Application of fusion protein in treating age-related macular degeneration

Abstract

To provide use of a fusion protein in the treatment of age-related macular degeneration.SOLUTION: The present invention relates to use of a fusion protein in the treatment of age-related macular degeneration. In particular, the present invention relates to use of a bispecific fusion protein inhibiting the activation of a complement pathway and a vascular endothelial growth factor (VEGF) pathway for the treatment of age-related macular degeneration. The present invention also relates to a pharmaceutical composition comprising the fusion protein and a method for treating age-related macular degeneration using the fusion protein.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to the use of a bispecific fusion protein that inhibits activation of the complement pathway and the vascular endothelial growth factor (VEGF) pathway in the treatment of age-related macular degeneration. The present invention further relates to pharmaceutical compositions comprising said fusion protein and methods of using said fusion protein to treat age-related macular degeneration. [Background technology]

[0002] Age-related macular degeneration (AMD, also known as senile macular degeneration) is a chronic progressive disease of the retinal fovea. Senile macular degeneration mainly occurs in people over 45 years of age, and the incidence rate increases with age. It is now a serious disease that causes blindness in the elderly. There are approximately 30 million age-related macular degeneration patients worldwide, and approximately 500,000 people become blind each year as a result. In Japan, the incidence of AMD is increasing year by year with the progress of economic development and the aging of the population, and it is now the third leading cause of blindness in Japan.

[0003] AMD mainly manifests as a decline in the ability of the retinal pigment epithelium (RPE) to phagocytose and digest the disk membrane of the photoreceptor outer segment, resulting in the formation of drusen when remnants of the incompletely digested disk membrane remain in the basal cell cytoplasm, spill out of the cell, and are deposited in Bruch's membrane. The pigment epithelium, Bruch's membrane, and photoreceptor cells in drusen are degenerated, hyperplastic, or atrophic to varying degrees. The National Eye Institute's "Age-Related Eye Disease Research" group classifies AMD into early, intermediate, and late AMD. Early AMD is characterized primarily by drusen, has a high incidence rate, but a low rate of blindness, and when it progresses to the late stage, it seriously affects the patient's vision. It can be classified into atrophic and exudative types according to its pathological characteristics. Exudative AMD is also called wet AMD or neovascular AMD. Its main pathological characteristics are increased release of vascular endothelial growth factor (VEGF), immature neovascularization between the pigment epithelial cells of the retina centralis or the photoreceptors, i.e., choroidal neovascularization (CNV), subretinal rupture hemorrhage, and destruction of the retinal pigment epithelium and Bruch's membrane. Although the incidence rate of exudative AMD is low, the rate of blindness is high.

[0004] Although the pathological mechanism of MD has not been fully elucidated, it is now generally accepted that angiogenesis induced by increased expression of VEGF is the main cause of the development of wet AMD. In addition, inflammatory responses mediated by complement gene mutations and abnormal complement activation are also thought to be important causes of the development of AMD. Activation of the complement system has a direct effect on RPE damage, which, on the one hand, causes RPE atrophy and induces atrophy of cells in the retinal fovea, resulting in the development of GA (atrophic AMD). On the other hand, it destroys the blood-retinal barrier, causing the development of inflammation, high VEGF expression, and angiogenesis, resulting in the development of neovascular AMD (wet AMD).

[0005] Anticomplement drugs are mainly used for dry AMD with geographic atrophy, and their effectiveness is unclear in wet AMD, where the possibility of vision loss is higher, and there is a possibility that their benefits will not be shown unless they are combined with anti-VEGF drugs. However, the conventional combination therapy involves intravitreal injection of anticomplement drugs and anti-VEGF drugs, respectively, and there is no dual inhibitor of anticomplement and anti-VEGF yet. Since intravitreal injection is risky and long-term repeated administration leads to relatively poor patient compliance, such combination therapy increases the risk of injection operations and brings huge psychological and economic burdens to patients, so developing a drug that can simultaneously inhibit VEGF and complement has potential clinical value. In addition, complement activation plays an important role in the formation of geographic atrophy, and for patients with wet AMD with geographic atrophy, a fusion protein of both anticomplement and anti-VEGF may have important clinical value.

[0006] WO2013082563A1 discloses a novel fusion protein that inhibits the VEGF pathway and the complement pathway. However, WO2013082563A1 only verifies the activity of the fusion protein in animals, and research on whether it is effective for human AMD disease is still ongoing. Considering the complexity of AMD damage in human eyes, the operational limitations and peculiarities of ocular administration and drug dosage, etc., there is still a need for advanced research and improvement on the method of use and specific plan of such fusion protein for human AMD disease. Summary of the Invention

[0007] 1. Treatment method A first aspect of the invention relates to a method of preventing or treating age-related macular degeneration (AMD) in an individual comprising administering to the individual a fusion protein that inhibits the VEGF pathway and the complement pathway.

[0008] In one embodiment, the fusion protein comprises the sequence of SEQ ID NO:1.

[0009] (Sequence number 1).

[0010] In a preferred embodiment, the sequence of the fusion protein is SEQ ID NO: 1, and for convenience of description, the fusion protein is referred to as IBI302 in this application, and its production method is referred to in WO2013082563A1.

[0011] In one embodiment, the AMD is wet AMD.

[0012] In one embodiment, the wet AMD has one or more symptoms and signs of vision loss, metamorphopsia, central scotoma, dyslexia, macular edema, fundus hemorrhage, neovascularization, cicatricial fibrosis, geographic atrophy, and the like, or any combination thereof.

[0013] In one embodiment, the wet AMD comprises choroid neovascularization (CNV).

[0014] In one embodiment, the wet AMD is AMD characterized by the following: 1) Active subfoveal CNV secondary to wet AMD in the study eye; and / or 2) central foveal thickness of 250 μm or more as determined by optical coherence tomography (OCT) scanning.

[0015] In one embodiment, the individual is a human individual.

[0016] In a preferred embodiment, the individual is a human individual and has a disease, condition and / or trait as described in any one of the above embodiments.

[0017] In a preferred embodiment, the individual is a human individual and is a patient with wet AMD accompanied by geographic atrophy.

[0018] In a preferred embodiment, the individual is afflicted with wet AMD, characterized by the following: 1) Active subfoveal CNV secondary to wet AMD in the study eye; and / or 2) central foveal thickness of 250 μm or more as determined by optical coherence tomography (OCT) scanning. In a preferred embodiment, the treatment comprises administering to an individual: 1) A decrease in central foveal thickness compared to baseline; 2) The area of ​​choroidal neovascularization (CNV) is reduced. 3) improvement in best corrected visual acuity (BCVA) compared to baseline; 4) Delay in onset of geographic atrophy in patients with wet AMD; and / or 5) Delaying the onset of geographic atrophy in patients with wet AMD, and one or more of these effects can be achieved.

[0019] In a preferred embodiment, the treatment comprises administering to an individual: 1) Improve best corrected visual acuity (BCVA), and / or 2) reducing central foveal thickness, and / or 3) Reducing the area of ​​choroidal neovascularization (CNV), one or more of the effects of which can be achieved.

[0020] In a preferred embodiment, the treatment comprises administering to an individual: 1) Best corrected visual acuity (BCVA) is improved by at least one letter on the ETDRS chart compared to a baseline level, preferably by at least 5 letters on the ETDRS chart, more preferably by 5 to 35 letters on the ETDRS chart, for example, by 5 to 25 letters on the ETDRS chart, for example, by 5 to 10 letters, 5 to 15 letters, 5 to 20 letters, 10 to 15 letters, 10 to 20 letters, 10 to 25 letters, characters, 15 to 20 characters, or 15 to 25 characters, for example, 5 characters, 6 characters, 7 characters, 8 characters, 9 characters, 10 characters, 11 characters, 12 characters, 13 characters, 14 characters, 15 characters, 16 characters, 17 characters, 18 characters, 19 characters, 20 characters, 21 characters, 22 characters, 23 characters, 24 characters, 25 characters, 26 characters, 27 characters, 28 characters, 29 characters, 30 characters, 31 characters, 32 characters, 33 characters, 34 characters, or 35 characters, and / or 2) Best corrected visual acuity (BCVA) is improved by 5% or more compared to the baseline level, preferably by 10% or more, for example, 10% to 200%, preferably 10% to 150%, more preferably 10% to 100%, even more preferably 20% to 100%, even more preferably 50% to 100%, 60% to 100%, 20% to 80%, or 30% to 70%, even more preferably 50% to 70%. 0%, more preferably 60% to 70%, for example 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190% or 200% improvement, and / or 3) Central foveal thickness (CST) is reduced by 25 μm or more compared to the baseline level, for example, by 25 μm to 350 μm, preferably by 50 μm to 300 μm, more preferably by 50 μm to 200 μm, for example, by 25 μm, 50 μm, 75 μm, 100 μm, 125 μm, 150 μm, 175 μm, 200 μm, 225 μm, 250 μm, 275 μm, 300 μm, 325 μm a decrease of 5% or more compared to baseline levels, for example, a decrease of 10% to 70%, preferably a decrease of 10% to 60%, more preferably a decrease of 30% to 50%, even more preferably a decrease of 40% to 50%, for example, a decrease of 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65% or 70%, and / or 4) Choroidal neovascularization (CNV) area is reduced by 0.1 mm compared to baseline level 2 For example, 0.1 mm or less 2 ~20mm 2 , preferably 0.2 mm 2 ~5mm 2 , more preferably 0.3 mm 2 ~2mm 2 Decreased, for example, by 0.1 mm 2 , 0.2mm 2 , 0.3mm 2 , 0.4mm 2 , 0.5mm 2 , 0.6mm 2、0.7mm 2 、0.8mm 2 、0.9mm 2 、1mm 2 、1.1mm 2 、1.2mm 2 、1.3mm 2 、1.4mm 2 、1.5mm 2 、1.6mm 2 、1.7mm 2 、1.8mm 2 、1.9mm 2 、2mm 2 、2.1mm 2 、2.2mm 2 、2.3mm 2 、2.4mm 2 、2.5mm 2 、2.6mm 2 、2.7mm 2 、2.8mm 2 、2.9mm 2 、3mm 2 、3.1mm 2 、3.2mm 2 、3.3mm 2 、3.4mm 2 、3.5mm 2 、3.6mm 2 、3.7mm 2 、3.8mm 2 、3.9mm 2 、4mm 2 、4.1mm 2 、4.2mm 2 、4.3mm 2 、4.4mm 2 、4.5mm 2 、4.6mm 2 、4.7mm 2 、4.8mm 2 、4.9mm 2 、5mm 2 、5.5mm 2 、6mm 2 、6.5mm 2 、7mm 2 、7.5mm 2 、8mm 2 、8.5mm 2 、9mm 2 、9.5mm 2 、10mm2 , 10.5mm 2 , 11mm 2 , 11.5mm 2 , 12mm 2 , 12.5mm 2 , 13mm 2 , 13.5mm 2 , 14mm 2 , 14.5mm 2 , 15mm 2 , 15.5mm 2 , 16mm 2 , 16.5mm 2 , 17mm 2 , 17.5mm 2 , 18mm 2 , 18.5mm 2 , 19mm 2 , 19.5mm 2 Or 20mm 2 One or more of the following effects can be achieved: a decrease, or a decrease of 5% or more compared to baseline levels, for example, a 10% to 70%, preferably a 10% to 60%, more preferably a 30% to 50%, and even more preferably a 40% to 50%, for example, a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65% or 70% decrease.

