynucleotide sequence is compared to the reference sequence.

In one embodiment of the present invention, the composition may be administered by any one method selected from the group consisting of intraperitoneal administration, intravenous administration, and oral administration, but is not limited thereto.

In one embodiment of the present invention, the composition may be administered twice a week at 20 to 30 μg, but is not limited thereto.

In one embodiment of the present invention, the composition may be characterized by, but is not limited to, one or more of the following:

Decreased anti-dsDNA autoantibodies in serum;

Decreased urine albumin creatinine ratio (uACR); and

Increase in marginal zone B cells (MZ B cells) and regulatory B cells.

In the present invention, systemic lupus erythematosus can be expressed identically to lupus.

The composition of the present invention has been confirmed with specific data to have an effect of not only treating lupus, but also alleviating and improving the symptoms of lupus nephritis, which is the most representative complication of lupus. Therefore, the composition of the present invention can prevent or have an effect not only on lupus nephritis, but also on complications caused by lupus nephritis. In addition, the “treatment” may mean alleviating or improving the progression of lupus or lupus nephritis.

The “pharmaceutical composition” according to the present invention may further include suitable carriers, excipients and diluents commonly used in the manufacture of pharmaceutical compositions. The excipients may be, for example, at least one selected from the group consisting of diluents, binders, disintegrants, lubricants, adsorbents, moisturizers, film-coating materials, and controlled-release additives.

The pharmaceutical composition according to the present invention may be formulated and used in the form of external preparations such as powders, granules, sustained-release granules, enteric-coated granules, liquids, eye drops, ellipses, emulsions, suspensions, alcohols, troches, aromatic waters, limonades, tablets, sustained-release tablets, enteric-coated tablets, sublingual tablets, hard capsules, soft capsules, sustained-release capsules, enteric capsules, pills, tinctures, soft extracts, dry extracts, fluid extracts, injections, capsules, irrigants, ointments, pastes, sprays, inhalants, patches, sterile injection solutions, or aerosols, and the external preparations may have formulations such as creams, gels, patches, sprays, ointments, ointments, lotions, liniments, pastes, or cataplasmas.

Carriers, excipients and diluents that may be included in the pharmaceutical composition according to the present invention include lactose, dextrose, sucrose, oligosaccharides, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

When formulating, it is usually prepared using diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrants, and surfactants.

The additives of the tablets, powders, granules, capsules, pills and troches according to the present invention include excipients such as corn starch, potato starch, wheat starch, lactose, sucrose, glucose, fructose, D-mannitol, precipitated calcium carbonate, synthetic aluminum silicate, calcium monohydrogen phosphate, calcium sulfate, sodium chloride, sodium bicarbonate, purified lanolin, microcrystalline cellulose, dextrin, sodium alginate, methylcellulose, sodium carboxymethyl cellulose, kaolin, urea, colloidal silica gel, hydroxypropyl starch, hydroxypropyl methyl cellulose (HPMC) 1928, HPMC 2208, HPMC 2906, HPMC 2910, propylene glycol, casein, calcium lactate and Primogel; Gelatin, gum arabic, ethanol, agar powder, cellulose acetate phthalate, carboxymethylcellulose, calcium carboxymethylcellulose, glucose, purified water, sodium caseinate, glycerin, stearic acid, sodium carboxymethylcellulose, sodium methylcellulose, methylcellulose, microcrystalline cellulose, dextrin, hydroxycellulose, hydroxypropyl starch, hydroxymethylcellulose, refined shellac, starch starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, polyvinyl pyrrolidone, and binders such as hydroxypropyl methylcellulose, corn starch, agar powder, methylcellulose, bentonite, hydroxypropyl starch, sodium carboxymethylcellulose, sodium alginate, Disintegrants such as carboxymethylcellulose calcium, calcium citrate, sodium lauryl sulfate, anhydrous silicic acid, 1-hydroxypropyl cellulose, dextran, ion exchange resin, polyvinyl acetate, formaldehyde-treated casein and gelatin, alginic acid, amylose, guar gum, baking soda, polyvinyl pyrrolidone, calcium phosphate, gelled starch, gum arabic, amylopectin, pectin, sodium polyphosphate, ethylcellulose, sucrose, magnesium aluminum silicate, di-sorbitol solution, and light anhydrous silicic acid; Lubricants that can be used include calcium stearate, magnesium stearate, stearic acid, hydrogenated vegetable oil, talc, lycopodium dentata, kaolin, petrolatum, sodium stearate, cocoa butter, sodium salicylate, magnesium salicylate, polyethylene glycol 4000, PEG 6000, liquid paraffin, hydrogenated soybean oil (Lubri wax), aluminum stearate, zinc stearate, sodium lauryl sulfate, magnesium oxide, macrogol, synthetic aluminum silicate, anhydrous silicic acid, higher fatty acids, higher alcohols, silicone oil, paraffin oil, polyethylene glycol fatty acid ether, starch, sodium chloride, sodium acetate, sodium oleate, dl-leucine, and light anhydrous silicic acid.

