Use of alpha-2,6-sialylated immunoglobulin for the prevention or treatment of xerophthalmia or inflammatory eye diseases

Abstract

The present invention relates to the use of human blood-derived α-2,6-sialylated immunoglobulin for the prevention or treatment of xerophthalmia or inflammatory eye diseases. Compared to IVIG, the α-2,6-sialylated immunoglobulin of the present invention has the advantages of exhibiting excellent therapeutic effects on xerophthalmia even at low doses without side effects such as corneal fibrosis, and also exhibiting excellent therapeutic effects on intractable inflammatory eye diseases of various severity levels.

Description

[Technical Field]

[0001] The present invention relates to the use of α-2,6-sialylated immunoglobulins for the prevention or treatment of xerophthalmia or inflammatory eye diseases, and more particularly to the use of α-2,6-sialylated immunoglobulins derived from human blood for the prevention or treatment of xerophthalmia or inflammatory eye diseases using the function of inducing immune tolerance via DC-SIGN. [Background technology]

[0002] The asparagine residue at position 297 (Asn297) in the CH2 domain of immunoglobulin (Ig) Fc region is glycosylated in over 30 different ways. Among these, α-2,6-sialylated immunoglobulin (α-2,6-SA-IG) is an Ig in which sialic acid is attached to the terminal 2 and 6 positions of the sugar moiety attached to Asn297. The glycosylation form of Ig is crucial for its function. However, intact α-2,6-SA-IG accounts for less than 5% of total blood Ig. Furthermore, since over 30 types of covalently linked glycans have been discovered in the immunoglobulin CH2 domain to date, the content of α-2,6-SA-IG may be even lower.

[0003] Sialic acid capping, which is added to the terminus of the glycan, is a major factor determining the lifespan of glycoproteins in the body, and glycoproteins without terminal sialic acid are rapidly eliminated in the body. In the case of immunoglobulins, the glycan attached to Asn297 is located inside the dimer of two heavy chains, and the type and structure of the glycan attached to the Fc changes the tertiary structure of the Fc, which in turn affects the interaction between the Fc region of the antibody and Fc receptors (Fcγ, FcγII, FcγIII, etc.).

[0004] Since Fc-induced ADCC (antibody dependent cell cytotoxicity) and CDC (complement dependent cytotoxicity) determine the therapeutic efficacy of antibodies, the form of the attached glycan determines the antibody's performance. Antibodies without glycosylation on the Fc exhibit severely impaired functions (Nature Rev Immunol 8:34-47).

[0005] Mouse SIGN-R1 / human DC-SIGN is a receptor that recognizes α-2,6-sialylated IgG Fc, which is essential for the anti-inflammatory effects of IVIG (Proc Natl Acad Sci US A. 2008 Dec 16;105(50):19571-8). Furthermore, it has been reported that upon infusion of IVIG, the sialylated Fc of IVIG binds to monocytes expressing human DC-SIGN and produces IL-33. IL-33 activates Fcε endogenous leukocytes to produce IL-4, and then increases FcRIIb in macrophages, thereby increasing the threshold required for inducing an inflammatory response and preventing the inflammatory response from occurring easily (Nature. 2011 Jun 19;475(7354):110-3).

[0006] IVIG is made by extracting only the Ig component from blood separated from the human body, so securing healthy blood and storing it stably is essential, and the cost per injection is currently very high. It is also used in a variety of ways to treat various immune system diseases, and when administered intravenously, it induces a strong anti-inflammatory effect, so demand for it is constantly increasing.

[0007] The present inventors have developed a method for isolating α-2,6-SA-IG from IVIG and have confirmed that intravenous administration of α-2,6-SA-IG (HB α-2,6-SA-IVIG) isolated from IVIG induces DC-SIGN-mediated immune tolerance and significantly improves immune imbalance in pregnant women with preeclampsia, in which the number of DC-SIGN-expressing Hofbauer cells and IL-10 expression are significantly reduced at the time of delivery. They have also demonstrated that HB α-2,6-SA-IVIG can be used to prevent or treat preeclampsia (Korean Patent Registration No. 10-2549282). However, the therapeutic use of HB α-2,6-SA-IVIG for ophthalmic diseases remains unknown.

[0008] Xerophthalmia is an eye disease caused by insufficient tear production, excessive tear evaporation, or an imbalance in tear components, which damages the surface of the eye and causes symptoms such as stinging, irritation, a foreign body sensation, and dryness. When xerophthalmia develops, the tear layer that uniformly covers and protects the surface of the eye rapidly dries out, causing symptoms such as stinging, a sandy foreign body sensation, and blurred vision. In severe cases, it can even cause headaches. In particular, the number of xerophthalmia patients has been increasing recently due to exposure to various media environments, side effects of LASIK and LASEK surgery, and air pollution, making the treatment and management of xerophthalmia increasingly important.

[0009] Inflammatory eye diseases include various types of inflammation that can affect parts of the eye or surrounding tissues. The wide range of known inflammatory eye diseases includes common diseases such as allergic conjunctivitis caused by hay fever, as well as rarer and more dangerous diseases such as uveitis, scleritis, optic neuritis, keratitis, retinal vasculitis, or chronic vasculitis, all of which can threaten the vision of affected individuals.

[0010] Artificial tear eye drops and lacrimation promoters are mainly used to treat dry eye syndrome, but disposable artificial tear eye drops are expensive, and while administering artificial tears improves the symptoms of dry eye syndrome, they have no therapeutic effect, and reusable types contain preservatives that can induce inflammation in the eyes. Furthermore, lacrimation promoters only promote mucus and water secretion without suppressing inflammatory symptoms, so they have the disadvantage of being less effective in treating severe dry eye syndrome.

[0011] In addition, anti-inflammatory drugs administered to treat inflammatory eye diseases are effective when used for a short period of time, but can increase infections due to immunosuppression, increase the incidence of cataracts and glaucoma, and induce side effects that appear throughout the body when used for a long period of time.

[0012] Thus, while the incidence of dry eye syndrome and inflammatory eye diseases is increasing, there are still not enough suitable therapeutic agents for treating these ophthalmic diseases, and the development of more effective and safe therapeutic agents is urgently needed. Summary of the Invention [Problem to be solved by the invention]

[0013] The present inventors have made extensive efforts to develop a safe yet highly effective therapeutic agent for dry eye syndrome and inflammatory eye diseases. As a result, they have confirmed that HBα-2,6-SA-IVIG, which was isolated from IVIG currently approved for use as a therapeutic agent, can be used to prevent, improve, and / or treat dry eye syndrome and inflammatory eye diseases, thereby completing the present invention.

