Ophthalmic Formulation, Its Use, and Kit

Description

1 / 89 Ophthalmic Formulation, Its Use, and Kit. Separated from BR112021008548-3, filed on November 8, 2019. CROSS-REFERENCE TO RELATED REQUESTS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 757,641, filed November 8, 2018, and U.S. Provisional Patent Application No. 62 / 855,253, filed May 31, 2019, which are incorporated herein by reference in their entirety. STATEMENT REGARDING RESEARCH FUNDED BY THE FEDERAL GOVERNMENT

[0002] This disclosure was made with the support of the government under grant number R01 EY024966 granted by the National Eye Institute (NEI) / National Institutes of Health (NIH). The government has certain rights to the disclosure. FIELD OF DISSEMINATION

[0003] This disclosure refers to an ophthalmic formulation capable of reducing the concentration or deleterious actions of autoantibodies on the ocular surface and / or inside the eye to prevent or treat inflammatory, immunological, allergic, infectious and traumatic diseases of the ocular surface and / or intraocular eye diseases. BACKGROUND OF THE DISCLOSURE

[0004] Inflammatory, immunological, allergic, infectious, and traumatic diseases of the ocular surface and intraocular structures can cause various signs and symptoms, including, but not limited to, ocular discomfort, ocular redness, dry eye syndrome, conjunctivitis, keratitis, symblepharon formation, fornix eshortening, keratinization of the palpebral / conjunctival margin, and subconjunctival fibrosis. More specific types of ocular surface diseases include ocular graft-versus-host disease (oGVHD), Stevens-Johnson syndrome, and pemphigoid. Petition 870260076737, dated 07 / 31 / 2026, page 8 / 256 2 / 89 ocular cicatricial eye disease (OCP), mild, moderate and severe dry eye disease due to lacrimal deficiency (DED), meibomian gland disease, ocular rosacea, hordeolum, blepharitis, superior limbic keratoconjunctivitis (SLK), DED due to lacrimal sufficiency, floppy eyelid syndrome, neurotrophic eye disease, signal-symptom disconnection (discordant DED), neuropathic pain, thyroid eye disease (Grave's ophthalmopathy), rheumatoid arthritis-related eye disease, lupus-related eye disease, Sjögren's syndrome, secondary Sjögren's syndrome, ocular rosacea, allergic (vernal) keratoconjunctivitis, viral keratoconjunctivitis (adenovirus EKC, herpesvirus), Thygeson's keratitis, aniridia, keratitis or a postoperative / posttraumatic condition, peripheral ulcerative keratitis, keratitis, episcleritis, Scleritis, retinal gliosis, uveitis (anterior or posterior), and glaucoma (open angle, or closed angle, or normal tension).

[0005] Conventional treatments for some of these ocular surface diseases, particularly dry eye syndrome, include (i) instillation of artificial tears for tear supplementation and stimulation and (ii) the use of anti-inflammatory drugs to reduce ocular surface inflammation. Generally, current dry eye treatment involves topical application of artificial tear products / lubricants, tear retention management, tear secretion stimulation, topical application of antibiotics (e.g., erythromycin or bacitracin ointments), oral administration of tetracyclines (e.g., tetracycline, doxycycline, or minocycline), application of anti-inflammatory compounds, and corticosteroids. Conventional treatments for some intraocular diseases include (i) treatments to reduce intraocular pressure and (ii) intraocular steroid injections.These treatments are often lengthy, frustrating, and frequently ineffective or of variable effectiveness. Furthermore, Petition 870260076737, dated 07 / 31 / 2026, page 9 / 256 3 / 89 Although conventional treatment is effective in reducing the symptoms of dry eye syndrome to some extent, it has many undesirable side effects, such as burning and stinging sensations. Reducing local side effects and increasing patient comfort and response to treatment is one of the objectives of this publication.

[0006] Another weakness of conventional treatment for ocular surface disease is the inconsistent absorption of active pharmaceutical ingredients into corneal cells and their residence time in the cornea to effectively treat ocular surface disease syndrome without continuous application. While ointment or cream formulations may allow for a longer residence time, such formulations may not break through the stratum corneum (superficial cornified layers of the skin) and may not reach the blood vessels and nerves that are present deeper in the eyelid tissue.

[0007] Yet another problem associated with conventional treatment is that no underlying cause has been directly addressed. Discovering the cause of ocular surface diseases allows for more effective treatment. Conventional treatments mostly only treat the symptoms of ocular surface disease.

[0008] Consequently, there is a continuing need for diagnostic kits, compositions, and methods for the effective treatment of clinical conditions associated with ocular surface and intraocular diseases. Furthermore, it is necessary to address the underlying cause of ocular surface and intraocular disease. SUMMARY OF THE DISCLOSURE

[0009] Some aspects of the disclosure provide an ophthalmic formulation comprising: (a) one or more pharmaceutically acceptable ophthalmic excipients and (b) an immunoglobulin G (IgG) or a fragment thereof. Petition 870260076737, dated 07 / 31 / 2026, p. 10 / 256 4 / 89

[0010] Some aspects of the disclosure provide an ophthalmic formulation comprising: (a) one or more pharmaceutically acceptable ophthalmic excipients and (b) combined plasma-derived human immunoglobulin G (IgG).

[0011] In addition, the disclosure provides an ophthalmic formulation comprising: (a) one or more pharmaceutically acceptable ophthalmic excipients and (b) a pharmaceutically active ocular compound for the treatment of a selected clinical condition from the group consisting of inflammatory, infectious, immunological, allergic and / or traumatic ocular surface disease or intraocular disease, wherein the pharmaceutically active compound comprises IgG.

[0012] In several respects, the disclosure provides an ophthalmic formulation comprising a pharmaceutically active compound capable of reducing the amount or deleterious biological effects of autoantibodies on the ocular surface or within the eye, such autoantibodies being generated in response to a citrullinated protein (referred to herein as ACPA autoantibodies that are generated in response to protein citrullination) or an autoantibody generated in response to a homocitrulinated protein (referred to herein as anti-CarP antibodies that are generated in response to protein carbamylation) – or native autoantibodies generated in response to native proteins. Citrullination and carbamylation are two types of post-translational modification (PTM) of proteins. In related respects, the pharmaceutically active compound comprises immunoglobulin G (IgG) or a fragment thereof.These ophthalmic formulations may also comprise one or more pharmaceutically acceptable ophthalmic excipients.

[0013] In several respects, the disclosed ophthalmic formulations comprise one or more of the pharmaceutical ophthalmic excipients Petition 870260076737, dated 07 / 31 / 2026, page 11 / 256 5 / 89 acceptable. For example, pharmaceutically acceptable ophthalmic excipients are selected from cyclodextrins, carbopol, or carbomer or acrylic acid polymers, poloxamers, xyloglucan, methylcellulose, hydroxypropylmethylcellulose, ethyl (hydroxyethyl) cellulose, pseudolatoxes, cellulose acetate phthalate, gellan gum, alginate, carrageenans, hyaluronic acid, sodium acetate, disodium edetate, hypromellose, acetic acid, alcohol, alginic acid, amerchol-cab, antipyrine, benzalkonium chloride, benzododecinium bromide, boric acid, caffeine, calcium chloride, carbomer 1342, carbomer 934P, carbomer 940, type B carbomer homopolymer (crosslinked allyl pentaerythritol), sodium carboxymethylcellulose, castor oil, cetyl alcohol, chlorobutanol, citric acid, citric acid monohydrate, creatinine, divinylbenzene styrene copolymer, ethylene vinyl acetate copolymer, gellan gum (low acyl), glycerin, glyceryl stearate, hypromellose,lanolin, lauraconium chloride, lauroyl sarcosine, magnesium chloride, methylparaben, mineral oil, nonoxynol-9, octoxinol-40, petrolatum, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric nitrate, polyhydronium chloride, poloxamer 188 or 407, polycarbophil, polyethylene glycol 400 or 8000, polyoxyl 35 castor oil, hydrogenated polyoxyl 40 castor oil, polyoxyl 40 stearate castor oil, polypropylene glycol, polysorbate 20, polyvinyl alcohol, potassium chloride, potassium sorbate, povidone K29 / 32, povidone K30, povidone K90, povidones, propylene glycol, propylparaben, sodium ash, sodium acetate, sodium bisulfate, borate sodium decahydrate, sodium carbonate, sodium chloride, sodium citrate, sodium metabisulfite, sodium nitrate, sodium sulfate, sodium sulfite, sodium thiosulfate, sorbic acid, sorbitol, stabilized oxychloro complex, sulfuric acid, thimerosal, titanium dioxide, tocofersolan, dehydrated trisodium citrate,tromethamine, tyloxapol, xanthan gum, zinc chloride, or a combination thereof.

[0014] Yet another aspect of disclosure provides a formulation Petition 870260076737, dated 07 / 31 / 2026, p. 12 / 256 6 / 89 ophthalmic comprising (a) a pharmaceutically acceptable ophthalmic excipient; (b) a therapeutically effective amount of a pharmaceutically active compound comprising combined human immunoglobulin G (IgG) and / or (c) a therapeutically effective amount of combined human plasma proteins, combined human plasma lipids or a combination thereof. As used in this document, the term therapeutically effective includes having an immunomodulatory effect or the ability to neutralize autoantibodies.

[0015] In any of the disclosed ophthalmic formulations, the pharmaceutically active compound may comprise purified autologous IgG from autologous plasma / serum; a multimerized IgG1 Fc molecule, an IgG1 Fc hexamer; IgG2a Fc multimers, estradomers; multivalent Fc structures; genetically engineered glycosylated sialylated IgG; IgG-Fc glycosylation; Synthetic IgG and fragments thereof, or a combination thereof.

[0016] In several respects, any of the disclosed ophthalmic formulations may further comprise a second pharmaceutically active compound selected from a steroid, an anti-inflammatory agent such as methylprednisone, prednisone, dexamethasone, cyclosporine, Lifitegrast®, a non-steroidal anti-inflammatory drug, a mucolytic agent such as N-acetylcysteine, nacysteine, N-acetylglucosamine, a PAD enzyme inhibitor such as paclitaxel, glucocorticoids or Cl-amidine or a NET dismantling agent (DNase or heparin), targeted Fab antibody fragments, Fc receptor blocking peptides, Fc receptor blocking antibodies, recombinant peptide containing pathogenic epitopes, conventional synthetic DMARDs (methotrexate, leflunomide / teriflunomide, sulfasalazine, chloroquine / hydroxychloroquine), TNF-α-targeted therapy (infliximab, adalimumab, etanercept, golimumab, certolizumab pegol), therapy Petition 870260076737, dated 07 / 31 / 2026, page 13 / 256 7 / 89 targeted B-cell therapy (rituximab, ofatumumab, belimumab, atacicept, talamumab), T-cell targeted therapy (abatacept, belatacept), interleukin-targeted therapy (tocilizumab, anakinra, canakinumab, rilonacept, secukinumab), growth and differentiation factors (denosumab, mavrilimumab), JAK pathway inhibitors (tofacitinib, baricitinib, filgotinib), and a combination thereof.

[0017] In some forms, the concentration or quantity of The IgG present in the aforementioned ophthalmic formulation varies from approximately 0.01 mg / ml by weight to approximately 1 g / ml (1,000 mg / ml) by weight, for example, or from approximately 0.05 mg / ml by weight to approximately 1 g / ml by weight, or from approximately 0.1 mg / ml by weight to approximately 1 g / ml, or from approximately 0.1 mg / ml by weight to approximately 0.5 mg / ml, or 0.05 mg / ml by weight to approximately 0.5 mg / ml by weight, or 0.01 mg / ml by weight to approximately 0.1 mg / ml by weight. In certain embodiments, the concentration or quantity of IgG may be approximately 0.01 mg / ml; in other embodiments, the concentration or quantity of IgG may be approximately 0.05 mg / ml. In certain modalities, the concentration or quantity of IgG may be around 1 mg / ml, while in other modalities, the concentration or quantity of IgG may be around 10 mg / ml.

[0018] In various forms, the concentration or quantity of IgG pode ser de cerca de 0,01 mg / ml, 0,02 mg / ml, 0,03 mg / ml, 0,04 mg / ml, 0,05 mg / ml, 0,06 mg / ml, 0,07 mg / ml, 0,08 mg / ml, 0,09 mg / ml, 0,1 mg / ml, 0,15 mg / ml, 0,2 mg / ml, 0,25 mg / ml, 0,3 mg / ml, 0,35 mg / ml, 0,4 mg / ml, 0,45 mg / ml, 0,5 mg / ml, 0,55 mg / ml, 0,6 mg / ml, 0,65 mg / ml, 0,7 mg / ml, 0,75 mg / ml, 0,8 mg / ml, 0,85 mg / ml, 0,9 mg / ml, 0,95 mg / ml, 1,0 mg / ml, 1,5 mg / ml, 2,0 mg / ml, 2,5 mg / ml, 3,0 mg / ml, 3,5 mg / ml, 4 mg / ml, 4,5 mg / ml, 5 mg / ml, 5,5 mg / ml, 6 mg / ml, 6,5 mg / ml, 7 mg / ml, 7,5 mg / ml, 8 mg / ml, 8,5 mg / ml, 9 mg / ml, 9,5 mg / ml, 10 mg / ml, 20 mg / ml, 30 mg / ml, 40 mg / ml, 50 mg / ml, 60 mg / ml, 70 mg / ml, 80 mg / ml, 90 mg / ml, 100 mg / ml, 150 mg / ml, 200 mg / ml, 250 mg / ml, 300 mg / ml, 350 mg / ml, Petição 870260076737, de 31 / 07 / 2026, pág. 14 / 256 8 / 89 400 mg / ml, 450 mg / ml, 500 mg / ml, 550 mg / ml, 600 mg / ml, 650 mg / ml, 700 mg / ml, 750 mg / ml, 800 mg / ml, 850 mg / ml, 900 mg / ml, 950 mg / ml ou 1.000 mg / ml.

[0019] In several exemplary modalities, the quantity of IgG is approximately 10 mg / ml or less. In certain embodiments, the ophthalmic formulation may include an IgG concentration or quantity of approximately 0.1 mg / ml or less, approximately 0.15 mg / ml or less, 0.2 mg / ml, approximately 0.25 mg / ml or less, approximately 0.3 mg / ml or less, approximately 0.35 mg / ml or less, approximately 0.4 mg / ml or less, approximately 0.45 mg / ml or less, approximately 0.5 mg / ml or less, approximately 0.55 mg / ml or less, approximately 0.6 mg / ml or less, approximately 0.65 mg / ml or less, approximately 0.7 mg / ml or less, approximately 0.75 mg / ml or less, approximately 0.8 mg / ml or less, approximately 0.85 mg / ml or less, approximately 0.9 mg / ml or less, approximately 0.95 mg / ml or less, or approximately or 1.0 mg / ml or less.

[0020] The term combined human immunoglobulin G derived from combined plasma refers to unfractionated combined plasma from multiple donors followed by fractionation to separate the immunoglobulin G. This disclosure provides ophthalmic compositions comprising combined plasma from multiple donors that is dispensed unfractionated in single-use droppers or multidose vials in various dilutions based on IgG concentration (0.01% to 10%). Plasma combining can also be done prior to processing steps. This combined plasma and immunoglobulin (PPIG) preparation differs from conventional plasma products (e.g., PRP) in that conventional plasma products are prepared from the blood of one individual, while the PPIG preparation is made from combined plasma from several hundred to thousands of healthy individuals. The final product comprises IgG and plasma proteins. Petition 870260076737, dated 07 / 31 / 2026, page 15 / 256 9 / 89 combined matics, with or without platelets and platelet activation products. Combined plasma-derived IgG may also include plasma lipids.

[0021] In yet another iteration, combined human immunoglobulin G derived from combined plasma (concentration of 0.01% to 10%) from several hundred to thousands of healthy individuals is formulated in plasma or serum (allogeneic or autologous) with ophthalmic excipient (or ophthalmic excipients). This ophthalmic formulation will provide a combination of autoantibody-neutralizing combined IgG and serum / plasma-promoting proteins, cytokines, and growth factors.

[0022] In several respects, the IgG present in any of the disclosed ophthalmic formulations comprises serum / plasma-derived combined immunoglobulin G (OSIG: ocular surface immunoglobulin), multimerized IgG1 Fc molecule (IgG1 Fc hexamer), IgG2a Fc multimers (stradomers), multivalent Fc structures, or a combination thereof.

[0023] In several respects, the IgG present in any of the disclosed ophthalmic formulations is an antigen-binding fragment, in which one or more antibody domains are truncated or absent, genetically modified antibodies or protein-binding fragments thereof, single-chain antibodies or antibodies that can bind to more than one epitope or antibodies that can bind to one or more different antigens. For example, the IgG fragment is an antigen-binding fragment, single-chain antibodies, Fv fragment, Fab fragment, Fab' fragment or F(ab)2 fragment.

[0024] In several respects, the IgG present in any of the disclosed ophthalmic formulations comprises IgG1, IgG2, IgG3 and Petition 870260076737, dated 07 / 31 / 2026, p. 16 / 256 10 / 89 IgG4 or a combination thereof. Alternatively, IgG may include or be derived from any suitable source, such as IgG-containing stem cell preparations, IgG stem cells or cells manufactured with IgG, genetically modified glycosylated IgG, IgG-Fc glycosylation or the like, or a combination thereof.

[0025] In several respects, the IgG present in any of the disclosed ophthalmic formulations comprises a pre-selected concentration of autologous IgG purified from autologous plasma / serum using a separation process, such as affinity chromatography using protein A beads or other IgG separation process.

[0026] In several respects, the IgG present in any of the disclosed ophthalmic formulations neutralizes an autoimmune antibody or an antibody that specifically binds to a citrulated protein.

[0027] In several respects, the pH of any of the disclosed ophthalmic formulations is from about pH 6 to about pH 8, or from about pH 6.2 to about pH 7.2, from about pH 6.4 to about pH 7.4, or from about pH 6.5 to about pH 7.5, from about pH 6.6 to about pH 7.6, from about pH 6.8 to about pH 7.8. For example, the pH is approximately 6.0 or approximately 6.1, or approximately 6.2, or approximately 6.3, or approximately 6.4, or approximately 6.5, or approximately 6.6, or approximately 6.7, or approximately 6.8, or approximately 6.9, or approximately 7.0, or approximately 7.1, or approximately 7.2, or approximately 7.3, or approximately 7.4, or approximately 7.5, or approximately 7.6, or approximately 7.7, or approximately 7.8, or approximately 7.9, or approximately 8.0.

[0028] In several respects, any of the disclosed ophthalmic formulations comprises one or more pharmaceutically acceptable excipients comprising polyvinyl alcohol, povidone, hydroxypropylmethylcellulose, poloxamers, polyols, carbopol, pluronic acid, carbomers, Petition 870260076737, dated 07 / 31 / 2026, page 17 / 256 11 / 89 carboxymethylcellulose, hydroxyethylcellulose, cyclodextrins, phosphate buffer, citrate buffer, tris buffer, sodium chloride, potassium chloride, polysorbate 80, vegetable oil, preservative or a combination thereof.

[0029] Any of the disclosed ophthalmic formulations can be used to treat an inflammatory, infectious, or immune disease of the mucosa or to exhibit an immunomodulatory effect on the mucosa. The ophthalmic formulations can treat an inflammatory, infectious, or immune disease or have an immunomodulatory effect on the mucosa in the oral cavity, nasal cavity, bladder, tracheobronchial passages, ear cavity and canal, synovial cavity (joint), vaginal cavity, or on the skin.

[0030] In several respects, the disclosed ophthalmic formulation comprises multidose vials with preservative or a sterile single-dose container without preservative.

[0031] In several respects, the disclosure provides a method of treating a clinical condition in a patient in need comprising a step of administering to the patient an ophthalmic formulation as disclosed herein, wherein the clinical condition is an inflammatory disease of the ocular surface or intraocular eye diseases, an infectious disease of the ocular surface or intraocular eye diseases, and / or an immunological disease of the ocular surface or intraocular eye disease. In several respects, the disclosure provides a method of treating an inflammatory, infectious, and / or immunological eye disease in a patient in need comprising a step of administering to a patient an ophthalmic formulation as disclosed herein.