[0021] In some embodiments, the fusion protein of the present invention is formulated and administered as a liquid pharmaceutical composition. Usable carriers and solvents include water, Ringer's solution, phosphate buffered saline, isotonic sodium chloride solution, etc. In addition, sterile non-volatile oils can be used as a solvent or suspension medium in some cases. For this purpose, any mixed non-volatile mineral oils or non-mineral oils, including synthetic monoglycerides or diglycerides, can be used. In addition, fatty acids such as oleic acid can be used to prepare injections.

[0022] In some embodiments, the pharmaceutical composition comprising the fusion protein of the present invention is a solution or dry powder formulation for injection. For example, the composition is a lyophilized powder, which can be reconstituted in a pharmaceutically acceptable liquid carrier to form an injection solution. The pharmaceutically acceptable liquid carrier can be, for example, sterile water, Ringer's solution, phosphate buffered saline, isotonic sodium chloride solution, etc.

[0023] In some embodiments, the fusion proteins of the invention are administered locally.

[0024] In some embodiments, the fusion proteins of the invention are administered by intravenous injection.

[0025] In some embodiments, the fusion proteins of the invention are administered intralesionally.

[0026] In some embodiments, a pharmaceutical composition comprising a fusion protein of the invention is administered directly to the eye or ocular tissue, hi some embodiments, the pharmaceutical composition is administered topically to the eye.

[0027] In some embodiments, the pharmaceutical composition is administered by injection into the eye (intraocular injection) or into tissues related to the eye. For example, the composition is administered by intraocular injection, periocular injection, subretinal injection, intravitreal injection, transseptal injection, subscleral injection, intrachoroidal injection, intracameral injection, subconjunctival injection, subtenon injection, retrobulbar injection, peribulbar injection, or posterior juxtascleral delivery. Also, for example, the composition is administered into the vitreous, optic nerve, aqueous humor, sclera, conjunctiva, the area between the sclera and conjunctiva, retina-choroidal tissue, macula, or other areas in or near the eye of an individual. Preferably, the composition is administered by intravitreal injection.

[0028] In some embodiments, the administration frequency of the fusion protein of the present invention is 3 times a day, 2 times a day, 1 time a day, 1 time every 2 days, 2 times a week, 1 time a week, 1 time every 2 weeks, 1 time every 4 weeks, 1 time every 5 weeks, 1 time every 6 weeks, 1 time every 7 weeks, 1 time every 8 weeks, or 1 time a month, 1 time every 2 months, or longer. The administration period of the fusion protein of the present invention can be 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, or longer, and the interval between each administration period can be the same or different. In a preferred embodiment, each administration period is administered once or twice, preferably once, and the administration method is to administer on the first day of each period.

[0029] In each of the above embodiments, the single administration dose of the fusion protein of the present invention may be selected from 0.01 mg / eye to 10 mg / eye, preferably 0.05 mg / eye to 8 mg / eye, more preferably 0.05 mg / eye to 6 mg / eye, even more preferably 0.5 mg / eye to 5 mg / eye, even more preferably 1 mg / eye to 5 mg / eye, and even more preferably 2 mg / eye to 5 mg / eye, for example, 0.5 mg / eye to 2 mg / eye, 1 mg / eye to 3 mg / eye, 2 mg / eye to 4 mg / eye, 2 mg / eye to 3 mg / eye, or 3 mg / eye to 5 mg / eye, for example, 0.05 mg / eye, 0.1mg / eye, 0.15mg / eye, 0.2mg / eye, 0.25mg / eye, 0.3mg / eye, 0.35mg / eye, 0.4mg / eye, 0.45mg / eye, 0.5mg / eye, 0.55mg / eye, 0.6mg / eye, 0.65mg / eye, 0.7mg / eye, 0.75mg / eye, 0.8mg / eye, 0.85mg / eye, 0.9mg / eye, 0.95mg / eye, 1mg / eye, 1.1mg / eye, 1.2mg / eye, 1.3mg / eye, 1.4mg / eye, 1.5mg / eye, 1.6mg / eye, 1.7mg / eye, 1.8mg / eye, 1.9mg / eye, 2mg / eye, 2.1mg / eye, 2.2mg / eye, 2.3mg / eye, 2.4mg / eye, 2.5mg / eye, 2.6mg / eye, 2.7mg / eye, 2.8mg / eye, 2.9mg / eye, 3mg / eye, 3.1mg / eye, 3.2mg / eye, 3.3mg / eye, 3.4mg / eye, 3.5mg / eye, 3.6 mg / eye, 3.7mg / eye, 3.8mg / eye, 3.9mg / eye, 4mg / eye, 4.1mg / eye, 4.2mg / eye, 4.3mg / eye, 4.4mg / eye, 4.5mg / eye, 4.6mg / eye, 4.7mg / eye, 4.8mg / eye, 4.9mg / eye, 5mg / eye, 5.1mg / eye, 5.2mg / eye, 5.3mg / eye, 5.4mg / eye, 5.5mg / eye, 5.6mg / eye, 5.7mg / eye, 5.8mg / eye, 5.9mg / eye, 6mg / eye, 6.1mg / eye, 6.2mg / eye, 6.3mg / eye, 6.4mg / eye, 6.5mg / eye, 6.6mg / eye, 6.7 mg / eye, 6.8mg / eye, 6.9mg / eye, 7mg / eye, 7.1mg / eye, 7.2mg / eye, 7.3mg / eye, 7.4mg / eye, 7.5mg / eye, 7.6mg / eye, 7.7mg / eye, 7.8mg / eye, 7.9mg / eye, 8mg / eye, 8.5mg / eye, 9mg / eye, 9.The dosage is preferably 5 mg / eye, 10 mg / eye, and preferably 2 mg / eye or 4 mg / eye. The dosage is preferably administered by administering the pharmaceutical composition comprising the fusion protein of the present invention directly to the eye or ocular tissue, for example, by administering the pharmaceutical composition topically to the eye, or by injecting the pharmaceutical composition into the eye (intraocular injection) or into tissues related to the eye, for example, by administering the liquid composition by intraocular injection, periocular injection, subretinal injection, intravitreal injection, transseptal injection, subscleral injection, intrachoroidal injection, intracameral injection, subconjunctival injection, sub-Tenon injection, retrobulbar injection, peribulbar injection, or posterior juxtascleral delivery. Also, for example, the composition is administered to the vitreous, optic nerve, aqueous humor, sclera, conjunctiva, the area between the sclera and conjunctiva, retina-choroidal tissue, macula, or other areas in or near the eye of an individual. Preferably, it is administered by intravitreal injection.

[0030] In some embodiments, the fusion protein of the present invention or a pharmaceutical composition thereof may be administered alone or in combination with other drugs at the same time.

[0031] In some embodiments of the above method, the individual's foveal retinal thickness level is reduced by 25 μm or more, for example, by 25 μm to 350 μm, preferably by 50 μm to 300 μm, more preferably by 50 μm to 200 μm, at 2 weeks, 3 weeks, or 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 3 months, 4 months, or 5 months after administration, compared to the pre-administration level of the individual's foveal retinal thickness. A decrease of 5 μm, 100 μm, 125 μm, 150 μm, 175 μm, 200 μm, 225 μm, 250 μm, 275 μm, 300 μm, 325 μm, 350 μm, or a decrease of 5% or more compared to the level before administration, for example, a decrease of 10% to 70%, preferably 10% to 60%, more preferably 30% to 50%, even more preferably 40% to 50%, for example, a decrease of 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65% or 70%.