[0014] Therefore, an object of the present invention is to provide a novel composition for preventing, ameliorating or treating dry eye syndrome and inflammatory eye diseases. [Means for solving the problem]

[0015] To achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating xerophthalmia or inflammatory eye diseases, comprising a sialylated immunoglobulin. In the present invention, the immunoglobulin is characterized by being isolated from intravenous immunoglobulin (IVIG).

[0016] In the present invention, the sialylated immunoglobulin is characterized in that it is an α-2,6-sialylated immunoglobulin.

[0017] In the present invention, the inflammatory eye disease is characterized by being an inflammatory eye disease of the eyeball, the surface of the eyeball, the posterior surface of the eyeball, or the periphery of the eyeball. In the present invention, the inflammatory eye disease is characterized by being any one or more selected from the group consisting of hordeolum (stye), blepharitis, wiper's eyelid epitheliopathy, chalazion, eyelid infection, keratitis, conjunctivitis, anterior uveitis, corneal ulcer, conjunctival ulcer, iridocyclitis, scleritis, optic neuritis, retinal vasculitis, chronic vasculitis, posterior uveitis, panuveitis, meibomianitis, and dacryoadenitis.

[0018] In the present invention, the pharmaceutical composition is characterized in that it is administered in combination with other therapeutic agents for dry eye syndrome or inflammatory eye diseases. In the present invention, the other therapeutic agent for xerophthalmia and / or inflammatory eye diseases is characterized by being one or more selected from the group consisting of anti-inflammatory agents, immunosuppressants, antiglaucoma drugs, artificial tears, lacrimation promoters, and antibiotics.

[0019] In the present invention, the pharmaceutical composition is characterized in that it is in the form of an eye drop liquid or ointment. In the present invention, the α-2,6-sialylated immunoglobulin has the following characteristics compared to general intravenous immunoglobulin: (i) increasing the expression of the anti-inflammatory cytokine IL-10 in ocular cells by 50% or more; and / or (ii) It is characterized by not inducing side effects of corneal stromal tissue fibrosis.

[0020] The present invention also provides an ophthalmic composition comprising an α-2,6-sialylated immunoglobulin. In the present invention, the ophthalmic composition is characterized in that it is in the form of a liquid or ointment.

[0021] In the present invention, the ophthalmic composition is characterized in that it is an artificial tear composition. The present invention also provides a method for preventing or treating xerophthalmia or an inflammatory eye disease, comprising administering the α-2,6-sialylated immunoglobulin or the pharmaceutical composition to a subject in need thereof.

[0022] In the present invention, the subject may be an animal, including a human, or a non-human animal. In the present invention, the pharmaceutical composition is characterized in that it is administered simultaneously, separately, or sequentially with other therapeutic agents for dry eye syndrome or inflammatory eye diseases.

[0023] The present invention also provides use of α-2,6-sialylated immunoglobulin or the pharmaceutical composition for the prevention or treatment of xerophthalmia or inflammatory eye diseases.

[0024] The present invention also provides a use of an α-2,6-sialylated immunoglobulin or said pharmaceutical composition for the manufacture of a medicament for the prevention or treatment of dry eye syndrome or an inflammatory eye disease. [Effects of the Invention]

[0025] The α-2,6-sialylated immunoglobulin of the present invention has the advantages of being free from side effects such as corneal tissue fibrosis, exhibiting excellent therapeutic effects on xerophthalmia even at low doses, and exhibiting excellent therapeutic effects on intractable inflammatory eye diseases of various severity levels, compared to IVIG. [Brief explanation of the drawings]

[0026] [Figure 1] Figure 1 shows a schematic diagram of the separation of HB α-2,6-SA-IVIG from human blood-derived mixed IVIG and the immunoblotting results of the separation of HB α-2,6-SA-IVIG from human blood-derived mixed IVIG. The loading amount was 1 μg, and the first Biotin-SNA was treated at room temperature for 30 minutes at 0.2 μg / ml, and the second SA-HRP was treated at room temperature for 30 minutes at 0.1 μg / ml. After elution, a light chain band and an upper heavy chain band were observed. [Figure 2] Figure 2 shows the results confirming that DC-SIGN (CD209) mRNA is highly expressed in the rabbit conjunctiva. [Figure 3] Figure 3 shows the construction process of the rabbit experimental model of xerophthalmia. [Figure 4] Figure 4 shows the increase in the anti-inflammatory cytokine IL-10 and the decrease in MMP9 and TFG-β by HB α-2,6-SA-IVIG on day 20 of drug instillation in a rabbit experimental model of xerophthalmia. [Figure 5] FIG. 5 shows the method for measuring ocular damage by the NIBUT (tear film break-up time test) method. [Figure 6] FIG. 6 shows a method for measuring ocular damage using a vital staining method. [Figure 7] FIG. 7 shows the results confirming that DC-SIGN mRNA is highly expressed in the canine conjunctiva. [Figure 8a] Figure 8a shows the results of confirming the therapeutic effects of combined administration of HB α-2,6-SA and IVIG on corneal epithelial defects, keratitis, and keratoconjunctivitis sicca in canine clinical patients. [Figure 8b]Figure 8b shows the results of confirming the therapeutic effect of combined administration of HB α-2,6-SA and IVIG on blepharitis and keratoconjunctivitis sicca in canine clinical patients. [Figure 8c] Figure 8c shows the results of confirming the temporary therapeutic effect of combined administration of HB α-2,6-SA and IVIG on chronic keratitis caused by retrobulbar rupture in a canine clinical patient. [Figure 8d] Figure 8d shows the results of confirming the therapeutic effect of combined administration of HB α-2,6-SA and IVIG on keratitis caused by corneal perforation in a prosthetic eye in a canine clinical patient. [Figure 8e] Figure 8e shows the results of confirming the therapeutic effect of combined administration of HB α-2,6-SA and IVIG on qualitative dry eye and chicken allergic keratoconjunctivitis in both eyes in canine clinical patients. [Figure 8f] FIG. 8f shows the results of confirming the therapeutic effects of combined administration of HB α-2,6-SA and IVIG on epiphora, blepharitis, qualitative xerophthalmia, and allergic conjunctivitis in canine clinical patients. [Figure 8g] Figure 8g shows the results of confirming the therapeutic effects of combined administration of HB α-2,6-SA and IVIG on keratitis, superficial corneal ulcers, and conjunctivitis in canine clinical patients. [Figure 8h] Figure 8h shows the results of confirming the therapeutic effect of combined administration of HB α-2,6-SA and IVIG on chronic corneal ulcers in canine clinical patients. DETAILED DESCRIPTION OF THE INVENTION

[0027] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one skilled in the art to which this invention belongs. Generally, the nomenclature used herein is that which is widely known and commonly used in the art.

