CN116059312A

CN116059312A - Integrin GPIIb/IIIa antagonists and their use in combination with anti-VEGF antibodies

Info

Publication number: CN116059312A
Application number: CN202210867481.0A
Authority: CN
Inventors: 杨少伟; 俞金泉; 李胜峰
Original assignee: Bio Thera Solutions Ltd
Current assignee: Bio Thera Solutions Ltd
Priority date: 2021-07-23
Filing date: 2022-07-22
Publication date: 2023-05-05
Also published as: WO2023001288A1

Abstract

The present invention discloses integrin GPIIb/IIIa antagonists and their use in combination with VEGF antagonists for the treatment of ophthalmic disorders, the methods of treatment comprising administering to a patient in need thereof an effective amount of an integrin GPIIb/IIIa antagonist or an integrin GPIIb/IIIa antagonist and a VEGF antagonist.

Description

Integrin GPIIb/IIIa antagonists and their use in combination with anti-VEGF antibodies

Technical Field

The invention belongs to the field of biological medicine, and in particular relates to an integrin GPIIb/IIIa antagonist and application of the integrin GPIIb/IIIa antagonist and anti-VEGF antibody combined drug.

Background

Macular degeneration is a medical condition that is primarily found in the elderly, where the center of the lining of the eye, known as the macular region of the retina, thins, atrophy, and in some cases bleeding. This may result in a loss of central vision, which prevents the patient from seeing more detail. Macular degeneration is a major cause of central vision loss (blindness) in the elderly, as reported by the american society of ophthalmology. Although some macular dystrophies (macular dystrophies) affecting young people are sometimes referred to as macular degeneration, the term is generally referred to as age-related macular degeneration (age-related maculardegeneration, AMD).

Age-related maculopathy is a disease of irreversible vision deterioration or loss caused by degeneration of retinal pigment epithelial cells and neural retina. The eye diseases are caused by the eyes of patients over 50 years old, and the eyes are ill successively or simultaneously, and the vision is damaged progressively, so that the eye diseases are fundus lesions which seriously threaten the visual function of the old. As the population ages, it has become the first blinding eye disease in western countries and the incidence of it has also increased in asia.

Disclosure of Invention

The present invention discloses methods or uses of integrin GPIIb/IIIa antagonists for treating ophthalmic conditions. In some embodiments, the method or use comprises: administering to a patient in need thereof an effective amount of an integrin GPIIb/IIIa antagonist. In another aspect, the invention discloses the use of an integrin GPIIb/IIIa antagonist in the manufacture of a medicament for the treatment of an ocular disorder.

In another aspect, the invention also discloses a kit comprising an integrin GPIIb/IIIa antagonist (or formulation) and instructions for directing the administration of the integrin GPIIb/IIIa antagonist (or formulation) to a patient in need thereof.

In some embodiments, the ocular disease is a VEGF-overexpressed ocular disease such as a VEGF-overexpressed fundus disease. In some embodiments, the ocular disease is selected from the group consisting of macular degeneration, age-related macular degeneration (AMD), corneal neovascularization, diseases associated with corneal neovascularization, retinal neovascularization, diseases associated with retinal/choroidal neovascularization, choroidal neovascularization secondary to pathological myopia, iris neovascularization, intraocular neovascularization, ocular neovascular disease, neovascular glaucoma, macular edema, diabetic macular edema (DME, including localized, non-central DME and diffuse, including central DME), cystoid Macular Edema (CME), retinopathy, diabetic retinopathy (DR, including Proliferative DR (PDNPR), non-proliferative DR (DR), and high altitude DR), other ischemia-related retinopathies, retinopathy of prematurity (ROP), familial Exudative Vitreoretinopathy (FEVR), hypertensive retinopathy, retinal Vein Occlusion (RVO) (including branch retinal vein occlusion and central retinal vein occlusion), CNV (including myopia CNV), pathologic myopia, hipe-lindau disease, crown's disease, norubic, osteoporosis-pseudoglioma syndrome (OPPG), subconjunctival hemorrhage, rubeosis, retinitis Pigmentosa (RP), retinal hemangioma hyperplasia, macular telangiectasia, retinal degeneration, vasculitis, optic disc edema, retinitis, conjunctivitis (including infectious conjunctivitis and non-infectious (e.g., allergic) conjunctivitis), leber congenital amaurosis, uveitis (including infectious and non-infectious uveitis), choroiditis, ocular histoplasmosis, blepharitis, dry eye, traumatic eye injury, and sjogren's disease.

In another aspect, the invention discloses an ophthalmic pharmaceutical composition comprising an integrin GPIIb/IIIa antagonist. In some embodiments, the ophthalmic pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

In some embodiments, the use of an integrin GPIIb/IIIa antagonist or a pharmaceutical composition thereof for enhancing the effect of a VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) in the treatment of an ocular disease such as an ocular disease that is overexpressed by VEGF.

In another aspect, the invention discloses methods or uses of a combination of a VEGF antagonist (e.g., an anti-VEGF antibody or antigen binding fragment, abelmoschus) and an integrin GPIIb/IIIa antagonist for treating an ocular disorder such as an ocular disorder in which VEGF is overexpressed. In some embodiments, the method or use comprises: an effective amount of a VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) and an integrin GPIIb/IIIa antagonist is administered to a patient in need thereof. In another aspect, the invention discloses the use of a VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) and an integrin GPIIb/IIIa antagonist in the manufacture of a medicament for the treatment of an ocular disorder such as an ocular disorder in which VEGF is overexpressed.

In another aspect, the invention also discloses a kit comprising a VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) (or formulation), an integrin GPIIb/IIIa antagonist (or formulation), and instructions for directing administration of the VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) (or formulation) and the integrin GPIIb/IIIa antagonist (or formulation) to a patient in need thereof. In some embodiments, the invention also discloses kits comprising a composition (or formulation) of a VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) and an integrin GPIIb/IIIa antagonist, and instructions for directing administration of the composition (or formulation) of the VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) and an integrin GPIIb/IIIa antagonist to a patient in need thereof.

In another aspect, the invention also discloses pharmaceutical compositions suitable for injection comprising a VEGF antagonist (e.g., an anti-VEGF antibody or antigen binding fragment, abelmoschus) and an integrin GPIIb/IIIa antagonist. In some embodiments, the mass ratio of VEGF antagonist to integrin GPIIb/IIIa antagonist is (0.5-7): 1. In some embodiments, the mass ratio of VEGF antagonist to integrin GPIIb/IIIa antagonist is (1-7): 1. In some embodiments, the mass ratio of VEGF antagonist to integrin GPIIb/IIIa antagonist is (1-4): 1. In some embodiments, the mass ratio of VEGF antagonist to integrin GPIIb/IIIa antagonist is 1:1. In some embodiments, the mass ratio of VEGF antagonist to integrin GPIIb/IIIa antagonist is 2:1. In some embodiments, the mass ratio of VEGF antagonist to integrin GPIIb/IIIa antagonist is 4:1. In some embodiments, the pharmaceutical composition comprises at least 0.1% of a VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) and 0.1% of an integrin GPIIb/IIIa antagonist. The percentage of VEGF antagonist (e.g., anti-VEGF antibody or antigen-binding fragment, aflibercept) and integrin GPIIb/IIIa antagonist can vary and can be between about 2% and about 90% by weight of a given dosage form. The VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) and the integrin GPIIb/IIIa antagonist in such a therapeutically useful pharmaceutical composition may be administered in an effective amount.

On the other hand, the invention also discloses a preparation method of the pharmaceutical composition, which comprises the following steps: the VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) and the integrin GPIIb/IIIa antagonist (or a combination of a VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) and an integrin GPIIb/IIIa antagonist) are separately admixed with a pharmaceutically acceptable carrier suitable for injection (e.g., water for injection, physiological saline, etc.). Methods of mixing VEGF antagonists (e.g., anti-VEGF antibodies or antigen-binding fragments, aflibercept) and integrin GPIIb/IIIa antagonists with pharmaceutically acceptable carriers are generally known in the art.

In another aspect, the invention also discloses the use of a VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) and an integrin GPIIb/IIIa antagonist in the manufacture of a pharmaceutical composition for the treatment of an ocular disorder such as an ocular disorder in which VEGF is overexpressed.

In some embodiments, a VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment thereof) in combination with an integrin GPIIb/IIIa antagonist is used to treat an ocular disorder such as an ocular disorder in which VEGF is overexpressed. The invention provides methods for alleviating symptoms by using a VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) (or formulation) and an integrin GPIIb/IIIa antagonist (or formulation) in the treatment of an ocular disorder, such as an ocular disorder in which VEGF is overexpressed.

In some embodiments, a VEGF antagonist (e.g., anti-VEGF antibodies or antigen binding fragments, aflibercept) (or formulations), integrin GPIIb/IIIa antagonists (or formulations) and other therapeutic methods for the treatment of ocular disorders such as VEGF over-expression, e.g., surgical, laser, physical rehabilitation and pharmaceutical therapies (e.g., aflibercept)

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In some embodiments, the VEGF antagonist is an anti-VEGF antibody or antigen-binding fragment.

In some embodiments, the anti-VEGF antibody or antigen-binding fragment comprises at least one or more of HCDR1 shown in SEQ ID NO. 1, HCDR2 shown in SEQ ID NO. 2, HCDR3 shown in SEQ ID NO. 3, LCDR1 shown in SEQ ID NO. 4, LCDR2 shown in SEQ ID NO. 5, LCDR3 shown in SEQ ID NO. 6.