[0032] In some embodiments of the above method, the area of ​​choroidal neovascularization (CNV) of the individual is reduced by 0.1 mm or less at 2 weeks, 3 weeks, or 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 3 months, 4 months, or 5 months after administration, compared to a pre-administration level of the area of ​​CNV of the individual. 2 For example, 0.1 mm or less 2 ~20mm 2 , preferably 0.2 mm 2 ~5mm 2 , more preferably 0.3 mm 2 ~2mm 2 Decreased, for example, by 0.1 mm 2 , 0.2mm 2 , 0.3mm 2 , 0.4mm 2 , 0.5mm 2 , 0.6mm 2 , 0.7mm 2 , 0.8mm 2 , 0.9mm 2 , 1mm 2 , 1.1mm 2 , 1.2mm 2 , 1.3mm 2 , 1.4mm 2 , 1.5mm 2 , 1.6mm 2 , 1.7mm 2 , 1.8mm 2 , 1.9mm 2 , 2mm 2 , 2.1mm 2 , 2.2mm 2 , 2.3mm 2 , 2.4mm 2 , 2.5mm 2 , 2.6mm 2 , 2.7mm 2 , 2.8mm 2 , 2.9mm 2 , 3mm 2 , 3.1mm 2 , 3.2mm 2 , 3.3mm 2 , 3.4mm 2 , 3.5mm 2 , 3.6mm 2 , 3.7mm2 , 3.8mm 2 , 3.9mm 2 , 4mm 2 , 4.1mm 2 , 4.2mm 2 , 4.3mm 2 , 4.4mm 2 , 4.5mm 2 , 4.6mm 2 , 4.7mm 2 , 4.8mm 2 , 4.9mm 2 , 5mm 2 , 5.5mm 2 , 6mm 2 , 6.5mm 2 , 7mm 2 , 7.5mm 2 , 8mm 2 , 8.5mm 2 , 9mm 2 , 9.5mm 2 , 10mm 2 , 10.5mm 2 , 11mm 2 , 11.5mm 2 , 12mm 2 , 12.5mm 2 , 13mm 2 , 13.5mm 2 , 14mm 2 , 14.5mm 2 , 15mm 2 , 15.5mm 2 , 16mm 2 , 16.5mm 2 , 17mm 2 , 17.5mm 2 , 18mm 2 , 18.5mm 2 , 19mm 2 , 19.5mm 2 Or 20mm 2 It is decreased, or decreased by 5% or more compared to the pre-administration level, for example, 10% to 70%, preferably 10% to 60%, more preferably 30% to 50%, and even more preferably 40% to 50%, for example, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65% or 70% decreased.

[0033] In some embodiments of the above methods, the subject's best corrected visual acuity (BCVA) is improved by at least one letter on the ETDRS chart, preferably by at least five letters on the ETDRS chart, and more preferably at least two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, nine weeks, ten weeks, three months, four months, or five months after administration, compared to a pre-administration level of the individual's BCVA. Preferably, the improvement is 5 to 35 letters on the ETDRS visual acuity chart, for example, 5 to 25 letters on the ETDRS visual acuity chart, for example, 5 to 10 letters, 5 to 15 letters, 5 to 20 letters, 10 to 15 letters, 10 to 20 letters, 10 to 25 letters, 15 to 20 letters, or 15 to 25 letters, for example, 5 letters, 6 letters, 7 letters, 8 letters, 9 letters, 10 letters, 11 letters, 12 letters, 13 letters, 14 letters, 15 letters, 16 letters, 17 ... 1, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 characters, or improved by 5% or more compared to the pre-administration level, preferably improved by 10% or more, for example, 10% to 200%, preferably 10% to 150%, more preferably 10% to 100%, even more preferably 20% to 100%, and even more preferably 50%. An improvement of up to 100%, 60% to 100%, 20% to 80% or 30% to 70%, more preferably 50% to 70%, and even more preferably 60% to 70%, for example, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190% or 200%.

[0034] In some embodiments of the above methods, following administration, the individual does not experience a serious adverse event.

[0035] In some embodiments of the above methods, following administration, the individual has an adverse event rate comparable to individuals receiving a placebo.

[0036] In some embodiments of the above methods, the individual is a human.

[0037] In some specific embodiments of the above method, the method comprises administering the fusion protein at a dose of about 0.01 mg / eye to 10 mg / eye, preferably 0.05 mg / eye to 8 mg / eye, more preferably 0.05 mg / eye to 6 mg / eye, still more preferably 0.5 mg / eye to 5 mg / eye, still more preferably 1 mg / eye to 5 mg / eye, still more preferably 2 mg / eye to 5 mg / eye, for example, 0.5 mg / eye to 2 mg / eye, 1 mg / eye to 3 mg / eye, 2 mg / eye to 4 mg / eye, 2 mg / eye to 3 mg / eye or 3 mg / eye to 5 mg / eye, for example, 0.05 mg / eye, 0.1 mg / eye, 0.15 mg / eye, 0.2 mg / eye, 0.25 mg / eye, 0.3 mg / eye, 0.35 mg / eye, 0.4 mg / eye, 0.45 mg / eye, 0.5 mg / eye, 0.55 mg / eye, 0.6 mg / eye, 0.65 mg / eye, 0.7 mg / eye, 0.75 mg / eye, 0.8 mg / eye, 0.85 mg / eye, 0.9 mg / eye, 0.95 mg / eye, 1 mg / eye, 1.1 mg / eye, 1.2 mg / eye, 1.3 mg / eye, 1.4 mg / eye, 1.5 mg / eye, 1.6 mg / eye, 1.7 mg / eye, 1.8 mg / eye, 1.9 mg / eye, 2 mg / eye, 2.1 mg / eye, 2.2 mg / eye, 2.3 mg / eye, 2.4 mg / eye, 2.5 mg / eye, 2.6 mg / eye, 2.7 mg / eye, 2.8 mg / eye, 2.9 mg / eye, 3 mg / eye, 3.1 mg / eye, 3.2 mg / eye, 3.3 mg / eye, 3.4 mg / eye, 3.5 mg / eye, 3.6 mg / eye, 3.7 mg / eye, 3.8 mg / eye, 3.9 mg / eye, 4 mg / eye, 4.1 mg / eye, 4.2 mg / eye, 4.3 mg / eye, 4.4 mg / eye, 4.5 mg / eye, 4.6 mg / eye, 4.7 mg / eye, 4.8 mg / eye, 4.9 mg / eye, 5 mg / eye, 5.1 mg / eye, 5.2 mg / eye, 5.3 mg / eye, 5.4 mg / eye, 5.5 mg / eye, 5.6 mg / eye, 5.7 mg / eye, 5.8 mg / eye, 5.9 mg / eye, 6 mg / eye, 6.1 mg / eye, 6.2 mg / eye, 6.3 mg / eye, 6.4 mg / eye, 6.5 mg / eye, 6.6 mg / eye, 6.7 mg / eye, 6.8 mg / eye, 6.9 mg / eye, 7 mg / eye, 7.1 mg / eye, 7.2 mg / eye, 7.3 mg / eye, 7.4 mg / eye, 7.5 mg / eye, 7.6 mg / eye, 7.7 mg / eye, 7.8 mg / eye, 7.9 mg / eye, 8 mg / eye, 8.5 mg / eye, 9 mg / eye, 9.The method includes intravitreally or intravenously administering to the individual a single dose of 5 mg / eye, 10 mg / eye, preferably 2 mg / eye or 4 mg / eye, once a day, once every two days, twice a week, once a week, once every two weeks, once every four weeks, once every five weeks, or once every six weeks, wherein, compared to the individual's pre-administration level of the foveal retinal thickness, 6 or 8 weeks after administration, the individual's foveal retinal thickness level is reduced by 25 μm or more, for example, 25 μm to 350 μm, preferably 50 μm to 300 μm, more preferably 50 μm to 200 μm. The level is decreased, for example, by 25 μm, 50 μm, 75 μm, 100 μm, 125 μm, 150 μm, 175 μm, 200 μm, 225 μm, 250 μm, 275 μm, 300 μm, 325 μm, or 350 μm, or by 5% or more compared to the level before administration, for example, by 10% to 70%, preferably 10% to 60%, more preferably 30% to 50%, and even more preferably 40% to 50%, for example, by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70%.