[0028] In the present invention, we have confirmed that when α-2,6-sialylated immunoglobulin is administered to experimental rabbits suffering from xerophthalmia and clinical dogs suffering from inflammatory eye diseases, xerophthalmia and inflammatory eye diseases can be effectively treated.

[0029] Specifically, α-2,6-sialylated immunoglobulin significantly increased the expression of the anti-inflammatory cytokine IL-10 in the eye compared to administration of IVIG, and did not cause the side effect of corneal stromal tissue fibrosis. It was confirmed that α-2,6-sialylated immunoglobulin exhibited significantly more advantageous effects than IVIG in the treatment of ophthalmic diseases, and in particular, was able to exert remarkable therapeutic effects on intractable or severe inflammatory eye diseases that could not be treated with existing treatment methods.

[0030] Thus, in one aspect, the present invention relates to a pharmaceutical composition for preventing or treating xerophthalmia and / or inflammatory eye diseases, comprising a sialylated immunoglobulin. In the present invention, the immunoglobulin may be derived from human blood and is characterized by being isolated from intravenous immunoglobulin (IVIG) or human immunoglobulin that has been separated, purified, and then lyophilized (e.g., https: / / www.pel-freez.com / human-igg-affinity-purified-lyophilized-34031), but is not limited thereto.

[0031] In the present invention, intravenous immunoglobulin (IVIG) refers to an injectable preparation in which immunoglobulin, a plasma protein containing antibodies against various pathogens, is formulated to have physical properties suitable for systemic injection via a vein.

[0032] Conventionally, immunoglobulins used as therapeutic agents have been prepared for subcutaneous or intramuscular injection using methods such as low-temperature ethanol fractionation. However, these administration routes have various drawbacks, including limited dosage, low content of immunoglobulin G (IgG), the core of antibody function, and degradation of immunoglobulin antibodies by proteases at the injection site. To address these issues with intramuscular injection, IVIG suitable for intravenous injection has been developed by removing aggregates formed during production and storage, and by removing impurities such as blood coagulation factors (fibrinogen, albumin, PKA, and transferrin) or IgA and IgE, thereby improving purity and safety. Therefore, the intravenous immunoglobulin of the present invention can be used without restriction with IVIGs commercially available in the industry, as well as new formulations of IVIG currently under development or to be developed in the future.

[0033] Commercially available IVIGs include, but are not limited to, Carimune®, Flebogamma®, Gammagard®, Gammaked®, Gammaplex, Gamunex®-C, Octagam®, and Privigen®.

[0034] In the present invention, the sialylated immunoglobulin is characterized as α-2,6-sialylated immunoglobulin. In the present invention, the α-2,6-sialylated immunoglobulin can be used as an abbreviation of HB α-2,6-SA-IVIG, which means α-2,6-sialylated immunoglobulin isolated from IVIG (e.g., lyophilized IVIG or commercial human IgG), and may be HB α-2,6-SA-IVIG. In another embodiment, the α-2,6-sialylated immunoglobulin according to the present invention can be isolated directly or indirectly from the human body via other routes and used.

[0035] It should be noted that, to achieve the objectives of the present invention, α-2,6-sialylated immunoglobulin can be administered via routes other than intravenous administration. In the present invention, the inflammatory eye disease is characterized by, but is not limited to, an inflammatory eye disease of the eyeball, the surface of the eyeball, the posterior surface of the eyeball, or the periphery of the eyeball.

[0036] Specifically, the peripheral part of the eyeball may be, but is not limited to, the upper eyelid, conjunctiva, eyelid, lacrimal gland, periocular gland, optic nerve, etc. In the present invention, the inflammatory eye disease is specifically characterized as being any one or more selected from the group consisting of styes, blepharitis, wiper's eyelid epitheliopathy, chalazions, eyelid infections, keratitis, conjunctivitis, anterior uveitis, corneal ulcers, conjunctival ulcers, iridocyclitis, scleritis, optic neuritis, retinal vasculitis, chronic vasculitis, posterior uveitis, panuveitis, meibomianitis, and dacryoadenitis, but is not limited to these.

[0037] In the present invention, the inflammatory eye disease may be caused by allergies, by existing therapeutic agents such as steroid injections, or by surgical procedures such as implants or physical irritation.

[0038] In the present invention, the α-2,6-sialylated immunoglobulin or a pharmaceutical composition containing the same may be administered alone for the treatment of xerophthalmia or inflammatory eye diseases in one embodiment, or may be administered in combination with other therapeutic agents for xerophthalmia or inflammatory eye diseases in another embodiment.

[0039] In the present invention, the other therapeutic agent for dry eye syndrome and / or inflammatory eye disease is characterized by being any one or more selected from the group consisting of anti-inflammatory agents, immunosuppressants, antiglaucoma drugs, artificial tears, lacrimation promoters, and antibiotics, but is not limited thereto.

[0040] In the present invention, the other therapeutic agent for dry eye syndrome and / or inflammatory eye disease may be, but is not limited to, one or more therapeutic agents selected from the group consisting of Optimmune® (0.2% Cyclosporine), an-HyPro (1.2% Hyaluronate eye gel), Maxitrol® (dexamethasone / neomycin sulfate / polymyxin B sulfate), Fumelon® (Fluorometholone), Tarivid® (Ofloxacine), Hamerone-P (0.3% sodium hyaluronate), Levofloxacin, Diquas, Fumelon, Chloramphenicol, and Hyaluronic acid (0.3%). In this case, the dosage of the therapeutic agent may be according to the manufacturer's recommendation or may be prescribed by a clinician (physician or veterinarian) to increase or decrease the appropriate dosage depending on the condition of the subject.