In some embodiments, the anti-VEGF antibody or antigen-binding fragment comprises HCDR1 shown as SEQ ID NO. 1, HCDR2 shown as SEQ ID NO. 2, HCDR3 shown as SEQ ID NO. 3, LCDR1 shown as SEQ ID NO. 4, LCDR2 shown as SEQ ID NO. 5, and LCDR3 shown as SEQ ID NO. 6.

In some embodiments, the heavy chain variable region of the anti-VEGF antibody or antigen binding fragment comprises the sequence set forth in SEQ ID NO. 7, or a sequence having at least 80% identity to the sequence set forth in SEQ ID NO. 7, or an amino acid sequence having one or more conservative amino acid substitutions as compared to the sequence set forth in SEQ ID NO. 7; and/or

The light chain variable region of the anti-VEGF antibody or antigen binding fragment comprises the sequence shown in SEQ ID NO. 8, or a sequence having at least 80% identity to the sequence shown in SEQ ID NO. 8, or an amino acid sequence having one or more conservative amino acid substitutions as compared to the sequence shown in SEQ ID NO. 8.

In some embodiments, the heavy chain variable region of the anti-VEGF antibody or antigen-binding fragment comprises the sequence set forth in SEQ ID NO. 7, and the light chain variable region of the anti-VEGF antibody or antigen-binding fragment comprises the sequence set forth in SEQ ID NO. 8.

In some embodiments, the heavy chain of the anti-VEGF antibody comprises the sequence set forth in SEQ ID NO. 9, or a sequence having at least 80% identity to the sequence set forth in SEQ ID NO. 9, or an amino acid sequence having one or more conservative amino acid substitutions as compared to the sequence set forth in SEQ ID NO. 9; and/or

The light chain of the anti-VEGF antibody comprises the sequence shown as SEQ ID NO. 10, or a sequence having at least 80% identity to the sequence shown as SEQ ID NO. 10, or an amino acid sequence having one or more conservative amino acid substitutions compared to the sequence shown as SEQ ID NO. 10.

In some embodiments, the heavy chain of the anti-VEGF antibody comprises the sequence shown in SEQ ID NO. 9 and the light chain of the anti-VEGF antibody comprises the sequence shown in SEQ ID NO. 10.

In some embodiments, the VEGF antagonist is selected from the group consisting of an anti-VEGF antibody or antigen-binding fragment, an anti-VEGF receptor antibody or antigen-binding fragment, a VEGF receptor fusion protein, an aptamer that specifically binds to VEGF, and a VEGFR tyrosine kinase inhibitor. In some embodiments, the anti-VEGF antibody is ibuprofen, bevacizumab, ranibizumab, or monoclonal antibody BAT5906 disclosed in ZL 201910585853.9. In some embodiments, the bevacizumab comprises

Or a biological analogue thereof, e.g. +.>

Prime Bei Xi, pogostemin, bei Anting, ai Ruituo, boyou, or BAT1706. In some embodiments, the ranibizumab comprises +.>

Or a biological analogue thereof. In some embodiments, the VEGF receptor fusion protein is selected from the group consisting of Abelmoschus->

And combretastatin. In some embodiments, the aptamer that specifically binds to VEGF is peganibu ∈>

In some embodiments, the VEGFR tyrosine kinase inhibitor is selected from the group consisting of: 4- (4-bromo-2-fluoroanilino) -6-methoxy-7- (1-methylpiperidin-4-ylmethoxy) quinazoline (ZD 6474), 4- (4-fluoro-2-methylindol-5-yloxy) -6-methoxy-7- (3-pyrrolidin-1-ylpropoxy) quinazoline (AZD 2171), valtalanib (PTK 787), semaxaminib (SU 5416) and sunitinib @ are all known per se >

In some embodiments, the VEGF antagonist protein may be expressed in cells such as CHO cells or HEK293 cells by genetic engineering and obtained by purification; purification can be performed by conventional methods, such as centrifugation of the cell suspension and collection of the supernatant. Methods such as affinity and ion exchange columns may be used to further purify the VEGF antagonist protein.

In some embodiments, the integrin GPIIb/IIIa antagonist is bat feban (XP 2094 disclosed in ZL 03112798.3) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt of batifeban is an inorganic acid salt, which may be: inorganic acids such as hypoiodic acid, hypochlorous acid, hypobromous acid, iodic acid, perchloric acid, peroxodisulfuric acid, peroxocarbonic acid, pyrophosphoric acid, pyrosulfurous acid, tetrasulfuric acid, phosphoric acid, thiosulfuric acid, sulfuric acid, chloric acid, metaphosphoric acid, hydroiodic acid, hydroazonic acid, hydrofluoric acid, hydrogen sulfuric acid, hydrochloric acid, hydrobromic acid, tetraboric acid, carbonic acid, nitric acid, hydrobromic acid, sulfurous acid, phosphorous acid, chlorous acid, hydrochloric acid, nitrous acid, orthophosphoric acid, orthosulfuric acid, and orthocarbonic acid. In some embodiments, the pharmaceutically acceptable salt of batifeban is an organic acid salt, which may be: tartaric acid, oxalic acid, malic acid, citric acid (citric acid), ascorbic acid, benzoic acid, salicylic acid, caffeic acid, lactic acid, sorbic acid, fumaric acid, formic acid, acetic acid, benzoic acid, oxalic acid, succinic acid, pyruvic acid, alpha-ketosuccinic acid, benzenesulfonic acid, or trifluoroacetic acid, maleic acid, tetrasulfonic acid, methanesulfonic acid, fumaric acid, amino acids, and the like. In some embodiments, the organic acid is citric acid (citric acid), malic acid, lactic acid, acetic acid, oxalic acid, an amino acid. In some embodiments, the pharmaceutically acceptable salt of batifeban is citrate. In some embodiments, the pharmaceutically acceptable salt of butifeban is a salt of butifeban with a metal ion (e.g., an alkali metal ion (such as sodium or potassium), an alkaline earth metal ion (such as calcium or magnesium), or an aluminum ion) or with an organic base (such as diethanolamine, triethanolamine, N-methylglucamine), and the like.

In some embodiments, the invention discloses a method for treating an ocular disease, such as an ocular disease that is over-expressed by VEGF, in a patient in need thereof, comprising administering an effective amount of a VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) and bat-terfeban or a pharmaceutically acceptable salt thereof, wherein the effective amount of the VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) administered is about 0.1mg to 15mg per treatment cycle. In some embodiments, one treatment cycle is 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 5 weeks, 6 weeks, 7 weeks, or a range between any two of these values (inclusive) or any value therein. In some embodiments, the VEGF antagonist is an anti-VEGF antibody or antigen-binding fragment. In some embodiments, the anti-VEGF antibody is antibody BAT5906. In some embodiments, the VEGF antagonist is aflibercept.

In some embodiments, VEGF antagonists (e.g., anti-VEGF antibody (e.g., antibody BAT 5906) or antigen-binding fragment, aflibercept) and BAT-terfenan or a pharmaceutically acceptable salt thereof (or a combination of a VEGF antagonist (e.g., anti-VEGF antibody or antigen-binding fragment, aflibercept) and BAT-terfenan or a pharmaceutically acceptable salt thereof) may be formulated separately into pharmaceutical compositions and administered to a patient in a variety of forms suitable for the chosen route of administration, e.g., by topical ocular administration, periocular injection, or intra-ocular injection. In some embodiments, the VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) (or formulation) may be administered by intravitreal injection and the butifeban or a pharmaceutically acceptable salt (or formulation) thereof is administered by instillation into the conjunctival sac. In some embodiments, the composition of a VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) and bat-tifiban or a pharmaceutically acceptable salt thereof is administered by intravitreal injection. Dosages of VEGF antagonists (e.g., anti-VEGF antibodies or antigen-binding fragments, aflibercept) and bat-terfeban or pharmaceutically acceptable salts thereof will depend on the nature of the drug, the degree of internalization, trafficking and release of the cell surface triggering drug, the disease being treated, the condition of the patient (e.g., age, sex, weight, etc.).

In some embodiments, the mass ratio of the dosage of VEGF antagonist to integrin GPIIb/IIIa antagonist is (0.5-7): 1. In some embodiments, the mass ratio of the dosages of VEGF antagonist and integrin GPIIb/IIIa antagonist is (1-7): 1. In some embodiments, the mass ratio of the dosages of VEGF antagonist and integrin GPIIb/IIIa antagonist is (1-4): 1. In some embodiments, the mass ratio of the dosage of the VEGF antagonist and the integrin GPIIb/IIIa antagonist is 1:1. In some embodiments, the mass ratio of the VEGF antagonist to the integrin GPIIb/IIIa antagonist dose is 2:1. In some embodiments, the mass ratio of the dosage of the VEGF antagonist and the integrin GPIIb/IIIa antagonist is 4:1.

In some embodiments, the VEGF antagonist (e.g., an anti-VEGF antibody (e.g., antibody BAT 5906) or antigen-binding fragment, aflibercept) is about 0.1 mg/eye to 7.5 mg/eye per administration or a formulation containing such a dose of VEGF antagonist (e.g., anti-VEGF antibody or antigen-binding fragment, aflibercept). Formulations containing a VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) may be formulations suitable for injectable use including sterile aqueous solutions (water-soluble herein) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intraocular injection, suitable carriers include physiological saline or bacteriostatic water, and the like. In some embodiments, the formulation comprises at least 0.1% of a VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept). The percentage of antibody may vary and may be between about 2% and 90% by weight of a given dosage form. In some embodiments, the VEGF antagonist is an anti-VEGF antibody (e.g., antibody BAT 5906) or an antigen binding fragment. In some embodiments, the VEGF antagonist is aflibercept.