[0032] In several respects, disclosure provides a method to reduce, alleviate, or prevent eye discomfort in a patient who so Petition 870260076737, dated 07 / 31 / 2026, page 18 / 256 12 / 89 fre of a clinical condition comprising a step in administering to the patient an ophthalmic formulation disclosed in this document, wherein the clinical condition is an inflammatory disease of the ocular surface or intraocular eye diseases, an infectious disease of the ocular surface or intraocular eye diseases, and / or an immunological disease of the ocular surface or intraocular eye disease. In any of these methods, ocular discomfort comprises one or more of the following: foreign body sensation, light sensitivity, burning, irritation, pain, dryness, stinging, redness, itching, or pruritus.

[0033] The disclosure provides a method of treating a clinical condition in a patient in need comprising a step of administering to the patient an ophthalmic formulation, as disclosed in this document, wherein the clinical condition is an inflammatory, infectious and / or immune disease of the mucosa of the oral cavity, nasal cavity, bladder, tracheobronchial passages, ear cavity and canal, synovial cavity (joint), vaginal cavity or on the skin.

[0034] The disclosure also provides a method for inducing an immunomodulatory effect on the mucosa in a patient in need, comprising a step of administering to the patient an ophthalmic formulation, as disclosed in this document, wherein the mucosa is in the oral cavity, nasal cavity, bladder, tracheobronchial passages, ear cavity and canal, synovial cavity (joint), vaginal cavity or on the skin.

[0035] The disclosure also provides for the use of any of the ophthalmic formulations for the preparation of a medicament for the treatment of a clinical condition in a patient in need, wherein the clinical condition is an inflammatory disease of the ocular surface or intraocular eye diseases, an infectious disease of the surface Petition 870260076737, dated 07 / 31 / 2026, page 19 / 256 13 / 89 ocular or intraocular eye diseases and / or an immunological disease of the ocular surface or intraocular eye disease. In several respects, the disclosure provides for the use of any of the ophthalmic formulations for the preparation of a medicament to reduce, relieve or prevent ocular discomfort in a patient suffering from a clinical condition, wherein the clinical condition is an inflammatory disease of the ocular surface or intraocular eye diseases, an infectious disease of the ocular surface or intraocular eye diseases and / or an immunological disease of the ocular surface or intraocular eye disease. In any of these uses, ocular discomfort comprises one or more of a foreign body sensation, pain, light sensitivity, burning, irritation, discomfort, dryness, stinging, redness, itching or pruritus.

[0036] The disclosure also provides for the use of an ophthalmic formulation disclosed in this document for the preparation of a medicament for the treatment of a clinical condition in a patient in need, wherein the clinical condition is an inflammatory, infectious and / or immune disease of the mucosa of the oral cavity, nasal cavity, bladder, tracheobronchial passages, ear cavity and canal, synovial cavity (joint), vaginal cavity or on the skin. Furthermore, the disclosure provides for the use of an ophthalmic formulation disclosed in this document for the preparation of a medicament to induce an immunomodulatory effect on the mucosa in a patient in need, wherein the mucosa is in the oral cavity, nasal cavity, bladder, tracheobronchial passages, ear cavity and canal, synovial cavity (joint), vaginal cavity or on the skin.

[0037] The disclosure also provides compositions comprising any of the ophthalmic formulations described in this document for use in the treatment of a clinical condition. In several respects, the compositions can be used to treat an occidental disease. Petition 870260076737, dated 07 / 31 / 2026, p. 20 / 256 14 / 89 inflammatory, infectious and / or immunological conditions in a patient in need. In many respects, the compositions comprising any of the ophthalmic formulations described in this document may be used to reduce, alleviate or prevent ocular discomfort in a patient suffering from a clinical condition, wherein the clinical condition is an inflammatory disease of the ocular surface or intraocular eye diseases, an infectious disease of the ocular surface or intraocular eye diseases and / or an immunological disease of the ocular surface or intraocular eye disease. In related respects, ocular discomfort comprises one or more of a foreign body sensation, pain, light sensitivity, burning, irritation, discomfort, stinging, dryness, redness, itching or pruritus.

[0038] The disclosure provides a composition for the treatment of a clinical condition in a patient in need, wherein the composition comprises an ophthalmic formulation, as disclosed herein, in which the clinical condition is an inflammatory, infectious and / or immune disease of the mucosa of the oral cavity, nasal cavity, bladder, tracheobronchial passages, ear cavity and canal, synovial cavity (joint), vaginal cavity or on the skin. Furthermore, the disclosure provides a composition for inducing an immunomodulatory effect on the mucosa in a patient in need, wherein the composition comprises an ophthalmic formulation, as disclosed herein, in which the mucosa is in the oral cavity, nasal cavity, bladder, tracheobronchial passages, ear cavity and canal, synovial cavity (joint), vaginal cavity or on the skin.

[0039] Exemplary clinical conditions treatable according to the exemplary methods, uses and compositions of this document include, but are not limited to, immune eye disease, metabolic eye disease, allergic eye disease, traumatic eye disease, disease. Petition 870260076737, dated 07 / 31 / 2026, page 21 / 256 15 / 89 Infectious ocular and genetic eye disease, such as, but not limited to, ocular graft-versus-host disease (oGVHD), Stevens-Johnson syndrome, ocular cicatricial pemphigoid (OCP), mild, moderate and severe dry eye disease due to lacrimal deficiency (DED), meibomian gland disease, hordeolum, ocular rosacea, blepharitis, superior limbic keratoconjunctivitis (SLK), DED due to lacrimal sufficiency, floppy eyelid syndrome, neurotrophic eye disease, signal-symptom disconnection (discordant DED), neuropathic pain, thyroid eye disease (Grave's ophthalmopathy), rheumatoid arthritis-related eye disease, lupus-related eye disease, Sjögren's syndrome, secondary Sjögren's syndrome, ocular rosacea, allergic (vernal) keratoconjunctivitis, viral keratoconjunctivitis (adenovirus EKC, herpesvirus), Thygeson's keratitis, retinal gliosis, viral keratoconjunctivitis (adenovirus EKC), Thygeson's keratitis, aniridia,Keratitis or a postoperative / posttraumatic eye condition, peripheral ulcerative keratitis, keratitis, episcleritis, scleritis, uveitis (anterior or posterior), retinitis, and glaucoma (open angle, narrow angle, or normal tension). For example, the exemplary methods in this document can be used to treat diseases resulting from various conditions, such as keratitis, due to sterile inflammation (e.g., PUK) or due to infection by viruses (e.g., adenoviral subepithelial infiltrates, herpesvirus dendritic epithelial ulcer), bacteria (e.g., staphylococcal infection, pseudomonas), or fungi (e.g., candida, acanthamoeba). Furthermore, the exemplary methods in this document can be used to treat post-operative / post-traumatic eye conditions or eye conditions associated with ocular surface reconstruction surgery, application of antimetabolites to the ocular surface, pterygium surgery, glaucoma surgery, cataract surgery,Refractive surgery (LASIK, LASEK or PRK), keratoprosthesis surgery, vitreoretinal surgery, or traumatic injury from radiation or chemicals (alkaline or acid). Petition 870260076737, dated 07 / 31 / 2026, page 22 / 256 16 / 89

[0040] In several respects, the patient has autoantibodies present in a biological sample. In related respects, the autoantibodies present in the biological sample are anti-citrullinated protein antibodies. In certain respects, the biological sample is ocular fluid. In several respects, the ocular fluid is lacrimal fluid, eye washing fluid, anterior aqueous humor, or posterior vitreous humor.

[0041] The disclosure provides methods for the treatment of an eye disease comprising the steps of administering a therapeutically effective amount of allogeneic or autologous IgG ophthalmic formulation to a patient in need of such treatment. The disclosure also provides the use of a therapeutic amount of allogeneic or autologous IgG ophthalmic formulation for the preparation of a medicament for the treatment of an eye disease in a patient in need of such treatment. Furthermore, the disclosure provides a composition for the treatment of an eye disease comprising a therapeutically effective amount of allogeneic or autologous IgG ophthalmic formulation for a patient in need of such treatment.

[0042] In any of the disclosed methods, uses, or compositions, the ophthalmic formulation is administered as an eye drop formulation, topical liquid, gel formulation, emulsion formulation, suspension formulation, ointment formulation, or injectable formulation. The ophthalmic formulation, medication, or composition may be administered at least once daily to an individual. In various embodiments, the IgG ophthalmic formulation is administered one, two, three, four, five, six, seven, eight, nine, or ten times daily to an individual. In one embodiment, the IgG ophthalmic formulation is administered at least once every one to three weeks to an individual. In various embodiments, one or more doses of the IgG ophthalmic formulation are administered Petition 870260076737, dated 07 / 31 / 2026, page 23 / 256 17 / 89 administered weekly, biweekly, monthly, or bimonthly. In several aspects, the IgG concentration is defined by a 5%, 10%, or 20% ocular surface immunoglobulin (OSIG) solution. In several embodiments, the IgG concentration administered is 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% OSIG solution. In yet another embodiment, the ophthalmic IgG formulation is administered into the eye as an intraocular injection. In one embodiment, the ophthalmic IgG formulation is administered to the ocular surface as eye drops or ointment.

[0043] In certain embodiments, the combined (modified or unmodified) ophthalmic IgG formulation is manufactured using blood from human subjects and then administered at a specific concentration to the ocular surface or within the eye of the same subject. To enable OSIG delivery through the tissues, a subconjunctival or subtenon injection is administered, or the OSIG preparation may be modified (using nanotechnology, such as polymeric / biological spheres, particles, or membranes (with or without surface modifications)). Other methods to increase OSIG penetration include the use of permeants, such as benzalkonium, charge-based strategies, such as iontophoresis, or increasing residence time on the ocular surface, such as by increasing viscosity or adsorption onto contact lenses or punctal plugs. OSIG eye drops may be formulated as microemulsions.The corneal contact time and bioavailability of OSIG eye drops can be increased by increasing viscosity using high molecular weight hydrophilic polymers that do not diffuse through biological membranes and form three-dimensional networks in water. Examples of such polymers include polyvinyl alcohol, poloxamers, hyaluronic acid, carbomers, carbopol, and polysaccharides, i.e., cellulose derivatives, gellan gum, and xanthan gum. Penetration into... Petition 870260076737, dated 07 / 31 / 2026, page 24 / 256 18 / 89 corneal and intraocular delivery of OSIG eye drops can be enhanced by modifying the continuity of the corneal epithelial structure using chelating agents, preservatives (such as benzalkonium chloride), surfactants, and bile acid salts, or by using cyclodextrin complexes. For intraocular delivery, or delivery to the cornea, subconjunctival gland, or lacrimal gland, OSIG polymeric, solid, and multicompartmental drug delivery systems are used.

[0044] Nanoparticles are polymeric carriers, constructed from biodegradable, biocompatible, natural or synthetic polymers, often with mucoadhesive properties. The ingredients used in their development, for application in the eyeball, are poly(alkyl cyanoacrylate), polylactic acid, poly(epsilon-caprolactone), poly(lactic-co-glycolic acid), chitosan, gelatin, sodium alginate, and albumin. These forms can be divided into nanospheres, solid and monolithic spheres constructed from a dense polymeric template in which the OSIG is dispersed, and nanocapsules, which consist of reservoirs constructed from a polymeric membrane that surrounds the OSIG in solid or liquid form. Liposomes are also used to deliver OSIG to ocular tissues.Liposomes are phospholipid drug carriers that are generally constructed from phosphatidylcholine, stearylamine, and varying amounts of cholesterol or lecithin and α-L-dipalmitoyl-phosphatidylcholine. Niosasomes, discosomes, and dendrimers are also used to deliver OSIG to ocular tissues.

[0045] In another embodiment, the disclosure provides a method for detecting the presence of autoantibodies in an individual, wherein the method comprises detecting the level of autoantibodies in an ocular fluid sample obtained from the individual, wherein the individual is suffering from or at risk of developing an ocular surface disorder. In related aspects, the method further comprises a step of comparing the level of autoantibodies in the sample obtained from the individual. Petition 870260076737, dated 07 / 31 / 2026, page 25 / 256 19 / 89 with autoantibody control level. For example, ocular fluid is lacrimal fluid, eye wash solution, aqueous humor of the anterior chamber, or vitreous humor of the posterior chamber.

[0046] The disclosure also provides a method for diagnosing, determining the risk of developing, or monitoring an ocular surface disorder in an individual, wherein the method comprises detecting the level of autoantibodies in a sample obtained from the individual and comparing the level of antibodies in the sample obtained from the individual with a control level of said autoantibodies, wherein the control level of autoantibodies is used to diagnose, determine the risk of developing, or monitor an ocular surface disorder in the individual. In related aspects, autoantibodies are native autoantibodies, anti-CarP autoantibodies, or ACPA antibodies. In various aspects, the autoantibody comprises a plurality of autoantibodies. In related aspects, the antigen that detects the autoantibodies comprises citrullinated proteins, citrullinated peptide sequences, or a combination thereof.In related aspects, the antigen that detects autoantibodies comprises carbamylated proteins, carbamylated peptide sequences, or a combination thereof.

[0047] In any of the disclosed methods, the sample is an ocular fluid, where the ocular fluid is lacrimal fluid, eye wash solution, aqueous humor of the anterior chamber or vitreous humor of the posterior chamber.

[0048] In any of the disclosed methods, the level of autoantibodies is detected by means of an enzymatic method, a spectrometric method, a chromatographic method, an immunological method, or a combination thereof. In one exemplary embodiment, a method may include a step to determine the progression of ocular surface disorder or to determine the effectiveness of a therapy. Petition 870260076737, dated 07 / 31 / 2026, page 26 / 256 20 / 89 in an individual who suffers from, is suspected of suffering from, or is predisposed to an ocular surface disorder. In any of the disclosed methods, the autoantibody control level comprises the level of said autoantibody in the individual before the start of therapy, the level of said autoantibody in the individual at a stage prior to therapy, or a combination thereof.

[0049] The disclosure also provides a diagnostic kit comprising an array of antigen panels for detecting autoantibodies comprising citrullinated proteins, citrullinated peptide sequences, or a combination thereof. The diagnostic kit can be used to perform any of the methods described herein.

[0050] In one exemplary embodiment, an Fc receptor blocking composition can be formulated for ocular applications. For example, the Fc receptor blocking composition can be further defined by a concentration of ocular Fc receptor blocking peptide and, optionally, by a suitable carrier. In another embodiment, the Fc receptor blocking composition can be further defined by a concentration of ocular Fc receptor blocking antibody and, optionally, by a suitable carrier. Furthermore, Fc blocking compositions can be used to treat an inflammatory, infectious, or immune mucosal disease, or to exhibit an immunomodulatory effect on the mucosa.Fc-blocking compositions can treat an inflammatory, infectious, or immune disease or have an immunomodulatory effect on the mucosa in the oral cavity, nasal cavity, bladder, tracheobronchial passages, ear cavity and canal, synovial cavity (joint), vaginal cavity, or on the skin.

[0051] The disclosure also provides an IgG composition of Petition 870260076737, dated 07 / 31 / 2026, page 27 / 256 21 / 89 concentrated mucosal or ocular site. In accordance with the principles described in this document, a concentrated ocular IgG composition is presented. The composition may also include an anti-inflammatory agent.

[0052] The disclosure also provides a therapeutic dosage for the treatment of an ocular immune disease, wherein the ocular immune disease is indicated by levels of anti-citrullinated protein autoantibodies determined from ocular fluid removed from a treatment site, and the therapeutic dosage may be formulated using a concentrated ocular IgG composition. In certain embodiments, the therapeutic dosage may be determined based on tears removed from an individual suffering from an immunological disease such as dry eye disease. In certain embodiments, a therapeutic dosage may additionally include a composition defined by a concentrated ocular IgG composition at a concentration to reduce the concentrated amounts of ACPA antibodies and / or effects through application to a treatment site.For example, therapeutic dosages may include a concentrated ocular IgG composition that ranges from approximately 0.01 mg / ml by weight to approximately 1 g / ml by weight.

[0053] In some embodiments, a diagnostic kit includes a test device to determine a concentration of anti-citrullinated protein autoantibodies in an ocular fluid, such as tears; and a dosing device to indicate dosage and therapeutic treatment regimen sufficient to treat and / or reduce the harmful effects of the concentration of anti-citrullinated protein autoantibodies in the ocular fluid. In related aspects, ocular fluid is lacrimal fluid, eye wash solution, anterior aqueous humor, or posterior vitreous humor. Petition 870260076737, dated 07 / 31 / 2026, p. 28 / 256 22 / 89

[0054] In an exemplary embodiment, a method of manufacturing a treatment dosage for an immune lesion detected in ocular fluid removed from a treatment site comprises providing an IgG concentration configured to reduce the levels and / or effects of anti-citrullinated protein autoantibodies when administered to the treatment site; and adding a carrier to the IgG concentration, thereby forming a treatment dosage configured to enable delivery of IgG to the treatment site.

[0055] In another exemplary embodiment, a method of manufacturing a treatment dosage may include providing an IgG concentration within a range of about 0.01% to about 20% ocular surface immunoglobulin (OSIG), or a range of about 0.1% to about 0.5% OSIG, or an OSIG solution range of about 0.4% to about 1%. For example, the IgG concentration is approximately 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% of OSIG solution. In one embodiment, a formulation was created using 5% DIF Phlebogama OSIG to test its toxicity in human cells (Figure 19). A concentration of 4 mg / ml of 5% DIF Phlebogama is not toxic to human epithelial cells and is therefore a suitable exemplary embodiment. OSIG solutions can be manufactured with any commercially available IgG or combined plasma IgG.Other modalities formulated with non-toxic concentrations of OSIG solution using commercially available preparations are also suitable examples according to the principles of this document. In related aspects, the method further comprises the step of periodically delivering the treatment dosage to the treatment site for a treatment period defined by the response detected with the diagnostic kit at least once or twice a day and twice a day. Petition 870260076737, dated 07 / 31 / 2026, p. 29 / 256 23 / 89 month, or any other suitable period of time to obtain an improvement in the immune or inflammatory condition, or until the test device indicates that the concentration is within normal ranges.

[0056] In one embodiment, a B-cell targeted ocular composition may include a suitable B-cell composition, such as rituximab, formulated as eye drops or another suitable delivery method to treat ocular diseases or other mucosal diseases. For example, the B-cell targeted ocular composition is immunomodulatory in mucosa, such as in the oral cavity, nasal cavity, bladder, tracheobronchial passages, ear cavity and canal, synovial cavity (joint), vaginal cavity, or on the skin.

[0057] In addition to applying the compositions described in this document to the eye, these IgG compositions can be applied to the mucosa of other sites, for example, in the oral cavity, nasal cavity, bladder, tracheobronchial passages, ear cavity and canal, synovial cavity (joint), vaginal cavity, and on the skin. The IgG compositions can be used to treat inflammatory and / or immunological diseases in these mucosal sites. Specifically, the IgG compositions can be formulated for delivery to the mucosa in various sites, such as the eyes, oral cavity, nasal cavity, bladder, tracheobronchial passages, ear cavity and canal, synovial cavity (joint), vaginal cavity, and on the skin to treat inflammatory and / or immune diseases in these mucosal sites.

[0058] In yet another illustrative example, B-cell targeted therapies (rituximab, ofatumumab, belimumab, atacicept, tabalumab) can form a combination for the treatment of immune eye diseases, metabolic eye diseases, allergic eye diseases, traumatic eye diseases, infectious eye diseases, and genetic eye diseases, such as, but not limited to, ocular graft-versus-host disease (oGVHD), Stevens syndrome. Petition 870260076737, dated 07 / 31 / 2026, page 30 / 256 24 / 89 Johnson, ocular cicatricial pemphigoid (OCP), mild, moderate, and severe dry eye disease due to lacrimal deficiency (DED), meibomian gland disease, superior limbic keratoconjunctivitis (SLK), DED due to lacrimal sufficiency, floppy eyelid syndrome, neurotrophic eye disease, signal-symptom disconnection (discordant DED), neuropathic pain, thyroid eye disease (Grave's ophthalmopathy), rheumatoid arthritis-related eye disease, lupus-related eye disease, Sjögren's syndrome, secondary Sjögren's syndrome, ocular rosacea, allergic (vernal) keratoconjunctivitis, viral keratoconjunctivitis (adenovirus EKC), Thygeson's keratitis, retinal gliosis, aniridia, keratitis or a postoperative / posttraumatic eye condition, peripheral ulcerative keratitis, keratitis, episcleritis, scleritis, uveitis, retinitis and glaucoma. For example, rituximab can be formulated as eye drops or another suitable delivery method to treat eye diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0059] Figure 1 is a box plot graph showing data on the presence of ACPA in ocular surface washes from healthy individuals.