[0041] In another embodiment of the present invention, the α-2,6-sialylated immunoglobulin or a pharmaceutical composition containing the same can be administered in combination with a surgical procedure or operation. In the present invention, the pharmaceutical composition is characterized by being in the form of a liquid dosage form for eye drops, but is not limited thereto.

[0042] In the present invention, the α-2,6-sialylated immunoglobulin is characterized by, but not limited to, (i) increasing the expression level of the anti-inflammatory cytokine IL-10 in ocular cells by 50% or more and / or (ii) not inducing fibrotic side effects in corneal stromal tissue, compared to general intravenous immunoglobulin (IVIG). Due to these characteristics, the α-2,6-sialylated immunoglobulin can exhibit superior effects on xerophthalmia and / or inflammatory eye diseases, compared to general IVIG.

[0043] The pharmaceutical compositions of the present invention may further comprise various excipients, including pharmaceutically acceptable diluents or carriers. In some embodiments, the pharmaceutical compositions of the present invention can be provided in a manner that allows them to be administered to a subject as needed. In some embodiments, the pharmaceutical compositions of the present invention can be administered to humans.

[0044] The pharmaceutical compositions of the present invention can be administered to a patient either alone or in combination. Co-administration includes simultaneous or sequential administration, either individually or in combination (with one or more other drugs). Thus, the pharmaceutical compositions of the present invention can also be prepared as a single dosage form with one or more other drugs.

[0045] The pharmaceutical composition of the present invention can be formulated and used in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols, topical preparations, suppositories, or sterile injection solutions, according to conventional methods.

[0046] For example, the pharmaceutical composition of the present invention can be formulated as an injection, ointment, gel, lotion, capsule, tablet, liquid, suspension, spray, inhalant, eye drop, adhesive, patch, or the like.

[0047] The pharmaceutical composition of the present invention can be administered orally or parenterally (for example, intravenously, subcutaneously, intramuscularly, intraperitoneally, intranasally, intravaginally, intrathecally, intraarticularly or topically) depending on the purpose.

[0048] Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations can be prepared by mixing at least one or more excipients, for example, starch, calcium carbonate, sucrose, lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc can also be used.

[0049] Liquid preparations for oral administration include suspensions, oral solutions, emulsions, syrups, etc., and in addition to water and liquid paraffin, which are frequently used simple diluents, various excipients such as wetting agents, sweeteners, flavoring agents, preservatives, etc. may be contained.

[0050] Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, and suppositories. Non-aqueous solvents and suspensions that can be used include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.

[0051] The pharmaceutical compositions may be prepared as sterile injectable aqueous or oleaginous suspensions. These suspensions may be formulated using suitable dispersing or wetting agents (e.g., Tween 80) and suspending agents according to techniques known in the art. The sterile injectable preparations may also be prepared as sterile injectable solutions or suspensions in nontoxic, parenterally acceptable diluents or solvents (e.g., solutions in 1,3-butanediol). Acceptable vehicles and solvents include glycine, proline, sorbitol, maltose, sucrose, mannitol, water, Ringer's solution, and isotonic sodium chloride solution. Sterile, fixed oils may also be used as solvents or suspending media. For this purpose, any mild, fixed oil, including synthetic mono- or diglycerides, may be used. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.

[0052] The pharmaceutical compositions of the present invention can also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the compounds of the present invention with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

[0053] Parenteral administration of the pharmaceutical compositions of the present invention is particularly useful when the desired treatment involves areas or organs easily accessible by topical application. For topical application to the skin, the pharmaceutical composition should be formulated in a suitable ointment containing the active ingredient suspended or dissolved in a carrier. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutical compositions of the present invention can be formulated in a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. The pharmaceutical compositions of the present invention can also be applied topically to the lower intestinal tract via rectal suppository or in a suitable enema. Topically applied transdermal patches are also included in the present invention.

[0054] The pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions may be prepared by techniques well known in the art and may be prepared as a solution in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art.

[0055] The relative amounts of the active ingredient, pharmaceutically acceptable excipient, and / or optional additional ingredients in the pharmaceutical composition of the present invention will vary depending on the identity, size, and / or disorder of the subject being treated, and on the route by which the composition is administered. For example, the content of the active ingredient in the pharmaceutical composition of the present invention may be, but is not limited to, 0.0001 to 100% by weight, for example, 0.001 to 50% by weight, more preferably 0.01 to 10% by weight, based on the total weight of the final composition.

[0056] In the present invention, pharmaceutically acceptable excipients include any and all solvents, dispersion media, diluents, or other liquid vehicles, dispersion or suspension aids, surfactants, isotonicity agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, etc., suitable for the purpose of a particular dosage form. Remington's The Science and Practice of Pharmacy, 21st Edition, A.R. Gennaro (Lippincott, Williams & Wilkins, Baltimore, MD, 2006) discloses various excipients used in the preparation of pharmaceutical compositions and known techniques for their manufacture. Any conventional carrier medium is considered within the scope of the present invention, except those that are incompatible with the substance or its derivatives by causing any undesirable biological effects or interacting in a deleterious manner with any other components of the pharmaceutical composition. Pharmaceutically acceptable excipients are at least 95%, 96%, 97%, 98%, 99%, or 100% pure.

[0057] The excipients are approved for human and veterinary use. In some embodiments, the excipients are approved by the U.S. Food and Drug Administration. In some embodiments, the excipients are pharmaceutical grade. In some embodiments, the excipients meet the standards of the United States Pharmacopoeia (USP), the European Pharmacopoeia (EP), the British Pharmacopoeia, and / or the International Pharmacopoeia (EP).

[0058] The term "prevention" as used herein includes preventing or delaying the future appearance of clinical or subclinical symptoms of a condition, disorder or condition in a mammal, particularly in an individual suffering from or susceptible to a condition, disorder or condition, but who has not yet experienced or manifested clinical or subclinical symptoms of the condition, disorder or condition.

[0059] The term "treatment" as used herein means (1) inhibiting a condition, disorder, or pathology (e.g., inhibiting, reducing, or delaying the onset of a disease or, in the case of maintenance treatment, the recurrence of at least one clinical or subclinical symptom); and / or (2) Alleviating the condition, disorder, or pathological condition (i.e., inducing regression of the condition, disorder, or pathological condition, or at least one of its clinical or subclinical symptoms).