In some embodiments, the VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) administered at a time is about 0.1 mg/eye, about 0.2 mg/eye, about 0.3 mg/eye, about 0.5 mg/eye, about 0.9 mg/eye, about 1 mg/eye, about 1.25 mg/eye, about 2 mg/eye, about 2.5 mg/eye, about 3 mg/eye, about 4 mg/eye, about 5 mg/eye, about 6 mg/eye, about 7.5 mg/eye, or a range between any two of these values (inclusive), or any value therein, or a formulation comprising such a dose of VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept). In some embodiments, the VEGF antagonist is an anti-VEGF antibody (e.g., antibody BAT 5906) or an antigen binding fragment. In some embodiments, the VEGF antagonist is aflibercept.

In some embodiments, an effective dose of VEGF antagonist (e.g., an anti-VEGF antibody (e.g., antibody BAT 5906) or antigen binding fragment, aflibercept) is administered at about 0.1mg to 15mg per dose. In some embodiments, an effective dose of VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) is administered at about 0.1mg to 8mg per dose. In some embodiments, an effective dose of VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) is administered at about 8mg to 15mg per dose. In some embodiments, an effective amount of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., antibody BAT 5906) or antigen binding fragment, aflibercept) is administered from 0.1mg to 15mg once every 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks. In some embodiments, an effective amount of a VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) administered is about 0.1mg, about 0.2mg, about 0.3mg, about 0.4mg, about 0.6mg, about 1mg, about 1.25mg, about 2mg, about 2.5mg, about 3mg, about 4mg, about 4.5mg, about 5mg, about 6mg, about 7mg, about 8mg, about 9mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg (or a range between any two of these values (inclusive) or any value therein) once every 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks. In some embodiments, an effective amount of a VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) is administered at about 0.2mg, about 0.3mg, about 0.6mg, about 1mg, about 1.25mg, about 2mg, about 2.5mg, about 4mg, about 5mg, or about 8mg once every 3 weeks, 4 weeks, or 5 weeks. In some embodiments, an effective amount of a VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) is administered at about 9mg, about 10mg, about 11mg, 12mg, about 13mg, about 14mg, about 15mg once every 3 weeks, 4 weeks, or 5 weeks. In some embodiments, the VEGF antagonist is an anti-VEGF antibody (e.g., antibody BAT 5906) or an antigen binding fragment. In some embodiments, the VEGF antagonist is aflibercept.

In some embodiments, an effective amount of antibody BAT5906 is administered about 1-5 mg/eye once every 4 weeks. In some embodiments, an effective amount of antibody BAT5906 is administered about 1 mg/eye, about 1.25 mg/eye, about 2 mg/eye, about 2.5 mg/eye, or about 4 mg/eye once every 4 weeks.

In some embodiments, a therapeutically effective amount of bat, or a pharmaceutically acceptable salt thereof, and a VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) are administered to the patient separately or simultaneously. The dosing period of the bat or a pharmaceutically acceptable salt thereof, and the VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) may be the same or different. VEGF antagonists (e.g., anti-VEGF antibodies or antigen-binding fragments, aflibercept) and bat-tifiban or pharmaceutically acceptable salts thereof may be administered in the same or different ways. In some embodiments, the VEGF antagonist is an anti-VEGF antibody (e.g., antibody BAT 5906) or an antigen binding fragment. In some embodiments, the VEGF antagonist is aflibercept.

In some embodiments, the anti-VEGF antibody or antigen-binding fragment is administered by intravitreal injection. In some embodiments, the aflibercept is administered by intravitreal injection. In some embodiments, the administration of the bat, or a pharmaceutically acceptable salt thereof, is by instillation into the conjunctival sac. In some embodiments, the bat or pharmaceutically acceptable salt thereof is administered by intravitreal injection.

In some embodiments, the VEGF antagonist (e.g., an anti-VEGF antibody (e.g., antibody BAT 5906) or antigen binding fragment, aflibercept) and BAT rofiban, or a pharmaceutically acceptable salt thereof, are each independently administered units, in combination. In some embodiments, the VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) may be administered prior to, after, or simultaneously with the administration of the bat or pharmaceutically acceptable salt thereof. In some embodiments, the VEGF antagonist is an anti-VEGF antibody (e.g., antibody BAT 5906) or an antigen binding fragment. In some embodiments, the VEGF antagonist is aflibercept.

In some embodiments, the VEGF antagonist (e.g., an anti-VEGF antibody (e.g., antibody BAT 5906) or antigen binding fragment, aflibercept) and BAT rofiban or a pharmaceutically acceptable salt thereof) are administered in combination together forming a combined dosing unit. In some embodiments, the composition of a VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) and bat-tifiban or a pharmaceutically acceptable salt thereof is administered by intravitreal injection. In some embodiments, the VEGF antagonist is an anti-VEGF antibody (e.g., antibody BAT 5906) or an antigen binding fragment. In some embodiments, the VEGF antagonist is aflibercept.

In some embodiments, the ocular disease in which VEGF is overexpressed is a VEGF-overexpressed fundus disease. In some embodiments, the ocular disease in which VEGF is overexpressed is selected from the group consisting of macular degeneration, age-related macular degeneration (AMD), corneal neovascularization, diseases associated with corneal neovascularization, retinal neovascularization, diseases associated with retinal/choroidal neovascularization, choroidal neovascularization secondary to pathological myopia, iris neovascularization, intraocular neovascularization, ocular neovascular disease, neovascular glaucoma, macular edema, diabetic macular edema (DME, including localized, non-central DME and diffuse, including central DME), cystoid Macular Edema (CME), retinopathy, diabetic retinopathy (DR, including Proliferative DR (PDR), non-proliferative DR (NPDR), and high altitude DR), other ischemia-related retinopathies, retinopathy of prematurity (ROP), familial Exudative Vitreoretinopathy (FEVR), hypertensive retinopathy, retinal Vein Occlusion (RVO) (including branch retinal vein occlusion and central retinal vein occlusion), CNV (including myopia CNV), pathologic myopia, hipe-lindau disease, crown's disease, norubic disease, osteoporosis-pseudoglioma syndrome (OPPG), subconjunctival hemorrhage, redness, retinitis Pigmentosa (RP), retinal hemangioma hyperplasia, macular telangiectasia, retinal degeneration, vasculitis, optic disc edema, retinitis, conjunctivitis (including infectious conjunctivitis and non-infectious (e.g., allergic) conjunctivitis), and, leber congenital amaurosis, uveitis (including infectious and non-infectious uveitis), choroiditis, ocular histoplasmosis, blepharitis, dry eye, traumatic eye injury, and sjogren's disease.

In some embodiments, an effective amount of the bat or pharmaceutically acceptable salt thereof is administered from about 0.1mg to 6mg per treatment cycle. In some embodiments, one treatment cycle is 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 5 weeks, 6 weeks, 7 weeks, or a range between any two of these values (inclusive) or any value therein. In some embodiments, the effective amount of the butifeban or a pharmaceutically acceptable salt thereof administered is about 0.1mg to 3mg 1 time every 3 weeks, 4 weeks, or 5 weeks. In some embodiments, an effective amount of the bat or pharmaceutically acceptable salt thereof administered is about 0.1mg, about 0.2mg, about 0.3mg, about 0.4mg, about 0.6mg, about 1mg, about 1.25mg, about 1.5mg, about 2mg, about 2.5mg, about 3mg (or a range between any two of these values (inclusive), or any value therein) 1 time every 3 weeks, every 4 weeks, or every 5 weeks. In some embodiments, an effective amount of the bat or pharmaceutically acceptable salt thereof is administered from about 3mg to about 6mg once every 3 weeks, 4 weeks, or 5 weeks. In some embodiments, an effective amount of the bat or pharmaceutically acceptable salt thereof administered is about 3.1mg, about 3.5mg, about 4mg, about 4.6mg, about 5mg, about 5.3mg, about 6mg (or a range between any two of these values (inclusive) or any value therein) once every 3 weeks, 4 weeks, or 5 weeks.

In some embodiments, the invention discloses a method of treating an ocular disease, such as an ocular disease that is overexpressed by VEGF, comprising administering to a patient in need thereof an effective amount of a VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) (or formulation) and batifeban (or formulation); wherein the effective amount of a VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) is from about 0.1 mg/eye to 7.5 mg/eye (or a formulation containing such a dose of VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept)) per single administration. In some embodiments, the VEGF antagonist is an anti-VEGF antibody (e.g., antibody BAT 5906) or an antigen binding fragment. In some embodiments, the VEGF antagonist is aflibercept.

In some embodiments, the effective amount of butifeban is about 0.1 mg/eye to 3 mg/eye per single administration (or formulation containing such dose of butifeban). The dosage schedule and mode of administration depends on the risk assessment of benefit of the batafiban (or formulation), VEGF antagonists (e.g., anti-VEGF antibodies or antigen binding fragments, aflibercept) (or formulation) and general clinical practice guidelines in certain patient populations.