[0060] Figure 2 is a box plot graph showing data on the presence of ACPA autoantibodies in ocular surface washes in patients with various ocular surface diseases.

[0061] Figure 3 is a graph showing the percentage of all patients with a specific ocular surface disease who tested positive for ACPA in ocular surface washes.

[0062] Figure 4 is a box plot graph showing data on ACPA levels in the tear fluid of patients with Sjogren's syndrome before and after the start of treatment.

[0063] Figure 5 is a box plot graph showing data on ACPA levels in the tear fluid of patients with Ocular GVHD before and after the start of treatment. Petition 870260076737, dated 07 / 31 / 2026, page 31 / 256 25 / 89

[0064] Figure 6 is an immunofluorescence staining photograph of an impression cytology specimen of the ocular surface showing the presence of citrullinated proteins in non-epithelial cells in patients with Sjögren's syndrome. Sjögren's - cit / k14 or cit / NE ^ N=5; Healthy - cit / k14 ^ N=2.

[0065] Figure 7 is an immunofluorescence staining photograph of an impression cytology specimen of the ocular surface showing the presence of citrullinated proteins in neutrophils in patients with Sjögren's syndrome. cit / NE ^ N=2.

[0066] Figure 8 is an immunofluorescence staining photograph of an impression cytology specimen of the ocular surface showing the presence of citrullinated proteins in epithelial cells in patients with ocular GVHD (oGVHD). oGVHD def., cit / k14 ^ N=4; Without oGVHD, cit / k14 ^ N=2.

[0067] Figure 9 is an immunofluorescence staining photograph of mucoid films from the ocular surface showing the presence of inducible Fc-gamma receptors in neutrophils. Isolated neutrophils N=1; Mucoid Pt N=2.

[0068] Figure 10 is an immunofluorescence staining photograph of an impression cytology specimen of the ocular surface showing the presence of Fc-gamma receptors in non-epithelial cells (neutrophils and mononuclear cells). FcR+ NE: N=5 different individuals, 4 different diseases.

[0069] Figure 11 is a dot-blot analysis photograph and graph showing that ACPA in tears is reactive to NET citrullinated proteins.

[0070] Figure 12 is a dot-blot analysis photograph and graph showing that tears that tested positive for ACPA show polyclonality of autoantibodies. Petition 870260076737, dated 07 / 31 / 2026, page 32 / 256 26 / 89

[0071] Figure 13 is an immunofluorescence staining photograph of mucoid films from the ocular surface showing the presence of a citrullinated protein H4R3cit in the patient's mucocellular aggregates.

[0072] Figure 14 shows photographs of mouse corneas that show ocular surface staining with fluorescein in order to show corneal epithelial disease. The data show that ACPA antibodies can cause corneal epithelial disease, but not all ACPA antibodies can do so.

[0073] Figure 15 is an immunofluorescence staining photograph of a mouse corneal impression cytology specimen showing the ACPA No. 1 antibody that causes NETosis and induces citrullination in the mouse corneal epithelium.

[0074] Figure 16 presents photographs of mouse corneas showing ocular surface staining with fluorescein to demonstrate corneal epithelial disease. The data show that the pathological effect induced by ACPA in the cornea is mediated through Fc receptors. Mouse IgG competes with ACPA antibodies for binding to Fc receptors, and the Fc receptor blocker blocks all Fc receptors. This competitive and peptide blockade may have abolished the pathological effect of ACPA in the cornea, suggesting the use of methodologies that prevent the interaction of ACPA antibodies with Fc receptors, and this may be a potential therapeutic strategy in the treatment of citrullination-related ocular diseases.

[0075] Figure 17 is an immunofluorescence staining photograph of neutrophils showing that ACPA-H4R3cit induces NETosis in vitro.

[0076] Figure 18 presents data showing the cytotoxicity of OSIG in human corneal epithelial cells. The concentrations of Petition 870260076737, dated 07 / 31 / 2026, page 33 / 256 27 / 89 OSIG levels of 1 mg / ml to 4 mg / ml do not cause cytotoxicity, as evidenced by no increase in LDH levels.

[0077] Figure 19 provides an illustrative image of an eye with high levels of autoantibodies (ACPA) in the tear fluid and severe ocular surface disease.

[0078] Figures 20A and 20B provide illustrative images of an eye with high levels of autoantibodies (ACPA) in the tear fluid, but without systemic autoimmune disease and serum negative for ACPA autoantibodies and rheumatoid arthritis.

[0079] Figures 21A and 21B provide illustrative images of an eye with asymmetric ocular disease; the eye with the more severe ocular surface disease has higher levels of autoantibodies (ACPA) in the tear fluid.

[0080] Figures 22A and 22B provide images of a 20-year-old woman with severe lacrimal deficiency and severe ocular surface disease due to ocular graft-versus-host disease (case study 1). These images demonstrate that treatment with OSIG reduced the signs and symptoms of severe dry eye, as well as reduced the level of an inflammatory biomarker in the lacrimal fluid.

[0081] Figure 23 provides images of a 31-year-old woman with severe lacrimal deficiency and severe ocular surface disease due to ocular graft-versus-host disease (case number 2). These images demonstrate that treatment with OSIG reduced the symptoms of neurotrophic keratitis.

[0082] Figure 24 provides images of a 74-year-old man with neurotropic keratitis due to a history of previous LASIK eye surgery in the left eye (case study 3). These images demonstrate that OSIG treatment reduced the signs and symptoms of severe dry eye, as well as reduced the level of an inflammatory biomarker in the tear fluid. Petition 870260076737, dated 07 / 31 / 2026, page 34 / 256 28 / 89

[0083] Figure 25 provides images of a 29-year-old man with lacrimal deficiency and severe ocular surface disease due to Stevens-Johnson syndrome (case study 6). These images demonstrate that OSIG treatment reduced the signs and symptoms of severe dry eye following Stevens-Johnson syndrome. DETAILED DESCRIPTION

[0084] According to the principles described in this document, autoantibodies such as anti-citrullinated protein antibodies (ACPAs) have been found in the tear fluid of patients with ocular diseases such as dry eye disease (DED), Sjögren's syndrome, meibomian gland disease, superior limbic keratoconjunctivitis (SLK), ocular cicatricial pemphigoid, Stevens-Johnson syndrome, graft-versus-host disease, peripheral ulcerative keratitis, episcleritis, scleritis, and such autoimmune diseases. Surprisingly, ACPA autoantibodies were present in the tear fluid of patients, although ACPA and rheumatoid factor were not detected in serum, suggesting that tear fluid autoantibodies are produced locally in / around ocular tissues.This result was surprising, since it was not expected that ACPA autoantibodies would be present in the tear fluid of patients with ocular diseases, as their serum did not contain ACPA or rheumatoid factor and they showed no evidence of systemic autoimmune disease. Patients with unilateral disease showed higher levels of ACPA in the tear fluid of the eye with more severe disease. Furthermore, eyes with very high levels of ACPA in the tear fluid often showed evidence of serious diseases, such as keratomalacia syndrome and scarring, and were inadequately controlled despite aggressive treatments. In the studies described in this document, citrullinated proteins were identified on the ocular surface of these patients and... Petition 870260076737, dated 07 / 31 / 2026, page 35 / 256 29 / 89 also the presence of Fc receptors. Laboratory experiments have confirmed that exposure of mouse corneas to ACPAs can cause ocular surface diseases and that the deleterious effects of ACPAs on ocular surface diseases were reduced by targeting their interaction with ocular tissues using IgG or Fc receptor blockade. Taken together, combined IgG and / or synthetic variants thereof are a suitable form of therapy for ocular diseases caused by or affected by autoantibodies. Furthermore, polyclonality of autoantibodies has been identified in tear fluid (e.g., presence of histone cytos, alpha-enolase cytos, fibrinogen cytos, etc. in tear fluid), which makes combined IgG an attractive therapy, since targeting individual antibodies is unattractive and laborious.

[0085] As used in this descriptive report and the accompanying claims, the singular forms a, an and the include plural references, unless the content clearly indicates otherwise.

[0086] In an exemplary embodiment, an ophthalmic formulation comprises: (a) a pharmaceutically active compound that is capable of reducing the amount of autoantibodies on the ocular surface or within the eye, wherein such autoantibodies are generated in response to citrullinated protein (ACPA autoantibodies due to protein citrullination) or autoantibodies that are generated in response to homocitrulated protein (anti-CarP antibodies due to protein carbamylation) or autoantibodies generated in response to native proteins; (b) optionally, a second pharmaceutically active compound selected from the group consisting of a PAD enzyme inhibitor, NET dismantling agent and Fc receptor blockers, and a combination thereof; and Petition 870260076737, dated 07 / 31 / 2026, page 36 / 256 30 / 89 (c) a pharmaceutically acceptable ophthalmic excipient. Unless the context requires otherwise, the term pharmaceutically active compound refers to a compound that is pharmaceutically active when applied topically to the ocular surface or injected into the eye. Thus, for example, the term a pharmaceutically active NSAID refers to an NSAID that is pharmaceutically active when applied topically to the ocular surface or injected into the eye.

[0087] Yet another aspect of the disclosure provides an ophthalmic formulation which includes: (a) a pharmaceutically acceptable ophthalmic excipient; (b) a therapeutically effective amount of a pharmaceutically active compound comprising immunoglobulin G (IgG) and (c) optionally, a second pharmaceutically active compound selected from the group consisting of a steroid, an anti-inflammatory agent, a mucolytic agent, a PAD enzyme inhibitor, a NET dismantling agent and an Fc receptor blocker, and a combination thereof. The pharmaceutically active compound comprising immunoglobulin G (IgG) is capable of treating a selected clinical condition from the group consisting of inflammatory and immunological disease of the ocular surface that may cause symptoms of ocular discomfort, dry eye syndrome, keratitis, symblepharon formation, fornix eshortening, keratinization of the palpebral / conjunctival margin and subconjunctival fibrosis.A therapeutically effective amount means the amount of a compound that, when administered to a mammal for the treatment of a disease or clinical condition, is sufficient to effect such treatment for the disease. The therapeutically effective amount will vary depending on the compound, the disease or clinical condition and its severity, and the age, weight, etc., of the mammal being treated. Treat or treatment of. Petition 870260076737, dated 07 / 31 / 2026, p. 37 / 256 31 / 89 a disease or clinical condition includes: (1) preventing the disease or clinical condition, that is, causing the clinical symptoms of the condition or disease not to develop in a mammal that may be susceptible to the disease or clinical condition, but which does not yet have or does not show symptoms of the disease or clinical condition; (2) inhibiting the disease or clinical condition, that is, interrupting or reducing the development of the disease or clinical condition or its symptoms; or (3) alleviating the disease or clinical condition, that is, causing the regression of the disease or clinical condition or its symptoms.

[0088] Yet another aspect of the disclosure provides an ophthalmic formulation which includes: (a) a pharmaceutically acceptable ophthalmic excipient; (b) a therapeutically effective amount of a pharmaceutically active compound comprising combined human immunoglobulin G (IgG); and / or (c) a therapeutically effective amount of combined human plasma proteins (in dilutions ranging from 0.1% to 99% of human plasma protein) and combined human plasma lipids (in dilutions ranging from 0.1% to 99%).

[0089] Ophthalmic disclosure formulations are useful for the treatment of various clinical conditions associated with inflammatory and immunological diseases of the ocular surface. Exemplary clinical conditions that can be treated by ophthalmic disclosure formulations include, but are not limited to, ocular surface disease that can cause symptoms of ocular discomfort, dry eye syndrome, mucocellular aggregates / debris in the tear film, symblepharon formation, fornix fornix, keratinization of the palpebral / conjunctival margin, and subconjunctival fibrosis. More specific types of ocular surface diseases include ocular graft-versus-host disease (oGVHD), Stevens-Johnson syndrome. Petition 870260076737, dated 07 / 31 / 2026, page 38 / 256 32 / 89 son, ocular cicatricial pemphigoid (OCP), mild, moderate and severe dry eye disease due to lacrimal deficiency (DED), meibomian gland disease, superior limbic keratoconjunctivitis (SLK), DED due to lacrimal sufficiency, floppy eyelid syndrome, neurotrophic eye disease, signal-symptom disconnection (discordant DED), neuropathic pain, thyroid eye disease (Grave's ophthalmopathy), rheumatoid arthritis-related eye disease, lupus-related eye disease, Sjögren's syndrome, secondary Sjögren's syndrome, ocular rosacea, allergic (vernal) keratoconjunctivitis, aniridia, keratitis due to sterile inflammation or due to a viral, bacterial or fungal infection, a postoperative / posttraumatic eye condition, peripheral ulcerative keratitis, episcleritis, scleritis, uveitis and glaucoma.Exemplary postoperative / post-traumatic eye conditions that can be treated with the use of ophthalmic formulations disclosed include, but are not limited to, eye conditions associated with ocular surface reconstruction surgery, application of antimetabolites to the ocular surface, pterygium surgery, glaucoma surgery, cataract surgery, laser vision correction surgery (LASIK, LASEK, EPI-LASIK), keratoprosthesis surgery, and radiation injury.

[0090] Other ocular clinical conditions that can be treated with the use of ophthalmic formulations of the disclosure include, but are not limited to, dry eye syndrome (keratoconjunctivitis sicca), Sjögren's syndrome, congenital alacrima, xerophthalmia (dry eye due to vitamin A deficiency), keratomalacia, thyroid eye disease, ocular rosacea, eyelid disorders, meibomian gland disease, meibomian gland dysfunction, ectropion, blepharitis, blepharochalasia, sarcoidosis, stye, hordeolum, chalazion, ptosis, pterygium, eyelid edema, eyelid dermatitis, trichiasis, madarosis, dacryoadenitis, Stevens-Johnson syndrome, graft-versus-host disease, dacryocystitis, conjunctivitis, Petition 870260076737, dated 07 / 31 / 2026, page 39 / 256 33 / 89 keratoconjunctivitis, blepharoconjunctivitis, blepharokeratoconjunctivitis, allergic conjunctivitis, vernal conjunctivitis, conjunctival suffusion, conjunctivochalasis, subconjunctival hemorrhage, pterygium, pinguecula, chemosis, iritis, iridocyclitis, anterior uveitis, glaucoma, red eye, keratitis, scleritis, episcleritis, peripheral ulcerative keratitis, neurotrophic keratitis, neurotrophic eye disease, corneal ulcer, ulcerative keratitis, corneal abrasion, photokeratitis, ultraviolet keratitis, exposure keratitis, superficial punctate keratitis, Thygeson's superficial punctate keratopathy, herpes simplex keratitis, herpes zoster keratitis, acneic rosacea, postoperative inflammation following eye surgery (i.e., eyelid surgery, cataract surgery, corneal surgery, surgery Refractive surgery, including photorefractive keratectomy, glaucoma surgery, lacrimal gland surgery, conjunctival surgery, and eye muscle surgery.Ocular surface conditions caused by chemical burns, thermal burns, or physical trauma; ocular conditions caused by the following autoimmune or vascular diseases: rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, Reiter's syndrome, enteropathic arthritis, psoriatic arthritis, discoid and systemic lupus erythematosus, multiple sclerosis, Graves' disease, antiphospholipid syndrome, sarcoidosis, Wegener's granulomatosis, Behcet's syndrome, polyarteritis nodosa, Takayasu's arteritis, dermatomyositis, psoriasis, relapsing polychondritis, vasculitis, and sickle cell anemia.

[0091] In some modalities, ophthalmic formulations of the dissemination are used to treat dry eye syndrome. There are two main classes of dry eye syndrome: (i) dry eye with aqueous tear deficiency (DEDD) and (ii) evaporative dry eye (EDE). There are also cases of mixed mechanism dry eye (i.e., both DEDD and EDE). DEDD occurs mainly due to failure of lacrimal tear secretion. DEDD can be further subdivided into Sjögren's syndrome dry eye (in which the lacrimal and salivary glands are impaired). Petition 870260076737, dated 07 / 31 / 2026, p. 40 / 256 34 / 89 directed by an autoimmune process, for example, rheumatoid arthritis) and dry eye not associated with Sjögren's syndrome (lacrimal dysfunction, but the systemic autoimmune features of Sjögren's syndrome are excluded, for example, age-related dry eye). In contrast, EDE occurs primarily due to excessive water loss from the exposed ocular surface in the presence of normal lacrimal secretory function. Its causes can be extrinsic (e.g., ocular surface disorder due to some extrinsic exposure, contact lens use, or vitamin A deficiency) or intrinsic (e.g., meibomian gland dysfunction and palpebral opening disorders). Meibomian glands secrete a mixture of lipids and other components that form the outer layer of the preocular tear film. This lipid layer acts by decreasing tear film evaporation. Meibomian gland dysfunction (MGD) leads to evaporative dry eye disease.One of the most well-recognized clinical findings in MGD is the presence of numerous telangiectatic blood vessels running along the eyelid margin. MGD can also accompany dry eye disease due to tear deficiency, as seen in ocular graft-versus-host disease (oGVHD).Other specific dry eye syndromes that can be treated with the use of the compositions in the disclosure include keratoconjunctivitis, dry eye caused by conjunctivitis, dry eye caused by allergic conjunctivitis, dry eye caused by blepharitis, dry eye caused by keratitis, dry eye caused by dacryoadenitis, dry eye caused by ocular rosacea, dry eye caused by Boehm's syndrome, dry eye caused by conjunctivochalasis, dry eye caused by blepharoconjunctivitis, dry eye caused by blepharokeratoconjunctivitis, dry eye caused by superficial punctate keratitis, dry eye caused by Thygeson's superficial punctate keratopathy, dry eye caused by oGVHD, Sjögren's dry eye syndrome, and dry eye caused by Stevens' syndrome. Petition 870260076737, dated 07 / 31 / 2026, page 41 / 256 35 / 89 Johnson, MGD, dry eye caused by meibomian gland disease, dry eye induced by vitamin A deficiency, pharmacologically induced dry eye (i.e., hormone replacement therapy, blood pressure medication, antihistamines, antidepressants, anticholinergic medications, glaucoma medications, antihypertensives, diuretics, sedatives, isotretinoin, nasal decongestants, oral contraceptives, beta-blockers, phenothiazines, atropine, opioid analgesics), pregnancy-induced dry eye, dry eye induced by LASIK surgery or refractive surgery, dry eye induced by collagen vascular diseases (i.e., systemic lupus erythematosus, Wegener's granulomatosis, rheumatoid arthritis, relapsing polychondritis), dry eye caused by infiltration of the lacrimal glands by tumors or sarcoidosis, dry eye caused by post-radiation fibrosis of tear-producing glands, dry eye caused by lacrimal gland,Meibomian gland or goblet cell ablation, dry eye caused by sensory denervation, dry eye caused by thermal or chemical burns, dry eye caused by underlying diabetic conditions, dry eye caused by viral, fungal, or bacterial infection, dry eye caused by prolonged use of contact lenses, dry eye caused by eyelid disorders or eyelid injury (i.e., bulging eyes, drooping eyelid), dry eye caused by corneal dystrophy, dry eye caused by autoimmune diseases, age-related dry eye, and a combination thereof.

[0092] In some particular modalities, ophthalmic disclosure formulations are used to treat meibomian gland dysfunction (MGD). In still other modalities, ophthalmic disclosure formulations are used to treat dry eye with aqueous tear deficiency (ADDE). In some cases, the methods for treating ADDE involve treating a patient with Petition 870260076737, dated 07 / 31 / 2026, p. 42 / 256 36 / 89 need for treatment for Sjögren's dry eye syndrome, ocular graft-versus-host disease (oGVHD), or dry eye not associated with Sjögren's syndrome. In other modalities, methods for treating dry eye syndrome include treating a patient requiring evaporative dry eye (EDE) treatment. In other modalities, disclosure methods include treating a patient requiring treatment for mixed-mechanism dry eye consisting of ADDE and EDE. In other modalities, disclosure methods include treating a patient suffering from dry eye syndrome due to a complication of refractive eye surgery or attributable to one or more of the following causes: vitamin A deficiency, ocular surface disorders, allergy, aging, contact lens use, medication use, or eyelid disorders.

[0093] Two forms of post-translational modification (PTM), citrullination and carbamylation, result in the generation of two non-standard amino acids in polypeptides, citrulline and homocitrulline, respectively, which are highly chemically related. There is growing evidence of a pathophysiological role for citrullination and carbamylation of proteins, such as the role of autoantibodies to these proteins in rheumatoid arthritis. However, the role of citrullination and carbamylation and ACPA in the context of ocular surface disease has not been previously described. The studies provided in this document identify the presence of ACPA in ocular surface fluid.