Additives that can be used in the liquid formulation according to the present invention include water, diluted hydrochloric acid, diluted sulfuric acid, sodium citrate, monostearate sucrose, polyoxyethylene sorbitol fatty acid esters (twin esters), polyoxyethylene monoalkyl ethers, lanolin ethers, lanolin esters, acetic acid, hydrochloric acid, ammonia water, ammonium carbonate, potassium hydroxide, sodium hydroxide, prolamine, polyvinylpyrrolidone, ethylcellulose, sodium carboxymethylcellulose, etc.

The syrup according to the present invention may use a solution of white sugar, other sugars or sweeteners, and may also use a flavoring agent, a coloring agent, a preservative, a stabilizer, a suspending agent, an emulsifier, a viscosity increasing agent, etc., as needed.

Purified water may be used in the emulsion according to the present invention, and an emulsifier, preservative, stabilizer, fragrance, etc. may be used as needed.

The suspension according to the present invention may use suspending agents such as acacia, tragacanth, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, sodium alginate, hydroxypropylmethylcellulose, HPMC 1828, HPMC 2906, and HPMC 2910, and may also use surfactants, preservatives, stabilizers, colorants, and fragrances as needed.

The injection according to the present invention includes: solvents such as distilled water for injection, 0.9% sodium chloride injection, Ringer's injection, dextrose injection, dextrose + sodium chloride injection, PEG, lactated Ringer's injection, ethanol, propylene glycol, nonvolatile oils such as sesame oil, cottonseed oil, peanut oil, soybean oil, corn oil, ethyl oleate, isopropyl myristate, and benzene benzoate; solubilizers such as sodium benzoate, sodium salicylate, sodium acetate, urea, urethane, monoethylacetamide, butazolidine, propylene glycol, Tween, nitrile acid amide, hexamine, and dimethylacetamide; buffers such as weak acids and their salts (acetic acid and sodium acetate), weak bases and their salts (ammonia and ammonium acetate), organic compounds, proteins, albumin, peptone, and gums; Isotonic agents such as sodium chloride; stabilizers such as sodium bisulfite (NaHSO ₃ ), carbon dioxide gas, sodium metabisulfite (Na ₂ S ₂ O ₅ ), sodium sulfite (Na ₂ SO ₃ ), nitrogen gas (N ₂ ), and ethylenediaminetetraacetic acid; sulfating agents such as sodium bisulfide 0.1%, sodium formaldehyde sulfoxylate, thiourea, disodium ethylenediaminetetraacetic acid disodium, and acetone sodium bisulfite; analgesics such as benzyl alcohol, chlorobutanol, procaine hydrochloride, glucose, and calcium gluconate; and suspending agents such as sodium cisplatinum, sodium alginate, Tween 80, and aluminum monostearate.

The suppository according to the present invention comprises cocoa butter, lanolin, witepsol, polyethylene glycol, glycerogelatin, methylcellulose, carboxymethylcellulose, a mixture of stearic acid and oleic acid, subanal, cottonseed oil, peanut oil, palm oil, cocoa butter + cholesterol, lecithin, ranette wax, glycerol monostearate, Tween or Span, Imhausen, monolene (propylene glycol monostearate), glycerin, Adeps solidus, Buytyrum Tego-G, Cebes Pharma 16, hexalide base 95, Cotomar, Hydroxocote SP, S-70-XXA, S-70-XX75 (S-70-XX95), Mechanisms such as Hydrokote 25, Hydrokote 711, Idropostal, Massa estrarium (A, AS, B, C, D, E, I, T), Massa-MF, Masupol, Masupol-15, Neosupostal-N, Paramound-B, Suposiro (OSI, OSIX, A, B, C, D, H, L), Suppository type IV (AB, B, A, BC, BBG, E, BGF, C, D, 299), Supostal (N, Es), Wecovi (W, R, S, M, Fs), Tezester triglyceride basis (TG-95, MA, 57) can be used.

Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations are prepared by mixing the extract with at least one excipient, such as starch, calcium carbonate, sucrose or lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used.