In some embodiments, the effective amount of VEGF antagonist (e.g., anti-VEGF antibody (e.g., antibody BAT 5906) or antigen-binding fragment, albesibandrogen) administered per treatment cycle to the patient is about 0.1mg to 15mg (or a formulation containing such dose of VEGF antagonist (e.g., anti-VEGF antibody or antigen-binding fragment, albesibandrogen)), and the effective amount of BAT to be administered per treatment cycle to the patient is about 0.1mg to 6mg (or a formulation containing such dose of BAT). In some embodiments, the VEGF antagonist is an anti-VEGF antibody (e.g., antibody BAT 5906) or an antigen binding fragment. In some embodiments, the VEGF antagonist is aflibercept.

In some embodiments, an effective amount of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., antibody BAT 5906) or antigen-binding fragment, aflibercept) administered to a patient per treatment cycle is about 0.1mg, about 0.2mg, about 0.3mg, about 0.4mg, about 0.6mg, about 0.8mg, about 1mg, about 1.2mg, about 1.25mg, about 2mg, about 2.5mg, about 3mg, about 4mg, about 5mg, about 6mg, about 7mg, about 8mg, about 9mg, about 10mg, about 11mg, about 12mg, about 13mg, about 14mg, about 15mg, or a range between any two of these values (inclusive), or a formulation containing such a dose of a VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept). In some embodiments, one treatment cycle is 1 to 7 weeks of administration. In some embodiments, the effective amount of VEGF antagonist (e.g., anti-VEGF antibody or antigen-binding fragment, aflibercept) administered per treatment cycle is about 0.1mg to 8mg, or a formulation containing such dose of VEGF antagonist (e.g., anti-VEGF antibody or antigen-binding fragment, aflibercept); wherein one treatment cycle is about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, or a range between any two of these values (inclusive) or any value therein. In some embodiments, one treatment cycle is about 2 weeks, about 3 weeks, about 4 weeks, or about 5 weeks. In some embodiments, the effective amount of a VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) administered to the patient per treatment cycle is from about 8mg to about 15mg, or a formulation containing such a dose of a VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept); wherein one treatment cycle is about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, or a range between any two of these values (inclusive) or any value therein. In some embodiments, the effective amount of a VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) administered to a patient per treatment cycle is about 0.2mg, about 0.3mg, about 0.4mg, about 0.6mg, about 1mg, about 1.25mg, about 2mg, about 2.5mg, about 3mg, about 4mg, about 5mg, about 6mg, about 7mg, about 8mg, about 9mg, about 10mg, about 11mg, about 12mg, about 14mg, about 15mg, or a range between any two of these values (inclusive), or any value therein, or a formulation containing such a dose of a VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept); wherein one treatment cycle is about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, or about 6 weeks. In some embodiments, the VEGF antagonist is an anti-VEGF antibody (e.g., antibody BAT 5906) or an antigen binding fragment. In some embodiments, the VEGF antagonist is aflibercept.

In some embodiments, the effective amount of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., antibody BAT 5906) or antigen-binding fragment, aflibercept) is about 0.2mg to 0.9mg, or a formulation containing such a dose of VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) for each treatment cycle in a patient; such as about 0.6mg (0.3 mg/eye) administered 1 time. In some embodiments, the effective amount of a VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) administered to the patient per treatment cycle is about 0.6mg, or a formulation containing such a dose of a VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept); wherein one treatment cycle is about 3 weeks, about 4 weeks, or about 5 weeks. In some embodiments, the VEGF antagonist is an anti-VEGF antibody (e.g., antibody BAT 5906) or an antigen binding fragment. In some embodiments, the VEGF antagonist is aflibercept.

In some embodiments, the effective amount of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., antibody BAT 5906) or antigen-binding fragment, aflibercept) is about 1mg to 1.3mg, or a formulation containing such a dose of VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) per treatment cycle in a patient; such as about 1.2mg (0.6 mg/eye) administered 1 time. In some embodiments, the effective amount of a VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) administered to the patient per treatment cycle is about 1.2mg, or a formulation containing such a dose of a VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept); wherein one treatment cycle is about 3 weeks, about 4 weeks, or about 5 weeks. In some embodiments, the VEGF antagonist is an anti-VEGF antibody (e.g., antibody BAT 5906) or an antigen binding fragment. In some embodiments, the VEGF antagonist is aflibercept.

In some embodiments, the effective amount of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., antibody BAT 5906) or antigen-binding fragment, aflibercept) is about 1.5mg to 3mg, or a formulation containing such a dose of VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) per treatment cycle in a patient; such as about 2mg (1 mg/eye) or about 2.5mg (1.25 mg/eye) for 1 time. In some embodiments, the effective amount of a VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) is about 2mg or about 2.5mg, or a formulation containing such a dose of a VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) per treatment cycle in a patient; wherein one treatment cycle is about 3 weeks, about 4 weeks, or about 5 weeks. In some embodiments, the VEGF antagonist is an anti-VEGF antibody (e.g., antibody BAT 5906) or an antigen binding fragment. In some embodiments, the VEGF antagonist is aflibercept.

In some embodiments, the effective amount of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., antibody BAT 5906) or antigen-binding fragment, aflibercept) administered to the patient per treatment cycle is about 3mg to 6mg, or a formulation containing such a dose of a VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept); such as about 4mg (2 mg/eye) for 1 administration. In some embodiments, the effective amount of a VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) administered to the patient per treatment cycle is about 4mg, or a formulation containing such a dose of a VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept); wherein one treatment cycle is about 3 weeks, about 4 weeks, or about 5 weeks. In some embodiments, the VEGF antagonist is an anti-VEGF antibody (e.g., antibody BAT 5906) or an antigen binding fragment. In some embodiments, the VEGF antagonist is aflibercept.

In some embodiments, the effective amount of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., antibody BAT 5906) or antigen-binding fragment, aflibercept) administered to the patient per treatment cycle is about 6mg to 9mg, or a formulation containing such a dose of a VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept); such as about 8mg (4 mg/eye) for 1 administration. In some embodiments, the effective amount of a VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) administered to the patient per treatment cycle is about 8mg, or a formulation containing such a dose of a VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept); wherein one treatment cycle is about 3 weeks, about 4 weeks, or about 5 weeks. In some embodiments, the VEGF antagonist is an anti-VEGF antibody (e.g., antibody BAT 5906) or an antigen binding fragment. In some embodiments, the VEGF antagonist is aflibercept.

In some embodiments, the effective amount of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., antibody BAT 5906) or antigen-binding fragment, aflibercept) administered to the patient per treatment cycle is about 9mg to 11mg, or a formulation containing such a dose of a VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept); such as about 10mg (5 mg/eye) for 1 administration. In some embodiments, the effective amount of a VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) administered to the patient per treatment cycle is about 10mg, or a formulation containing such a dose of a VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept); wherein one treatment cycle is about 3 weeks, about 4 weeks, or about 5 weeks. In some embodiments, the VEGF antagonist is an anti-VEGF antibody (e.g., antibody BAT 5906) or an antigen binding fragment. In some embodiments, the VEGF antagonist is aflibercept.

In some embodiments, the effective amount of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., antibody BAT 5906) or antigen-binding fragment, aflibercept) is about 13mg to 15.2mg, or a formulation containing such a dose of VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) per treatment cycle in a patient; such as about 15mg (7.5 mg/eye) for 1 administration. In some embodiments, the effective amount of a VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) administered to the patient per treatment cycle is about 15mg, or a formulation containing such a dose of a VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept); wherein one treatment cycle is about 3 weeks, about 4 weeks, or about 5 weeks. In some embodiments, the VEGF antagonist is an anti-VEGF antibody (e.g., antibody BAT 5906) or an antigen binding fragment. In some embodiments, the VEGF antagonist is aflibercept.

In some embodiments, the effective amount of a VEGF antagonist (e.g., an anti-VEGF antibody (e.g., antibody BAT 5906) or antigen binding fragment, aflibercept) is about 0.1mg to 15mg once every 4 weeks. In some embodiments, the effective amount of a VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) is about 0.1mg, about 0.2mg, about 0.3mg, about 0.4mg, about 0.6mg, about 1mg, about 1.25mg, about 2mg, about 2.5mg, about 3mg, about 4mg, about 5mg, about 160mg, about 6mg, about 7mg, about 8mg, about 9mg, about 10mg, about 11mg, about 12mg, about 14mg, about 15mg once every 3 weeks or 4 weeks. In some embodiments, the effective amount of a VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) is about 0.1 mg/eye, about 0.15 mg/eye, about 0.2 mg/eye, about 0.3 mg/eye, about 0.5 mg/eye, about 0.6 mg/eye, about 1 mg/eye, about 1.25 mg/eye, about 1.5 mg/eye, about 2 mg/eye, about 2.5 mg/eye, about 3 mg/eye, about 3.5 mg/eye, about 4 mg/eye, about 4.5 mg/eye, about 5 mg/eye, about 5.5 mg/eye, about 6 mg/eye, about 7 mg/eye, about 7.5 mg/eye once every 3 weeks or 4 weeks. In some embodiments, the effective amount of a VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) is about 0.2 mg/eye, about 0.3 mg/eye, about 0.5 mg/eye, about 0.6 mg/eye, about 1 mg/eye, about 1.25 mg/eye, about 1.5 mg/eye, about 2 mg/eye, about 2.5 mg/eye, about 3 mg/eye, about 3.5 mg/eye, about 4 mg/eye once every 4 weeks. In some embodiments, the VEGF antagonist is an anti-VEGF antibody (e.g., antibody BAT 5906) or an antigen binding fragment. In some embodiments, the VEGF antagonist is aflibercept.