[0094] In some embodiments, the ophthalmic formulation comprises immunoglobulin G (IgG) as a pharmaceutically active ingredient. The type of IgG that may be used in ophthalmic formulations of the disclosure includes, but is not limited to, (i) serum / plasma-derived combined immunoglobulin G (OSIG); (ii) purified autologous IgG from Petition 870260076737, dated 07 / 31 / 2026, p. 43 / 256 37 / 89 autologous plasma / serum; (iii) multimerized IgG1 Fc molecule (IgG1 Fc hexamer); (iv) IgG2a Fc multimers (stradomers); (v) multivalent Fc structures; (vi) genetically engineered glycosylated sialylated IgG; and (vii) IgG-Fc glycosylation, or a combination thereof. In some embodiments, commercially available OSIG preparations are formulated with ophthalmic excipients (diluted or concentrated as needed) to achieve an IgG concentration that is three to six times the IgG concentration that is normally present (physiologically or pathologically) at the application site and then dispensed as eye drops, injectables, or another appropriate delivery method.Examples of commercially available IgG solutions include Bivigam 10%, Cuvitru (20%), Flebogama DIF 5% and 10%, Gammagard Liquid 10%, Gammagard S / D 5% and 10%, Gammaked 10%, Gammaplex 5% and 10%, Gamunex-C 10%, Hizentra 20%, HYQVIA 10%, Octagam 5% and 10%, Privigen 10%. These commercially available IgG solutions can be combined with an ophthalmic excipient to achieve the desired IgG concentration, for example, 4 mg / ml, and the desired pH of at least 6.0 to manufacture the disclosed OSIG compositions.

[0095] In some embodiments, the ophthalmic formulation consists of functional equivalents of the intact IgG antibody, such as antigen-binding fragments in which one or more antibody domains are truncated or absent (e.g., Fv, Fab, Fab', or F(ab)2 fragments), as well as genetically modified antibodies or protein-binding fragments thereof, including single-chain antibodies or antibodies that can bind to more than one epitope (e.g., bispecific antibodies), or antibodies that can bind to one or more different antigens (e.g., bi- or multispecific antibodies), may also be employed in the dissemination. Petition 870260076737, dated 07 / 31 / 2026, page 44 / 256 38 / 89

[0096] Immunoglobulins are a group of closely related glycoproteins, composed of 82% to 96% protein and 4% to 18% carbohydrates. These glycoproteins of approximately 150 kDa are present in plasma at an average concentration of 7 to 12 g / L, depending on individual variations and the level of environmental exposure to antigens. Immunoglobulin G (IgG), one of the main effector molecules of the humoral immune response in humans, accounts for approximately 75% of the total Igs in the plasma of healthy individuals. The basic Ig molecule has a four-chain structure, comprising two identical heavy (H) chains and two identical light (L) chains, linked together by interchain disulfide bonds. IgG has dual functions characterized by the ability to recognize and react specifically with the antigen and to perform a series of non-specific effector functions in which the antigen becomes harmless and is eventually eliminated.This functional dichotomy of IgG is reflected in the molecule's structure, which comprises two variable regions responsible for antigen binding (Fab) and a constant region (the Fc or crystallizable fragment) that mediates specific effector functions. The presence of a complex oligosaccharide structure modulates IgG functions, especially complement activation and FcyR binding. In some modalities, the ophthalmic formulation of the dissemination will consist of immunoglobulin G (IgG) with enhanced sialylation (sialylated IgG), where such sialylation is achieved using standard chemical processes.

[0097] In some embodiments, the IgG concentration in the ophthalmic formulation of the dissemination is defined by a 10% ocular surface immunoglobulin (OSIG) solution or any other suitable concentration. OSIGs are a therapeutic preparation of human, polyspecific, normal and combined IgGs obtained from Petition 870260076737, dated 07 / 31 / 2026, p. 45 / 256 39 / 89 serum / plasma from a large number of healthy donors. The preparation contains antibodies to microbial antigens, autoantigens (natural autoantibodies), and anti-idiotypic antibodies that recognize other antibodies. The plasma used in OSIG production has two origins: approximately 20 percent from blood donors and the other 80 percent from plasma donors. Individual plasmas are combined; the combination size is at least 1,000 donors, but can reach 100,000 donors. The many thousands of donors who contribute to a typical plasma combination used for immunoglobulin isolation represent a wide range of antibody specificities against infectious agents, such as bacteria and viruses, and also a large number of autoantigens reflecting the cumulative exposure of the donor population to the environment.OSIG preparations consist of intact IgG molecules with a distribution of IgG subclasses (IgG1, IgG2, IgG3, and IgG4) corresponding to that of normal serum. Primary purification processes for OSIG production may include: (i) fractionation, for example, polyethylene glycol (PEG) is a synthetic polymer that is also used to separate proteins by fractional precipitation from a natural mixture such as plasma via an exclusion mechanism; and (ii) chromatography, for example, anion exchange chromatography, hydrophobic charge induction chromatography, or size exclusion chromatography. The biological effects of OSIG that may contribute to the efficacy of the ophthalmic disclosure formulation include: (i) functional blockade of Fc receptors. Saturation of Fc receptors by OSIG leads to decreased cell destruction as a consequence of Fc-mediated biological effects, (ii) neutralization of autoantibodies and inhibition of autoantibody production.OSIG preparations contain antiidiotypic antibodies, that is, antibodies that are capable of interacting specifically with the variable region (antigen recognition site) of. Petition 870260076737, dated 07 / 31 / 2026, page 46 / 256 40 / 89 autoantibodies. This interaction has the potential to neutralize an autoantibody and hinder its production through binding to autoreactive B lymphocytes, (iii) complement inhibition. The Fc portion of OSIG can bind C3b and C4b complement fragments and thus inhibit their tissue deposition as well as the generation of C5 convertase, (iv) cytokine modulation (including IL-1, -2, -3, -4, -5, -10, TNF-alpha and GM-CSF) and cytokine antagonist production (IL-1 receptor antagonist) and (v) signaling through the inhibitory Fc receptor, Fc gamma RIIB.

[0098] The amount of IgG in the ophthalmic formulation of the disclosure may vary from about 0.01 mg / ml to about 1 g / ml, typically from about 1 mg / ml to about 10 mg / ml. In certain embodiments, the concentration or amount of IgG may be about 0.01 mg / ml; in other embodiments, the concentration or amount of IgG may be about 0.05 mg / ml. In certain embodiments, the concentration or amount of IgG may be about 1 mg / ml; in other embodiments, the concentration or amount of IgG may be about 10 mg / ml. In several embodiments, the concentration or amount of IgG may be 1.0 mg / ml. 1.5 mg / ml, 2.0 mg / ml, 2.5 mg / ml, 3.0 mg / ml, 3.5 mg / ml, 4 mg / ml, 4.5 mg / ml, 5 mg / ml, 5.5 mg / ml, 6 mg / ml, 6.5 mg / ml, 7 mg / ml, 7.5 mg / ml, 8 mg / ml, 8.5 mg / ml, 9 mg / ml, 9.5 mg / ml or 10 mg / ml,

[0099] This disclosure covers the presence of autoantibodies on the ocular surface (tear fluid) or intraocular surface (aqueous and vitreous) in various ocular diseases, of which anti-citrullinated protein antibodies (ACPAs) are the prototype example. The autoantibodies that may be present and are encompassed by this disclosure include antibodies to the following proteins: e2-Glycoprotein, C1q, CENP-B (Centromere Protein B), CENP-A (Centromere Protein A), Jo-1, Ku, Mi-2, Myeloperoxidase (MPO), PCNA (Proliferative Cell Nuclear Antigen A), PL-12 (Alanyl-tRNA synthetase), PM / Scl 100, Proteinase 3, RNP (ribonucleoprotein), RNP / Smith (RNP / Sm), ribosomal P, Scl-70, Sm, Petition 870260076737, dated 07 / 31 / 2026, page 47 / 256 41 / 89 SSB / La (Sjogren's syndrome-related antigen B / La), SSA / R06O (Sjogren's syndrome-related antigen A / Ro60 kDa), SSA / Ro52 (Sjogren's syndrome-related antigen A / Ro52 kDa). Although not intended to be exhaustive / complete, the autoantibodies (ACPA or non-ACPA) covered by this disclosure may be derived from the proteins or fragments thereof (citrullinated or native) listed in Table 1: Table 1. Aggrecan ssRNA La / SSB Ro / SSA (60 kDa) alpha Fodrin (Sptan1) dsDNA Laminin S100 alpha-actinin EBNA1 LC1 Scl-70 Amyloid Elastin LKM1 Sm AQP4 recombinant Entactin EDTA Antigen M2 Sm / RNP BP1 Factor I Matrigel SmD C1q Factor P MDA5 SmD1 Cardolipin Factor B Mi-2 SmD2 CENP-A Factor D Mitochondrial antigen SmD3 CENP-B Factor H MPO SP100 Chondroitin sulfate C Fibrinogen IV Muscarinic receptor Sphingomyelin Chromatin Fibrinogen S Myelin basic protein (MBP) SPR54 Collagen I Fibronectin Myelin-associated glycoprotein-FC ssDNA Collagen II GBM (this) Myosin T1F1 Gamma Collagen Collagen III Genomic DNA Nucleolin Thyroglobulin Collagen IV Gliadin (IgG) Nucleosome antigen TNFα Collagen V Glycated albumin Nup62 Topoisomerase I Collagen VI GP2 PCNA TPO complement C1q gP210 Peroxiredoxin 1 TTG Petition 870260076737, dated 07 / 31 / 2026, page 48 / 256 42 / 89 Complement C3 Histone H1 Phosphatidylinositol U1-snRNP-68 Complement C3a Histone H2A PL-12 U1-snRNP-A Complement C3b Histone H2B PL-7 U1-snRNP-BB' Complement C4 Histone H3 PM / Scl-100 U1-snRNP-C Complement C5 Histone H4 PM / Scl-75 Vimentin Complement C6 Hemocyanin POLB Vitronectin Complement C7 Heparan HSPG PR3 β2-glycoprotein I Complement C8 Heparin Proteoglycan β2-microglobulin Complement C9 Heperan sulfate Prothrombin protein IgA - human and mouse CPR antigen (human) Histone (total) Ribophosphate P1 IgE - human Cytochrome C Intrinsic factor Ribophosphate P2 IgG - human and mouse mouse Decorin-bovine Jo-1 Ribofasphoprotein P0 IgM - human and mouse DGPS KU (P70 / P80) Ro / SSA (52KDa) Anti-IgG, IgA and anti-IgM

[0100] Pharmaceutically acceptable excipient or pharmaceutically acceptable ophthalmic excipient means an excipient that is useful in the preparation of a pharmaceutical composition of the disclosure. Such an excipient is considered by a person skilled in the art to be generally safe, non-toxic and neither biologically active nor otherwise undesirable, and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use. A pharmaceutically acceptable excipient, as used in the descriptive report and claims, includes one and more than one of these excipients. Exemplary pharmaceutically acceptable excipients include a salt (such as sodium chloride) or a tonicity agent, gum, resin, a solvent such as water, a non-aqueous solvent (such as an alcohol, an oil, a buffered solution to maintain pH), a pH modifying agent (e.g., a base such as sodium hydroxide and an acid). Petition 870260076737, dated 07 / 31 / 2026, page 49 / 256 43 / 89 (such as hydrochloric acid), an emulsifier, a thickening agent, a micro- or nanoemulsion-forming agent, a preservative, a surfactant, etc. Examples of pharmaceutically acceptable excipients that may be used in ophthalmic disclosure formulations include, but are not limited to, water, benzyl alcohol, sodium hydroxide, hydrochloric acid, Castrol oil, citrate buffer, Tris buffer, phosphate buffer, as well as other excipients known to a person skilled in the art.

[0101] In some embodiments, the ophthalmic formulations of the disclosure may also include salts, such as sodium chloride. In still other embodiments, the ophthalmic formulation of the disclosure may also include a non-aqueous solvent, such as benzyl alcohol, ethanol, or other non-aqueous solvents known to a person skilled in the art.

[0102] In still other embodiments, the pH of the ophthalmic formulations of the disclosure is adjusted from a pH of about 5.0 to a pH of about 8.5, typically from a pH of about 5.0 to a pH of about 8.0, and often from a pH of about 5.0 to a pH of about 7.5. Additional exemplary pH ranges are from approximately pH 6 to approximately pH 8, or approximately pH 6.2 to approximately pH 7.2, approximately pH 6.4 to approximately pH 7.4, or approximately pH 6.5 to approximately pH 7.5, approximately pH 6.6 to approximately pH 7.6, and approximately pH 6.8 to approximately pH 7.8.For example, the pH is approximately 5.0, approximately 5.1, or approximately 5.2, or approximately 5.3, or approximately 5.4, or approximately 5.5, or approximately 5.6, or approximately 5.7, or approximately 5.8, or approximately. 5.9, or about 6.0, or about 6.1, or about 6.2, or about 6.3, or about 6.4, or about 6.5, or about 6.6, or about 6.7, or about 6.8, or about 6.9, or about 7.0, or about 7.1, or about 7.2, or about 7.3, or about 7.4, or about 7.5, or about 7.6, or approximately 7.7, or approximately 7.8, or approximately 7.9, or approximately 8.0. The pH of the ophthalmic formulations in the dissemination can be adjusted with Petition 870260076737, dated 07 / 31 / 2026, p. 50 / 256 44 / 89 the use of, for example, sodium hydroxide and / or hydrochloric acid, as needed to obtain a desired pH level.

[0103] The ophthalmic formulation may be formulated as eye drops, topical liquid, an ointment, emulsion, suspension, or a gel (e.g., sodium IgG in hydrogel). The ophthalmic formulation may also be formulated as an oil nanoemulsion or a suspension. In addition, the ophthalmic formulation may be formulated as an injectable formulation.

[0104] In some embodiments, the ophthalmic formulations of the disclosure are preservative-free and are formulated for single use or in multidose vials. If a preservative is used, suitable preservatives include, but are not limited to, benzalkonium, purite, chlorobutanol, sodium perborate, stabilized oxychloro complex (SOC), Polyquaternium-1 (Poliquad, PQ-1), thimerosal, benzyl alcohol, sorbic acid, methyl / propyl paraben, chlorhexidine, disodium EDTA, sofZia, and other preservatives known to a person skilled in the art of ophthalmology or ophthalmic formulation chemistry.

[0105] When present, the second pharmaceutically active compound is selected from the group consisting of a steroid, an anti-inflammatory agent, a mucolytic agent, and a combination thereof. Exemplary steroids that are suitable in ophthalmic disclosure formulations include, but are not limited to, methylprednisone, prednisone, dexamethasone, loteprednol etabonate, fluocinolone, difluprednate, fluorometholone, medrisone, fluocinolone, rimexolone, triamcinolone, and a combination thereof. When a steroid is used in ophthalmic disclosure formulations, the amount of steroid present in the formulation varies from about 0.01% w / w to 2% w / w; typically, from about 0.05% w / w to 1% w / w, frequently from about 0.1% w / w to about 0.3% w / w. It should be noted that the scope of the disclosure is not limited to these ranges. Petition 870260076737, dated 07 / 31 / 2026, page 51 / 256 45 / 89 specifics of the amount of steroid. In particular, the amount of steroid present in ophthalmic disclosure formulations generally depends on the steroid used. For example, the amount of steroid present may vary depending on the activity of the particular steroid used, the molecular weight of the steroid, as well as the purpose of using a steroid in ophthalmic disclosure formulations.

[0106] Exemplary anti-inflammatory agents that are suitable in ophthalmic disclosure formulations include, but are not limited to, cyclosporine, Lifitegrast®, tacrolimus, interleukin-1 receptor antagonist (anakinra), other NSAIDs such as ketorolac, diclofenac, flurbiprofen, bromfenac, nepafenac, and a combination thereof. When an anti-inflammatory agent is used in ophthalmic disclosure formulations, the amount of anti-inflammatory agent present in the formulation ranges from about 0.01% w / w to 2% w / w; typically, from about 0.05% w / w to 1% w / w, frequently from about 0.1% w / w to about 0.3% w / w. It should be noted that the scope of disclosure is not limited to these particular ranges of anti-inflammatory agent quantity.In particular, the amount of anti-inflammatory agent present in ophthalmic formulations generally depends on the particular anti-inflammatory agent used, such as the activity of the particular anti-inflammatory agent used, the molecular weight of the anti-inflammatory agent, etc.

[0107] Exemplary mucolytic agents that are useful in ophthalmic disclosure formulations include, but are not limited to, N-acetylcysteine, n-cysteine, dextran, DNase I (dornase alfa), gelsolin, thymosin P4, and 14- and 15-membered macrolide antibiotics (e.g., erythromycin, a non-antimicrobial derivative of erythromycin (e.g., EM703 and EM900), clarithromycin, roxithromycin, fidaxomicin, telithromycin, and azithromycin) and a combination thereof. It should be noted that when an antibiotic is used, it is primarily used Petition 870260076737, dated 07 / 31 / 2026, page 52 / 256 46 / 89 due to its mucolytic activity. When a mucolytic agent is used in ophthalmic disclosure formulations, the amount of mucolytic agent present in the formulation is in the range of about 0.01% w / w to 2% w / w; typically, about 0.05% w / w to 1% w / w, frequently about 0.1% w / w to about 0.3% w / w. It should be noted that the scope of disclosure is not limited to these particular ranges of mucolytic agent quantity. In particular, the amount of mucolytic agent present in ophthalmic disclosure formulations generally depends on the particular mucolytic agent used, such as the activity of the mucolytic agent, molecular weight of the mucolytic agent, etc.

[0108] Ophthalmic disclosure formulations may be homogeneous or heterogeneous. In some embodiments, ophthalmic disclosure formulations contain a fatty acid oil or ester. A fatty acid ester has the meaning commonly understood in the art, being an ester formed between an alcohol and a fatty acid. Exemplary fatty acid esters that are useful in disclosure formulations include, but are not limited to, triglyceride esters commonly known as vegetable oils, mono- and diglyceride esters of fatty acids, methyl esters of fatty acids, as well as other fatty acid esters known to a person skilled in the art. It should be noted that the fatty acid ester may be a mixture of several chemical compounds or an essentially pure compound. Typically, the fatty acid ester is a vegetable oil.Specific examples of vegetable oils that can be used include, but are not limited to, castor oil, sesame oil, soybean oil, cottonseed oil, olive oil, peanut oil, safflower oil, sunflower oil, palm oil, palm kernel oil, canola oil, and Miglyol oil®. Petition 870260076737, dated 07 / 31 / 2026, page 53 / 256 47 / 89

[0109] Various vehicles may be used in the ophthalmic formulations of the disclosure. These vehicles include, but are not limited to, purified water (aqua), polyvinyl alcohol, povidone, hydroxypropylmethylcellulose, poloxamers, carboxymethylcellulose, hydroxyethylcellulose, polyols, sodium hyaluronate, Pluronic acid, corbopol, cyclodextrin, and a mixture of two or more thereof. The vehicle is used in the formulation in amounts as needed to provide the concentration of the active compound (or active compounds) disclosed in this document. In one particular embodiment, the vehicle comprises water.

[0110] In some embodiments of this disclosure, an emulsion-stabilizing polymer is used. While not intended to limit the scope of the disclosure, emulsion-stabilizing polymers generally contain hydrophilic groups such as cellulose, sugars, ethylene oxide, hydroxide, carboxylic acids, or other polyelectrolytes. Without being limited by any theory, these polymers are believed to help stabilize emulsions by increasing the viscosity of the formulation as well as reducing interfacial tension. Surfactants, such as polysorbate 80 or other ophthalmic-appropriate surfactants, may be used to stabilize emulsions. Some examples of useful emulsion-stabilizing polymers in this disclosure include, but are not limited to, carbomers, Pemulen®, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, povidone, polyvinyl alcohol, polyethylene glycol, and a mixture of two or more thereof.