[0038] In some specific embodiments of the above method, the method comprises administering the fusion protein at about 0.01 mg / eye to 10 mg / eye, preferably 0.05 mg / eye to 8 mg / eye, more preferably 0.05 mg / eye to 6 mg / eye, still more preferably 0.5 mg / eye to 5 mg / eye, still more preferably 1 mg / eye to 5 mg / eye, still more preferably 2 mg / eye to 5 mg / eye, for example, 0.5 mg / eye to 2 mg / eye, 1 mg / eye to 3 mg / eye, 2 mg / eye to 4 mg / eye, 2 mg / eye to 3 mg / eye or 3 mg / eye to 5 mg / eye, for example, 0.05 mg / eye, 0.1 mg / eye, 0.15 mg / eye, 0.2 mg / eye, 0.25 mg / eye, 0.3 mg / eye, 0.35 mg / eye, 0.4 mg / eye, 0.45 mg / eye, 0.5 mg / eye, 0.55 mg / eye, 0.6 mg / eye, 0.65 mg / eye, 0.7 mg / eye, 0.75 mg / eye, 0.8 mg / eye, 0.85 mg / eye, 0.9 mg / eye, 0.95 mg / eye, 1 mg / eye, 1.1 mg / eye, 1.2 mg / eye, 1.3 mg / eye, 1.4 mg / eye, 1.5 mg / eye, 1.6 mg / eye, 1.7 mg / eye, 1.8 mg / eye, 1.9 mg / eye, 2 mg / eye, 2.1 mg / eye, 2.2 mg / eye, 2.3 mg / eye, 2.4 mg / eye, 2.5 mg / eye, 2.6 mg / eye, 2.7 mg / eye, 2.8 mg / eye, 2.9 mg / eye, 3 mg / eye, 3.1 mg / eye, 3.2 mg / eye, 3.3 mg / eye, 3.4 mg / eye, 3.5 mg / eye, 3.6 mg / eye, 3.7 mg / eye, 3.8 mg / eye, 3.9 mg / eye, 4 mg / eye, 4.1 mg / eye, 4.2 mg / eye, 4.3 mg / eye, 4.4 mg / eye, 4.5 mg / eye, 4.6 mg / eye, 4.7 mg / eye, 4.8 mg / eye, 4.9 mg / eye, 5 mg / eye, 5.1 mg / eye, 5.2 mg / eye, 5.3 mg / eye, 5.4 mg / eye, 5.5 mg / eye, 5.6 mg / eye, 5.7 mg / eye, 5.8 mg / eye, 5.9 mg / eye, 6 mg / eye, 6.1 mg / eye, 6.2 mg / eye, 6.3 mg / eye, 6.4 mg / eye, 6.5 mg / eye, 6.6 mg / eye, 6.7 mg / eye, 6.8 mg / eye, 6.9 mg / eye, 7 mg / eye, 7.1 mg / eye, 7.2 mg / eye, 7.3 mg / eye, 7.4 mg / eye, 7.5 mg / eye, 7.6 mg / eye, 7.7 mg / eye, 7.8 mg / eye, 7.9 mg / eye, 8 mg / eye, 8.5 mg / eye, 9 mg / eye, 9.The method comprises administering intravitreally or intravenously to the individual a single dose of 5 mg / eye, 10 mg / eye, preferably 2 mg / eye or 4 mg / eye, once per day, once every two days, twice per week, once per week, once every two weeks, once per four weeks, once per five weeks, or once per six weeks, wherein the area of ​​choroidal neovascularization (CNV) in the individual is reduced by 0.1 mm 6 or 8 weeks after administration compared to the pre-administration level of the area of ​​CNV in the individual. 2 For example, 0.1 mm or less 2 ~20mm 2 , preferably 0.2 mm 2 ~5mm 2 , more preferably 0.3 mm 2 ~2mm 2 Decreased, for example, by 0.1 mm 2 , 0.2mm 2 , 0.3mm 2 , 0.4mm 2 , 0.5mm 2 , 0.6mm 2 , 0.7mm 2 , 0.8mm 2 , 0.9mm 2 , 1mm 2 , 1.1mm 2 , 1.2mm 2 , 1.3mm 2 , 1.4mm 2 , 1.5mm 2 , 1.6mm 2 , 1.7mm 2 , 1.8mm 2 , 1.9mm 2 , 2mm 2 , 2.1mm 2 , 2.2mm 2 , 2.3mm 2 , 2.4mm 2 , 2.5mm 2 , 2.6mm 2 , 2.7mm 2 , 2.8mm 2 , 2.9mm 2 , 3mm 2 , 3.1mm 2 , 3.2mm 2 , 3.3mm 2 , 3.4mm 2 , 3.5mm 2, 3.6mm 2 , 3.7mm 2 , 3.8mm 2 , 3.9mm 2 , 4mm 2 , 4.1mm 2 , 4.2mm 2 , 4.3mm 2 , 4.4mm 2 , 4.5mm 2 , 4.6mm 2 , 4.7mm 2 , 4.8mm 2 , 4.9mm 2 , 5mm 2 , 5.5mm 2 , 6mm 2 , 6.5mm 2 , 7mm 2 , 7.5mm 2 , 8mm 2 , 8.5mm 2 , 9mm 2 , 9.5mm 2 , 10mm 2 , 10.5mm 2 , 11mm 2 , 11.5mm 2 , 12mm 2 , 12.5mm 2 , 13mm 2 , 13.5mm 2 , 14mm 2 , 14.5mm 2 , 15mm 2 , 15.5mm 2 , 16mm 2 , 16.5mm 2 , 17mm 2 , 17.5mm 2 , 18mm 2 , 18.5mm 2 , 19mm 2 , 19.5mm 2 Or 20mm 2 It is decreased, or decreased by 5% or more compared to the pre-administration level, for example, 10% to 70%, preferably 10% to 60%, more preferably 30% to 50%, and even more preferably 40% to 50%, for example, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65% or 70% decreased.

[0039] In some specific embodiments of the above method, the method comprises administering the fusion protein at about 0.01 mg / eye to 10 mg / eye, preferably 0.05 mg / eye to 8 mg / eye, more preferably 0.05 mg / eye to 6 mg / eye, even more preferably 0.5 mg / eye to 5 mg / eye, even more preferably 1 mg / eye to 5 mg / eye, even more preferably 2 mg / eye to 5 mg / eye, for example, 0.5 mg / eye to 2 mg / eye, 1 mg / eye to 3 mg / eye, 2 mg / eye to 4 mg / eye, 2 mg / eye to 3 mg / eye or 3 mg / eye to 5 mg / eye, for example, 0.05 mg / eye, 0.1 mg / eye, 0.15 mg / eye, 0.2 mg / eye, 0.25 mg / eye, 0.3 mg / eye, 0.35 mg / eye, 0.4 mg / eye, 0.45 mg / eye, 0.5 mg / eye, 0.55 mg / eye, 0.6 mg / eye, 0.65 mg / eye, 0.7 mg / eye, 0.75 mg / eye, 0.8 mg / eye, 0.85 mg / eye, 0.9 mg / eye, 0.95 mg / eye, 1 mg / eye, 1.1 mg / eye, 1.2 mg / eye, 1.3 mg / eye, 1.4 mg / eye, 1.5 mg / eye, 1.6 mg / eye, 1.7 mg / eye, 1.8 mg / eye, 1.9 mg / eye, 2 mg / eye, 2.1 mg / eye, 2.2 mg / eye, 2.3 mg / eye, 2.4 mg / eye, 2.5 mg / eye, 2.6 mg / eye, 2.7 mg / eye, 2.8 mg / eye, 2.9 mg / eye, 3 mg / eye, 3.1 mg / eye, 3.2 mg / eye, 3.3 mg / eye, 3.4 mg / eye, 3.5 mg / eye, 3.6 mg / eye, 3.7 mg / eye, 3.8 mg / eye, 3.9 mg / eye, 4 mg / eye, 4.1 mg / eye, 4.2 mg / eye, 4.3 mg / eye, 4.4 mg / eye, 4.5 mg / eye, 4.6 mg / eye, 4.7 mg / eye, 4.8 mg / eye, 4.9 mg / eye, 5 mg / eye, 5.1 mg / eye, 5.2 mg / eye, 5.3 mg / eye, 5.4 mg / eye, 5.5 mg / eye, 5.6 mg / eye, 5.7 mg / eye, 5.8 mg / eye, 5.9 mg / eye, 6 mg / eye, 6.1 mg / eye, 6.2 mg / eye, 6.3 mg / eye, 6.4 mg / eye, 6.5 mg / eye, 6.6 mg / eye, 6.7 mg / eye, 6.8 mg / eye, 6.9 mg / eye, 7 mg / eye, 7.1 mg / eye, 7.2 mg / eye, 7.3 mg / eye, 7.4 mg / eye, 7.5 mg / eye, 7.6 mg / eye, 7.7 mg / eye, 7.8 mg / eye, 7.9 mg / eye, 8 mg / eye, 8.5 mg / eye, 9 mg / eye, 9.and administering intravitreally or intravenously to said individual a single dose of 5 mg / eye, 10 mg / eye, preferably 2 mg / eye or 4 mg / eye, once daily, once every two days, twice weekly, once weekly, once every two weeks, once every four weeks, once every five weeks, or once every six weeks, wherein the individual's best corrected visual acuity (BCVA) is improved by at least one letter on the ETDRS visual acuity chart 6 or 8 weeks after administration compared to the individual's pre-administration level of BCVA, and preferably the ETDRS visual acuity chart 6 or 8 weeks after administration. The improvement is at least 5 letters on the RS visual acuity chart, more preferably 5 to 35 letters on the ETDRS visual acuity chart, for example, 5 to 25 letters on the ETDRS visual acuity chart, for example, 5 to 10 letters, 5 to 15 letters, 5 to 20 letters, 10 to 15 letters, 10 to 20 letters, 10 to 25 letters, 15 to 20 letters, or 15 to 25 letters, for example, 5 letters, 6 letters, 7 letters, 8 letters, 9 letters, 10 letters, 11 letters, 12 letters, 13 letters, 1 4 letters, 15 letters, 16 letters, 17 letters, 18 letters, 19 letters, 20 letters, 21 letters, 22 letters, 23 letters, 24 letters, 25 letters, 26 letters, 27 letters, 28 letters, 29 letters, 30 letters, 31 letters, 32 letters, 33 letters, 34 letters, or 35 letters improved, or improved by 5% or more compared to the level before administration, preferably improved by 10% or more, for example, 10% to 200%, preferably 10% to 150%, more preferably 10% to 100%, even more preferably 20% to 100%, and even more preferably The improvement is preferably 50% to 100%, 60% to 100%, 20% to 80% or 30% to 70%, more preferably 50% to 70%, and even more preferably 60% to 70%, for example, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190% or 200%.