Liquid preparations for oral administration include suspensions, solutions, emulsions, and syrups, and in addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, flavoring agents, and preservatives may be included. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.

The pharmaceutical composition according to the present invention is administered in a pharmaceutically effective amount. In the present invention, the “pharmaceutically effective amount” means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dosage level can be determined based on the type and severity of the patient’s disease, the activity of the drug, the sensitivity to the drug, the time of administration, the route of administration and the excretion rate, the treatment period, concurrently used drugs, and other factors well known in the medical field.

The pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or in multiple doses. It is important to administer an amount that can achieve the maximum effect with the minimum amount without side effects by taking all of the above factors into consideration, and this can be easily determined by a person skilled in the art to which the present invention belongs.

The pharmaceutical composition of the present invention can be administered to a subject by various routes. All modes of administration can be envisaged, for example, oral administration, subcutaneous injection, intraperitoneal administration, intravenous injection, intramuscular injection, intrathecal injection, sublingual administration, buccal mucosa administration, rectal insertion, vaginal insertion, ocular administration, otic administration, nasal administration, inhalation, spraying through the mouth or nose, skin administration, transdermal administration, etc.

The pharmaceutical composition of the present invention is determined according to the type of drug as an active ingredient, along with various related factors such as the disease to be treated, the route of administration, the age, sex, weight of the patient, and the severity of the disease. Specifically, the effective amount of the composition according to the present invention may vary depending on the age, sex, and weight of the patient, and is generally 0.001 to 150 mg per 1 kg of body weight, preferably 0.01 to 100 mg, administered daily or every other day, or divided into 1 to 3 times a day. However, since the dosage may increase or decrease depending on the route of administration, the severity of the disease, sex, weight, age, etc., the above dosage does not limit the scope of the present invention in any way.

In the present invention, “subject” means a subject requiring treatment for a disease, and more specifically, a mammal such as a human or non-human primate, mouse, rat, dog, cat, horse, and cow.

In the present invention, “administration” means providing a predetermined composition of the present invention to a subject by any appropriate method. In the present invention, “prevention” means any act of inhibiting or delaying the onset of a target disease, “treatment” means any act of improving or beneficially changing a target disease and its resulting metabolic abnormality symptoms by administering a pharmaceutical composition according to the present invention, and “improvement” means any act of reducing a parameter related to a target disease, for example, the degree of symptoms, by administering a composition according to the present invention.

The present invention provides a food composition for preventing or improving systemic lupus erythematosus or lupus nephritis, comprising PIBF1 as an active ingredient.

In one embodiment of the present invention, the food may be a health functional food, but is not limited thereto. The health functional food may have the advantage of having a more excellent effect when consumed in the form of an inner beauty food. The inner beauty is referred to as an ‘edible cosmetic or beauty food’, and refers to a food that changes the skin constitution to a healthy one by absorbing various ingredients that are good for the skin into the body. Just as you select cosmetics that fit your skin type, you can select and consume inner beauty foods that fit you by considering your skin condition and lifestyle. For example, when cosmetics and inner beauty foods are used together, the effect is much higher than when using only cosmetics or medicine, and you can have the advantage of seeing a more effective skin condition improvement effect.

When using the above effective ingredients as food additives, the effective ingredients can be added as is or used together with other foods or food ingredients, and can be used appropriately according to conventional methods. The mixing amount of the effective ingredients can be appropriately determined according to the purpose of use (prevention, health, or therapeutic treatment).

There are no special restrictions on the types of the above foods. Examples of foods to which the above substances can be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages, and vitamin complexes, and include all health functional foods in the conventional sense.

The health beverage composition according to the present invention may contain various flavoring agents or natural carbohydrates as additional ingredients, like conventional beverages. The natural carbohydrates mentioned above are monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As a sweetener, a natural sweetener such as thaumatin or stevia extract, or a synthetic sweetener such as saccharin or aspartame can be used. The proportion of the natural carbohydrate is generally about 0.01-0.20 g or about 0.04-0.10 g per 100 mL of the composition of the present invention.

In addition to the above, the composition of the present invention may contain various nutrients, vitamins, electrolytes, flavoring agents, coloring agents, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH regulators, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc. In addition, the composition of the present invention may contain fruit pulp for the production of natural fruit juice, fruit juice drinks, and vegetable drinks. These components may be used independently or in combination. The proportion of these additives is not particularly important, but is generally selected in the range of 0.01-0.20 parts by weight per 100 parts by weight of the composition of the present invention.