[0111] The ophthalmic formulations of this disclosure may be packaged in various packaging forms known in the field of topical ophthalmology. In one particular embodiment, the ophthalmic formulation is packaged in sterile, preservative-free single-use packages, or in bottles or containers (i.e., unit-dose bottles). Each bottle, for example, as small as 0.9 ml, may be produced from low-density polyethylene so as to contain Petition 870260076737, dated 07 / 31 / 2026, page 54 / 256 48 / 89 a small quantity of the formulation, for example, 0.4 ml for a single use. In this way, where the ophthalmic formulation is sterilized and contained in disposable single-dose containers for topical use in drop form, several bottles in the form of a set of 30 bottles, 60 bottles and so on can be packaged in a tray with a lid, for example, a polypropylene tray with a detachable aluminum lid. The entire contents of each tray can be dispensed intact and one bottle or package is used at a time and immediately discarded after each use. For example, ampoules, bottles or plastic containers can be manufactured using blow-fill-seal (BFS) technology. BFS processes may involve plastic extrusion, molding, aseptic filling and hermetic sealing in a sequential operation and these processes are known in the art.In another embodiment, the formulation is packaged in multidose vials so that materials can be dispensed as sterile each time, using a specialized container / closure that maintains sterility. In yet another embodiment, the ophthalmic formulation is packaged in conventional vials / containers, as a sterile product.

[0112] In some embodiments, the dosage form of the disclosure is heterogeneous aqueous solution eye drops, eye drop formulations.

[0113] In a particular embodiment, the ophthalmic formulation comprising IgG (OSIG) is formulated as eye drops and is used to treat inflammatory and immunological diseases of the ocular surface that may cause symptoms of ocular discomfort, mucocellular aggregates / debris in the tear film, symblepharon formation, fornix eshortening, keratinization of the eyelid / conjunctival margin, or subconjunctival fibrosis. Specific clinical conditions that may be treated Petition 870260076737, dated 07 / 31 / 2026, page 55 / 256 49 / 89 Contraindications with the use of ophthalmic formulations include diseases such as graft-versus-host disease (oGVHD), Stevens-Johnson syndrome, ocular cicatricial pemphigoid (OCP), mild, moderate and severe dry eye disease (DED) (secondary to Sjögrens syndrome, non-Sjögrens syndrome, idiopathic and other causes), meibomian gland disease (dysfunction or atrophy), superior limbic keratoconjunctivitis (SLK), DED due to insufficient lacrimal function (concordant or discordant), floppy eyelid syndrome, neurotrophic eye disease, aniridia and postoperative / posttraumatic pathologies, for example, after ocular surface reconstruction surgery, application of antimetabolite to the ocular surface (mitomycin-C, 5-fluorouracil and others) or keratoprosthesis surgery or radiation injury.

[0114] In yet another aspect of the disclosure, a method is provided for the treatment of an eye disease in an individual in need of such treatment. This method generally involves administering a therapeutically effective amount of a subanticoagulant quantity of an IgG ophthalmic formulation to the individual to treat an eye disease. In some embodiments, the IgG ophthalmic formulation is administered at least twice daily to the individual in question. In still other embodiments, the IgG ophthalmic formulation is administered at least twice monthly to the individual in question. The ophthalmic formulation may be an aqueous solution, aqueous suspension, gel, etc.

[0115] Another aspect of the disclosure provides a method for diagnosing or monitoring an ocular surface disorder in an individual. The method involves comparing the level of autoantibodies in a sample obtained from an individual with the control level of said autoantibodies to diagnose or monitor the ocular surface disorder in the individual. As used in this document, the term Petition 870260076737, dated 07 / 31 / 2026, page 56 / 256 50 / 89 autoantibody control level refers to the level against which the autoantibody level in the test sample can be compared, including (i) those of an individual who does not have an ocular surface disorder, (ii) those of an individual who has an ocular surface disorder, (iii) the autoantibody level of the same individual before treatment, shortly after the start of treatment, or before presenting any symptoms of an ocular surface disorder.

[0116] In some modalities, the control level may be a normal level, meaning the level in a sample from a normal patient, i.e., an individual who does not have an ocular surface disorder. This control level may be referred to more specifically as a negative control. This allows for a determination based on the autoantibody level control, where a sample to be evaluated for an ocular surface disease has a measurable difference or substantially no difference in the level of autoantibodies compared to the control level.

[0117] In another embodiment, the control level may be the level of autoantibodies established in a sample of the individual or a population of individuals believed to have an ocular surface disease. This may be more specifically referred to as a positive control level. The term positive control, as used in this document, refers to a level of autoantibody expression or biological activity established in a sample of an individual, another individual, or a population of individuals, where the sample has been considered, based on the data from that sample, to have the disease.

[0118] In other modalities, the level of control can be established from a previous sample of the individual being tested, so that the progression or regression of the individual's disease can be monitored over time and / or the effectiveness of the treatment. Petition 870260076737, dated 07 / 31 / 2026, page 57 / 256 51 / 89 can be evaluated.

[0119] Unless otherwise indicated or the context requires otherwise, the term monitor refers to determining the progression of an ocular surface disease or determining the effectiveness of a specific treatment protocol or drug. The term diagnosis refers to a process of determining the presence or absence of an ocular surface disease in an individual. It may also include determining which specific ocular surface disease is present in the individual.

[0120] Autoantibodies can be used to diagnose ocular surface diseases in order to initiate appropriate therapy or treatment, for example, with IgG eye drops or other appropriate pharmaceutical product.

[0121] Changes in autoantibody levels can be used to assess the response or effectiveness of therapy. Treatment intensity can also be titrated to autoantibody levels.

[0122] The method can be used to provide a rapid, office-based test result to diagnose and manage ocular surface diseases and to initiate / titrate IgG eye drop therapy for such diseases, as a single agent or in combination with other active pharmacological agents. The test can be designed to measure components of tears or other ocular fluid. Concentrations lower than 5 have not been considered noteworthy to date, as discussed in relation to Figure 1. However, levels above 5 may indicate a treatable condition and are contemplated within the scope of this disclosure.

[0123] Treatment can occur periodically, as IgG compositions are stable over a long period of time. Treatments can be designed for delivery at least twice a day. Petition 870260076737, dated 07 / 31 / 2026, page 58 / 256 52 / 89 doses per day or at least twice a month, or according to any other suitable treatment regimen, provided that the treatment is sufficient to reduce the levels or reduce the deleterious biological actions resulting from the autoantibodies present in the ocular fluid.

[0124] Disclosure methods that utilize autoantibodies can also be used to diagnose or monitor ocular surface disorders, such as GVHD or Sjögren's syndrome and other dry eye diseases. Such methods typically include measuring the level of one or more autoantibodies present in a biological sample taken from a test subject (e.g., tear fluid, blood / serum, or ocular surface cells) and comparing it to a control level. The control level may be the subject's previous autoantibody level, the autoantibody level of a healthy subject, or the autoantibody level of a subject (or subjects) with an ocular surface disease.

[0125] Another aspect of the disclosure provides sensors, biosensors, multianalyte panels, arrays, assays, and kits for determining the level of one or more autoantibodies obtained from the individual. Autoantibodies and the methods in which they are employed can be used to aid in diagnosis and to assess the onset and development of ocular surface disorders. The disclosure also refers to the use of autoantibodies in clinical screening, prognostic assessment, therapy evaluation, drug screening, and drug development.

[0126] In one particular aspect, disclosure provides a method for diagnosing or monitoring ocular surface disorders in an individual comprising: obtaining a biological sample from the individual and comparing the level of one or more autoantibodies in the biological sample with the control level.

[0127] The level of autoantibodies can be easily determined Petition 870260076737, dated 07 / 31 / 2026, page 59 / 256 53 / 89 using any of the conventional methods available to a person skilled in the art. Exemplary methods include, but are not limited to, direct or indirect methods, such as coupled or uncoupled enzymatic methods, electrochemical methods, spectrometric methods (e.g., spectrophotometric, such as using a UV / VIS spectrometer, fluorometric, luminometric, polarimetric, etc.), chromatographic methods (e.g., HPLC, gas chromatography, MPLC, LPLC, etc.), an immunological method, such as ELISA, dot-blot analysis, etc.

[0128] Yet another aspect of disclosure provides a method for diagnosing or monitoring ocular surface disorders or predispositions to them. Such a method involves comparing the level of one or more autoantibodies present in a biological sample taken from a test individual and comparing it with the control level. In a particular embodiment, the disclosure method is used to monitor the effectiveness of a therapy (e.g., a therapeutic substance) in an individual who has, is suspected of having, or is predisposed to an ocular surface disorder.

[0129] Yet another aspect of the disclosure provides a multianalyte panel or array capable of detecting one, two, three, four, or more (hundreds) of the disclosure’s autoantibodies. The multianalyte panel is capable of detecting several different analytes. An array is capable of detecting a single analyte in multiple samples or, as a multianalyte array, is capable of detecting a range of different analytes in one sample. A multianalyte panel or a multianalyte array, according to the disclosure, is capable of detecting one or more autoantibodies as described in this document, and is capable of detecting autoantibodies in addition to those specifically described in this document. Detection methods may include bead-based methods (e.g., Luminex platform) or Phadia ImmunoCap. Petition 870260076737, dated 07 / 31 / 2026, p. 60 / 256 54 / 89

[0130] A diagnostic or monitoring test kit suitable for performing a method according to the disclosure is also provided, optionally together with instructions for use of the kit. The diagnostic or monitoring kit may comprise one or more biosensors according to the disclosure, a single sensor, or biosensor or a combination of sensors and / or biosensors may be included in the kit. A diagnostic or monitoring kit may comprise a panel or array according to the disclosure. A diagnostic or monitoring kit may comprise an assay or combination of assays according to the disclosure.

[0131] Furthermore, the use of a method, sensor, biosensor, panel, matrix, or multianalyte kit, as disclosed, is provided for identifying a substance capable of modulating or treating ocular surface disorders. A substance capable of modulating or treating ocular surface disorders may be an anti-inflammatory, immunomodulatory, immunosuppressive, antibiotic, or palliative substance (artificial tears, contact lenses, or punctal plugs) useful for the treatment of ocular surface disorders.

[0132] Throughout this descriptive report and the attached claims, the term treat or treatment of a disease includes: (1) to prevent the disease, that is, to ensure that the clinical symptoms of the disease do not develop in an individual or someone predisposed to the disease, but who does not yet have or exhibit symptoms of the disease; (2) to inhibit the disease, that is, to interrupt or reduce the development of the disease or its clinical symptoms or (3) to alleviate the disease, that is, to cause the regression of the disease or its clinical symptoms.

[0133] A higher level of autoantibodies in the biological test sample compared to the negative control level (e.g., level of Petition 870260076737, dated 07 / 31 / 2026, page 61 / 256 A biomarker (or biomarker levels) of 55 / 89 in an individual without ocular surface disease is indicative of the presence of an ocular surface disorder, such as oGVHD, Sjögren's syndrome, and other dry eye diseases.

[0134] Monitoring, risk assessment, and diagnostic methods, as disclosed, are useful for confirming the existence of an ocular surface disorder or a predisposition to it; for monitoring the development of the ocular surface disorder by assessing its onset and progression or by assessing the improvement or regression of the disorder. Monitoring and diagnostic methods are also useful in clinical screening, prognosis, therapy selection, and assessment of therapeutic benefit, i.e., for drug screening and development.Efficient diagnostic and monitoring methods provide powerful solutions for patients with the potential to improve prognosis by establishing the correct diagnosis, allowing for the rapid identification of the most appropriate treatment (thus reducing unnecessary exposure to the side effects of harmful drugs), and reducing downtime and relapse rates.

[0135] Methods for monitoring the effectiveness of a therapy can be used to monitor the therapeutic efficacy of existing and new therapies in human subjects and in non-human animals (e.g., in animal models). These monitoring methods can be incorporated into screenings of new drug substances and combinations of substances. Modulation of a protein biomarker level is useful as an indicator of the state of the ocular surface disorder or predisposition to it. An increase in the level of autoantibodies over time is indicative of onset or progression, i.e., worsening of the disorder, while a decrease in the level of biomarker Petition 870260076737, dated 07 / 31 / 2026, page 62 / 256 56 / 89 protein detector indicates improvement or remission of the disorder. The identification of autoantibodies for ocular surface disorders allows for the integration of diagnostic procedures and therapeutic regimens.

[0136] Currently, there are no methodologies available to determine effective treatment, and to date, it has not been possible to perform a rapid assessment of drug response. Traditionally, many therapies for ocular surface diseases require treatment trials lasting weeks to months for a given therapeutic approach. Disclosure autoantibody detection can be used to select individuals prior to their participation in clinical trials. Autoantibodies provide a means to indicate therapeutic response, failure to respond, unfavorable side effect profile, degree of adherence to medication, and achievement of adequate serum drug levels. Autoantibodies can be used to alert to adverse drug response, a major problem encountered with all medications for ocular surface diseases.Autoantibodies are useful in developing personalized therapies for ocular surface diseases, as response assessment can be used to adjust dosage, minimize the number of prescribed medications, reduce delays in achieving effective therapy, and avoid adverse drug reactions. By monitoring autoantibody levels, patient care can be precisely tailored to match their needs as determined by the disorder and the patient's pharmacogenomic profile; therefore, autoantibodies can be used to titrate the optimal dose, predict a positive therapeutic response, and identify those patients at high risk of serious side effects.

[0137] The measurement of autoantibodies can be performed by a direct or indirect detection method. Biomarkers can be detected directly or indirectly, through interaction with a ligand. Petition 870260076737, dated 07 / 31 / 2026, page 63 / 256 57 / 89 or ligands, such as an enzyme, binding receptor or carrier protein, antibody, peptide, aptamer or oligonucleotide, or any synthetic chemical receptor or compound capable of specifically binding the biomarker. The ligand may possess a detectable marker, such as a luminescent, fluorescent or radioactive label and / or an affinity label.

[0138] In a particular embodiment, the autoantibodies of the disclosure are detected and measured using techniques based on mass spectrometry; techniques based on chromatography; enzymatic detection systems (by direct or indirect measurements); or using sensors, for example, with sensor systems with amperometric, potentiometric, conductimetric, impedance, magnetic, optical, acoustic or thermal transducers. A sensor may incorporate a physical, chemical or biological detection system. An example of a sensor is a biosensor, that is, a sensor with a biological recognition system, for example, based on a nucleic acid, such as an oligonucleotide probe or aptamer, or a protein, such as an enzyme, binding protein, receptor protein, carrier protein or antibody. The biosensor may incorporate an immunological method for biomarker detection, an electrical, thermal, magnetic, optical (e.g., hologram) or acoustic technology.With the use of such biosensors, it is possible to detect target autoantibodies at the predicted concentrations found in biological samples. Dissemination methods are suitable for clinical screening, prognostic assessment, monitoring of therapy outcomes, identification of patients most likely to respond to a particular therapeutic treatment, drug screening and development, and to assist in the identification of new drug treatment targets. The identification of disease-specific essential autoantibodies is fundamental for the integration of diagnostic procedures. Petition 870260076737, dated 07 / 31 / 2026, page 64 / 256 58 / 89 and therapeutic regimens.

[0139] Methods involving the detection and / or quantification of disclosure autoantibodies can be performed using benchtop instruments or can be incorporated into disposable diagnostic or monitoring platforms that can be used in a non-laboratory setting, for example, in the doctor's office or at the patient's bedside. Suitable sensors or biosensors for performing disclosure methods include credit cards with optical or acoustic readers. Sensors or biosensors can be configured to allow the collected data to be transmitted electronically to the physician for interpretation and thus can form the basis for e-medicine.

[0140] The preceding discussion of the disclosure was presented for illustrative and descriptive purposes. The preceding content is not intended to limit the disclosure to the form or forms disclosed in this document. Although the description of the disclosure has included the description of one or more embodiments and certain variations and modifications, other variations and modifications are encompassed within the scope of the disclosure, for example, as may be encompassed by the skill and knowledge of persons skilled in the art, after understanding the present disclosure. It is intended to obtain rights that include alternative embodiments to the extent permitted, including alternative, interchangeable and / or equivalent structures, functions, ranges or steps to those claimed, whether or not such alternative, interchangeable and / or equivalent structures, functions, ranges or steps are disclosed in this document, and without the intention of publicly dedicating any patentable subject matter.

[0141] In addition to the following examples, clinically significant results related to disclosure are also provided in Kwon et al., Pathological consequences of anti-citrullinated protein antibodies in tear fluid and therapeutic potential of pooled human immune globulin Petition 870260076737, dated 07 / 31 / 2026, page 65 / 256 59 / 89 eye drops in dry eye disease, Ocul Surf. October 10, 2019. (pii: S1542-0124(19)30377-5. doi: 10.1016 / j.jtos.2019.10.004) available at https: / / doi.org / 10.1016 / j.jtos.2019.10.004. Kwon et al. is incorporated herein by reference in its entirety. EXAMPLES EXAMPLE 1: AUTOANTIBODY LEVELS (ACPA) IN HEALTHY INDIVIDUALS AND OCULAR SURFACE DISEASES

[0142] The presence of autoantibodies (ACPA) was demonstrated in ocular surface washes from healthy individuals (Figure 1) to establish a cutoff for the diagnosis of an ACPA-positive individual. Ocular surface washes were performed on healthy individuals (without dry eye disease due to lacrimal deficiency (DED)), using 50 μL of artificial tears and 10 μL of recovered washes which were analyzed for ACPA levels by ELISA using commercial plates (CCP3). All negative values ​​were considered as 0. The mean + 3SD was used to establish the cutoff for positive ACPA values. ACPA, all negative = 0, mean was 0.57 and 3SD of 1.2 = 4.17. Therefore, a cutoff of 5.0 was established.

[0143] The presence of autoantibodies (ACPA) has also been demonstrated in ocular surface washes from patients with ocular surface disease (Figures 2 and 3). As shown in Figure 2, ACPA levels were determined in ocular surface washes from patients with ocular surface disease. These patients were being treated with appropriate topical eye drops (artificial tears, restasis, xiidra, or steroids). ACPA levels in tear fluid were positive (i.e., ACPA > 5.0) in several ocular autoimmune diseases, such as Sjögren's syndrome, dry eye disease due to lacrimal deficiency, mixed-mechanism DED, ocular cicatricial pemphigoid (OCP), Petition 870260076737, dated 07 / 31 / 2026, page 66 / 256 60 / 89 Stevens-Johnson syndrome and ocular graft-versus-host disease (oGVHD). Patients with evaporative DED, such as meibomian gland dysfunction, also presented high ACPA levels. Superior limbic keratoconjunctivitis (SLK) and neurotrophic keratitis also presented high ACPA levels. Surprisingly, patients with signal-symptom disconnection (discordant DED) also presented high ACPA levels. Thus, all these ocular diseases, including others such as autoimmune / inflammatory intraocular glaucoma, would benefit from treatment with OSIG eye drops to reduce the contribution of autoantibodies to the signs and symptoms of ocular diseases. The data in Figure 3 show the percentage of all patients with a specific ocular disease who tested positive for ACPA in ocular surface washes. EXAMPLE 2: THE INADEQUATE EFFECT OF CONVENTIONAL TREATMENTS ON ACPA LEVELS

[0144] Experiments were conducted to demonstrate the inadequate effect of conventional treatments on ACPA levels in ocular surface washes (Figures 4 and 5). Figure 4 shows ACPA levels in the tear fluid of patients with Sjögren's syndrome before and after the start of conventional treatment. Compared to ACPA levels in Sjögren's patients already undergoing treatment, patients not yet receiving treatment (pre-Rx Sjögren's) have significantly higher ACPA levels. After the start of treatment (post-Rx Sjögren's), levels are lower, but still significantly higher compared to healthy individuals.These data show that even if patients with Sjögren's syndrome are receiving treatment, ACPA levels in the tear fluid are high, thus making it specifically appropriate to target ACPA, such as with OSIG therapy, to reduce the contribution of ACPA to ocular surface disease. Petition 870260076737, dated 07 / 31 / 2026, page 67 / 256 61 / 89

[0145] ACPA levels in the tear fluid of oGVHD patients before and after the start of treatment. ACPA levels in oGVHD patients not yet receiving treatment (pre-Rx oGVHD) are significantly higher than ACPA levels after the start of treatment (post-Rx oGVHD) (Figure 5). ACPA levels one month after the start of treatment are significantly higher than those of healthy individuals. These data show that even if oGVHD patients are receiving treatment, ACPA levels in the tear fluid are high, thus making it specifically the case to target ACPA, such as with OSIG therapy, to reduce the contribution of ACPA to ocular surface disease. EXAMPLE 3: CITRULINATED PROTEINS ARE PRESENT ON THE OCULAR SURFACE IN PATIENTS WITH OCULAR SURFACE DISEASE

[0146] It was subsequently demonstrated that citrullinated proteins are present on the ocular surface in patients with ocular surface disease. As shown in Figure 6, citrulline is expressed in non-epithelial cells in Sjögren's - impression cytology. The aim of this experiment was to examine whether the ocular surface cells of patients with Sjögren's are citrullinated. Approval for the study was obtained from the Institutional Review Committee of the University of Illinois at Chicago (UIC). Informed consent was obtained from all participants after the nature and potential consequences of the study were explained. The research was conducted in accordance with the requirements of the Health Insurance Accountability and Portability Act (HIPAA) and the principles of the Declaration of Helsinki.