[0040] 2. Use A second aspect of the invention relates to the use of a fusion protein that inhibits the VEGF pathway and the complement pathway in the manufacture of a medicament for preventing or treating age-related macular degeneration (AMD) in an individual.

[0041] A third aspect of the invention relates to a fusion protein that inhibits the VEGF pathway and the complement pathway for preventing or treating age-related macular degeneration (AMD) in an individual.

[0042] The second and third aspects are further limited as follows:

[0043] In one embodiment, the fusion protein comprises the sequence of SEQ ID NO:1.

[0044] (Sequence number 1).

[0045] In a preferred embodiment, the sequence of the fusion protein is SEQ ID NO: 1, and for convenience of description, the fusion protein is referred to as IBI302 in this application, and its production method is referred to in WO2013082563A1.

[0046] In one embodiment, the AMD is wet AMD.

[0047] In one embodiment, the wet AMD has one or more symptoms and signs of reduced vision, metamorphopsia, central scotoma, dyslexia, macular edema, fundus hemorrhage, neovascularization, cicatricial fibrosis, geographic atrophy, or any combination thereof.

[0048] In one embodiment, the wet AMD comprises choroidal neovascularization (CNV).

[0049] In one embodiment, the wet AMD is AMD characterized by: 1) Active subfoveal CNV secondary to wet AMD in the study eye; and / or 2) central foveal thickness of 250 μm or greater as determined by optical coherence tomography (OCT) scanning.

[0050] In one embodiment, the individual is a human individual.

[0051] In a preferred embodiment, the individual is a human individual and has a disease, condition and / or trait as described in any one of the above embodiments.

[0052] In a preferred embodiment, the individual is a human individual and is a patient with wet AMD accompanied by geographic atrophy.

[0053] In a preferred embodiment, the individual is afflicted with wet AMD, characterized by the following: 1) Active subfoveal CNV secondary to wet AMD in the study eye; and / or 2) central foveal thickness of 250 μm or more as determined by optical coherence tomography (OCT) scanning.

[0054] In a preferred embodiment, the treatment comprises administering to an individual: 1) A decrease in central foveal thickness compared to baseline; 2) The area of ​​choroidal neovascularization (CNV) is reduced. 3) improvement in best corrected visual acuity (BCVA) compared to baseline; 4) Delay in onset of geographic atrophy in patients with wet AMD; and / or 5) Delaying the onset of geographic atrophy in patients with wet AMD, and one or more of these effects can be achieved.

[0055] In a preferred embodiment, the treatment comprises administering to an individual: 1) Improve best corrected visual acuity (BCVA), 2) reducing central foveal thickness, and / or 3) Reducing the area of ​​choroidal neovascularization (CNV), one or more of the effects of which can be achieved.

[0056] In a preferred embodiment, the treatment comprises administering to an individual: 1) Best corrected visual acuity (BCVA) is improved by at least one letter on the ETDRS chart compared to a baseline level, preferably by at least 5 letters on the ETDRS chart, more preferably by 5 to 35 letters on the ETDRS chart, for example, by 5 to 25 letters on the ETDRS chart, for example, by 5 to 10 letters, 5 to 15 letters, 5 to 20 letters, 10 to 15 letters, 10 to 20 letters, 10 to 25 letters, characters, 15 to 20 characters, or 15 to 25 characters, for example, 5 characters, 6 characters, 7 characters, 8 characters, 9 characters, 10 characters, 11 characters, 12 characters, 13 characters, 14 characters, 15 characters, 16 characters, 17 characters, 18 characters, 19 characters, 20 characters, 21 characters, 22 characters, 23 characters, 24 characters, 25 characters, 26 characters, 27 characters, 28 characters, 29 characters, 30 characters, 31 characters, 32 characters, 33 characters, 34 characters, or 35 characters, and / or 2) Best corrected visual acuity (BCVA) is improved by 5% or more compared to the baseline level, preferably by 10% or more, for example, 10% to 200%, preferably 10% to 150%, more preferably 10% to 100%, even more preferably 20% to 100%, even more preferably 50% to 100%, 60% to 100%, 20% to 80%, or 30% to 70%, even more preferably 50% to 70%. 0%, more preferably 60% to 70%, for example 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190% or 200% improvement, and / or 3) Central foveal thickness (CST) is reduced by 25 μm or more compared to the baseline level, for example, by 25 μm to 350 μm, preferably by 50 μm to 300 μm, more preferably by 50 μm to 200 μm, for example, by 25 μm, 50 μm, 75 μm, 100 μm, 125 μm, 150 μm, 175 μm, 200 μm, 225 μm, 250 μm, 275 μm, 300 μm, 325 μm a decrease of 5% or more compared to baseline levels, for example, a decrease of 10% to 70%, preferably a decrease of 10% to 60%, more preferably a decrease of 30% to 50%, even more preferably a decrease of 40% to 50%, for example, a decrease of 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65% or 70%, and / or 4) Choroidal neovascularization (CNV) area is reduced by 0.1 mm compared to baseline level 2 For example, 0.1 mm or less 2 ~20mm 2 , preferably 0.2 mm 2 ~5mm 2 , more preferably 0.3 mm 2 ~2mm 2 Decreased, for example, by 0.1 mm 2 , 0.2mm 2 , 0.3mm 2 , 0.4mm 2 , 0.5mm 2 , 0.6mm 2 , 0.7mm 2 , 0.8mm 2 , 0.9mm 2 , 1mm 2 , 1.1mm 2 , 1.2mm 2 , 1.3mm 2 , 1.4mm 2 , 1.5mm 2 , 1.6mm 2 , 1.7mm 2 , 1.8mm 2 , 1.9mm 2 , 2mm 2 , 2.1mm 2 , 2.2mm 2 , 2.3mm 2 , 2.4mm 2 , 2.5mm 2、2.6mm 2 、2.7mm 2 、2.8mm 2 、2.9mm 2 、3mm 2 、3.1mm 2 、3.2mm 2 、3.3mm 2 、3.4mm 2 、3.5mm 2 、3.6mm 2 、3.7mm 2 、3.8mm 2 、3.9mm 2 、4mm 2 、4.1mm 2 、4.2mm 2 、4.3mm 2 、4.4mm 2 、4.5mm 2 、4.6mm 2 、4.7mm 2 、4.8mm 2 、4.9mm 2 、5mm 2 、5.5mm 2 、6mm 2 、6.5mm 2 、7mm 2 、7.5mm 2 、8mm 2 、8.5mm 2 、9mm 2 、9.5mm 2 、10mm 2 、10.5mm 2 、11mm 2 、11.5mm 2 、12mm 2 、12.5mm 2 、13mm 2 、13.5mm 2 、14mm 2 、14.5mm 2 、15mm 2 、15.5mm 2 、16mm 2 、16.5mm 2 、17mm 2 、17.5mm 2 、18mm 2 、18.5mm 2 、19mm 2 、19.5mm2 Or 20mm 2 One or more of the following effects can be achieved: a decrease, or a decrease of 5% or more compared to baseline levels, for example, a 10% to 70%, preferably a 10% to 60%, more preferably a 30% to 50%, and even more preferably a 40% to 50%, for example, a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65% or 70% decrease.

[0057] In some embodiments, the administration frequency of the fusion protein of the present invention is 3 times a day, 2 times a day, 1 time a day, 1 time every 2 days, 2 times a week, 1 time a week, 1 time every 2 weeks, 1 time every 4 weeks, 1 time every 5 weeks, 1 time every 6 weeks, 1 time every 7 weeks, 1 time every 8 weeks, or 1 time a month, 1 time every 2 months, or longer. The administration period of the fusion protein of the present invention can be 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, or longer, and the intervals of each administration period can be the same or different. In a preferred embodiment, each administration period is administered once or twice, preferably once, and the administration method is to administer on the first day of each period.

[0058] In each of the above embodiments, the single administration dose of the fusion protein of the present invention is selected from 0.01 mg / eye to 10 mg / eye, preferably 0.05 mg / eye to 8 mg / eye, more preferably 0.05 mg / eye to 6 mg / eye, even more preferably 0.5 mg / eye to 5 mg / eye, even more preferably 1 mg / eye to 5 mg / eye, and still more preferably 2 mg / eye to 5 mg / eye, for example, 0.5 mg / eye to 2 mg / eye, 1 mg / eye to 3 mg / eye, 2 mg / eye to 4 mg / eye, 2 mg / eye to 3 mg / eye, or 3 mg / eye to 5 mg / eye, for example, 0.05 mg / eye Eye, 0.1mg / eye, 0.15mg / eye, 0.2mg / eye, 0.25mg / eye, 0.3mg / eye, 0.35mg / eye, 0.4mg / eye, 0.45mg / eye, 0.5mg / eye, 0.55mg / eye, 0.6mg / eye, 0.65mg / eye, 0.7mg / eye, 0.75mg / eye , 0.8mg / eye, 0.85mg / eye, 0.9mg / eye, 0.95mg / eye, 1mg / eye, 1.1mg / eye, 1.2mg / eye, 1.3mg / eye, 1.4mg / eye, 1.5mg / eye, 1.6mg / eye, 1.7mg / eye, 1.8mg / eye, 1.9mg / eye, 2mg / eye, 2. 1mg / eye, 2.2mg / eye, 2.3mg / eye, 2.4mg / eye, 2.5mg / eye, 2.6mg / eye, 2.7mg / eye, 2.8mg / eye, 2.9mg / eye, 3mg / eye, 3.1mg / eye, 3.2mg / eye, 3.3mg / eye, 3.4mg / eye, 3.5mg / eye, 3.6m g / eye, 3.7mg / eye, 3.8mg / eye, 3.9mg / eye, 4mg / eye, 4.1mg / eye, 4.2mg / eye, 4.3mg / eye, 4.4mg / eye, 4.5mg / eye, 4.6mg / eye, 4.7mg / eye, 4.8mg / eye, 4.9mg / eye, 5mg / eye, 5.1mg / eye, 5 .2mg / eye, 5.3mg / eye, 5.4mg / eye, 5.5mg / eye, 5.6mg / eye, 5.7mg / eye, 5.8mg / eye, 5.9mg / eye, 6mg / eye, 6.1mg / eye, 6.2mg / eye, 6.3mg / eye, 6.4mg / eye, 6.5mg / eye, 6.6mg / eye, 6.7 mg / eye, 6.8mg / eye, 6.9mg / eye, 7mg / eye, 7.1mg / eye, 7.2mg / eye, 7.3mg / eye, 7.4mg / eye, 7.5mg / eye, 7.6mg / eye, 7.7mg / eye, 7.8mg / eye, 7.9mg / eye, 8mg / eye, 8.5mg / eye, 9mg / eye, 9.The dose is 5 mg / eye, 10 mg / eye, and preferably 2 mg / eye or 4 mg / eye.