[0060] The benefit to the patient receiving the treatment is statistically significant or at least perceptible to the patient and / or physician. However, one of ordinary skill in the art will recognize that when a drug is administered to a patient to treat a disease, the result is not always effective treatment.

[0061] Although the pharmaceutical compositions provided herein are primarily intended for administration to humans, those skilled in the art will understand that such compositions are generally suitable for administration to all types of animals. That is, the pharmaceutical compositions according to the present invention can also be administered to animals requiring veterinary treatment, such as other mammals, including livestock (e.g., dogs, cats, etc.), farm animals (e.g., cows, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). A skilled veterinary pharmacologist, familiar with the modifications of pharmaceutical compositions for administration to various animals, can design and / or perform such modifications, if necessary, with simple routine experimentation.

[0062] The pharmaceutical compositions described herein may be prepared by any method known in the art of pharmacology or as described below. In general, such methods include the step of bringing the active ingredient into association with an excipient and / or one or more other accessory ingredients, followed by, if necessary, shaping and / or packaging the product into the desired single- or multi-dose unit.

[0063] The pharmaceutical compositions of the present invention can be manufactured, packaged, and / or sold in single-dose and / or multiple-dose units, or can be sold unpackaged. As used herein, the term "unit dose" refers to a discrete amount of pharmaceutical composition containing a predetermined amount of active ingredient. The amount of active ingredient is generally the same as the dose of active ingredient administered to a subject and / or a convenient fraction of such a dose, such as 1 / 2 or 1 / 3 of the dose.

[0064] In the present invention, "administration" means introducing a predetermined substance into a patient by an appropriate method, and the administration route of the pharmaceutical composition can be any common route as long as the drug can reach the target tissue. The administration routes include, but are not limited to, intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, intranasal administration, intrapulmonary administration, intrarectal administration, intravaginal administration, intraspinal administration, and intraarticular administration.

[0065] The pharmaceutical composition of the present invention can be administered in a pharmaceutically effective amount. As used herein, the term "pharmaceutically effective amount" can refer to a "therapeutically effective amount," which refers to an amount of a compound or composition (e.g., a compound or composition of the present invention) sufficient to achieve a beneficial or desired result. A pharmaceutically effective amount can be administered in one or more administrations, applications, or dosages, and is not intended to be limited to a particular formulation or route of administration.

[0066] In the present invention, HB α-2,6-SA-IVIG can be administered in a daily dose of about 0.01 μg to 100 μg, preferably about 0.1 μg to 20 μg. The HB α-2,6-SA-IVIG of the present invention showed remarkable effects on canine ophthalmic diseases when instilled at 5 μg / 100 μl per day (2.5 μg / 50 μl twice a day, in PBS solution). However, α-2,6-SA-IVIG is derived from human immunoglobulin and has stronger binding affinity to human DC-SIGN, and when administered to humans, it exhibits exceptionally excellent signal transduction and production of the immunosuppressive cytokine IL-10 (Clin Immunol. 2023 Jan. 246:109215. doi:10.1016 / j.clim.2022.109215).

[0067] Therefore, for human ophthalmic diseases, HB α-2,6-SA-IVIG is expected to have therapeutic effects against xerophthalmia and inflammatory eye diseases at even lower doses, for example, at a daily dose of about 0.1 to 3 μg, preferably about 0.1 to 1 μg.

[0068] However, the effective dose level can be determined by factors including the severity of the disease, the activity of the drug, the age, weight, health, sex, and drug sensitivity of the patient, the administration time, route of administration, and excretion rate of the composition of the present invention used, the duration of treatment, drugs used in combination with or simultaneously with the composition of the present invention used, and other factors well known in the medical field.

[0069] The pharmaceutical composition of the present invention can be administered as an individual therapeutic agent or in combination with other therapeutic agents, and can be administered sequentially or simultaneously with conventional therapeutic agents. It can also be administered in a single dose or multiple doses. Taking all of the above factors into consideration, it is important to administer an amount that provides maximum efficacy with minimal side effects.

[0070] The dosage of the pharmaceutical composition of the present invention can be determined by one skilled in the art taking into consideration the purpose of use, the severity of the disease, the age, weight, sex, medical history of the patient, or the type of substance used as an active ingredient.

[0071] In another aspect, the present invention relates to an ophthalmic composition comprising an α-2,6-sialylated immunoglobulin. In the present invention, the ophthalmic composition is characterized by being in a liquid dosage form (e.g., an aqueous liquid dosage form) or an ointment dosage form, but is not limited thereto.

[0072] The ophthalmic composition may be formulated as a solution, ointment, or gel. In one embodiment, the ophthalmic composition is a composition for artificial tears. In yet another aspect, the present invention relates to a method for preventing or treating xerophthalmia or an inflammatory eye disease, comprising administering the α-2,6-sialylated immunoglobulin or the pharmaceutical composition to a subject in need thereof.

[0073] In the present invention, the subject may be a human or a non-human animal. In the present invention, the α-2,6-sialylated immunoglobulin or pharmaceutical composition is characterized in that it is administered simultaneously, separately, or sequentially with other therapeutic agents for dry eye syndrome or inflammatory eye diseases.

[0074] In yet another aspect, the present invention relates to use of α-2,6-sialylated immunoglobulin or the pharmaceutical composition for preventing or treating xerophthalmia or inflammatory eye diseases.

[0075] In yet another aspect, the present invention relates to use of an α-2,6-sialylated immunoglobulin or the pharmaceutical composition for the manufacture of a medicament for the prevention or treatment of dry eye syndrome or an inflammatory eye disease.

[0076] With respect to the above-mentioned treatment methods and uses, the explanations regarding the pharmaceutical compositions shall apply mutatis mutandis unless mutually inconsistent. As used herein, the terms "individual," "patient," and "subject" are used interchangeably and include any animal, including mammals, e.g., mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, including humans. As used herein, the terms "about" or "approximately" mean within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean within 1 or more standard deviations, according to practice in the art. Alternatively, "about" can mean within 20% or less, 10% or less, 5% or less, or 1% or less of a given value or range. Alternatively, particularly in the context of biological systems or processes, the term can mean within 5-fold or 2-fold magnitude of a particular value. When particular values ​​are described in the present application and claims, unless otherwise specified, it should be assumed that the term "about" means within an acceptable error range for the particular value.