[0147] The antibiotic was applied to a patient's eye and a filter paper (PALL, No. 60298) was applied to the temporal conjunctiva and pallor. Petition 870260076737, dated 07 / 31 / 2026, p. 68 / 256 62 / 89 lower pebra to remove the superficial layer of the ocular surface epithelium. Filter papers were fixed with 4% paraformaldehyde (PFA) for 20 minutes in a Petri dish, subsequently washed in 1X PBS for 5 minutes and attached to a microscope slide using an adhesive tab. A water-resistant barrier was created with a Pap pen around the sample, followed by one hour of permeabilization with PBS-T (0.025% Triton in 1X PBS). The filter papers were washed once with 1X PBS for 5 minutes with gentle agitation and then blocked with 2.5% equine serum (secondary host species reared in) and 1% BSA in 1X PBS for at least one hour. The filter papers were then incubated with primary antibodies overnight at 4°C. The primary antibodies used were mouse monoclonal antibody anticitrulline (1:1,000; Millipore, MABN328) and rabbit polyclonal antibody anticytokeratin 14 (1:1,000; BioLegend, No. 905301).

[0148] The following day, the filter papers were washed 3 times with 1X PBS for 5 minutes with gentle agitation, followed by incubation of secondary antibodies at room temperature for 1 hour. The secondary antibodies used were: Alexa Fluor 594 equine anti-mouse IgG (1:1,000; Jackson ImmunoResearch Lab, No. 715-585-150) and Alexa Fluor 488 equine anti-rabbit IgG (1:1,000; Jackson ImmunoResearch Lab, No. 711-546-152). After incubation, the filter papers were washed 3 times with 1X PBS for 5 minutes with gentle agitation in the dark. The slides were dried and mounted with Antifade Gold ProLong™ Mount with DAPI (Invitrogen, P36931). A coverslip was placed and sealed with nail polish. The slides were completely dried before imaging. The images were captured using a Zeiss LSM 710 confocal microscope (Leica, UIC Ophthalmology Core) at 63X magnification and analyzed with the software. Petition 870260076737, dated 07 / 31 / 2026, page 69 / 256 63 / 89 tware Zeiss LSM Image. Impression cytology was performed on the patient with Sjögren's syndrome and it was found that citrulline was expressed in non-epithelial cells (neutrophils). Non-epithelial cells can be neutrophils, supported by the presence of NETs. These data demonstrated that non-epithelial cells in patients with Sjögren's syndrome were citrullinated. EXAMPLE 4: CITRULINATED PROTEINS ARE ABSENT IN HEALTHY INDIVIDUALS

[0149] In Sjogrens, citrullinated proteins appear to be predominantly neutrophilic (Figures 6 and 7). The aim of this experiment was to verify whether non-epithelial citrullinated cells are neutrophilic (Figure 7). Impression cytology was performed as described above in Example 3.

[0150] The primary antibodies used were mouse anti-citrulline monoclonal antibody (1:1000; Millipore, MABN328) and rabbit antineutrophil elstase monoclonal antibody (1:500; Abcam, ab131260). The following day, the filter papers were washed 3 times with 1X PBS for 5 minutes with gentle agitation, followed by incubation of secondary antibodies at room temperature for one hour. The secondary antibodies used were as follows: Alexa Fluor 594 equine anti-mouse IgG (1:1000; Jackson ImmunoResearch Lab, No. 715-585-150) and Alexa Fluor 488 equine anti-rabbit IgG (1:1000; Jackson ImmunoResearch Lab, No. 711-546-152). After incubation, the filter papers were washed 3 times with 1X PBS for 5 minutes with gentle agitation in the dark. The slides were dried and mounted with Antifade Gold ProLong™ mount with DAPI (Invitrogen, P36931). A coverslip was placed and sealed with nail polish. The slides were completely dried before imaging.The images were captured using a Zeiss LSM 710 confocal microscope (Leica, UIC Ophthalmology Core) at 63X magnification and analyzed. Petition 870260076737, dated 07 / 31 / 2026, page 70 / 256 64 / 89 with Zeiss LSM Image software.

[0151] Citrullin-positive cells were neutrophils, as suggested by multilobed nuclei. This implies that the main source of citrullin on the ocular surface was neutrophils. Citrullinated neutrophil proteins may be the source of the ACPA response. This was validated by the findings of the dot blot assay. ACPA-positive tears react with citrullinated neutrophil proteins. These data suggest that neutrophils were the source of citrullination and that citrullinated neutrophil proteins may be the source of the ACPA response. EXAMPLE 5: IN oGVHD, CITRULINATED PROTEINS APPEAR TO BE PREDOMINANTLY EPITHELIAL

[0152] It was subsequently demonstrated that citrulline was expressed in epithelial cells in definitive oGVHD. The aim of this experiment was to compare citrulline expression between patients with Sjögren's syndrome and those with definitive oGVHD (Figure 8). The antibiotic was applied to a patient's eye, and a filter paper (PALL, No. 60298) was applied to the temporal conjunctiva and lower eyelid to remove the superficial layer of the ocular surface epithelium. The filter papers were fixed with 4% paraformaldehyde (PFA) for 20 minutes in a Petri dish. They were then washed in 1X PBS for 5 minutes and attached to a microscope slide using an adhesive tab. A water-resistant barrier was created with a Pap pen around the sample, followed by 1 hour of permeabilization with PBS-T (0.025% Triton in 1X PBS).The filter papers were washed once with 1X PBS for 5 minutes with gentle agitation and then blocked with 2.5% equine serum (secondary host species reared in) and 1% BSA in 1X PBS for at least one hour. The filter papers were then incubated overnight with primary antibodies at 4°C. The primary antibodies used were mouse monoclonal anticitrulline antibody (1:1000; Millipore, MABN328) and antibody. Petition 870260076737, dated 07 / 31 / 2026, p. 71 / 256 65 / 89 rabbit polyclonal anticytokeratin 14 (1:1,000; BioLegend, No. 905301). The following day, the filter papers were washed 3 times with 1X PBS for 5 minutes with gentle agitation, followed by incubation of secondary antibodies at room temperature for one hour. The secondary antibodies used were as follows: equine anti-mouse IgG Alexa Fluor 594 (1:1,000; Jackson ImmunoResearch Lab, N° 715-585-150) and IgG anticoelho de equino Alexa Fluor 488 (1:1,000; Jackson ImmunoResearch Lab, N° 711-546152).

[0153] After incubation, the filter papers were washed 3 times with 1X PBS for 5 minutes with gentle agitation in the dark. The slides were dried and mounted with Antifade Gold ProLong™ Mount with DAPI (Invitrogen, P36931). A coverslip was placed and sealed with nail polish. The slides were completely dried before imaging. Images were captured using a Zeiss LSM 710 confocal microscope (Leica, UIC Ophthalmology Core) at 63X magnification and analyzed with Zeiss LSM Image software. Unlike Sjögren's syndrome, where neutrophils were the main source of citrulline, patients with definite oGVHD have completely citrullinated epithelial cells, which correlates with high levels of citrulline and the PAD4 enzyme. These data showed that the strong citrullination of epithelial cells supports the high levels of citrulline and the PAD4 enzyme.Of the patients tested, there was no colocalization of citrulline and K14 in two different patients with Sjögren's syndrome, but there was colocalization of citrulline and K14 in patients with oGVHD. Furthermore, colocalization of citrulline with neutrophils was observed in two different patients with Sjögren's syndrome. EXAMPLE 6: INDUCIBLE FC RECEPTOR EXPRESSED IN NEUTROPHILS

[0154] Citrullinated proteins were absent in patients without Petition 870260076737, dated 07 / 31 / 2026, page 72 / 256 66 / 89 oGVHD. These findings demonstrate that a source of autoantibody production is citrullinated neutrophils and / or ocular surface cells in patients with DED. It has also been shown that Fc receptors (receptors for IgG) are present on the ocular surface and that ACPA antibodies interact with Fc receptors to produce surface diseases. It is assumed that Fc receptors are not expressed on naive neutrophils, but are inducible. Fc receptors are expressed on neutrophils in mucocellular aggregates.

[0155] The aim of this experiment was to support the hypothesis of an inducible Fc receptor in neutrophils. Peripheral blood was collected by venipuncture in BD vacutainer sodium heparin tubes (BD Biosciences, No. 367878) and immediately transported to the laboratory for neutrophil isolation. Neutrophils were isolated by immunomagnetic depletion of non-target cells using MACSxpress beads (MACSxpress Neutrophil Isolation Kit, Miltenyi Biotech, No. 130-104-434), according to the manufacturer's instructions. Residual erythrocytes were removed using the MACSxpress Erythrocyte Depletion Kit (Miltenyi Biotech, No. 130-094-183). Isolated neutrophils were resuspended with 3 ml of phenol red-free and serum-free RPMI-1640 medium (GIBCO, No. 11835-030). After measuring the cell count, 50,000 cells / 200 µl of neutrophils were loaded into a single Cytofunnel EZ (Thermo Scientific, No. A78710003).The patient's mucoid sample was prepared with 4 U / ml DNasel and 1x buffer in 100 µl of solution, and incubated for 30 minutes at 37°C to obtain a single-cell suspension. A 10-fold diluted mucoid sample was loaded into a single Cytofunnel EZ (Thermo Scientific, No. A78710003). The samples were centrifuged at 1000 rpm for 5 minutes using a Cytospin 4 (Thermo Scientific, Kalamazoo, MI) to obtain a monolayer of cell deposition in a defined area of ​​the cytoslide (Thermo Scientific, No. 5991056). Petition 870260076737, dated 07 / 31 / 2026, page 73 / 256 67 / 89 After centrifugation, the slides were air-dried for 5 minutes and then fixed with 4% paraformaldehyde (PFA) solution (Electron Microscopy Sciences, Hatfield, PA, No. 15710) for 20 minutes. A water-resistant barrier was created with a Pap pen around the sample, followed by one hour of permeabilization with PBS-T (0.025% Triton in 1X PBS). The samples were washed once with 1X PBS for 5 minutes with gentle agitation and then blocked with 2.5% equine serum (secondary host species reared in) and 1% BSA in 1X PBS for at least one hour. The samples were then incubated with primary antibodies overnight at 4°C.The primary antibodies used were mouse anti-CD64 monoclonal antibody (1:1000; Santa Cruz, sc-1184), mouse anti-IgMK monoclonal antibody (1:2500; Novus Biologicals, NBP1-96975), rabbit antineutrophil elstase monoclonal antibody (1:500; Abcam, ab131260), and rabbit monoclonal IgG antibody (0.03 ug / ml; Abcam, ab172730).

[0156] The following day, the samples were washed 3 times with 1X The samples were incubated in PBS for 5 minutes with gentle agitation, followed by incubation of secondary antibodies at room temperature for one hour. The secondary antibodies used were: equine anti-mouse IgG Alexa Fluor 594 (1:1,000; Jackson ImmunoResearch Lab, No. 715-585-150) and equine anti-rabbit IgG Alexa Fluor 488 (1:1,000; Jackson ImmunoResearch Lab, No. 711-546-152). After incubation, the samples were washed 3 times with 1X PBS for 5 minutes with gentle agitation in the dark. The slides were dried and mounted with Antifade Gold ProLong™ Mount with DAPI (Invitrogen, P36931). A coverslip was placed and sealed with nail polish. The slides were completely dried before imaging. The images were captured using a Zeiss LSM 710 confocal microscope (Leica, UIC Ophthalmology Core) at 63X magnification and analyzed. Petition 870260076737, dated 07 / 31 / 2026, page 74 / 256 68 / 89 with Zeiss LSM Image software.

[0157] As shown in Figure 9, Fc receptors are expressed only on neutrophils stimulated by PMA and patient mucoid, implying that the neutrophils were activated. The staining was confirmed positive with isotype control and negative control. In summary, naive neutrophils do not express the Fc receptor, while activated neutrophils do, confirming that the expression of Fc receptors is inducible.

[0158] An additional experiment was performed to confirm the presence of Fc receptor-positive neutrophils on the ocular surface. Impression cytology was performed as described above in Example 3. The primary antibodies used were mouse anti-CD64 monoclonal antibody (1:1,000; Santa Cruz, sc-1184) and rabbit anti-cytokeratin 14 polyclonal antibody (1:1,000; BioLegend, No. (905301). The following day, the filter papers were washed 3 times with 1X PBS for 5 minutes with gentle agitation, followed by incubation of secondary antibodies at room temperature for one hour. The secondary antibodies used were: equine anti-mouse IgG Alexa Fluor 594 (1:1,000; Jackson ImmunoResearch Lab, No. 715-585-150) and equine anti-rabbit IgG Alexa Fluor 488 (1:1,000; Jackson ImmunoResearch Lab, No. 711-546-152). After incubation, the filter papers were washed 3 times with 1X PBS for 5 minutes with gentle agitation in the dark. The slides were dried and mounted with Antifade Gold ProLong™ Mount with DAPI (Invitrogen, P36931). A coverslip is placed and sealed with nail polish. The slides were completely dried before imaging. Images were captured using a Zeiss LSM 710 confocal microscope (Leica, UIC Ophthalmology Core) at 63X magnification and analyzed with Zeiss LSM Image software.After immunofluorescence staining, the same filter papers were stained with hematoxylin and eosin. Petition 870260076737, dated 07 / 31 / 2026, page 75 / 256 69 / 89 The filter papers were stained with hematoxylin (Fisher Scientific, SH26-500D), rinsed with acid, immersed in a bluish solution, and counterstained with eosin (Thermo Scientific, Waltham, MA). The slides were examined using an Axioscope 100 vertical microscope (Carl Zeiss Meditec GmbH, Hamburg, Germany), photographed using a Zeiss MRc color camera, and analyzed using Zeiss Axiovision.

[0159] Figure 10 demonstrates that Fc receptors were expressed in K14-negative cells (non-epithelial cells), interspersed with epithelial cells. Some of these non-epithelial cells have multilobed nuclei (white box) reminiscent of neutrophils, suggesting neutrophils, and this is subsequently confirmed by H&E staining. Other cells are large mononuclear cells that may be T cells. K14-positive cells do not have Fc receptors, which is confirmed by the literature.

[0160] In addition, an experiment was performed to determine if ACPA in tears is reactive to NET citrullinated proteins. The dot blot assay was performed using a Bio-Dot microfiltration apparatus (Bio-Rad, No. 170-6545), with a nitrocellulose membrane (Company, Cat. No.). The general protocol was followed according to the manufacturer's instructions. The membrane was pre-wetted in TBS; it was rehydrated as needed. 1 pg / 100 µl of total protein from the lysate was applied to the membrane, incubated for one hour with the vacuum chamber open to air, allowing the protein to filter through the membrane by gravity. 200 µl of blocking solution (1% BSA-TBS) were added to each well and allowed to filter by gravity, followed by washing. 200 pl of washing solution (0.05% Tween-TBS) was added and vacuumed, and repeated once more.100 ml of the patient's tears diluted 1:80 (diluted in 1% BSA-TTBS) were added and allowed to filter through. Petition 870260076737, dated 07 / 31 / 2026, page 76 / 256 70 / 89 gravity, followed by washing the membrane with 200 μL of TTBS. The membrane was incubated with 100 μL of HRP-conjugated human IgG antibody (No. A112P, EMD). The spots were incubated with the maximum sensitivity substrate SuperSignal West Femto enhanced chemiluminescence (34095, Thermo Fisher) and the signal was detected using the ImageQuant LAS 4000 system (GE Lifesciences Inc). The intensity of the dot blots was determined using ImageJ software.

[0161] Neutrophils were stimulated with calcium ionophore for hours to induce hypercitrullination and RPMI for the same period, which served as a control. After stimulation, neutrophils were lysed to extract the total protein, which is immobilized on the membrane. As shown in Figure 11, it was found that ACPA in tears reacts with NET proteins, confirming that neutrophilic citrullinated proteins can be a source of ACPA stimulation. The results were expressed as the fold ratio was calculated using the following formula: Fold = intensity of citrullinated protein / intensity of wild-type protein. ACPA-positive tears show greater reactivity to stimulated NET proteins (92.8 ± 7.85) than unstimulated tears (54.1 ± 5.46), while ACPA-negative tears showed no difference (45.0 ± 3.19 vs. 49.3 ± 4.79). In summary, ACPA in tears is reactive to NET proteins.

[0162] Another experiment was performed to determine if polyclonal ACPA was present in tears. The dot blot assay was performed using Direct Detect assay blank cards (No. DDAC00010-GR) obtained from Millipore (Burlington, MA). 2 μL of recombinant protein (1 μg) were applied to the membranes and allowed to dry at room temperature (RT) for 20 min. Then, the membranes were blocked with 10% BSA and Petition 870260076737, dated 07 / 31 / 2026, p. 77 / 256 71 / 89 Tween-20 at 0.05% prepared in 1X PBS (pH 7.4) for 30 min at room temperature. Membranes that were rinsed with rinsing buffer (1% BSA and 0.05% Tween 20 in 1X PBS) and probed with the patient's tear sample (1:40 dilution, diluted with sterile water) were applied to the membranes and incubated for 30 min at room temperature. The membranes were washed three times with rinsing buffer and subsequently incubated with HRP-conjugated human IgG antibody (no. A112P, EMD) for 30 min at room temperature. The membranes were washed three times with rinsing buffer. The spots were incubated with the maximum sensitivity substrate SuperSignal West Femto enhanced chemiluminescence (34095, Thermo Fisher) and the signal was detected using the ImageQuant LAS 4000 system (GE Lifesciences Inc). The intensity of the dot blots was determined using ImageJ software.The results presented in Table 2 are expressed as a fold ratio, as calculated using the following formula: Fold = intensity of citrullinated protein / intensity of wild-type protein (Table 2).

[0163] As shown in Figure 12, positive tears for ACPAs show the presence of polyclonality, and ACPA reacts with several citrullinated proteins. The fold change of citrullinated fibrinogen or enolase relative to its wild type was greater than 1.5 in both Sjögren's and definitive oGVHD patients. In Sjögren's patients, citrullinated vimentin was greater than 1.5 in fold change relative to its wild type, while in definitive oGVHD, citrullinated histone H4 was greater than its wild type. Tears from two diseased patients demonstrated ACPA polyclonality, while neurotropic and healthy tears were negative for ACPA. In summary, ACPA-positive tears show polyclonality. (+) : >1.5. Petition 870260076737, dated 07 / 31 / 2026, page 78 / 256 72 / 89 TABLE 2: FOLD CHANGE OF CITRULINATED PROTEIN COMPARED TO WILD-TYPE PROTEIN Change in citrullinated protein fold relative to wild-type protein Histone H4 Histone H3 Fibrinogen Vimentin Enolase Neurotropic 1 1 1.2 1.06 1.4 Healthy 1 1 0.7 0.9 1 Sjogren's 1.6 1.09 2.1 2.8 4.1 Definitive oGVHD 2.3 0.8 3.36 1.17 6.2 EXAMPLE 7: ACPA H4R3cit ANTISEROL IN OCULAR SURFACE DISEASE

[0164] Next, the possibility of a specific autoantibody – ACPA (antiserum H4R3cit) – causing ocular surface disease in an experimental model was examined. Specifically, this experiment investigates whether H4R3cit was present in the patient's mucocellular aggregates. Mucocellular aggregates (MCA) were collected from patients' eyes using sterile jeweler's forceps and transferred to 0.2 ml PCR tubes containing Refresh Optive and stored in an ice box. Fresh MCA samples were embedded in Tissue-Tek® OCT compound (Sakura Finetek, Torrance, CA, No. 4583) and flash-frozen. Frozen sections were cut to 10 µm thickness using a cryostat (Thermo Scientific, CryoStar NX50, No. 957130). These specific MCAs were collected from a patient who was diagnosed with definite oGHVD. For immunostaining, the slides were air-dried and then fixed with 4% PFA for 20 minutes.Then, the samples were permeabilized with 0.025% Triton X-100 (Fisher. Petition 870260076737, dated 07 / 31 / 2026, page 79 / 256 73 / 89 Samples were blocked with 10% equine serum prepared fresh with 1% bovine serum albumin (Gemini Bio-Products, No. 700-100P) for two hours. Samples were incubated overnight with primary antibodies at 4°C. The following primary antibodies were used: mouse anti-human monoclonal neutrophil elastase (NE) (1:100; Dako, No. M0752), rabbit anti-histone H4 (citrulline R3) polyclonal antiserum (1:1000; Abcam, ab81797), and rabbit polyclonal IgG (1:1000; Abcam, ab37415). Slides were washed three times with 1X PBS for 5 minutes with gentle shaking and incubated with secondary antibodies diluted in blocking buffer at room temperature for 1.5 hours. The secondary antibodies used were the following: Alexa Fluor 594 equine anti-mouse IgG (1:1,000; Jackson ImmunoResearch Lab, No. 715-585-150) and Alexa Fluor 488 equine anti-rabbit IgG (1:1,000; Jackson ImmunoResearch Lab, No. 711-546-152).The slides were washed twice with 1X PBS, contrasted with Hoechst 33342 (2 μI / ml) (Thermo Scientific, No. 62249) for 10 minutes, a quick wash with PBS, and covered with a drop of Gold ProLong™ antifade reagent (Invitrogen, No. P36930). Images were captured using a Zeiss LSM 710 confocal microscope (Leica, UIC Ophthalmology Core) at 100X magnification and analyzed with Zeiss LSM Image software.