In some embodiments, the effective amount of bat for each treatment cycle in a patient is about 0.1mg, about 0.2mg, about 0.3mg, about 0.4mg, about 0.6mg, about 1mg, about 1.25mg, about 1.5mg, about 2mg, about 2.5mg, about 3mg, about 4mg, about 5mg, about 6mg, or a range between any two of these values (inclusive), or any value therein, or a formulation containing such a dose of bat. In some embodiments, one treatment cycle is 1 to 7 weeks of administration. In some embodiments, the effective amount of the bat of baltifiban administered per treatment cycle is about 0.1mg to 3mg, or a formulation containing such a dose of bat of baltifiban; wherein a treatment cycle is about 1 to about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, or a range between any two of these values (inclusive) or any value therein. In some embodiments, one treatment cycle is about 3 weeks, about 4 weeks, or about 5 weeks. In some embodiments, the effective amount of the bat of baltifiban administered per treatment cycle to the patient is about 3mg to about 6mg, or a formulation containing such a dose of bat of baltifiban; wherein one treatment cycle is about 3 weeks, about 4 weeks, or about 5 weeks. In some embodiments, the effective amount of butifeban administered per treatment cycle to the patient is about 0.2mg, about 0.3mg, about 0.4mg, about 0.6mg, about 1mg, about 1.25mg, about 1.5mg, about 2mg, about 2.5mg, about 3mg, or a range between any two of these values (inclusive), or any value therein, or a formulation containing such dose of butifeban; wherein one treatment cycle is about 3 weeks, about 4 weeks, or about 5 weeks.

In some embodiments, the effective amount of the bat of baltifiban administered per treatment cycle to the patient is about 0.1mg to 0.22mg, or a formulation containing such a dose of bat of baltifiban; such as about 0.2mg (0.1 mg/eye) administered 1 time. In some embodiments, the effective amount of the bat of baltifiban administered to the patient per treatment cycle is about 0.2mg, or a formulation containing such a dose of bat of baltifiban; wherein one treatment cycle is about 3 weeks, about 4 weeks, or about 5 weeks.

In some embodiments, the effective amount of the bat to be administered to the patient per treatment cycle is about 0.2mg to 0.38mg, or a formulation containing such a dose of bat; such as about 0.3mg (0.15 mg/eye) administered 1 time. In some embodiments, the effective amount of the bat of baltifiban administered to the patient per treatment cycle is about 0.3mg, or a formulation containing such a dose of bat of baltifiban; wherein one treatment cycle is about 3 weeks, about 4 weeks, or 4 weeks.

In some embodiments, the effective amount of the bat of baltifiban administered per treatment cycle to the patient is about 0.3mg to 0.5mg, or a formulation containing such a dose of bat of baltifiban; such as about 0.4mg (0.2 mg/eye) administered 1 time. In some embodiments, the effective amount of the bat of baltifiban administered to the patient per treatment cycle is about 0.4mg, or a formulation containing such a dose of bat of baltifiban; wherein one treatment cycle is about 3 weeks, about 4 weeks, or about 5 weeks.

In some embodiments, the effective amount of the bat of baltifiban administered per treatment cycle to the patient is about 1mg to 1.4mg, or a formulation containing such a dose of bat of baltifiban; such as about 1.2mg (0.6 mg/eye) administered 1 time. In some embodiments, the effective amount of the bat of baltifiban administered per treatment cycle to the patient is about 1.2mg, or a formulation containing such a dose of bat of baltifiban; wherein one treatment cycle is about 3 weeks, about 4 weeks, or about 5 weeks.

In some embodiments, the effective amount of the bat of baltifiban administered per treatment cycle to the patient is about 1.6mg to 2.1mg, or a formulation containing such a dose of bat of baltifiban; such as about 2mg (1 mg/eye) for 1 administration. In some embodiments, the effective amount of the bat of baltifiban administered to the patient per treatment cycle is about 2mg, or a formulation containing such a dose of bat of baltifiban; wherein one treatment cycle is about 3 weeks, about 4 weeks, or about 5 weeks.

In some embodiments, the effective amount of the bat of baltifiban administered per treatment cycle to the patient is about 2.2mg to 3mg, or a formulation containing such a dose of bat of baltifiban; such as about 2.5mg (1.25 mg/eye) administered 1 time. In some embodiments, the effective amount of the bat of baltifiban administered to the patient per treatment cycle is about 2.5mg, or a formulation containing such a dose of bat of baltifiban; wherein one treatment cycle is about 3 weeks, about 4 weeks, or about 5 weeks.

In some embodiments, the effective amount of the bat of baltifiban administered per treatment cycle to the patient is about 2.4mg to 4mg, or a formulation containing such a dose of bat of baltifiban; such as about 3mg (1.5 mg/eye) for 1 administration. In some embodiments, the effective amount of the bat to be administered to the patient per treatment cycle is about 3mg, or a formulation containing such a dose of bat; wherein one treatment cycle is about 3 weeks, about 4 weeks, or about 5 weeks.

In some embodiments, the VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) and the bat (or a combination of VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) and bat) are administered once per treatment cycle, respectively, to the patient. In some embodiments, the VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) and the bat (or a combination of VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) and bat) are administered multiple times, e.g., 2, 3, 4, or 5 times, respectively, per treatment cycle. In some embodiments, the patient can only be administered 1, 2, 3, 4, 5, or 6 times per treatment cycle. In some embodiments, the VEGF antagonist is an anti-VEGF antibody (e.g., antibody BAT 5906) or an antigen binding fragment. In some embodiments, the VEGF antagonist is aflibercept.

The term "one or more administrations" as used herein is with respect to each eye of a patient. In some embodiments, the patient has an ocular disease in which VEGF is overexpressed in both eyes, "1 administration" means that both eyes need to be administered 1 time. In some embodiments, the patient has only one eye with an ocular disease associated with VEGF, and 1 administration refers to 1 administration of one eye.

In some embodiments, the patient receives one treatment cycle. In some embodiments, the patient receives multiple (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17) treatment cycles of treatment. In some embodiments, the patient receives treatment until the condition is alleviated without further treatment.

In some embodiments, the invention discloses a method for treating an ocular disease that is overexpressed by VEGF, the method comprising: administering to a patient in need thereof about 0.1 mg/eye to 1.25 mg/eye, about 1.25 mg/eye to 2.5 mg/eye, about 2.5 mg/eye to 4 mg/eye, about 4 mg/eye to 6 mg/eye, about 6 mg/eye to 7.5 mg/eye, such as about 0.1 mg/eye, 0.2 mg/eye, 0.3 mg/eye, 0.4 mg/eye, 0.5 mg/eye, 0.6 mg/eye, 0.8 mg/eye, 1 mg/eye, 1.25 mg/eye, 1.3 mg/eye, 2 mg/eye, 2.5 mg/eye, 3 mg/eye, 4 mg/eye, 5 mg/eye, 6 mg/eye, 7.5 mg/eye of a VEGF antagonist (e.g., an anti-VEGF antibody or antigen binding fragment, an aflibercept), or a formulation comprising such a dose of a VEGF antagonist (e.g., an anti-VEGF antibody or antigen binding fragment, aflibercept); also administered to a patient in need thereof is about 0.1 mg/eye to 1.25 mg/eye, about 1.25 mg/eye to 2.5 mg/eye, about 2.5 mg/eye to 3 mg/eye, such as about 0.1 mg/eye, 0.2 mg/eye, 0.3 mg/eye, 0.4 mg/eye, 0.5 mg/eye, 0.6 mg/eye, 0.8 mg/eye, 1 mg/eye, 1.25 mg/eye, 1.3 mg/eye, 2 mg/eye, 2.5 mg/eye, 3 mg/eye of batifeban, or a formulation containing such a dose of batifeban. In some embodiments, the patient is treated with a single dose of a VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) and batifeban. In some embodiments, the patient is treated with a single dose of a VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) and a bat composition.

In some embodiments, the VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) and batifeban are administered once every 3 weeks or 4 weeks.

In some embodiments, the symptoms of the patient are alleviated after a single dose administration. In some embodiments, symptoms after a single dose of administration are not expected to be alleviated after the patient, and about 0.1 mg/eye to 7.5 mg/eye of a VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) and about 0.1 mg/eye to 3 mg/eye of bat-tifiban are administered to the patient separately or simultaneously.

In some embodiments, the anti-VEGF antibody is antibody BAT5906.

In some embodiments, the invention discloses a method for treating an ocular disease that is overexpressed VEGF, the method comprising administering to a patient in need thereof a single dose, or once every 7 weeks, or once every 3 weeks or 4 weeks, 0.1 mg/eye to 7.5 mg/eye of antibody BAT5906 and 0.1 mg/eye to 3 mg/eye of batifenpban. In some embodiments, the method comprises administering to a patient in need thereof 0.25 mg/eye, 0.3 mg/eye, 0.6 mg/eye, 1 mg/eye, 1.25 mg/eye, 2 mg/eye, 2.5 mg/eye, or 4 mg/eye of antibody BAT5906, and 1 mg/eye, or 0.5 mg/eye of batafiban, once per week to once per 7 weeks, or once per 3 weeks or 4 weeks. In some embodiments, the method comprises administering to a patient in need thereof 0.25 mg/eye, 0.3 mg/eye, 0.6 mg/eye, 1 mg/eye, 1.25 mg/eye, 2 mg/eye, 2.5 mg/eye, or 4 mg/eye of antibody BAT5906, and 1.5 mg/eye, or 3 mg/eye of BAT once per week to once per 7 weeks, or once per 3 weeks or 4 weeks.