[0077] Example The present invention will be described in more detail below with reference to examples. It will be apparent to those skilled in the art that these examples are merely for illustrative purposes and are not intended to limit the scope of the present invention.

[0078] Example 1. Separation of HB α-2,6-SA-IVIG from IVIG Commercially available IVIG preparations in clinical use contain a mixture of various immunoglobulin forms (e.g., IgG1, IgG2, IgG3) and over 300 different glycosylation patterns. We have established a method to separate HB α-2,6-SA-IVIG from the mixed IVIG (Fig. 1a).

[0079] The experimental materials were purchased from the following sources: SNA lectin (Vector, Cat. #: AL-1303) and Econo-column (Bio-Rad, Cat. #: 7371007). The wash buffer contained 1X TBS and 0.1 mM CaCl2 and was stored at 4°C after filtration. Elution buffer (1) (0.5 M lactose in TBS) and elution buffer (2) (0.5 M lactose in acetic acid) were dissolved at 56°C and then cooled to -20°C or -80°C. The agarose-bound SNA lectin was washed with TBS before use, and 2 ml of the washed agarose-bound SNA lectin was added to the column. IVIG was diluted to 20 mg / 2 ml with TBS and 0.1 mM CaCl2. The diluted IVIG (20 mg / 2 ml) was then applied to the agarose-bound SNA lectin, allowing the beads to float. The beads were then incubated at room temperature for 10 minutes, and the passed-through material (2 ml, 2,6 SA(-)-IVIG) was collected. The collected material was washed with 4 ml of TBS and 0.1 mM CaCl2 and gently added to prevent the beads from floating. The passed-through material was then collected and washed with 4 ml of TBS and 0.1 mM CaCl2 and gently added to prevent the beads from floating. The passed-through material was then collected for a second wash, and 2 ml of 0.5 M lactose dissolved in TBS (elution buffer (1)) was added and incubated at room temperature for 10 minutes. The beads were then added so that they were floating, and the passed-through material was collected and eluted. 2 ml of 0.5 M lactose dissolved in 0.2 M acetic acid (elution buffer (2)) was added and incubated at room temperature for 10 minutes. The beads were then added so that they were floating, and the passed-through material was collected and eluted. The beads were then washed several times with 4 ml of TBS and 0.1 mM CaCl2.

[0080] The fractions were dialyzed against PBS and concentrated using a centrifugal filter (10 kDa, Amicon, Millipore). The fractions were then concentrated to 1 ml with PBS three times the fraction volume. After the fractions reached approximately 1 ml, 10 ml of PBS was added and the concentration was continued until the final volume was 0.5 ml (2000 rcf, 4°C).

[0081] The sialylation of HB α-2,6-SA-IVIG was confirmed by Western blot analysis using biotin-polymerized Sambucus Nigra Lectin (SNA) (Vector, USA) at each stage of isolating HB α-2,6-SA-IVIG from human blood-derived mixed IVIG purchased from SK and Green Cross using the procedure described above. Results confirmed that HB α-2,6-SA-IVIG with increased sialylation from the IVIG raw materials of the two companies was collected only in the elution and post-elution fractions (both the heavy and light chains of HB α-2,6-SA-IVIG were observed to have bands larger in size than IVIG).

[0082] Example 2: Confirmation of therapeutic effect in experimental rabbit animals with dry eye syndrome 2-1. Confirmation of DC-SIGN expression in rabbit conjunctiva Conjunctiva, liver, spleen, and lymph nodes were collected from rabbits (CoreTech, Korea). Total RNA was isolated using RNAiso Plus (Takara) according to the manufacturer's instructions. The isolated RNA was quantified and cDNA was synthesized using High-Capacity cDNA Reverse Transcription Kits (appliedbiosystems). 1 μl of the synthesized cDNA was mixed with 0.2 mM of each gene-specific primer, and the resulting mixture was then diluted with Platinum. TM PCR was performed using II Taq Hot-Start DNA polymerase. PCR was performed by repeating 35 cycles of 94°C for 15 seconds, 60°C for 15 seconds, and 68°C for 15 seconds. The resulting PCR products were electrophoresed on a 2% agarose gel and stained with ethidium bromide to confirm the expression level of each gene.

[0083] Rabbit DC-SIGN amplification primers F: 5'-TGTGCTTCACGCTGTTCACT-3' R: 5'-CTCCTCAGCACTTTGGACGA-3' Rabbit GAPDH amplification primers F:5'-TGACGACATCAAGAAGGTGGTG-3' R: 5'-GAAGGTGGAGGAGTGGGTGGC-3' As a result, we confirmed that DC-SIGN was expressed not only in the spleen and lymph nodes of rabbits, but also in the conjunctival tissue (Figure 2).

[0084] 2-2. Construction of a rabbit experimental animal model of xerophthalmia and drug treatment An experimental rabbit model of xerophthalmia was established by treating the rabbit's eyeballs with 0.2% benzalkonium chloride (Figure 3).

[0085] The rabbits were then randomly divided into three groups of five rabbits each: the control group (0.9% saline-treated group), test group 1 (0.4% IVIG (4 mg / mL in 0.9% saline)), and test group 2 (0.04% HB α-2,6-SA-IVIG (4 mg / mL in 0.9% saline)). Each eye drop was instilled twice daily for a total of 20 days, and all groups also received antibiotic eye drops. The volume of each eye drop was 100 μl (IVIG: 400 μg, α-2,6-SA-IVIG: 40 μg). The total dose was 16 mg of IVIG (0.8 mg / 200 μl / day for 20 days) and 1.6 mg of HB α-2,6-SA-IVIG (0.08 mg / 200 μl / day for 20 days).

[0086] Rabbit corneas were collected on days 0, 7, 14, 19, 24, 29, and 34 (amount collected per collection: 0.15 mm 2 ) 2-3. Analysis of the anti-inflammatory cytokine induction effect of α-2,6-SA-IVIG HB α-2,6-SA-IVIG was administered to a rabbit experimental model of xerophthalmia, and changes in the expression levels of anti-inflammatory cytokines IL-10, MMP-9, and TGF-β were examined.