[0059] In some embodiments, the fusion protein of the present invention or a pharmaceutical composition thereof may be administered alone or in combination with other drugs at the same time.

[0060] In some embodiments, the individual's foveal retinal thickness level is reduced by 25 μm or more, for example, by 25 μm to 350 μm, preferably by 50 μm to 300 μm, more preferably by 50 μm to 200 μm, for example, by 25 μm, 50 μm, 75 μm, or 80 μm, at 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 3 months, 4 months, or 5 months after administration, compared to the pre-administration level of the individual's foveal retinal thickness. , 100 μm, 125 μm, 150 μm, 175 μm, 200 μm, 225 μm, 250 μm, 275 μm, 300 μm, 325 μm, 350 μm, or a decrease of 5% or more compared to the pre-administration level, for example, a decrease of 10% to 70%, preferably 10% to 60%, more preferably 30% to 50%, even more preferably 40% to 50%, for example, a decrease of 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65% or 70%.

[0061] In some embodiments, the area of ​​choroidal neovascularization (CNV) in the individual is reduced by 0.1 mm2 or more at 2 weeks, 3 weeks, or 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 3 months, 4 months, or 5 months after administration, compared to a pre-administration level of the area of ​​CNV in the individual. 2 For example, 0.1 mm or less 2 ~20mm 2 , preferably 0.2 mm 2 ~5mm 2 , more preferably 0.3 mm 2 ~2mm 2 Decreased, for example, by 0.1 mm 2 , 0.2mm 2 , 0.3mm2 、0.4mm 2 、0.5mm 2 、0.6mm 2 、0.7mm 2 、0.8mm 2 、0.9mm 2 、1mm 2 、1.1mm 2 、1.2mm 2 、1.3mm 2 、1.4mm 2 、1.5mm 2 、1.6mm 2 、1.7mm 2 、1.8mm 2 、1.9mm 2 、2mm 2 、2.1mm 2 、2.2mm 2 、2.3mm 2 、2.4mm 2 、2.5mm 2 、2.6mm 2 、2.7mm 2 、2.8mm 2 、2.9mm 2 、3mm 2 、3.1mm 2 、3.2mm 2 、3.3mm 2 、3.4mm 2 、3.5mm 2 、3.6mm 2 、3.7mm 2 、3.8mm 2 、3.9mm 2 、4mm 2 、4.1mm 2 、4.2mm 2 、4.3mm 2 、4.4mm 2 、4.5mm 2 、4.6mm 2 、4.7mm 2 、4.8mm 2 、4.9mm 2 、5mm 2 、5.5mm 2 、6mm 2 、6.5mm 2 、7mm 2 、7.5mm 2 、8mm 2, 8.5mm 2 , 9mm 2 , 9.5mm 2 , 10mm 2 , 10.5mm 2 , 11mm 2 , 11.5mm 2 , 12mm 2 , 12.5mm 2 , 13mm 2 , 13.5mm 2 , 14mm 2 , 14.5mm 2 , 15mm 2 , 15.5mm 2 , 16mm 2 , 16.5mm 2 , 17mm 2 , 17.5mm 2 , 18mm 2 , 18.5mm 2 , 19mm 2 , 19.5mm 2 Or 20mm 2 It is decreased, or decreased by 5% or more compared to the pre-administration level, for example, 10% to 70%, preferably 10% to 60%, more preferably 30% to 50%, and even more preferably 40% to 50%, for example, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65% or 70% decreased.

[0062] In some embodiments, the subject's best corrected visual acuity (BCVA) is improved by at least one letter on the ETDRS chart, preferably by at least five letters on the ETDRS chart, and more preferably at least two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, nine weeks, ten weeks, three months, four months, or five months after administration, compared to a pre-administration level of the individual's BCVA. An improvement of 5 to 35 letters in the ETDRS visual acuity chart, for example, an improvement of 5 to 25 letters in the ETDRS visual acuity chart, for example, an improvement of 5 to 10 letters, 5 to 15 letters, 5 to 20 letters, 10 to 15 letters, 10 to 20 letters, 10 to 25 letters, 15 to 20 letters, or 15 to 25 letters, for example, an improvement of 5 letters, 6 letters, 7 letters, 8 letters, 9 letters, 10 letters, 11 letters, 12 letters, 13 letters, 14 letters, 15 letters, 16 letters, 17 letters, 18 letters, 19 letters, 20 letters, 21 letters, 22 letters, 23 letters, 24 letters, 25 letters, 26 letters, 27 letters, 28 letters, 29 letters, 30 letters, 31 letters, 32 letters, 33 letters, 34 letters, or 35 letters, or improved by 5% or more compared to the pre-administration level, preferably improved by 10% or more, for example, 10% to 200%, preferably 10% to 150%, more preferably 10% to 100%, even more preferably 20% to 100%, even more preferably 50% to 1 00%, 60% to 100%, 20% to 80% or 30% to 70%, more preferably 50% to 70%, and even more preferably 60% to 70%, for example, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190% or 200% improvement.

[0063] In some embodiments, following administration, the individual experiences no serious adverse events.

[0064] In some embodiments, following administration, the individual's incidence of adverse events is comparable to individuals receiving a placebo.

[0065] In some embodiments, the individual is a human.

[0066] In some specific embodiments, the fusion protein is administered to the individual in a single dose of about 0.01 mg / eye to 10 mg / eye, preferably 0.05 mg / eye to 8 mg / eye, more preferably 0.05 mg / eye to 6 mg / eye, even more preferably 0.5 mg / eye to 5 mg / eye, even more preferably 1 mg / eye to 5 mg / eye, even more preferably 2 mg / eye to 5 mg / eye, for example, 0.5 mg / eye to 2 mg / eye, 1 mg / eye to 3 mg / eye, 2 mg / eye to 4 mg / eye, 2 mg / eye to 3 mg / eye, or 3 mg / eye to 5 mg / eye, administered intravitreally or intravenously once a day, once every two days, twice a week, once a week, once every two weeks, once every four weeks, once every five weeks, or once every six weeks, thereby improving the individual's pre-administration level of foveal retinal thickness. In comparison, 6 or 8 weeks after administration, the foveal retinal thickness level of the individual is reduced by 25 μm or more, for example, by 25 μm to 350 μm, preferably by 50 μm to 300 μm, more preferably by 50 μm to 200 μm, for example, by 25 μm, 50 μm, 75 μm, 100 μm, 125 μm, 150 μm, 175 μm, 200 μm, 225 μm, 250 μm, 275 μm, A decrease of 300 μm, 325 μm, 350 μm, or a decrease of 5% or more compared to pre-administration levels, for example, a decrease of 10% to 70%, preferably a decrease of 10% to 60%, more preferably a decrease of 30% to 50%, even more preferably a decrease of 40% to 50%, for example, a decrease of 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65% or 70%.