In some embodiments, the invention discloses a method for treating an ocular disease that is overexpressed by VEGF, the method comprising administering to a patient in need thereof a single dose, or once every 7 weeks, or once every 3 weeks or 4 weeks, 0.1 mg/eye to 7.5 mg/eye of albesipn and 0.1 mg/eye to 3 mg/eye of butifeban. In some embodiments, the method comprises administering to a patient in need thereof 0.25 mg/eye, 0.3 mg/eye, 0.6 mg/eye, 1 mg/eye, 1.25 mg/eye, 2 mg/eye, 2.5 mg/eye, or 4 mg/eye of aflibercept, and 0.5 mg/eye, 1 mg/eye, 1.5 mg/eye, or 3 mg/eye of bat per week, or once every 7 weeks or once every 3 weeks or 4 weeks.

In some embodiments, the VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) (or formulation), or bat-tifiban (or formulation) is administered by intravitreal injection. In some embodiments, the VEGF antagonist (e.g., an anti-VEGF antibody or antigen-binding fragment, aflibercept) (or formulation) is administered by intravitreal injection and the batifer (or formulation) is administered by drop administration.

Drawings

Fig. 1: rhesus monkey retinal thickness changes following intravitreal injection of the test subjects; wherein, pre-Laser: pre-dose: before administration.

Fig. 2: changes in rhesus choroid thickness following intravitreal injection of the subject; wherein, pre-Laser: pre-dose: before administration.

Fig. 3: rhesus fundus fluorescence leakage area change after intravitreal injection of the test subjects; wherein, pre-dose: before administration.

Fig. 4: changes in rhesus fundus fluorescence leakage intensity following intravitreal injection of the test subjects; wherein, pre-dose: before administration.

Terminology

Unless otherwise indicated, each term below shall have the meaning described below.

Definition of the definition

It should be noted that the term "an" entity refers to one or more of the entity, e.g. "an antibody" should be understood as one or more antibodies, and thus the terms "one" (or "one"), "one or more" and "at least one" can be used interchangeably herein.

The terms "comprising" or "including" as used herein mean that the compositions and methods, etc., include the recited elements, e.g., components or steps, but do not exclude the others. By "consisting essentially of … …" it is meant that the compositions and methods exclude other elements that have a fundamental impact on the characteristics of the combination, but do not exclude elements that have no essential impact on the compositions or methods. "consisting of … …" means that elements not specifically recited are excluded.

The term "polypeptide" is intended to encompass both the singular and the plural of "polypeptides" and refers to molecules composed of amino acid monomers that are linearly linked by amide bonds (also referred to as peptide bonds). The term "polypeptide" refers to any single chain or multiple chains of two or more amino acids, and does not refer to a particular length of product. Thus, the definition of "polypeptide" includes peptides, dipeptides, tripeptides, oligopeptides, "proteins", "amino acid chains" or any other term used to refer to two or more amino acid chains, and the term "polypeptide" may be used in place of, or in addition to, any of the terms described above. The term "polypeptide" is also intended to refer to products of modification of the polypeptide after expression, including but not limited to glycosylation, acetylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, or non-naturally occurring amino acid modification. The polypeptide may be derived from a natural biological source or produced by recombinant techniques, but it need not be translated from the specified nucleic acid sequence, and it may be produced in any manner including chemical synthesis.

"amino acid" refers to an organic compound containing both amino and carboxyl groups, such as an alpha-amino acid, which may be encoded by a nucleic acid directly or in precursor form. A single amino acid is encoded by a nucleic acid consisting of three nucleotides, a so-called codon or base triplet. Each amino acid is encoded by at least one codon. The same amino acid is encoded by different codons called "degeneracy of the genetic code". Amino acids include natural amino acids and unnatural amino acids. Natural amino acids include alanine (three-letter code: ala, one-letter code: a), arginine (arg, R), asparagine (asn, N), aspartic acid (asp, D), cysteine (cys, C), glutamine (gln, Q), glutamic acid (glu, E), glycine (gly, G), histidine (his, H), isoleucine (ile, I), leucine (leu, L), lysine (lys, K), methionine (met, M), phenylalanine (phe, F), proline (pro, P), serine (ser, S), threonine (thr, T), tryptophan (trp, W), tyrosine (tyr, Y), and valine (val, V).

"conservative amino acid substitution" refers to the substitution of one amino acid residue with another amino acid residue that contains a side chain (R group) that is similar in chemical properties (e.g., charge or hydrophobicity). In general, conservative amino acid substitutions will not substantially alter the functional properties of the protein. Examples of classes of amino acids containing chemically similar side chains include: 1) Aliphatic side chain: glycine, alanine, valine, leucine and isoleucine; 2) Aliphatic hydroxyl side chains: serine and threonine; 3) Amide-containing side chains: asparagine and glutamine; 4) Aromatic side chain: phenylalanine, tyrosine, and tryptophan; 5) Basic side chain: lysine, arginine, and histidine; 6) Acidic side chain: aspartic acid and glutamic acid.

The number of amino acids of a "conservative amino acid substitution of VL, VH" may be about 1, about 2, about 3, about 4, about 5, about 6, about 8, about 9, about 10, about 11, about 13, about 14, about 15 conservative amino acid substitutions, or a range between any two of these values (inclusive) or any value therein. The number of amino acid substitutions of "conservative amino acid substitutions of a heavy or light chain" may be about 1, about 2, about 3, about 4, about 5, about 6, about 8, about 9, about 10, about 11, about 13, about 14, about 15, about 18, about 19, about 22, about 24, about 25, about 29, about 31, about 35, about 38, about 41, about 45 conservative amino acid substitutions, or a range between any two of these values (inclusive) or any value therein.

The term "encoding" when applied to a polynucleotide refers to a polynucleotide referred to as "encoding" a polypeptide, which polypeptide and/or fragment thereof may be produced by transcription and/or translation in its natural state or when manipulated by methods well known to those skilled in the art.

Antibodies, antigen binding fragments or derivatives of the disclosure include, but are not limited to, polyclonal, monoclonal, multispecific, fully human, humanized, primatized, chimeric antibodies, single chain antibodies, antigen binding fragments (e.g., fab 'and F (ab') ₂ )、scFv)。

The term "recombinant" refers to a polypeptide or polynucleotide, meaning a form of the polypeptide or polynucleotide that does not exist in nature, and non-limiting examples can be combined to produce a polynucleotide or polypeptide that does not normally exist.

"homology" or "identity" or "similarity" refers to sequence similarity between two peptides or between two nucleic acid molecules. Homology can be determined by comparing the positions in each sequence that can be aligned. When a position in the compared sequences is occupied by the same base or amino acid, then the molecules are homologous at that position. The degree of homology between sequences is a function of the number of matched or homologous positions shared by the sequences.

"at least 80% identical" is about 80% identical, about 81% identical, about 82% identical, about 83% identical, about 85% identical, about 86% identical, about 87% identical, about 88% identical, about 90% identical, about 91% identical, about 92% identical, about 94% identical, about 95% identical, about 98% identical, about 99% identical, or a range between any two of these values (inclusive) or any value therein.

A nucleic acid or polynucleotide sequence (or polypeptide or antibody sequence) has a certain percentage (e.g., 90%, 95%, 98%, or 99%) of "identity" or "sequence identity" with another sequence, meaning that when the sequences are aligned, the percentage of bases (or amino acids) in the two sequences that are compared are identical. The percentage of alignment identity or sequence identity may be determined using visual inspection or software programs known in the art, such as the software program described in Ausubel et al eds. (2007) in Current Protocols in MolecularBiology. Preferably, the alignment is performed using default parameters. One such alignment program is BLAST using default parameters, such as BLASTN and BLASTP, both of which use the following default parameters: genetics code = standard; filter = none; strand = both; cutoff = 60; expect=10; matrix = BLOSUM62; descriptive = 50sequences; sortby=highscore; databases = non-redundants; genbank+embl+ddbj+pdb+genbank cdstransplations+swi ssprotein+spldate+pir. Biologically equivalent polynucleotides are those that have the indicated percent identity and encode polypeptides having the same or similar biological activity.

An "antibody" or "antigen-binding fragment" refers to a polypeptide or complex of polypeptides that specifically recognizes and binds an antigen. The antibody may be an intact antibody, any antigen-binding fragment thereof, or a single chain thereof. The term "antibody" thus includes any protein or peptide comprising at least a portion of an immunoglobulin molecule having biological activity for binding to an antigen in a molecule. Antibodies and antigen binding fragments include, but are not limited to, complementarity Determining Regions (CDRs), heavy chain variable regions (VH), light chain variable regions (VL), heavy chain constant regions (CH), light chain constant regions (CL), framework Regions (FR) or any portion thereof, or at least a portion of a binding protein, of a heavy chain or light chain or ligand binding portion thereof. The CDR regions include the CDR regions of the light chain (LCDR 1-3) and the heavy chain (HCDR 1-3).