The present invention provides a kit for preventing or treating systemic lupus erythematosus or lupus nephritis, comprising a composition comprising PIBF1 as an active ingredient and an instruction manual.

In addition to the above components, the “kit” of the present invention may include other components, devices, materials, etc. that are usually necessary for enhancing the therapeutic effect of the composition of the present invention on lupus or lupus nephritis, or for a method for storing or managing the composition of the present invention. In addition, all components included in the kit may be used at least once without limitation on the number of times, there is no limitation on the order in which each substance is used, and the application of each substance may be performed simultaneously or microscopically.

The kit of the present invention may include a container in addition to the formulation and instructions. The container may serve to package the composition, and may also serve to store and fix it. The material of the container may take the form of, for example, a bottle, a tub, a sachet, an envelope, a tube, an ampoule, and the like, and these may be formed partly or wholly from plastic, glass, paper, foil, wax, and the like. The container may be initially equipped with a completely or partially detachable stopper, which may be a part of the container or may be attached to the container by mechanical, adhesive, or other means, and may also be equipped with a stopper for allowing access to the contents by means of a syringe needle. The kit may include an outer package, which may include, but is not limited to, instructions for the use of the components.

The present invention provides a method for characterizing a responder to a therapeutic agent for treating systemic lupus erythematosus or lupus nephritis, comprising the following steps:

(S1) a step of measuring the level of CXCL10 in a blood sample isolated from a subject; and

(S2) If the level of CXCL10 measured in the above step (S1) is increased compared to the control group, a step of determining the responder to a treatment for systemic lupus erythematosus or lupus nephritis;

A method wherein the above treatment comprises PIBF1 as an active ingredient.

The present invention provides a composition for assessing a patient with systemic lupus erythematosus or lupus nephritis in need of administration of the composition, comprising as an active ingredient an agent for measuring the level of CXCL10 in blood isolated from a subject.

In the present invention, “companion diagnostic” may mean one of the diagnostic tests for confirming the possibility of applying a specific therapeutic drug (including a targeted therapeutic agent) to a specific patient. That is, according to the present invention, since the level of CXCL10 in a blood sample isolated from a subject or a composition containing PIBF1 of the present invention as an active ingredient can be used as a method and composition for applying the same to a patient with lupus or lupus nephritis through a preparation for measuring the same, CXCL10 may be referred to as a companion diagnostic marker of lupus or lupus nephritis.

In the present invention, “discrimination” may mean distinguishing a subject according to a specific criterion. For example, in the present invention, when the level of CXCL10 is higher than the level of the control group, it may be used to mean distinguishing whether or not a subject has drug resistance to the composition containing PIBF1 of the present invention as an active ingredient, or distinguishing whether or not a subject has sensitivity to the composition of the present invention.

In the present invention, “targeted therapeutic agent” may include any therapeutic agent targeting a specific disease. In the present invention, it may mean PIBF1 protein, but is not limited thereto.

In the present invention, “resistance” is also referred to as “tolerance” and means not showing a significant cellular or biological response to a specific drug. Specifically, it may mean, but is not limited to, that the rate of cell death or cell death associated with lupus or lupus nephritis is not shown or is reduced in response to treatment with the drug.

In addition, in the present invention, the “need for administration” refers to determining whether to administer a therapeutic agent (drug) to a subject that can obtain or is expected to obtain a therapeutic effect from the therapeutic agent (drug), and the determination can be performed by measuring the copy number or expression level of the companion diagnostic marker of the present invention and comparing it with a reference value.

Additionally, in the present invention, the “control group” may mean an individual that may not be diagnosed with the disease, and in the present invention, may mean an individual that is not diagnosed with lupus or lupus nephritis.

In addition, the present invention provides a use of PIBF1 or a composition containing it as an active ingredient for preventing, improving or treating systemic lupus erythematosus or lupus nephritis.

In addition, the present invention provides a use for manufacturing a preparation for preventing, improving or treating systemic lupus erythematosus or lupus nephritis using PIBF1 or a composition containing it as an active ingredient.

In addition, the present invention provides a method for preventing or treating systemic lupus erythematosus or lupus nephritis, comprising a step of administering PIBF1 or a composition containing it as an active ingredient to a subject in need thereof.

The present invention also provides a use for characterizing responders to a therapeutic agent for treating systemic lupus erythematosus or lupus nephritis, comprising PIBF1 or a composition comprising the same as an active ingredient.

Hereinafter, preferred examples are presented to help understand the present invention. However, the following examples are provided only to help understand the present invention more easily, and the content of the present invention is not limited by the following examples.