[0067] In some specific embodiments, the fusion protein is administered at a concentration of about 0.01 mg / eye to 10 mg / eye, preferably 0.05 mg / eye to 8 mg / eye, more preferably 0.05 mg / eye to 6 mg / eye, even more preferably 0.5 mg / eye to 5 mg / eye, even more preferably 1 mg / eye to 5 mg / eye, even more preferably 2 mg / eye to 5 mg / eye, for example, 0.5 mg / eye to 2 mg / eye, 1 mg / eye to 3 mg / eye, 2 mg / eye to 4 mg / eye, or is administered to the individual by intravitreal or intravenous administration at a single dose of 2 mg / eye, 2 mg / eye to 3 mg / eye, or 3 mg / eye to 5 mg / eye once a day, once every two days, twice a week, once a week, once every two weeks, once every four weeks, once every five weeks, or once every six weeks, and the area of ​​choroidal neovascularization (CNV) of the individual is reduced by 0.1 mm or more 6 weeks or more 8 weeks after administration compared to the area of ​​CNV of the individual before administration. 2 For example, 0.1 mm or less 2 ~20mm 2 , preferably 0.2 mm 2 ~5mm 2 , more preferably 0.3 mm 2 ~2mm 2 Decreased, for example, by 0.1 mm 2 , 0.2mm 2 , 0.3mm 2 , 0.4mm 2 , 0.5mm 2 , 0.6mm 2 , 0.7mm 2 , 0.8mm 2 , 0.9mm 2 , 1mm 2 , 1.1mm 2 , 1.2mm 2 , 1.3mm 2 , 1.4mm 2 , 1.5mm 2 , 1.6mm 2 , 1.7mm 2 , 1.8mm 2 , 1.9mm 2 , 2mm 2 , 2.1mm 2 , 2.2mm 2 , 2.3mm 2 , 2.4mm 2 , 2.5mm 2、2.6mm 2 、2.7mm 2 、2.8mm 2 、2.9mm 2 、3mm 2 、3.1mm 2 、3.2mm 2 、3.3mm 2 、3.4mm 2 、3.5mm 2 、3.6mm 2 、3.7mm 2 、3.8mm 2 、3.9mm 2 、4mm 2 、4.1mm 2 、4.2mm 2 、4.3mm 2 、4.4mm 2 、4.5mm 2 、4.6mm 2 、4.7mm 2 、4.8mm 2 、4.9mm 2 、5mm 2 、5.5mm 2 、6mm 2 、6.5mm 2 、7mm 2 、7.5mm 2 、8mm 2 、8.5mm 2 、9mm 2 、9.5mm 2 、10mm 2 、10.5mm 2 、11mm 2 、11.5mm 2 、12mm 2 、12.5mm 2 、13mm 2 、13.5mm 2 、14mm 2 、14.5mm 2 、15mm 2 、15.5mm 2 、16mm 2 、16.5mm 2 、17mm 2 、17.5mm 2 、18mm 2 、18.5mm 2 、19mm 2 、19.5mm2 Or 20mm 2 It is decreased, or decreased by 5% or more compared to the pre-administration level, for example, 10% to 70%, preferably 10% to 60%, more preferably 30% to 50%, and even more preferably 40% to 50%, for example, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65% or 70% decreased.

[0068] In some specific embodiments, the fusion protein is administered at a concentration of about 0.01 mg / eye to 10 mg / eye, preferably 0.05 mg / eye to 8 mg / eye, more preferably 0.05 mg / eye to 6 mg / eye, even more preferably 0.5 mg / eye to 5 mg / eye, even more preferably 1 mg / eye to 5 mg / eye, even more preferably 2 mg / eye to 5 mg / eye, for example, 0.A single dose of 5 mg / eye to 2 mg / eye, 1 mg / eye to 3 mg / eye, 2 mg / eye to 4 mg / eye, 2 mg / eye to 3 mg / eye, or 3 mg / eye to 5 mg / eye is administered to the individual by intravitreal or intravenous administration once a day, once every two days, twice a week, once a week, once every two weeks, once every four weeks, once every five weeks, or once every six weeks, and the individual's best corrected visual acuity (BCVA) is reduced or improved on the ETDRS visual acuity chart 6 or 8 weeks after administration compared to the individual's pre-administration level. The improvement is at least one letter, preferably at least 5 letters on the ETDRS visual acuity chart, more preferably 5 to 35 letters on the ETDRS visual acuity chart, for example, 5 to 25 letters on the ETDRS visual acuity chart, for example, 5 to 10 letters, 5 to 15 letters, 5 to 20 letters, 10 to 15 letters, 10 to 20 letters, 10 to 25 letters, 15 to 20 letters, or 15 to 25 letters, for example, 5 letters, 6 letters, 7 letters, 8 letters, 9 letters, 10 letters, 11 letters, 12 letters, 13 letters, 14 letters, 15 letters, 16 letters, 17 letters, 18 letters, 19 letters, 20 letters, 21 letters, 22 letters, 23 letters, 24 letters, 25 letters, 26 letters, 27 letters, 28 letters, 29 letters, 30 letters, 31 letters, 32 letters, 33 letters, 34 letters, 35 letters, 36 letters, 37 letters, 38 letters, 39 letters, 40 letters, 41 letters, 42 letters, 43 letters, 44 letters, 45 letters, 46 letters, 47 letters, 48 ​​letters, 49 letters, 50 letters, 50 letters, 50 letters, 50 letters, 50 letters, 50 letters, 60 letters, 70 letters, 80 letters, 90 letters, 100 letters, 110 letters, 120 letters, 130 letters, 140 letters, 150 letters, 160 letters, 170 letters, 180 letters, 190 letters, 210 letters, 220 letters, 230 letters, 240 letters, 250 letters, 260 letters, 27 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 characters, or improved by 5% or more, preferably 10% or more, compared to the pre-administration level, for example, 10% to 200%, preferably 10% to 150%, more preferably 10% to 100%, and even more preferably 20% to 1 00%, more preferably 50% to 100%, 60% to 100%, 20% to 80% or 30% to 70%, more preferably 50% to 70%, still more preferably 60% to 70%, for example, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190% or 200% improvement.

[0069] It should be understood that the technical solution obtained by any combination of any technical features described in the above second and third aspects and any technical features of the technical solution described in the first aspect is also included in the present application.

[0070] 3. Single-dose drug units or drug kits A fourth aspect of the invention relates to a single drug dosage unit comprising a fusion protein that inhibits the VEGF pathway and the complement pathway.

[0071] In one embodiment, the fusion protein comprises the sequence of SEQ ID NO:1.

[0072] (Sequence number 1).

[0073] In a preferred embodiment, the sequence of the fusion protein is SEQ ID NO: 1, and for convenience of description, the fusion protein is referred to as IBI302 in this application, and its production method is referred to in WO2013082563A1.

[0074] In some embodiments, the single drug dosage unit is from 0.01 mg to 10 mg, preferably from 0.05 mg to 8 mg, more preferably from 0.05 mg to 6 mg, even more preferably from 0.5 mg to 5 mg, even more preferably from 1 mg to 5 mg, even more preferably from 2 mg to 5 mg, for example, from 0.5 mg to 2 mg, 1 mg to 3 mg, 2 mg to 4 mg, 2 mg to 3 mg, or 3 mg to 5 mg, for example, 0.05 mg, 0.1 mg, 0 .15mg, 0.2mg, 0.25mg, 0.3mg, 0.35mg, 0.4mg, 0.45mg, 0.5mg, 0.55mg, 0.6mg, 0.65mg, 0.7mg, 0.75mg, 0.8mg, 0.85m g, 0.9mg, 0.95mg, 1mg, 1.1mg, 1.2mg, 1.3mg, 1.4mg, 1.5mg, 1.6mg, 1.7mg, 1.8mg, 1.9mg, 2mg, 2.1mg, 2.2mg, 2.3mg, 2 .4mg, 2.5mg, 2.6mg, 2.7mg, 2.8mg, 2.9mg, 3mg, 3.1mg, 3.2mg, 3.3mg, 3.4mg, 3.5mg, 3.6mg, 3.7mg, 3.8mg, 3.9mg, 4m g, 4.1mg, 4.2mg, 4.3mg, 4.4mg, 4.5mg, 4.6mg, 4.7mg, 4.8mg, 4.9mg, 5mg, 5.1mg, 5.2mg, 5.3mg, 5.4mg, 5.5mg, 5.6mg, The fusion protein may be administered in a dose of 5.7mg, 5.8mg, 5.9mg, 6mg, 6.1mg, 6.2mg, 6.3mg, 6.4mg, 6.5mg, 6.6mg, 6.7mg, 6.8mg, 6.9mg, 7mg, 7.1mg, 7.2mg, 7.3mg, 7.4mg, 7.5mg, 7.6mg, 7.7mg, 7.8mg, 7.9mg, 8mg, 8.5mg, 9mg, 9.5mg, 10mg, preferably 2mg or 4mg.

[0075] A fifth aspect of the invention relates to a pharmaceutical kit comprising a fusion protein according to any one of the above single pharmaceutical dose unit embodiments.

[0076] A sixth aspect of the present invention relates to the use of the single drug dose unit as defined above or the drug kit as defined above in the manufacture of a medicament for preventing or treating age-related macular degeneration (AMD).

[0077] A seventh aspect of the present invention relates to a single pharmaceutical dosage unit as described above or a pharmaceutical kit as described above for preventing or treating age-related macular degeneration (AMD).

[0078] It should be understood that the present application also includes technical solutions obtained by any combination of any of the technical features described in the above fourth to seventh aspects and any of the technical features of the technical solutions described in the first to third aspects.

[0079] "Definition" The terms used herein have the following definitions. If not defined herein, the definitions in patent application WO2013082563A1 apply. If not defined in both, the terms used in the present invention have the meanings commonly understood in the art.

[0080] The following definitions will be used to interpret this specification, and where appropriate, terms used in the singular may also include the plural and vice versa. It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0081] As used herein, the term "and / or" refers to any one of selectable options or two or more of selectable options.

[0082] As used herein, the term "containing" or "comprising" means including the recited elements, integers, or steps, but not excluding any other elements, integers, or steps. When the term "containing" or "comprising" is used herein, it also covers the recited elements, integers, or steps, unless otherwise specified. For example, when it is referred to as "comprising" an antibody variable region of a certain sequence, it is also intended to cover an antibody variable region consisting of that sequence.

[0083] An "individual" includes mammals. Mammals include, but are not limited to, domestic animals (e.g., cows, goats, cats, dogs, horses), primates (e.g., humans, non-human primates such as monkeys), rabbits, and rodents (e.g., mice, rats). In some embodiments, an individual is a human, including children, adolescents, and adults.

[0084] The term "administered in combination" refers to the administration of two or more therapeutic agents to treat a disease as described in this disclosure. Such administration includes the co-administration of these therapeutic agents at substantially the same time, for example in the form of a single composition having a fixed ratio of active ingredients. Alternatively, such administration includes the co-administration of each active ingredient in multiple or separate containers (e.g., tablets, capsules, powders, liquids). The powders and / or liquids can be reconstituted or diluted to the desired dose before administration. Furthermore, such administration includes the sequential use of each type of therapeutic agent at substantially the same or different times. In either case, the treatment regimen provides the beneficial effect of the pharmaceutical combination in treating the disorder or condition as described herein.