[0087] Total RNA was isolated from the rabbit corneas collected in Example 2-2 using RNAiso Plus (Takara) according to the manufacturer's instructions. The isolated RNA was quantified and then cDNA was synthesized using High-Capacity cDNA Reverse Transcription Kits (appliedbiosystems). 1 μl of the synthesized cDNA was mixed with 0.2 mM of each gene-specific primer, and the resulting mixture was diluted with Platinum TM PCR was performed using II Taq Hot-Start DNA polymerase. PCR was performed by repeating 35 cycles of 94°C for 15 seconds, 60°C for 15 seconds, and 68°C for 15 seconds. The resulting PCR products were electrophoresed on a 2% agarose gel and stained with ethidium bromide to confirm the expression level of each gene.

[0088] Rabbit IL-10 amplification primers F: 5'-GAGAACCACAGTCCAGCCAT-3' R: 5'-CATGGCTTTGTAGACGCCTT-3' Rabbit MMP9 amplification primers F: 5'-GAGTACCTGTTCCGCTATG-3' R:5'-TGCCACTTGAGGTCACCCTCGAA-3' Rabbit TGF-β amplification primers F:5'-TGGCTGAACAACACATAGAACTG-3' R: 5'-ACGCAGGCAGCAATTATCCT-3' As a result, when a rabbit model of dry eye was treated with IVIG, no increase in IL-10 was observed compared to the control group. However, when HB α-2,6-SA-IVIG was treated, an increase in IL-10 was observed on the 5th day after instillation, even though the dose was 1 / 10 of that of IVIG, and IL-10 increased significantly on the 20th day after instillation. It was found that HB α-2,6-SA-IVIG in particular exerted an effective anti-inflammatory effect.

[0089] Furthermore, MMP-9 in tears promotes the shedding of corneal and conjunctival epithelial cells, inducing corneal and conjunctival erosions. Therefore, MMP-9 should be increased early to remove epithelial cells damaged by dry eye syndrome. However, as conjunctival erosions become chronic, keratoconjunctivitis develops, so its level must be reduced later in treatment. When IVIG and HB α-2,6-SA-IVIG were administered to a rabbit model of dry eye syndrome, MMP-9 levels increased up to 5 days after instillation, but decreased to normal levels by 20 days after instillation, confirming that both drugs are suitable for the treatment of dry eye syndrome.

[0090] TGF-β, a substance secreted from tears when the corneal stromal tissue is damaged, is necessary for maintaining corneal integrity and wound healing, but it also induces corneal stromal fibrosis and leads to scar tissue formation. When a rabbit model of xerophthalmia was treated with IVIG and HB α-2,6-SA-IVIG, IVIG continued to increase TGF-β on days 5 and 20 after instillation, while HB α-2,6-SA-IVIG only increased TGF-β on day 5 and then rapidly decreased on day 20. This indicates that HB α-2,6-SA-IVIG is particularly suitable as a therapeutic drug for xerophthalmia (Figure 4).

[0091] 2-4. Confirmation of the therapeutic effect of HB α-2,6-SA-IVIG on xerophthalmia using the NIBUT method As in Example 2-2, the therapeutic effect of dry eye disease was confirmed using the NIBUT (Non-Invasive Break Up Time) mode with SBM Sistemi's OSA-VET in a rabbit experimental model on the 5th, 10th, 15th, and 20th days after instilling the drug into the eyes. The subjects were instructed to blink once and then keep their eyes open without immediately closing them.

[0092] The NIBUT (tear film breakup time test) uses a light to project concentric lines onto the eye, and the machine measures and analyzes the point and time when the lines become irregular. If the light displayed remains in a white spiral for more than 20 seconds, it is diagnosed as normal, and if the white spiral becomes irregular within 20 seconds, it is diagnosed as damage (Figure 5).

[0093] [Table 1]

[0094] The experimental results showed that when IVIG was administered to rabbits with xerophthalmia, all 10 eyes recovered to normal within 15 days, and when HB α-2,6-SA-IVIG was administered, all 10 eyes recovered to normal within 10 days, even at 1 / 10 the amount of IVIG (Table 1).

[0095] 2-5. Confirmation of the therapeutic effect of HB α-2,6-SA-IVIG on xerophthalmia using vital staining method The vital staining method is a method for evaluating damage to the corneal epithelium using fluorescein dye, and as shown in Example 2-2, vital staining experiments were performed on the 5th, 10th, 15th, and 20th days after instillation of the drug in an experimental rabbit model of xerophthalmia.

[0096] A drop of saline was applied to a fluorescein test paper and then placed on the cornea of ​​a rabbit experimental model of xerophthalmia, staining the cornea with fluorescein dye. After carefully rinsing the staining solution with approximately 5 ml of saline, the stained area of ​​the cornea was examined under a slit lamp microscope. In normal eyes, the fluorescein dye was unable to stain the cornea, while the more damaged the eye, the greater the degree of fluorescein dye staining the cornea (Figure 6).

[0097] As a result of the experiment, in a rabbit experimental model of xerophthalmia, when IVIG was instilled, all 10 eyes recovered to normal within 15 days, and when HB α-2,6-SA-IVIG was instilled, all 10 eyes recovered to normal within 15 days at 1 / 10 the amount of IVIG (Table 2).

[0098] [Table 2]

[0099] Example 3. Confirmation of therapeutic effect on inflammatory eye disease in dogs 3-1. Confirmation of DC-SIGN expression in canine conjunctiva Conjunctiva, liver, kidney, and eyelids were collected from dogs (JA BIO, Korea), and total RNA was isolated using RNAiso Plus (Takara) according to the manufacturer's instructions. The isolated RNA was quantified and cDNA was synthesized using High-Capacity cDNA Reverse Transcription Kits (appliedbiosystems). 1 μl of the synthesized cDNA was mixed with 0.2 mM of each gene-specific primer, and the resulting cDNA was then purified using Platinum 1000. TM PCR was performed using II Taq Hot-Start DNA polymerase. PCR was performed by repeating 35 cycles of 94°C for 15 seconds, 60°C for 15 seconds, and 68°C for 15 seconds. The resulting PCR products were electrophoresed on a 2% agarose gel and stained with ethidium bromide to confirm the expression level of each gene.