[Example]

Construction of the murine model (Mouse model construction)

All mice were bred and maintained under specific pathogen-free conditions. The mice were divided into three groups as shown in Fig. 1. Specifically, female MRL/MpJ-Fas ^lpr /J (MRL/lpr) mice prone to lupus were ovariectomized at 6 weeks of age (n = 18). Half of the ovariectomized mice were treated with PIBF1 (MRL/lpr + OVX-PIBF1) from 8 to 26 weeks of age, and the other half were treated with PBS (control group; MRL/lpr + OVX-PBS). Female MRL/MpJ mice were used as negative controls. Blood sampling was performed every 2 weeks, and urine sampling was performed in all groups at the end (26 weeks). All mouse experiments were performed in accordance with the animal experiment guidelines approved by the Animal Experiment Ethics Committee of the Life Science Research Institute of Asan Medical Center, Seoul. For PIBF1 administration, the 35 kDa secreted form of PIBF1 was injected intraperitoneally (25 μg/animal/twice a week). PIBF1 was donated by Professor Yoo-Sook Cho (Department of Allergy and Clinical Immunology, Seoul Asan Medical Center, Ulsan University College of Medicine).

Flow Cytometry Analysis

Spleens were collected, lysed in PBS through a 70 μm filter, and centrifuged at 350 × g for 5 min. The pellet was resuspended in PBS and centrifuged again. The pellet was resuspended in red blood cell lysis buffer (BioLegend, USA) to remove red blood cells, and the lysis reaction was stopped by adding PBS. The pellet was washed with PBS to obtain a single spleen cell suspension. After single cell preparation, Fc receptors were blocked with anti-mouse-CD16/32 (clone: 93, BioLegend), and spleen and kidney cells were stained with cell surface markers anti-CD3-PE/Cy7 (clone: 17A2, BioLegend), anti-CD4-PerCP/Cy5.5 (clone: GK1.5, BioLegend), anti-CD8-FITC (clone: 5H10-1, BioLegend), anti-B220-APC (clone: RA3-6B2, BioLegend), anti-CXCR5-BV421 (clone: L138D7, BioLegend), anti-CD5-APC/Cy7 (clone: 53-7. 3, BioLegend), anti-CD1d-BV421 (clone: 1B1, BioLegend), anti-CD22-FITC (clone: The cells were stained with OX-97 (BioLegend).

Enzyme-Linked Immunosorbent Assay (ELISA)

Estradiol (17-beta Estradiol ELISA Kit, Abcam, UK) and progesterone levels (Immuno-Biological Laboratories, USA) were also detected by ELISA kits. All analytical procedures were performed according to the manufacturer's instructions. Serum anti-dsDNA antibody levels were measured using an ELISA kit (Mouse Anti-dsDNA Antibodies Total Ig, ALPHA DIAGNOSIC INTERNATIONAL, USA) according to the manufacturer's instructions. Specifically, diluted plasma was added to the dsDNA immobilized on the plate and incubated for 1 h at RT and washed four times. The wells were then incubated with HRP-conjugated anti-mouse Ig for 30 min and washed five times. After washing, the chromogenic substrate (TMB) was added for color development, and the reaction was terminated by adding the stop solution. The absorbance of each well was measured at a wavelength of 450 nm. Creatinine levels were measured using the Creatinine Colorimetric Detection Kit (Enzo Life Sciences, USA). Diluted urine and creatinine detection reagent were added to each well and incubated at room temperature for 30 minutes. The optical density was observed at a wavelength of 490 nm. Urine albumin concentration was measured using ELISA (Mouse Albumin ELISA Kit, Abcam, UK). Diluted samples were added to the wells and incubated for 2 hours and washed five times. Biotinylated albumin antibody was added and incubated for 1 hour and washed five times. Streptavidin-Peroxidase conjugate was added and incubated for 30 minutes and washed five times. Chromogenic substrate (TMB) was added until the optimal color intensity was achieved and stopped with stop solution. Absorbance was measured at a wavelength of 450 nm.

Kidney Histology Examinations

Before kidney isolation, mice were anesthetized and transcardially perfused with PBS. Kidneys were fixed in 10% neutral buffered formalin solution for histological examination. After fixation, organs were embedded in paraffin and sectioned into 4-μm-thick slices. Sections were then stained with hematoxylin and eosin (H&E), Masson’s trichome (MT), and periodic acid-Schiff (PAS).