[0165] To confirm the presence of H4R3cit on the ocular surface of the patient, MCA was collected from a patient with a definitive diagnosis of oGVHD, and it was analyzed by immunofluorescence staining. The immunofluorescence-stained cells showed a large number of neutrophils with multilobed nuclei and were confirmed with positive neutrophil elastase staining. It is known in the art that H4R3cit is expressed around the nucleus (perinuclear), which can be seen in Figure 6. As shown in Figure 13,. Petition 870260076737, dated 07 / 31 / 2026, page 80 / 256 74 / 89 H4R3cit in immunolocalized H cells relative to the ocular surface and dot blot analysis using tears from a patient with oGVHD shows a reaction with H4cit. Figure 13 also shows the presence of H4R3cit in the patient's mucocellular aggregates. The staining was confirmed as positive, since the isotype control showed negative staining. In summary, the patient's mucocellular aggregate possesses the H4R3cit antigen, which may be the source of the ACPA response.

[0166] In order to investigate whether ACPA antibodies cause ocular surface disease, 8- to 10-week-old Thy1-YFP mice were used for the treatment experiment. Thy1-YFP mice (n=5 / group) were anesthetized by intraperitoneal injection with a combination of ketamine (20 mg / kg; Phoenix Scientific, St. Joseph, MO) and xylazine (6 mg / kg; Phoenix Scientific). To assess the pathological effects of ACPA, ACPA antibodies were applied to the mouse cornea and the extent of antibody-induced corneal surface disease was determined and then compared with the application of non-ACPA antibodies. The following conditions were used: 1) non-ACPA antibody: anti-histone H4 antibody (100 ng / ml; Cell Signaling No. 2592), 2) ACPA No. 1 antibody: anti-histone H4 (citrulline R3) (H4R3cit) antiserum (100 ng / ml; Abcam No. ab81797), 3) ACPA No. 2 antibody: anti-histone H3 (citrulline R2+R8+R17) antiserum (100 ng / ml; Novus Biologicals No. NB10057135SS) was applied to the surface of the murine cornea (10 µl / cornea) and incubated for 40 minutes for 7 consecutive days. Since the ACPA antibodies used were in rabbit antiserum, normal application of rabbit serum (100 ng / ml; Abcam No. ab7487) was used as a control. Dilutions for all antibodies were made in Refresh Optive. For the fluorescein staining experiment, 10 µl of 0.2% fluorescein was instilled into the cornea of ​​mice for 1 minute and washed twice with 1X PBS. Staining with Petition 870260076737, dated 07 / 31 / 2026, p. 81 / 256 75 / 89 fluorescein was detected and photographed with a slit beam (Haag Streit, Bern, Switzerland), using cobalt blue illumination and a yellow barrier filter. Images of each group (n=5) were collected and the intensity of the fluorescein staining was measured by the Metamorph imaging system. (Metamorph, Universal Imaging, Downington, PA).

[0167] H4R3cit antiserum was applied to the mouse cornea and demonstrated a significant increase in ocular surface disease, as evidenced by fluorescein staining of the cornea. Fluorescein staining was significantly increased in several controls (rabbit serum, H3cit antiserum, and wild-type H4 antibody) (Figure 14). As shown in Figure 14, panels A1 and A5 show that application of non-ACPA antibody for 7 consecutive days to the mouse cornea did not result in corneal epithelial disease, as evidenced by the lack of fluorescein staining on day 7 (2.59x106 ± 5.41x104).Of the two ACPA antibodies used, only one resulted in corneal epithelial disease, as evidenced by the significant increase in corneal fluorescein staining on day 7. The ACPA antibody that caused corneal epithelial disease was ACPA antiserum No. 1-H4R3cit (fluorescence intensity of 1.85x10⁷ ± 3.19x10⁶ on day 7 compared to day 0 (3.00x10⁶ ± 6.05x10⁴; p = 0.0006; Figure 14. A2 and A6), while ACPA antiserum No. 2-H3cit did not cause corneal epithelial disease (fluorescence intensity of 3.34x10⁶ ± 4.90x10⁵ on day 7 compared to day 0 (3.36x10⁶ ± 3.05x10⁵; p = 0.97; Figure 14. A3 and A7). Vehicle control also did not cause corneal epithelial disease, as evidenced by the lack of fluorescein staining on Day 7 (3.11x10⁶ ± 3.49x10⁵; Figure 14. A4 and A8). In summary, these data show that ACPA antibodies caused corneal epithelial disease; however, not all ACPA antibodies may cause the same. Petition 870260076737, dated 07 / 31 / 2026, page 82 / 256 76 / 89 TABLE 3: FLUORESCENCE MEASUREMENTS FROM FLUORESCEIN STAINING OF MOUSE CORNEA Fluorescence Conditions Day 0 (Mean ± SEM, AU) Fluorescence Day 7 (Mean ± SEM, AU) P-value (two-tailed) No ACPA (WT H4 antibody) 2.22x10⁶ ± 1.04x10⁵ 2.59x10⁶ ± 5.41x10⁴ 0.013 ACPA No. 1 (H4R3cit antiserum) 3.00x10⁶ ± 6.05x10⁴ 1.85x10⁷ ± 3.19x10⁶ 0.0006 ACPA No. 2 (H3cit antiserum) 3.36x10⁶ ± 3.05x10⁵ 3.34x10⁶ ± 4.90x10⁵ 0.97 Control (Rabbit serum) 3.04x106 ± 2.14x105 3.11x106 ± 3.49x105 0.86

[0168] An experiment was also conducted to determine whether ACPA antibodies could induce NETosis. Thy1-YFP mice aged 8 to 10 weeks were used for the treatment experiment. Thy1-YFP mice (n=5 / group) were anesthetized by intraperitoneal injection with a combination of ketamine (20 mg / kg; Phoenix Scientific, St. Joseph, MO) and xylazine (6 mg / kg; Phoenix Scientific). The mice were divided into three groups: 1) RPMI (Gibco No. 11835030) treated, which served as a control, 2) ACPA antibody No. 1: H4R3cit antiserum or 3) ACPA antibody No. 2: H3cit antiserum treated. 10 μI of each treatment were applied to murine corneas. The eyes were treated for 7 consecutive days. At the end of the experiment, a filter paper stain was used to perform impression cytology of the murine cornea. An adhesive guide (EMS, No. 76760) was attached to a microscope slide.A sheet of filter paper (Millipore, No. JHWP02500) was cut to an ideal size. While a mouse was under anesthesia, a drop of proparacaine was applied to the mouse's eye for one minute and gently removed with Kimwipe. A piece of filter paper was placed in the eye. Petition 870260076737, dated 07 / 31 / 2026, page 83 / 256 77 / 89 cornea and gently pressed for 30 seconds. Then, it was gently lifted and placed on the adhesive tape, with the area that came into contact facing upwards. All subsequent steps were performed in a humid chamber, except for the washing steps. A water-resistant barrier was created with a Pap pen and the filter paper was fixed with 4% paraformaldehyde (PFA) for 20 minutes. The filter papers were washed with 1X PBS for 5 minutes with gentle agitation, followed by 10 minutes of permeabilization with PBS-T (0.025% Triton in 1X PBS). The filter papers were washed once with 1X PBS for 5 minutes with gentle agitation and then blocked with 2.5% equine serum (secondary host species reared in) and 1% BSA in 1X PBS for at least one hour. The filter papers were then incubated with primary antibodies overnight at 4°C. The primary antibodies used were mouse monoclonal anticitrulline antibody (1:1.000; Millipore, MABN328) and rabbit polyclonal antiserum anti-histone H4 (citrulline R3) (1:1,000; Abcam, ab81797). The following day, the filter papers were washed 3 times with 1X PBS for 5 minutes with gentle agitation, followed by incubation of secondary antibodies at room temperature for one hour. The secondary antibodies used were as follows: Alexa Fluor 594 equine anti-mouse IgG (1:1,000; Jackson ImmunoResearch Lab, No. 715-585150), Alexa Fluor 488 equine anti-rabbit IgG (1:1,000; Jackson ImmunoResearch Lab, No. 711-546-152), Alexa Fluor 594 equine anti-rabbit IgG (1:1,000; Invitrogen, No. A21207), and Alexa Fluor 488 equine anti-mouse IgG (1:1,000; Jackson ImmunoResearch Lab, No. 715-547-003). After incubation, the filter papers were washed 3 times with 1X PBS for 5 minutes with gentle agitation in the dark. The slides were dried and mounted using Antifade Gold ProLong™ Mount with DAPI (Invitogen, P36931). A coverslip was placed and sealed with nail polish.The slides were completely dried before imaging. Petition 870260076737, dated 07 / 31 / 2026, page 84 / 256 78 / 89 The images were captured using a Zeiss LSM 710 confocal microscope (Leica, UIC Ophthalmology Core) at 63X magnification and analyzed with Zeiss LSM Image software. After 7 days of treatment with 1) RPMI, 2) ACPA No. 2-H3cit antiserum, or 3) ACPA No. 1-H4R3cit antiserum, the mouse corneal epithelium was lifted onto filter paper to investigate other pathological effects.

[0169] As shown in Figure 15, NETosis was induced by ACPA-H4R3cit antiserum. The presence of neutrophils and neutrophil extracellular traps (NETs) was observed only in the group treated with ACPA No. 1-H4R3cit antiserum (Figure 15. A1); NETs were confirmed with neutrophil elastase staining (Figure 15. A2). This suggests that H4R3cit antiserum induced NETosis. In summary, ACPA No. 1 antibody caused NETosis and induced citrullination in the mouse corneal epithelium. These data suggest that ACPA antibodies contribute to a direct citrullination feeding cycle to further amplify citrullination-related eye diseases. EXAMPLE 8: INTERACTION OF ACPA (H4R3cit) BLOCKADE WITH FC RECEPTOR BLOCKADE STRATEGIES THAT ANNULLED ACPA-H4R3cit-INDUCED OCULAR SURFACE DISEASE

[0170] In order to determine whether the pathological effect of ACPA on the cornea is mediated via Fc receptors, 8-10 week old Thy1-YFP mice were used for the treatment experiment. A peptide that blocks all Fc receptors was used, followed by the application of the ACPA antibody. Using 10 µl of either 1) an azide-free Fc receptor blocker (Innovex Biosciences No. NB355) or 2) a scrambled peptide, the antibody was applied to the murine cornea and incubated for 30 minutes. This pre-incubation with peptides was performed without anesthesia. Subsequently, Thy1-YFP mice (n=5 / group) were anesthetized and 10 pl of ACPA No. 1-H4R3cit antiserum were administered. Petition 870260076737, dated 07 / 31 / 2026, page 85 / 256 79 / 89 dilutions were applied to both the Fc receptor-blocked and scrambled peptide-blocked groups and incubated for 40 minutes for 10 consecutive days. Dilutions were made in Refresh Optive. Murine corneas were stained with fluorescein, monitored, and photographed with a slit beam. Fluorescein intensity was measured using the Metamorph imaging system. To investigate whether competitive Fc receptor blockade would reproduce the same results as Fc receptor peptide blockade, mouse IgG was added along with the ACPA antibody. For the IgG competition experiment, 10 µl of a mixture of ACPA antibody (H4R3cyt antiserum) and mouse IgG (Abcam No. ab188776) at a 1:1 ratio were applied to a murine cornea and incubated for 40 minutes for 10 consecutive days. In the control experiment, only the ACPA antibody was used.Murine corneas were stained with fluorescein, monitored, and photographed with a slit beam. Fluorescein intensity was measured using the Metamorph imaging system. After 10 days, the corneas were collected, lysed, and subjected to Luminex for cytokine detection.

[0171] As shown in Figure 16, both strategies significantly reduced ocular surface diseases due to H4R3cit. An analysis of cytokines expressed in the cornea revealed that IL-2 was significantly increased under the ACPA condition, but not in the controls (Figure 16). Blocking the Fc receptor with the peptide blocker reproduced the reverse effect of the H4R3cit antiserum. Corneas were collected at the end of the experiment, lysed, and analyzed for cytokine profile. The IL-2 level decreased significantly in both competitive and peptide-blocked mouse corneas compared to unblocked ones. In summary, mouse IgG competes with ACPA antibodies for binding. Petition 870260076737, dated 07 / 31 / 2026, page 86 / 256 80 / 89 to Fc receptors and the Fc receptor blocker blocks all Fc receptors. This competitive and peptide-based blockade abolished the pathological effect of ACPA on the cornea, suggesting that the use of methodologies that prevent the interaction of ACPA antibodies with Fc receptors may be a potential therapeutic strategy in the treatment of citrullination-related eye diseases. EXAMPLE 9: ACPA-H4R3cit INDUCES NETose IN VITRO.

[0172] To determine whether ACPA can induce NETosis in vitro, peripheral blood was collected by venipuncture into BD vacutainer sodium heparin tubes (BD Biosciences, No. 367878) and immediately transported to the laboratory for neutrophil isolation. Neutrophils were isolated by immunomagnetic depletion of non-target cells using MACSxpress beads (MACSxpress Neutrophil Isolation Kit, Miltenyi Biotech, No. 130-104-434), according to the manufacturer's instructions. Residual erythrocytes were removed using the MACSxpress Erythrocyte Depletion Kit (Miltenyi Biotech, No. 130-094-183). Isolated neutrophils were resuspended with 3 ml of phenol red-free and serum-free RPMI-1640 medium (GIBCO, No. 11835-030).After measuring the cell count, 1.0 x 10⁶ cells / ml were plated onto a glass chamber slide (Millipore, No. PEZGS0416) and incubated with the following antibodies, along with the controls: 1) RPMI, as a negative control, 2) 1 nM PMA, as a positive control, 3) 100 ng / ml normal rabbit serum (Abcam, ab7487), 4) 100 ng / ml H3cit antiserum (Novusbio, NB10057135SS), 5) 100 ng / ml H4R3cit antiserum (Abcam, ab81797), 6) 100 ng / ml citrullinated fibrinogen antibody (Cayman Chemical, 17088), 7) 100 ng / ml citrullinated vimentin antibody (Cayman Chemical, 22054), 8) 100 ng / ml of citrullinated α-enolase antibody (Cayman Chemical, 23000) or 9) CCP antibody (Bioss, bs-1053R). Neutrophils were incubated overnight and stained with 1 N / mL of. Petition 870260076737, dated 07 / 31 / 2026, page 87 / 256 81 / 89 Sytox green (Molecular Probes, Invitrogen, cat. No. S7020) and 5 μM Hoechst (FisherScientific, Pittsburgh, PA, No. 33342). They were photographed immediately with a Zeiss Observer Z1 at 20X magnification.

[0173] As shown in Figure 17, in vitro experiments using isolated human neutrophils demonstrated that stimulation with ACPA-H4R3cit resulted in a significant increase in extracellular DNA strands, but not with the controls (another ACPA). Only PMA stimulation, ACPA-H4R3cit stimulation, and ACPA CCP stimulation produced significant extracellular DNA strands. In summary, ACPA-H4R3cit induces NETosis in vitro. EXAMPLE 10: DETERMINATION OF OCULAR SURFACE IMMUNOGLOBULIN (OSIG) CYTOTOXICITY IN HUMAN CORNEAL EPITHELIAL CELLS UNDER NORMAL CONDITIONS OR UNDER STRESS.

[0174] Primary human corneal epithelial cells used to determine OSIG cytotoxicity in human corneal epithelial cells under normal or stress conditions were acquired from EMD Millipore (EMD, No. SCCE016). The cells were cultured in EpiGRO™ Human Ocular Epithelia Complete MedUM (EMD, No. SCMC001). One day before cell scraping, 20,000 cells / well were seeded in a 96-well ImageLock plate (Essen Bioscience, No. 4379) and left to culture for 18 hours to achieve monolayer confluence. The ImageLock plate is a specially modified plate, and its technology is activated by fiducial markers on the underside of the plate that provide points from which imaging sites can be precisely referenced. Cell scraping (700-800 µm wide) is performed with a 96-pin IncuCyte incision instrument (Essen Bioscience, No. 4493).After scraping, the cells were washed twice with 100 µl of medium. Petition 870260076737, dated 07 / 31 / 2026, page 88 / 256 82 / 89 Phenol red-free RPMI-1640 (Gibco, No. 11835030). For the OSIG dose-dependent experiment (5% DIF Phlebogama), the medium was replaced with 200 μL of the following conditioned media: (1) EpiGRO, (2) 4 mg / ml OSIG, or (3) 8 mg / ml OSIG. OSIG dilutions were made in EpiGRO. Plates were incubated in an IncuCyte Zoom live cell analysis system (Essen Bioscience). Images were captured every 3 hours. Relative wound density (%) was determined over 69 hours using IncuCyte Zoom software. This metric is based on measuring the density of space cells in the wound area relative to the density of space cells outside the wound area at each time point. It is projected to be 0% at t=0 and 100% when the cell density inside the wound equals the cell density outside the initial wound. It is independent of the location of the cell boundaries.The cytotoxicity of HCE-T cells was determined by the LDH (lactose dehydrogenase) cytotoxicity assay (Thermo Scientific, No. 88954). Cell culture supernatants were collected, and 50 μl of the supernatant were mixed with 50 μl of the reaction mixture and incubated for 30 min. The mixture was then transferred to a 96-well flat-bottom plate. Absorbance at wavelengths (490-680 nm) was measured using a Cytation5 plate reader.