[0100] Canine DC-SIGN amplification primers F: 5'-CTCCCAGACCCAAAACACCT-3' R: 5'-CTGGCCTTGGGGAGCAAAAG-3' Canine GAPDH amplification primers F: 5'-GTCAAGGCTGAGAACGGGAA-3' R: 5'-CTCCGATGCCTGCTTCACTA-3' As a result, DC-SIGN was expressed in the liver, kidney, eyelid, and conjunctival tissues of dogs, with the expression level being particularly high in the conjunctival tissue (Figure 7).

[0101] For reference, the same PCR experiment was performed using a mouse DCEK cell line (provided by Rockefeller University, USA, after a material transfer agreement (MTA) was executed) that highly expresses human DC-SIGN. The results confirmed that the canine DC-SIGN PCR primers did not recognize human DC-SIGN at all (last lane in Figure 7), further confirming that the canine DC-SIGN PCR primers specifically recognize only canine DC-SIGN.

[0102] 3-2. Confirmation of therapeutic effects on clinical subjects with canine inflammatory eye diseases Canine subjects with ophthalmological disease were recruited to confirm the therapeutic efficacy of HB α-2,6-SA-IVIG, whose therapeutic efficacy for xerophthalmia and non-toxicity were demonstrated in a rabbit animal model of xerophthalmia at a secondary veterinary ophthalmology hospital.

[0103] The canine ophthalmic disease patients were (1) those who were unable to be treated with existing treatments at local hospitals and visited a second-tier ophthalmic veterinary hospital, where treatment with existing treatments was attempted at the second-tier ophthalmic veterinary hospital but was unsuccessful; (2) those who were unable to be treated with existing treatments at local hospitals and visited a second-tier ophthalmic veterinary hospital, where the dog's ophthalmic disease condition was so severe at the time of visiting the second-tier ophthalmic veterinary hospital that it was difficult to try existing treatments again; and (3) those whose ophthalmic disease was so severe that they visited a second-tier ophthalmic veterinary hospital without visiting a local hospital, where treatment with existing treatments was attempted but was unsuccessful.Specific cases are summarized in Table 3 below.

[0104] [Table 3]

[0105] Eight canine patients with ophthalmic diseases were administered HB α-2,6-SA-IVIG according to the present invention at a dose of 5 μg / 100 μl per day (2.5 μg / 50 μl twice a day, solution in PBS) in combination with the appropriate treatment doses according to the guidelines for existing therapeutic drugs. As a result, significant therapeutic effects were observed in all canine patients with ophthalmic diseases (Table 4, Figures 8a to 8h).

[0106] [Table 4] JPEG2025542423000006.jpg230170

[0107] Although specific aspects of the present invention have been described in detail above, it is clear to those skilled in the art that these specific techniques are merely preferred embodiments and should not be construed as limiting the scope of the present invention. Therefore, the true scope of the present invention should be defined by the appended claims and their equivalents.

[0108] Issue information [Project unique number]1345350798 [Project number] 2016R1D1A1B01012721 [Department name] Education Department [Name of issue management (specialized) organization] Korea Research Foundation [Research project name] Individual basic research (Ministry of Education) [Research title] Research into IVIG alternatives that induce anti-inflammatory effects mediated by DC-SIGN [Contribution rate] 1 / 2 [Name of the organization carrying out the project] Konkuk University [Research Period] 2021.03.01~2022.02.28

[0109] [Project unique number]1711191936 [Project number] 2022R1A2C1009466 [Department name] Ministry of Science, ICT and Communication [Name of issue management (specialized) organization] Korea Research Foundation [Research project name] Individual basic research (Ministry of Science, Technology, Information and Communication) [Research title] Development of anti-inflammatory antibody therapeutics using ST6GAL1 genetically engineered myeloma cell lines [Contribution rate] 1 / 2 [Name of the organization carrying out the project] Konkuk University [Research Period] 2022-03-01~2025-02-28

Claims

1. A pharmaceutical composition for preventing or treating xerophthalmia or inflammatory eye diseases, comprising a sialylated immunoglobulin.

2. 2. The pharmaceutical composition of claim 1, wherein the immunoglobulin is isolated from intravenous immunoglobulin (IVIG).

3. 2. The pharmaceutical composition according to claim 1, wherein the sialylated immunoglobulin is α-2,6-sialylated immunoglobulin.

4. 2. The pharmaceutical composition according to claim 1, wherein the inflammatory eye disease is an inflammatory eye disease of the eyeball, the surface of the eyeball, the posterior surface of the eyeball, or the peri-ocular area.

5. 5. The pharmaceutical composition of claim 4, wherein the inflammatory eye disease is any one or more selected from the group consisting of stye, blepharitis, wiper's epitheliopathy of the eyelid, chalazion, eyelid infection, keratitis, conjunctivitis, anterior uveitis, corneal ulcer, conjunctival ulcer, iridocyclitis, scleritis, optic neuritis, retinal vasculitis, chronic vasculitis, posterior uveitis, panuveitis, meibomianitis, and dacryoadenitis.

6. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is administered in combination with other therapeutic agents for dry eye syndrome or inflammatory eye diseases.

7. 7. The pharmaceutical composition according to claim 6, wherein the other therapeutic agent for dry eye syndrome or inflammatory eye disease is any one or more selected from the group consisting of anti-inflammatory agents, immunosuppressants, anti-glaucoma drugs, artificial tears, lacrimation promoters, and antibiotics.

8. The pharmaceutical composition according to claim 7, wherein the pharmaceutical composition is in the form of an eye drop liquid or ointment.

9. The α-2,6-sialylated immunoglobulin has the following properties compared to general intravenous immunoglobulin: (i) increasing the expression level of the anti-inflammatory cytokine IL-10 in ocular cells by 50% or more; and / or (ii) The pharmaceutical composition according to claim 3, characterized in that it does not induce side effects of corneal stromal tissue fibrosis.

10. An ophthalmic composition comprising an α-2,6-sialylated immunoglobulin.

11. The ophthalmic composition according to claim 10, wherein the ophthalmic composition is in the form of a liquid or ointment.

12. The ophthalmic composition according to claim 10, wherein the ophthalmic composition is an artificial tear.

13. 10. A method for treating xerophthalmia or inflammatory eye disease in a non-human animal, comprising administering to an animal in need thereof a pharmaceutical composition according to any one of claims 1 to 9.

14. The method of claim 13, wherein the pharmaceutical composition is administered simultaneously, separately, or sequentially with other therapeutic agents for dry eye syndrome or inflammatory eye diseases.

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