Pathologic features of renal histology were examined using a semiquantitative grading system. Disease activity indicators such as intracapillary hypercellularity, neutrophil lysis, glomerular capillary loops, fibrinoid necrosis, hyaline deposition, and interstitial inflammation were examined. The overall disease activity score was calculated as the sum of these indicators. Chronicity indicators included the total percentage of glomerular sclerosis and interstitial fibrosis. A chronicity score was additionally calculated as the sum of these indicators. Disease severity was assessed on a 0–3 point scale according to the glomerular percentage for each indicator: 0 point = no glomeruli, 1 point = <25% glomeruli, 2 points = 25–50% glomeruli, and 3 points = ≥50% glomeruli. The criteria for this grading system were adopted from “Bajema, IM, et al., Revision of the International Society of Nephrology/Renal Pathology Society classification for lupus nephritis: clarification of definitions, and modified National Institutes of Health activity and chronicity indices . Kidney Int, 2018. 93(4): p. 789-796.”

Serum Cytokine Analysis by Luminex Multiplex Cytokine Assay

Serum samples were prepared from all mouse groups at 16 (n = 33) and 24 (n = 29) weeks of age. Cytokines were analyzed using the Luminex Multiplex cytokine assay. Blood was allowed to clot for 1 h at RT and then centrifuged at 10,000 × g for 10 min at 4°C. Serum concentrations of the following cytokines were measured using a Magnetic Bead-based 7-plex immunoassay: IFN-r, IL-2, IL-6, IL-10, IL-12 (IL-12 p70), and IL-21 (Procreate Mouse custom plex, Thermo-Scientific).

Specifically, the standards were diluted in 4-fold serial dilutions. The serum samples and diluted standards were combined with antibody-conjugated magnetic beads and incubated for 2 h at RT on a shaker at 500 rpm. After washing, the plates were incubated with detection antibodies for 30 min at RT. After three washes, the plates were resuspended in streptavidin-PE and incubated for 30 min at RT. Three additional washes were performed and the plates were resuspended in reading buffer. Each sample was measured along with the standards (4-fold serial, 7-point dilutions) and buffer controls. The plates were read using the Luminex Bio-plex 200 system (Bio-Rad Corporation, USA) for quantitative analysis.

Statistical Analysis

All statistical analyses were performed using GraphPad Prism 8 (GraphPad Software, San Diego, USA). Comparisons between groups were performed using the Mann-Whitney test. All data are expressed as mean ± SEM. A P value of <0.05 was considered significant.

Example 1. Confirmation of decreased estradiol and progesterone levels in ovariectomized rats

Serum estradiol and progesterone levels were measured by ELISA to confirm that the ovariectomy was performed correctly.

As a result, the levels of the two hormones were significantly decreased in the group that underwent oophorectomy (Fig. 2). Specifically, the concentration of estradiol was significantly decreased at 12 weeks, and the concentration of progesterone was significantly decreased at 8 weeks in the oophorectomy group (OVX; n=18) compared to the non-oophorectomy group (Non-OVX; n=10).

Example 2. Confirmation of the effect of suppressing the increase in autoantibody concentration by PIBF1

One of the most characteristic features of lupus is the level of anti-dsDNA autoantibodies in the blood. Therefore, to evaluate the role of PIBF1 in lupus progression, we measured the level of anti-dsDNA autoantibodies in the serum of mice every two weeks.

As a result, the anti-dsDNA level in the MRL/lpr+OVX-PBS group was found to gradually increase from the 14th week. On the other hand, the autoantibody level in the PIBF1 treatment group did not increase after the 18th week of life and showed a tendency to decrease somewhat thereafter (Fig. 3).

Example 3. Confirmation of the effect of reducing the urine albumin/creatinine ratio by PIBF1

The most representative complication of lupus disease is lupus nephritis. Therefore, to confirm the occurrence of kidney disease in a lupus mouse model, the urine albumin/creatinine ratio (uACR), which is the most important indicator of renal failure and lupus nephritis, was analyzed. Specifically, the urine albumin/creatinine ratio (uACR) in the urine of 26-week-old mice in all groups was measured by ELISA.

As a result, the uACR values of the two OVX groups were significantly higher than those of the MRL/MpJ group. However, the uACR of the OVX group treated with PIBF1 was significantly reduced compared to the OVX group not treated with PIBF1, and this was statistically significant, proving the therapeutic effect of PIBF1 on lupus and lupus nephritis (Fig. 4).