[0175] The human corneal epithelial cell line (HCE-T) was used for the epithelial scraping assay, and this cell line consists of human corneal cells transformed with SV40-Adeno vector (RIKEN Cell Bank RCB2280, Tsukuba, Japan). The cells were cultured in DMEM medium (GIBCO, No. 11965-092) supplemented with 10% FBS (Invitrogen, No. 26140-079) and a 1% antibiotic and antifungal solution containing 10,000 units / ml of penicillin, 10,000 pg / ml of streptomycin, and 25 pg / ml of amphotericin B (Thermo Fisher Scientific, No. 15240062) and incubated in an incubator. Petition 870260076737, dated 07 / 31 / 2026, page 89 / 256 83 / 89 tissue culture at 37°C, supplied with 5% CO2. One day before cell scraping, 30,000 cells / well were seeded onto a 96-well ImageLock plate (Essen Bioscience, No. 4379) and left to culture for 18 hours to achieve monolayer confluence. The ImageLock plate is a specially modified plate, and its technology is activated by fiducial markers on the underside of the plate that provide points from which imaging sites can be precisely referenced. Cell scraping (700-800 µm wide) was performed with a 96-pin IncuCyte incision tool (Essen Bioscience, No. 4493). After scraping, the cells were washed twice with 100 µl of phenol red-free RPMI-1640 medium (Gibco, No. 11835030).For the OSIG dose-dependent experiment (Phlebogama at 5% DIF), the medium was replaced with 200 μL of the following conditioned medium: (1) under normal conditions (Figure B): (i) whole medium (CM); (ii) OSIG at 4 mg / ml or (iii) OSIG at 10 mg / ml, (2) under stress condition (Figure C): (i) RPMI; (ii) OSIG at 4 mg / ml or (iii) 10 mg / ml. Plates were incubated in an IncuCyte Zoom live cell analysis system (Essen Bioscience). Images were captured every 3 hours. Relative wound density (%) was determined over 12 hours using IncuCyte Zoom software. This metric is based on measuring the density of spatial cells in the wound area relative to the density of spatial cells outside the wound area at each time point. It is projected to be 0% at t=0 and 100% when the cell density inside the wound equals the cell density outside the initial wound. It is independent of the location of the cell boundaries.The cytotoxicity of HCET cells was determined by the LDH (lactose dehydrogenase) cytotoxicity assay (Thermo Scientific, No. 88954). Cell culture supernatants were collected and 50 μl of the supernatant were mixed with 50 μl of the reaction mixture and incubated for 30 minutes. Petition 870260076737, dated 07 / 31 / 2026, page 90 / 256 84 / 89 and the mixture was transferred to a 96-well flat-bottom plate. Absorbance at wavelengths (490 to 680 nm) was measured with a Cytation5 plate reader. OSIG at 10 mg / ml showed toxicity in all three conditions, while 4 mg / ml proved to be toxic, which could serve as a working concentration (effective and non-toxic). As shown in Figure 18, toxicity did not change in relation to whether the cells were under normal conditions or under stress. In summary, OSIG at 4 mg / ml is the highest concentration without toxicity. EXAMPLE 11: THE ACPA RESPONSE ON THE OCULAR SURFACE IS AN OCULAR ANTIBODY PRODUCTION RESPONSE TO THE ACTIVE L

[0176] The number of patients with ocular surface disease who also presented high levels of ACPA in the tear fluid, despite not having these ACPA antibodies in serum and being rheumatoid factor negative, was investigated. 49% of 166 patients were cyclic citrullinated peptide (CCP) negative in serum, but were ACPA positive in the tear fluid. 69% of these patients were rheumatoid factor negative. This suggests that the response to ACPA on the ocular surface was an active local antibody production response and not a passive leakage of ACPA from the serum and does not require a concomitant systemic immunological disorder. Serum CCP+ Serum CCP- Tear fluid ACPA+ 19 Mean ACPA: 93 + 78 SD Median ACPA: 86 81 Mean ACPA: 28 + 36 SD Median ACPA: 12.6 RF+ 22 RF- 48 Tear fluid ACPA - 2 64 RF+ 18 RF- 32 Petition 870260076737, dated 07 / 31 / 2026, page 91 / 256 85 / 89 EXAMPLE 12: EXAMPLES OF PATIENT MODALITIES WITH HIGH LEVELS OF AUTOANTIBODIES (ACPA) IN TEAR FLUID AND SEVERE OCULAR SURFACE DISEASE

[0177] The first patient was a 38-year-old woman with Sjögren's syndrome. As shown in Figure 19, the patient had high levels of autoantibodies (ACPA) in the tear fluid and had keratomalacia syndrome in the right eye. Despite treatment with steroid eye drops, saline tears, and other conventional DED therapies, the patient remained severely symptomatic. This case demonstrates an association between high autoantibody levels and severe ocular surface disease. APCA in lacrimal fluid washes (normal levels are <5.0) 6 / 2018 10 / 2018 OD: 121.8 104.2 OS: 121.4 142.6

[0178] The second patient was a 39-year-old woman who was seen in 5 / 2018 with severe ocular discomfort. Examination revealed superior limbic keratoconjunctivitis (SLK) 3+ in both eyes. The patient began treatment with methylprednisolone eye drops. At follow-up in 6 / 2018, symptoms of ocular discomfort persisted despite treatment. ACPA levels in the tear fluid were very high. Serum was negative for ACPA and rheumatoid arthritis. Subsequent ACPA levels measured in 7 / 2018 were also high, and the patient still presented with severe symptoms. At the 10 / 2018 examination, ACPA levels decreased, although they were still high, and the patient's symptoms were somewhat reduced. As shown in Figure 20, this case demonstrates that autoantibodies (ACPA) were present on the eye, although there was an absence of autoantibodies in the blood. Petition 870260076737, dated 07 / 31 / 2026, page 92 / 256 86 / 89 and there were no systemic autoimmune diseases, such as rheumatoid arthritis. This suggests that the autoantibodies were produced locally in the ocular tissues. APCA IN LACRIMAL FLUID WASHINGS 6 / 2018 7 / 2018 10 / 2018 OD: 151.9 174.3 56.4 OS: 164.8 174.3 50.6

[0179] A third patient was a 47-year-old woman with asymmetric ocular disease. This patient was seen in 2 / 2017 with severe dry eye disease and ocular discomfort. Examination revealed that the right eye had more severe ocular surface disease than the left eye. Tear production in the right eye was much lower than in the left eye (Schirmer I was 1 mm in the right eye but 12 mm in the left eye). As shown in Figure 21, the right corneal staining was 8 / 15 and the left eye was 2 / 15. The conjunctival staining of the right eye was 6 / 6 and the left eye was 3 / 6. ACPA in the lacrimal fluid was high only in the right eye, but not in the left. The eye with more severe ocular surface disease has higher levels of autoantibodies (ACPA) in the lacrimal fluid. This case demonstrates that higher ACPA levels correlate with more severe ocular disease. EXAMPLE 13: ADDITIONAL PATIENT CASE STUDIES (CASE STUDIES 1 TO 6)

[0180] In the following case studies, patients received commercially available IVIG (Flebogama 10%), which was formulated to represent OSIG. The commercially available IVIG (10%) was diluted with the ophthalmic excipient, NaCl solution, so that the final concentration was 4 mg / ml of IgG (0.4%) with a pH of at least 6.0. A dropper was used to administer the 0.4% IgG formulation. Petition 870260076737, dated 07 / 31 / 2026, p. 93 / 256 87 / 89 resulting (referred to herein as OSIG) to patients as eye drops. OSIG is not currently commercially available and therefore was manufactured using commercially available IVIG (10% Phlebogam), but the OSIG formulation can be manufactured using any commercially available IgG or combined plasma-derived human immunoglobulin G. These case studies provide clinically significant results that are related to the ophthalmic formulations provided herein.

[0181] Case study 1 was of a 56-year-old woman with severe lacrimal deficiency and severe ocular surface disease due to ocular graft-versus-host disease (Figure 22). OSDI was 77.7 and corneal staining was 6 / 15 in the right eye. VBR showed ocular redness at 70 in the right eye. A corneal scar was present without any corneal neovascularization. Use of 0.4% OSIG eye drops was initiated twice daily.The patient reported a significant reduction in ocular discomfort after two weeks of treatment (OSDI reduced to 30.5), a significant reduction in corneal staining (2 / 15), and a significant reduction in VBR (50). In the two weeks following treatment, VBR was reduced to 30 and corneal staining reduced to 1 / 15. Extracellular DNA in the tear fluid was 56 pg / ml in the right eye and, after treatment with OSIG, it was reduced to 12.3 pg / ml. In this example, OSIG eye drops reduced the signs and symptoms of severe dry eye, as well as reducing the inflammatory biomarker in the tear fluid.

[0182] Case study 2 was of a 31-year-old woman with severe lacrimal deficiency and severe ocular surface disease due to ocular graft-versus-host disease (Figure 23). The patient had severe conjunctival keratinization outside the coverage area of ​​the PROSE contact lenses, but without corneal neovascularization and had severe symptoms of ocular discomfort. OSIG eye drops were initiated. Petition 870260076737, dated 07 / 31 / 2026, page 94 / 256 88 / 89 at 0.4% twice daily. After one month of treatment, conjunctival keratinization was reduced, and the patient reported a significant improvement in subjective ocular symptoms. In this example, OSIG eye drops reduced keratinization caused by severe dry eye, as well as significantly reducing ocular discomfort.

[0183] Case study 3 was of a 74-year-old man with neurotropic keratitis due to a history of previous LASIK ocular surgery in the left eye (Figure 24). The cornea showed a coloration of 2 / 15 in the left eye, and the patient reported an ocular discomfort intensity of 4 / 10. The corneas presented a faint scar at the edge of the LASIK flap without any corneal neovascularization. Overall, the examination was consistent with the diagnosis of signal-symptom disconnection (discordant DED). OSIG 0.4% eye drops were initiated twice daily. After one month of treatment, the patient showed subjective improvement (SGA), and the symptom intensity was reduced to 3. The corneal coloration disappeared (0 / 10) in the left eye. In this example, OSIG eye drops were beneficial in postoperative complications, leading to signal-symptom disconnection.

[0184] Case study 4 was of a 39-year-old man with severe lacrimal deficiency and severe ocular surface disease, ocular cicatricial pemphigoid. The cornea showed SPK staining of 1 / 15 in the right eye and 3 / 15 in the left eye without any corneal neovascularization. The patient reported an intensity of ocular discomfort of 3 / 10. OSIG 0.4% eye drops were started twice daily. After one month of treatment, the intensity of ocular discomfort reduced to 2 / 10 and the corneal staining disappeared in both eyes (0 / 10). This example demonstrates the beneficial effect of OSIG eye drops in ocular cicatricial pemphigoid.

[0185] Case study 5 was of a 33-year-old person with severe lacrimal deficiency and severe symptoms of ocular discomfort with Petition 870260076737, dated 07 / 31 / 2026, page 95 / 256 89 / 89 the diagnosis of signal-symptom disconnection (discordant DED). There was no corneal staining and no corneal neovascularization. The intensity of ocular discomfort was 6 / 10. OSIG eye drops at 0.4% were started twice daily. After one month of treatment, the intensity of ocular discomfort reduced to 3 / 10 in the right eye and 4 / 10 in the left. This example demonstrates the beneficial effect of OSIG eye drops in reducing ocular discomfort in patients with signal-symptom disconnection.

[0186] Case study 6 was of a 29-year-old man with lacrimal deficiency and severe ocular surface disease due to Stevens-Johnson syndrome (Figure 25). OSDI was 54.7 and symptom intensity was 8 / 10 (intense and horrible discomfort). OSIG 0.4% eye drops were initiated three times daily in both eyes. The patient reported a significant reduction in ocular discomfort after two weeks of treatment (OSDI reduced to 14.2) and symptom intensity reduced to 0 / 10 (no discomfort). Light sensitivity and grittiness in the eye were present all the time before OSIG treatment. After OSIG treatment, light sensitivity was only occasional and grittiness was no longer present. Eye redness was also reduced with OSIG treatment. In this example, OSIG eye drops significantly reduced the signs and symptoms of dry eye after Stevens-Johnson syndrome. Petition 870260076737, dated 07 / 31 / 2026, p. 96 / 256

Claims

1 / 9 CLAIMS 1. Ophthalmic formulation for the treatment of an eye condition, characterized in that it comprises a therapeutically active ingredient, wherein said ophthalmically active ingredient comprises combined human IgG, wherein said combined human IgG is derived from at least several hundred healthy donors.

2. An ophthalmic formulation for the treatment of an eye condition, characterized in that it comprises a therapeutically active ingredient, wherein said ophthalmically active ingredient comprises combined human plasma, wherein said combined human plasma is derived from at least several hundred healthy donors.

3. Ophthalmic formulation according to claim 1 or 2, characterized in that said therapeutically active ingredient further comprises: (a) combined human plasma proteins; (b) combined human plasma lipids; or (c) a combination thereof.

4. Ophthalmic formulation, according to any one of claims 1 to 3, characterized in that it comprises from about 0.01 mg / ml to about 1 g / ml of said combined human IgG.

5. Ophthalmic formulation, according to any one of claims 1 to 4, characterized in that it comprises from about 0.4% to about 4% of said combined human IgG.

6. Ophthalmic composition for use in the treatment or prevention of an ocular clinical condition associated with one eye of a patient in need of such treatment, characterized in that it comprises an ophthalmic formulation, as defined in any one of claims 1 to 5, wherein said ocular clinical condition comprises an inflammatory disease of the ocular surface, an inflammatory disease of the intraocular eye, an immunological disease of the ocular surface, an immunological disease of the intraocular eye, or a combination thereof.

7. Ophthalmic composition, according to claim 6, characterized in that said ocular clinical condition comprises ocular graft-versus-host disease (oGVHD), Stevens-Johnson syndrome, ocular cicatricial pemphigoid (OCP), mild, moderate and severe dry eye disease due to lacrimal deficiency (DED), meibomian gland disease, hordeolum, ocular rosacea, blepharitis, superior limbic keratoconjunctivitis (SLK), DED due to lacrimal sufficiency, floppy eyelid syndrome, neurotrophic eye disease, symptom-signal disconnection (discordant DED), neuropathic pain, thyroid eye disease (Grave's ophthalmopathy), rheumatoid arthritis-related eye disease, lupus-related eye disease, Sjögren's syndrome, secondary Sjögren's syndrome, allergic (vernal) keratoconjunctivitis, Thygeson's keratitis, retinal gliosis, Petition 870260076737, from 07 / 31 / 2026, page.98 / 256 3 / 9 aniridia, keratitis postoperative / posttraumatic eye condition, eye condition associated with postocular surface reconstruction surgery, condition associated with the application of antimetabolites to the ocular surface, condition associated with pterygium surgery, condition associated with glaucoma surgery, condition associated with cataract surgery, condition associated with refractive surgery (LASIK, LASEK or PRK), condition associated with keratoprosthesis surgery, radiation or chemical or traumatic injury, peripheral ulcerative keratitis, episcleritis, scleritis, uveitis, glaucoma, or a combination thereof.

8. Ophthalmic composition, according to any one of claims 6 to 7, characterized in that said ophthalmic formulation is used as an eye drop formulation, topical liquid, gel formulation, emulsion formulation, suspension formulation, ointment formulation or injectable formulation.

9. Ophthalmic composition, according to any one of claims 6 to 8, characterized in that the ophthalmic formulation is capable of corneal penetration, intraocular penetration, or both.

10. Use of an ophthalmic composition, as defined in Petition 870260076737, dated 07 / 31 / 2026, page 99 / 256 4 / 9, any of claims 1 to 5, characterized in that it is for the preparation of a medicament to treat and / or prevent an ocular clinical condition.

11. Use according to claim 10, characterized in that said ocular clinical condition comprises an inflammatory disease of the ocular surface, an inflammatory disease of the intraocular eye, an immunological disease of the ocular surface, an immunological disease of the intraocular eye, or a combination thereof.

12. Use, according to claim 10 or 11, characterized in that said ocular clinical condition comprises ocular graft-versus-host disease (oGVHD), Stevens-Johnson syndrome, ocular cicatricial pemphigoid (OCP), mild, moderate and severe dry eye disease due to lacrimal deficiency (DED), meibomian gland disease, hordeolum, ocular rosacea, blepharitis, superior limbic keratoconjunctivitis (SLK), DED due to lacrimal sufficiency, floppy eyelid syndrome, neurotrophic eye disease, symptom-signal disconnection (discordant DED), neuropathic pain, thyroid eye disease (Grave's ophthalmopathy), rheumatoid arthritis-related eye disease, lupus-related eye disease, Sjögren's syndrome, secondary Sjögren's syndrome, Petition 870260076737, dated 07 / 31 / 2026, p.100 / 256 5 / 9 allergic (vernal) keratoconjunctivitis, Thygeson keratitis, retinal gliosis, aniridia, keratitis, postoperative / posttraumatic eye condition, eye condition associated with postocular surface reconstruction surgery, condition associated with application of antimetabolites to the ocular surface, condition associated with pterygium surgery, condition associated with glaucoma surgery, condition associated with cataract surgery, condition associated with refractive surgery (LASIK, LASEK or PRK), condition associated with keratoprosthesis surgery, radiation or chemical or traumatic injury, peripheral ulcerative keratitis, episcleritis, scleritis, uveitis, glaucoma, or a combination thereof.

13. Use, according to claim 11 or 12, characterized in that said ocular clinical condition associated with the individual's eye comprises: foreign body sensation, pain, sensitivity to light, burning, irritation, pain, dryness, burning, redness, itching, pruritus, or a combination thereof.

14. Invention, characterized in that it is any form of its embodiment or in any applicable category of claim, for example, product, process or use, or any other type of claim encompassed by the matter initially described, disclosed or illustrated in the patent application; Ophthalmic formulation comprising: (a) one or more pharmaceutically acceptable ophthalmic excipients; (b) an immunoglobulin G (IgG) or a fragment thereof; Ophthalmic formulation comprising: (a) one or more pharmaceutically acceptable ophthalmic excipients; (b) a pharmaceutically active ocular compound for the treatment of a clinical condition selected from the group consisting of inflammatory, infectious and / or immunological ocular surface disease or intraocular disease, wherein said pharmaceutically active compound comprises immunoglobulin G (IgG);Ophthalmic formulation comprising a pharmaceutically active compound capable of reducing the amount or deleterious biological effects of autoantibodies on the ocular surface or within the eye, wherein the autoantibody is generated in response to a citrullinated protein, a homocitrullinated protein or a native protein; Ophthalmic formulation comprising (a) a pharmaceutically acceptable ophthalmic excipient; (b) a therapeutically effective amount of a pharmaceutically active compound comprising combined human immunoglobulin G (IgG); and (c) a therapeutically effective amount of combined human plasma proteins, combined human plasma lipids or a combination thereof; Composition, comprising the ophthalmic formulation, as defined in any one of claims 1 to 7; Use of: (a) i) one or more pharmaceutically acceptable ophthalmic excipients and ii) pooled human plasma;(b) i) one or more pharmaceutically acceptable ophthalmic excipients, ii) combined human plasma-derived immunoglobulin G (IgG) or a fragment thereof, and iii) combined human plasma proteins, combined human plasma lipids, or a combination thereof; or (c) i) one or more pharmaceutically acceptable ophthalmic excipients and ii) or a fragment thereof, Or use of a composition as defined in any of the above, wherein said use is for the preparation of an ophthalmic formulation and / or medicine and / or composition and / or product to prevent, improve or treat a disorder, disease or health condition; Method for detecting the presence of autoantibodies in an individual, comprising detecting the level of autoantibodies in a sample of ocular fluid obtained from the individual, in which the individual is Petition 870260076737, dated 07 / 31 / 2026, p. 103 / 256 8 / 9 suffering from or at risk of developing an ocular surface disorder;A method for diagnosing, determining the risk of developing, or monitoring an ocular surface disorder in an individual, comprising detecting the level of autoantibodies in a sample obtained from the individual and comparing the level of antibodies in the sample obtained from the individual with a control level of said autoantibodies, wherein the control level of autoantibodies is used to diagnose, determine the risk of developing, or monitor an ocular surface disorder in the individual; A diagnostic kit comprising an antigen panel array for detecting autoantibodies selected from the group consisting of citrullinated proteins, citrullinated peptide sequences, or a combination thereof; An Fc receptor blocking composition that is formulated for ocular or mucosal applications; An Fc receptor blocking composition that is further defined by a concentration of ocular Fc receptor blocking peptide and, optionally, a suitable carrier;Composition of concentrated IgG from ocular or mucosal site comprising the Fc receptor blocking composition, as defined above, optionally further comprising an anti-inflammatory agent; Method for manufacturing a treatment dosage for an immunological lesion detected in ocular fluid removed from a treatment site comprising: providing a concentration of IgG configured to reduce the levels and / or effects of anti-citrullinated protein autoantibodies when administered to the treatment site; and adding a carrier to the IgG concentration thus forming a treatment dosage configured to allow delivery of IgG to the treatment site;The method, according to the method described above, further comprises the step of periodically delivering the treatment dosage to the treatment site during a treatment period defined by the response detected with the diagnostic kit, as defined in claim 19, at least once twice a day and twice a month, or any other period of time suitable to achieve an improvement in the immunological or inflammatory condition or until the test device indicates that the concentration is within normal ranges;B-cell targeted ocular composition comprising rituximab formulated to treat ocular diseases. Composition for treating a clinical condition in a patient in need thereof, comprising an ophthalmic formulation, as defined in any of claims 1 to 23, wherein the clinical condition is an inflammatory disease of the ocular surface or intraocular eye diseases, an infectious disease of the ocular surface or intraocular eye diseases and / or an immunological disease of the ocular surface or intraocular eye disease; Composition that is for treating an inflammatory, infectious and / or immunological ocular disease in a patient in need thereof, the composition of an ophthalmic formulation, as defined in any of the above claims;Composition to reduce, alleviate or prevent ocular discomfort in a patient suffering from a clinical condition, comprising an ophthalmic formulation, as defined in any of the above claims, wherein the clinical condition is an inflammatory disease of the ocular surface or intraocular eye diseases, an infectious disease of the ocular surface or intraocular eye diseases and / or an immunological disease of the ocular surface or intraocular eye disease. Petition 870260076737, dated 07 / 31 / 2026, pp. 105 / 256;

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