The term "antibody" includes a wide variety of polypeptides that can be biochemically distinguished. Those skilled in the art will appreciate that the heavy chain classes include gamma, mu, alpha, delta or epsilon (γ, μ, α, δ, ε), some of which are also subclasses (e.g., γ1- γ4). The nature of this chain determines the "class" of antibody as IgG, igM, igA, igG or IgE, respectively. Immunoglobulin subclasses (isotypes), e.g., igG1, igG2, igG3, igG4, igG5, etc., have been well characterized and the functional specificities conferred are also known. All immunoglobulin classes are within the scope of the present disclosure. In some embodiments, the immunoglobulin molecule is an IgG class.

Light chains can be classified as kappa (kappa) or lambda (lambda). Each heavy chain may be associated with a kappa or lambda light chain. In general, when an immunoglobulin is produced from a hybridoma, B cell, or genetically engineered host cell, the light and heavy chains thereof are joined by covalent bonds, twoThe "tail" portion of the heavy chain is bound by covalent disulfide bonds or non-covalent bonds. In the heavy chain, the amino acid sequence extends from the N-terminus of the forked end of the Y-configuration to the C-terminus of the bottom of each chain. Immunoglobulin kappa light chain variable region vkappa; immunoglobulin lambda light chain variable region V _λ 。

The terms "constant" and "variable" are used in terms of function. The light chain variable region (VL) and the heavy chain variable region (VH) determine antigen recognition and specificity. The constant region (CL) of the light chain and the constant region (CH) of the heavy chain confer important biological properties such as secretion, transplacental movement, fc receptor binding, complement fixation, etc. Conventionally, the numbering of constant regions increases as they become farther from the antigen binding site or amino terminus of an antibody. The N-terminal portion is a variable region and the C-terminal portion is a constant region; the CH3 and CL domains actually comprise the carboxy-terminus of the heavy and light chains, respectively.

Where there are two or more definitions of terms used and/or accepted in the art, the definitions of terms used herein include all such meanings unless explicitly stated to the contrary. One specific example is the use of the term "complementarity determining regions" ("CDRs") to describe non-contiguous antigen binding sites found within the variable regions of heavy and light chain polypeptides. This particular region is described in Kabat et al, U.S. Dept. Of health and Human Services, sequences of Proteins of Immunological Interest (1983) and Chothia et al, J.mol. Biol.196:901-917 (1987), which are incorporated herein by reference in their entirety.

CDRs defined according to Kabat and Chothia include overlapping or subsets of amino acid residues when compared to each other. Nevertheless, it is within the scope of the invention to apply either definition to refer to the CDRs of an antibody or variant thereof. The exact residue number comprising a particular CDR will vary depending on the sequence and size of the CDR. One skilled in the art can generally determine which specific residues a CDR comprises based on the variable region amino acid sequence of an antibody.

Kabat et al also define a numbering system for variable region sequences suitable for use with any antibody. The "Kabat numbering" system can be applied to any variable region sequence by one of ordinary skill in the art independent of other experimental data than the sequence itself. "Kabat numbering" refers to the numbering system set forth by Kabat et al, U.S. Dept. Ofhealth and Human Services at "Sequence ofProteinsofImmunological Interest" (1983). Antibodies may also use EU or Chothia numbering systems.

"treatment" refers to therapeutic treatment and prophylactic or preventative measures, with the object of preventing, slowing, ameliorating, and halting an undesirable physiological change or disorder, such as the progression of a disease, including but not limited to, a decrease in symptoms, a decrease in the degree of a disease, stabilization (i.e., not worsening) of a disease state, a delay or slowing of disease progression, an amelioration or palliation of a disease state, a decrease or disappearance (whether partial or total), an extension and an expected lifetime without treatment, and the like, whether detectable or undetectable. Patients in need of treatment include those already with the condition or disorder, those prone to the condition or disorder, or those in need of prophylaxis of the condition or disorder, for whom the administration of the disclosed antibodies or compositions for detection, diagnostic procedures, and/or treatment would be expected to benefit.

"patient" refers to any mammal in need of diagnosis, prognosis or treatment, including humans, dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, and the like.

"about" refers to a conventional error range of corresponding numerical values as readily known to one of ordinary skill in the relevant art. In some embodiments, references herein to "about" refer to the values described and ranges thereof of ± 10%, ± 5% or ± 1%.

An "effective amount" refers to an amount of an active compound or agent that is capable of eliciting a biological or medical response in a tissue, system, animal, individual or human.

As used herein, the phrase "in need of" means that the patient has been identified as in need of a particular method or treatment. In some embodiments, the identification may be performed by any diagnostic means.

Preparation of antibodies

The DNA encoding the antibody may be synthesized according to the amino acid sequence design of the antibody described herein by conventional methods, placed into an expression vector, and then transfected into a host cell, and the transfected host cell is cultured in a medium to produce monoclonal antibodies. In some embodiments, the expression antibody vector comprises at least one promoter element, an antibody coding sequence, a transcription termination signal, and a polyA tail. Other elements include enhancers, kozak sequences, and donor and acceptor sites for RNA splicing flanking the insertion. Efficient transcription can be obtained by the early and late promoters of SV40, the long terminal repeats from retroviruses such as the early promoters of RSV, HTLV1, HIVI and cytomegalovirus, and other cellular promoters such as actin promoters may be used. Suitable expression vectors may include pIRES1neo, pRetro-Off, pRetro-On, PLXSN, or pLNCX, pcDNA3.1 (+/-), pcDNA/Zeo (+/-), pcDNA3.1/Hygro (+/-), PSVL, PMSG, pRSVcat, pSV dhfr, pBC12MI, pCS2, and the like. Commonly used mammalian cells include HEK293 cells, cos1 cells, cos7 cells, CV1 cells, murine L cells, CHO cells and the like.

All publications, patents, and patent applications cited herein are incorporated by reference in their entirety for all purposes.

Detailed Description

The technical solution of the present invention is further illustrated by the following specific examples, which do not represent limitations on the scope of the present invention. Some insubstantial modifications and adaptations of the invention based on the inventive concept by others remain within the scope of the invention.

Materials, reagents and the like used in the examples described below are commercially available unless otherwise specified.

Example 1 sequences of anti-VEGF antibodies

The amino acid sequence of the anti-VEGF antibody (BAT 5906) is shown in Table 1.

TABLE 1 amino acid sequence of antibody BAT5906

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Example 2 rhesus monkey choroidal neovascularization inhibition experiments

On days D1-D21 (days 1-21), rhesus monkeys were subjected to choroidal neovascularization induced by binocular fundus laser to construct an AMD model (new drug research center, shao-yan), D22 animals with 4-grade leak spots were selected into groups, and the groups and administration modes were shown in table 2, based on the average leak area of the 4-grade spots and the average leak rate of the 4-grade spots. 4 grades of leakage rating: the level 1 light spots do not have high fluorescence; level 2, high fluorescence of the light spot but no leakage of fluorescence; grade 3, high fluorescence of the light spots, slight fluorescence leakage, and leakage not exceeding the edge of the light spots; grade 4, high fluorescence of the light spots, severe fluorescence leakage exceeding the edges of the light spots.

All animals were observed once daily during the trial period and for mortality, morbidity, respiration, secretions, faeces, diet, drinking etc. Animals were weighed at screening, D21, D29, D36. All animals were screened, pre-molded, D21, D24, D29, D36, and the changes in the anterior ocular segment (conjunctiva, cornea, anterior chamber, iris, pupil, lens, etc.) of both eyes of the animals were observed using slit lamps, and the examination results were recorded. All animals were examined for FP (fundus photography) and FFA (fundus fluoroscopic) immediately after molding (D1, fundus photography only), D21, D29, D36 at the time of screening. All animals were screened for OCT (optical coherence tomography) examination with D21, D29, D36, and the examination area was covered with all laser photocoagulation spots.

Fluorescence leakage area improvement rate = fluorescence leakage area reduction/pre-dose fluorescence leakage area x 100%, fluorescence leakage area reduction = pre-dose fluorescence leakage area-post-dose fluorescence leakage area.

TABLE 2 grouping and administration modes

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1) No abnormalities were seen in clinical observations of all animals during the trial, no abnormal changes in body weight were seen.

2) As shown in table 3, co-administration of the butifeban and the antibodies BAT5906 and butifeban reduced the area of fluorescence leakage.

TABLE 3 improvement of fluorescence leakage area at day 36 (partial experimental data)

Example 3 pharmacodynamics of laser-induced model of rhesus choroidal neovascularization in vitreoform injection test Study of

Selecting

CNV modeling was performed on rhesus monkeys (common grade), and 3 weeks after modeling, the rhesus monkeys were randomly divided into 5 groups (10 animals including vehicle control group) according to four-grade fluorescence leakage conditions, and each group was divided into 2 animals, and the group and administration modes are shown in Table 4, and the Day of administration was named Day1 (i.e., D1). Detailed clinical observations were made for all animals during adaptation phase, modeling phase and experimental period; eye irritation test, ophthalmic examination, fundus examination (fundus photographing, OCT and FFA examination) were performed on all surviving experimental animals before molding, before administration (2 weeks after molding, D-1), and after administration, D7, D14.

Table 4 test design table

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Note that: * The group of the batifeban, the BAT5906 and the group of the batifeban, the Abelmoschus are combined medicines, and the two medicines are required to be mixed before administration and then injected into the vitreous body of the tested eye; the vehicle control, BAT5906 and Abelmoschus groups had a dosing volume of 50. Mu.L/eye, the BAT5906 group, the BATIFAN+BAT 5906 group, and the BATIFAN+Abelmoschus group had a dosing volume of 100. Mu.L/eye.