Example 4. Confirmation of the effect of PIBF1 on reducing disease activity and chronicity score in the kidney

To confirm the role of PIBF1 in lupus, renal biopsy was performed to analyze whether the disease activity and chronicity score of the kidney increased or decreased. At this time, the disease activity and chronicity score were scored according to the criteria published by the National Institutes of Health (NIH) (Table 2 and Table 3). After sacrifice at 26 weeks of age, kidney specimens were prepared and stained with hematoxylin and eosin (H&E), Masson's trichome (MT), and periodic acid-Schiff (PAS) stains (Fig. 5a). Disease activity indices include capillary hypercellularity, neutrophil lysis, hyaline deposition, cellular crescent, fibrin necrosis, and interstitial inflammation. Each index represents the influx of inflammatory cells, neutrophil apoptosis, subendothelial deposits (i.e., immune complexes), and lesions. Fibrin necrosis is known to be an indicator of the development of lupus nephritis. Chronicity indices include glomerular sclerosis, fibrous crescents, tubular atrophy, and interstitial fibrosis. Glomerular sclerosis is a condition in which the glomeruli are completely sclerotic and is a hallmark of lupus nephritis. Tubular atrophy and interstitial fibrosis can be considered interstitial infiltrates.

As a result, overall, the therapeutic role of PIBF1 in the kidney of MRL/lpr mice was demonstrated by histological examination in this study. Specifically, PIBF1 was confirmed to alleviate lupus disease progression and reduce overall activity and chronicity scores in the kidney. In particular, among these disease-related indices, interstitial inflammation and systemic glomerular sclerosis were found to be reduced after PIBF1 treatment. Both indices were related to renal tubular dysfunction and glomerular sclerosis, which may be signs of proteinuria. Therefore, investigating the effect of PIBF1 on renal tubular cells can be considered as a clue to approach how PIBF1 exerts its anti-inflammatory effect on lupus nephritis. Several disease-related parameters, including neutrophil lysis, fibrinogenoclesis, and parameters related to interstitial inflammation, were increased in MRL/lpr mice, whereas they were barely observed in the MRL/MpJ group (negative control group). The overall disease activity score, including interstitial inflammation, was significantly reduced compared to the PIBF1-untreated group (Fig. 5b). In addition, with respect to the disease chronicity index, the total glomerular sclerosing score as well as the total chronicity score were reduced in the ovariectomized group treated with PIBF1 (Fig. 5c).

Example 5. Confirmation of the treatment effect of systemic lupus erythematosus according to various indicators in spleen cells by PIBF1

To confirm the therapeutic effect of PIBF1 on systemic lupus erythematosus, spleen cells from all mouse groups at 26 weeks of age were analyzed by flow cytometry analysis using the method described in ‘Flow Cytometry Analysis’ above.

As a result, the proportion of T cells and CD4 ^- CD8- double ^- negative T cells (DNT cells) in the spleen cells of the whole MRL/lpr mice increased, whereas no statistical difference was found between the OVX-PBS and OVX-PIBF1 groups (Fig. 6a). B220 ⁺ T cells showed a similar trend. However, B220 ⁺ DNT cells decreased in the PIBF1-treated group (Fig. 6b).

Follicular helper T cells (Tfh cells) were increased in MRL/lpr mice, but there was no statistically significant difference between the two ovariectomized groups (Fig. 6c). B reg cells and MZ B cells, which are thought to perform a scavenging function for apoptotic debris, were decreased in the MRL/lpr group (Fig. 6d and 6e), whereas CD22-deficient B cells were increased (Fig. 6f). CD22 is also known as an inhibitor of BCR signaling. CD22 deficiency induces hyperresponsiveness of B cells, leading to autoantibody production, and a different tendency was observed after PIBF1 treatment.

Example 6. Confirmation of the inhibitory effect of PIBF1 on reducing pro-inflammatory cytokines

We measured the levels of serum cytokines known to be associated with lupus pathophysiology or the immune regulatory function of PIBF1. Specifically, serum samples were prepared from mice aged 16 and 24 weeks, and cytokine changes were examined after PIBF1 treatment.

As a result, the levels of pro-inflammatory cytokines IFN-r, IL-6, and IL-12 were significantly and highly expressed in all MRL/lpr mice. However, no statistically significant difference was found between the ovariectomized groups (Fig. 7).

Example 7. Confirmation of CXCL10 inhibition effect by PIBF1

The CXCL10 inhibitory effect of PIBF was confirmed using the MRL/MpJ-Faslpr/J mouse model that spontaneously develops lupus symptoms. Specifically, the experimental groups were set to four groups: wild-type MRL/MpJ, mutant MRL/MpJ-Faslpr/J, MRL/MpJ-Faslpr/J + ovariectomy, and MRL/MpJ-Faslpr/J + ovariectomy + PIBF treatment. After ovariectomy, 6-week-old MRL/MpJ-Faslpr/J mice were treated ip with PIBF twice per week starting at 8 weeks of age. Then, orbital blood collection was performed on 10-, 16-, and 24-week-old mice, and the serum was separated to measure the concentration of CXCL10.

As a result, the concentration of CXCL10 was significantly reduced in the PIBF-treated mice group after ovariectomy at 16 and 24 weeks of age compared to the ovariectomized control group (Fig. 8). According to these results, it was confirmed that PIBF delays the occurrence of lupus and suppresses the occurrence of nephritis through CXCL10 suppression.

The above description of the present invention is for illustrative purposes only, and those skilled in the art will understand that the present invention can be easily modified into other specific forms without changing the technical idea or essential characteristics of the present invention. Therefore, it should be understood that the embodiments described above are exemplary in all respects and not restrictive.

The pharmaceutical composition for preventing or treating systemic lupus erythematosus containing PIBF1 according to the present invention as an active ingredient specifically exhibits excellent lupus disease progression alleviation and treatment effects by significantly reducing both serum anti-dsDNA autoantibodies and urine albumin creatinine ratio (uACR), and also exhibits excellent lupus prevention effects by reducing B220+ DNT cells known to increase in a mouse model susceptible to lupus. Therefore, the composition can be usefully used as a composition for preventing or treating lupus and lupus nephritis, and thus has industrial applicability.

Claims (16)

A pharmaceutical composition for preventing or treating systemic lupus erythematosus or lupus nephritis, comprising PIBF1 (Progesterone-Induced Blocking Factor 1) as an active ingredient. In the first paragraph, A pharmaceutical composition, wherein the above PIBF1 is encoded by a nucleic acid sequence represented by sequence number 1. In the first paragraph, A pharmaceutical composition, wherein the composition is administered by any one method selected from the group consisting of intraperitoneal administration, intravenous administration, and oral administration. In the first paragraph, A pharmaceutical composition, wherein the composition is administered twice a week at 20 to 30 μg. In the first paragraph, A pharmaceutical composition characterized by one or more of the following: Decreased anti-dsDNA autoantibodies in serum; Decreased urine albumin creatinine ratio (uACR); and Increase in marginal zone B cells (MZ B cells) and regulatory B cells. A food composition for preventing or improving systemic lupus erythematosus or lupus nephritis, comprising PIBF1 as an active ingredient. In Article 6, A food composition wherein the above food is a health functional food. A kit for preventing or treating systemic lupus erythematosus or lupus nephritis, comprising a composition comprising PIBF1 as an active ingredient and an instruction manual. Method for characterizing responders to a therapeutic agent for the treatment of systemic lupus erythematosus or lupus nephritis comprising the following steps: (S1) a step of measuring the level of CXCL10 in a blood sample isolated from a subject; and (S2) If the level of CXCL10 measured in the above step (S1) is increased compared to the control group, a step of determining the responder to a treatment for systemic lupus erythematosus or lupus nephritis; A method wherein the above treatment comprises PIBF1 as an active ingredient. A composition for assessing a patient with systemic lupus erythematosus or lupus nephritis requiring administration of the composition of claim 1, comprising as an active ingredient an agent for measuring the level of CXCL10 in blood isolated from a subject. Use of PIBF1 or a composition containing it as an active ingredient for preventing, improving or treating systemic lupus erythematosus or lupus nephritis. Use of PIBF1 or a composition containing it as an active ingredient for preparing a preparation for preventing, improving or treating systemic lupus erythematosus or lupus nephritis. A method for preventing or treating systemic lupus erythematosus or lupus nephritis, comprising the step of administering PIBF1 or a composition containing it as an active ingredient to a subject in need thereof. Use of PIBF1 or a composition comprising it as an active ingredient to characterize responders to a therapeutic agent for treating systemic lupus erythematosus or lupus nephritis. Use of a preparation for measuring the level of CXCL10 in blood isolated from a subject or a composition containing the preparation as an active ingredient for the diagnosis of patients with systemic lupus erythematosus or lupus nephritis. A method for assessing a patient with systemic lupus erythematosus or lupus nephritis, comprising the step of measuring the level of CXCL10 in blood isolated from a subject using a preparation for measuring the level of CXCL10 in blood isolated from a subject or a composition containing the preparation as an active ingredient.

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