Eye irritation detection

The evaluation of eye irritation in each group of animals was non-irritating during both the adaptation phase and the modeling phase. During the dosing period, both eyes of animal #202 (BAT 5906 group) and animal #303 (BAT 5906 group) were slightly irritating at D7 and returned to normal at the time of the D14 examination; animal #301 (group of bat+bat 5906) showed left-eye endophthalmitis at D7, which was not recovered until the end of the animal experiment, and was probably caused by symptoms such as oedema in the eye tissue due to a small eyeball, a large volume of the vitreous injection preparation (100 μl), slight irritation to the right eye, and recovery from D14 detection; the rest animals have no irritation during administration period.

Ophthalmic examination

During the adaptation phase and the molding phase: all surviving animals were free of abnormal symptoms in the ophthalmic examination.

Between administrations: both eyes of animal #202 and animal #303 had slight cloudiness at D7 and recovered to normal at the time of the D14 examination; animal #403 (albesieged) left eye was slightly aqueous, shiny, and returned to normal upon D14 examination; the left eye of animal #301 (group of bat+bat 5906) has dark red conjunctival congestion, severe turbid cornea, moderate aqueous humor flash at D7, and can not observe inflammation phenomena such as fundus structure and the like until animal experiments are finished without recovery, which may be caused by symptoms such as intraocular tissue edema and the like caused by smaller eyeballs and larger volume (100 mu L) of vitreous injection preparation; the other animals had no abnormal symptoms during the dosing period of the ophthalmic examination.

Fundus detection result

The retina and choroid film thickness are summarized in tables 5 and 6 and figures 1 and 2, and the fluorescence leakage area and intensity are summarized in tables 7 and 8 and figures 3 and 4.

TABLE 5 retina thickness

Note that: % diff= (Dayn-Pre-dose)/Pre-dose x 100; pre-dose: before administration; * The left eye of 301 animals developed intra-ocular inflammation after administration, and the subsequent fundus examination data was not available.

TABLE 6 choroidal membrane thickness

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TABLE 7 fluorescence leakage area variation

Note that: % diff= (Dayn-Pre-dose)/Pre-dose x 100; pre-Laser: before molding; pre-dose: before administration; * The left eye of 301 animals developed intra-ocular inflammation after administration, and the subsequent fundus examination data was not available.

TABLE 8 fluorescence leakage intensity variation

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(1) Retina thickness: the animals showed an increase in thickness after molding, and the repair changes of retinal thickness after administration were, in order from high to low, the group of batifeban+BAT 5906, the group of batifeban+Abelmoschus, the group of BAT5906, the vehicle control group, the group of Abelmoschus. In addition to the self-recovery of retina with the experimental process, it is explained that three of the group of BAT feban+bat 5906, BAT feban+albesiex group, BAT5906 have a certain repair function on retina after administration.

(2) Choroidal membrane thickness: after the animals of each group are subjected to mould-making administration, the choroid film thickness has a certain damage, and after the administration, the repair change of the choroid film thickness change is from high to low, namely, the group consisting of the BAT (BAT) and the BAT5906, the group consisting of the BAT5906, the BAT (BAT) and the aflibercept, the solvent control group and the aflibercept, wherein, the repair of the group consisting of the BAT and the BAT5906 is optimal, and the group consisting of the BAT5906 and the BAT and the aflibercept are inferior, and the vehicle control group and the aflibercept are consistent.

(3) Fluorescence leakage change: fluorescence leakage (caused by choroidal neovascularization) gradually occurs after each group is molded, and the consistent repair of each group of fluorescence leakage changes (including area and intensity) after administration is represented by the effects of BAT feban+bat 5906> BAT feban+aflibercept > BAT5906, the effects of BAT feban+aflibercept being similar to BAT5906, and the administration of aflibercept alone being similar to the vehicle control group.

The above results varied, demonstrating that the rhesus monkeys in each dosing group had various degrees of recovery and improvement in retinal thickness, choroid thickness, and fluorescent leakage symptoms after dosing. Besides self-process repair, the group of the batafiban and the BAT5906, the group of the batafiban and the Abelmosil and the group of the BAT5906 have better repair and improvement effects on symptoms caused by animal models, of these, group BAT5906 with batifeban+bat was most effective.

Claims

1. Use of an integrin GPIIb/IIIa antagonist for the manufacture of a medicament for the treatment of an ocular disorder.

Use of a vegf antagonist and an integrin GPIIb/IIIa antagonist for the preparation of a pharmaceutical composition for the treatment of an ocular disorder.

Use of a vegf antagonist in the manufacture of a medicament for use in combination with an integrin GPIIb/IIIa antagonist in the treatment of an ocular disorder.

4. Use of an integrin GPIIb/IIIa antagonist or a pharmaceutical composition comprising an integrin GPIIb/IIIa antagonist for the manufacture of a medicament for enhancing the effect of a VEGF antagonist in the treatment of an ocular disorder.

5. A kit comprising a VEGF antagonist, an integrin GPIIb/IIIa antagonist, and instructions for administering the VEGF antagonist, the integrin GPIIb/IIIa antagonist to a patient in need thereof.

6. A pharmaceutical composition for treating an ocular disease comprising a VEGF antagonist and an integrin GPIIb/IIIa antagonist.

7. The pharmaceutical composition of claim 6, wherein the mass ratio of VEGF antagonist to integrin GPIIb/IIIa antagonist is (0.5-7): 1, or (1-4): 1, or 1:1,2:1, or 4:1.

8. The use, kit, or pharmaceutical composition of any one of claims 2-7, wherein the VEGF antagonist is selected from the group consisting of an anti-VEGF antibody or antigen-binding fragment, an anti-VEGF receptor antibody or antigen-binding fragment, a VEGF receptor fusion protein, an aptamer that specifically binds to VEGF, and a VEGFR tyrosine kinase inhibitor; alternatively, the anti-VEGF antibody is selected from the group consisting of ibuprofen, bevacizumab, and ranibizumab; alternatively, the VEGF receptor fusion protein is selected from the group consisting of Abelmoschus and Compositae; alternatively, the VEGFR tyrosine kinase inhibitor is selected from the group consisting of: 4- (4-bromo-2-fluoroanilino) -6-methoxy-7- (1-methylpiperidin-4-ylmethoxy) quinazoline, 4- (4-fluoro-2-methylindol-5-yloxy) -6-methoxy-7- (3-pyrrolidin-1-ylpropoxy) quinazoline, vastatin anib, semaxanib, and sunitinib; alternatively, the anti-VEGF antibody or antigen binding fragment comprises HCDR1 shown as SEQ ID NO. 1, HCDR2 shown as SEQ ID NO. 2, HCDR3 shown as SEQ ID NO. 3, LCDR1 shown as SEQ ID NO. 4, LCDR2 shown as SEQ ID NO. 5, and LCDR3 shown as SEQ ID NO. 6; alternatively, the anti-VEGF antibody or antigen-binding fragment comprises a heavy chain variable region and/or a light chain variable region; wherein the heavy chain variable region comprises the sequence shown in SEQ ID NO. 7, or a sequence having at least 80% identity to the sequence shown in SEQ ID NO. 7, or an amino acid sequence having one or more conservative amino acid substitutions to the sequence shown in SEQ ID NO. 7; and/or the light chain variable region comprises the sequence shown in SEQ ID NO. 8, or a sequence having at least 80% identity to the sequence shown in SEQ ID NO. 8, or an amino acid sequence having one or more conservative amino acid substitutions compared to the sequence shown in SEQ ID NO. 8; alternatively, the heavy chain of the anti-VEGF antibody comprises the sequence shown as SEQ ID NO. 9, or a sequence having at least 80% identity to the sequence shown as SEQ ID NO. 9, or an amino acid sequence having one or more conservative amino acid substitutions as compared to the sequence shown as SEQ ID NO. 9; and/or the light chain of the anti-VEGF antibody comprises the sequence shown as SEQ ID NO. 10, or a sequence having at least 80% identity to the sequence shown as SEQ ID NO. 10, or an amino acid sequence having one or more conservative amino acid substitutions as compared to the sequence shown as SEQ ID NO. 10.

9. The use, kit, or pharmaceutical composition of any one of claims 1-8, wherein the integrin GPIIb/IIIa antagonist is bat-tifiban or a pharmaceutically acceptable salt thereof.

10. The use of any one of claims 1-4, 8-9, wherein the ocular disease is an ocular disease in which VEGF is overexpressed; alternatively, the ocular disease is selected from macular degeneration, age-related macular degeneration, corneal neovascularization, a disease associated with corneal neovascularization, retinal neovascularization, a disease associated with retinal/choroidal neovascularization, a disease secondary to pathological myopia choroidal neovascularization, iris neovascularization, intraocular neovascularization, ocular neovascularization disease, neovascular glaucoma, macular edema, diabetic macular edema, cystoid macular edema, retinopathy, diabetic retinopathy, other ischemia-related retinopathy, retinopathy of prematurity, familial exudative vitreoretinopathy, hypertensive retinopathy, retinal vein occlusion, retinal branch vein occlusion, central retinal vein occlusion, CNV, pathological myopia, von hippel-lindau disease, crown-disease, noris disease, osteoporosis-pseudoglioma syndrome, subconjunctival hemorrhage, rubeosis, retinitis pigmentosa, hemangioma hyperplasia, telangiectasia, retinitis, optic disk edema, retinitis, uveitis, congenital amaurosis, uveitis, blepharitis, ocular injury, and ocular injury.