[0085] As used herein, "treatment" refers to alleviating, interrupting, slowing, ameliorating, halting, reducing, or reversing the progression or severity of an existing symptom, disorder, condition, or disease.

[0086] As used herein, "prevention" includes inhibition of the onset or progression of a disease, disorder, or symptom associated with a particular disease or disorder. In some embodiments, individuals with a family history are candidates for a prevention regimen. In general, the term "prevention" refers to administration of a drug before a disease or symptom occurs, particularly in individuals at risk.

[0087] The term "effective amount" refers to the amount or dosage of the formulation or fusion protein of the present invention that produces the desired effect in the treated patient after administration of one or more doses to the patient. The effective amount can be easily determined by the attending physician, who is skilled in the art, taking into account various factors such as, for example, the mammalian species, the volume, age, and health of the subject to be administered, the specific disease involved, the extent or severity of the disease, the response of the individual patient, the specific antibody administered, the form of administration, the bioavailability characteristics of the administered formulation, the selected dosing regimen, the application of combination therapy, etc.

[0088] "Therapeutically effective amount" refers to an amount to effectively achieve a desired therapeutic result at a given dose for a given period of time. The therapeutically effective amount of the formulation, antibody or antibody fragment, or conjugate or composition of the present invention can vary depending on various factors, such as, for example, the disease state, the age, sex, weight of the individual, and the ability of the antibody or antibody portion to induce a desired response in the individual. The therapeutically effective amount is also an amount such that any toxic or adverse effects of the formulation, antibody or antibody fragment, or conjugate or composition thereof are not offset by the beneficial effects of the treatment.

[0089] A "prophylactically effective amount" refers to an amount effective to achieve a desired prophylactic result at a given dosage over a given period of time. Generally, the prophylactically effective amount will be less than the therapeutically effective amount, since a prophylactic dose is applied prior to or at an earlier stage of disease in a subject.

[0090] The term "fusion protein" refers to a polypeptide having two or more moieties covalently linked to each other, each of which is derived from a different protein. The two or more moieties may be connected directly by a single peptide bond or by a peptide linker comprising one or more amino acid residues. Generally, the two moieties and the linker are both located in an open reading frame and are produced by recombinant techniques.

[0091] The term "fusion protein inhibiting the VEGF pathway and the complement pathway" comprises a complement inhibitory domain (CID), a VEGF inhibitory domain (VID) and a half-life prolonging domain, and in a preferred embodiment of the present invention, the VEGF fusion protein is selected from SEQ ID NO: 40 in WO2013082563A1, and the "CID", "VID" and "half-life prolonging domain" refer to WO2013082563A1.

[0092] The term "fovea" refers to the area located in the center of the retina where vision is most sensitive, and since the cone cells involved in photopic vision and color vision are distributed in this area, any lesion in this area will cause a clear decrease in central vision, and may also be accompanied by color vision abnormalities, metamorphopsia, central scotoma, etc., and lesions in this area may appear as bleeding, edema, increased thickness, atrophy, etc. The macula is located in the middle of the fovea region of the retina.

[0093] The term "choroidal neovascularization" refers to proliferative blood vessels derived from choriocapillaris that extend through breaks in Bruch's membrane and proliferate between Bruch's membrane and the retinal pigment epithelium, or between the neural retina and the retinal pigment epithelium, or between the retinal pigment epithelium and the choroid. Any of a number of diseases affecting the RPE-Bruch's membrane-choroidal capillary complex can cause choroidal neovascularization.

[0094] The term "best corrected visual acuity" is the visual acuity measured after complete correction of the refractive error of the eye. It reflects the actual visual ability of the eye.

[0095] As used herein, the term "formulation" or "pharmaceutical composition" refers to a composition comprising at least one active ingredient and at least one inactive ingredient suitable for administration to an animal, preferably a mammal (including a human). "Liquid formulation" or "liquid composition" refers to a formulation in liquid form. The liquid composition of the present invention comprises (i) a fusion protein according to the present invention, (ii) a buffering agent, and (iii) a solvent. The composition of the formulation of the present invention may be as shown in the above embodiment for the liquid pharmaceutical composition. The liquid formulation of the present invention is preferably an injection.

[0096] "Pharmaceutically acceptable carrier" refers to an ingredient of a pharmaceutical formulation other than the active ingredient that is not toxic to a subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, and preservatives.

[0097] As used herein, "buffer" refers to a pH buffering agent. For example, the buffering agent is selected from histidine, glutamate, phosphate, acetate, citrate, and tris(hydroxymethyl)aminomethane.

[0098] As used herein, the term "solvent" refers to a liquid for dissolving or suspending active and non-active ingredients to form a liquid formulation. Solvents that can be used in the present invention include, but are not limited to, water for injection, organic solvent for injection (including, but not limited to, oil for injection, ethanol, propylene glycol, etc.), or combinations thereof.

[0099] As used herein, the term "single drug dosage unit" refers to a single pharmaceutical dosage form containing a fusion protein of the invention that is administered to a patient at the time of administration, such as an injection vial, ampoule, pre-filled needle or pre-filled syringe containing a solution or lyophilized powder of the drug.

[0100] The term "about," when used in conjunction with a number or numerical value, is meant to cover a range of numbers or numerical values, with a lower limit of 10% less than the specified number or numerical value and an upper limit of 10% more than the specified number or numerical value. [Brief description of the drawings]

[0101] [Figure 1] 1 shows the inhibitory effect of IBI302 on VEGF-A-induced HUVEC proliferation. [Diagram 2] 1 shows the inhibitory effect of IBI302 on hemolysis mediated by the classical complement pathway. [Diagram 3] 1 shows the inhibitory effect of IBI302 on hemolysis mediated by the alternative complement pathway. [Figure 4] The inhibitory effect of each dose of IBI302 on CNV is shown, where * indicates P<0.05 compared to the PBS group, and # indicates P<0.05 compared to the IBI302 1 μg, 3 μg, or 5 μg groups. [Diagram 5] Inhibition of CNV formation and leakage by IBI302 is shown, where * indicates P<0.05 compared to the PBS group and # indicates P<0.05 compared to the IBI302 10 μg group. [Figure 6] The inhibitory effect of IBI302 on the aggregation of inflammatory cells is shown, where * indicates P<0.05 compared to the PBS group, and # indicates P<0.05 compared to the IBI302 10 μg group. [Figure 7] 1 shows the effect of IBI302 on fluorescent dye leakage in the fundus in a rhesus monkey CNV model (fluorescence angiography). [Figure 8] Representative images of CD31 immunohistochemical staining of the choroid are shown. [Figure 9] Representative images of C5b-9 immunohistochemical staining of the choroid are shown. [Figure 10] 1 shows serum drug concentration-time curves following intravenous and intravitreal injection of IBI302 in rhesus monkeys. [Figure 11] 1 shows the aqueous and vitreous humor drug concentration-time curves following intravitreal injection of IBI302 in rhesus monkeys. [Figure 12] 1 shows drug concentration-time curves in the lens, cornea, iris, retina, choroid, optic nerve, and sclera following intravitreal injection of IBI302 in rhesus monkeys. [Figure 13] 1 shows the mean blood drug concentration-time curves following the first intravenous and intravitreal injections of different doses of IBI302 in rhesus monkeys. [Figure 14] 1 shows the mean blood drug concentration-time curves after the last intravenous and intravitreal injections of different doses of IBI302 in rhesus monkeys. [Figure 15] FIG. 1 shows a schematic diagram of dose escalation in a Phase I clinical trial as described in Example 5. [Figure 16] FIG. 1 shows a schematic diagram of the study flow for the Phase I clinical trial described in Example 5. [Figure 17] 1 shows the trend of change in number of correctly identified characters and comparison with baseline as shown in early study results of the Phase I clinical trial described in Example 5. [Figure 18] 1 shows the trend of change in central foveal thickness (CST) and comparison with baseline (ΔCST) shown in the initial test results of the Phase I clinical trial described in Example 5. [Figure 19] The results of the overall study of the Phase I clinical trial described in Example 5 show the change in BCVA (ETDRS visual acuity chart number) test results over time for each dose group, where the baseline is the last non-missing value before the first dose of investigational drug (including data from the screening period). [Figure 20] The change in BCVA (ETDRS visual acuity chart number) over time for each dose group in the overall study results of the Phase I clinical trial described in Example 5 is shown, where the baseline is the last non-missing value before the first administration of the investigational drug (including data from the screening period). The change is defined as the average difference between the measured value at each visit and the baseline. [Figure 21] The change in macular central thickness over time as measured by ophthalmic OCT examination for each dose group in the overall study results of the Phase I clinical trial described in Example 5 is shown, where the baseline is the last non-missing value before the first administration of investigational drug (including data from the screening period). [Figure 22]The overall study results of the Phase I clinical trial described in Example 5 show the change in macular central foveal thickness over time for each dose group measured by ophthalmic OCT examination, where the baseline is the last non-missing value before the first administration of the investigational drug (including data from the screening period). The change is defined as the average difference between the measured value at each visit and the baseline. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0102] The present invention is further illustrated by the following examples which should not be construed as limiting the invention.

[0103] Abbreviation AMD Age-related Macular Degeneration BCVA best corrected visual acuity OCT Optical Coherence Tomography CNV choroidal neovascularization AE Adverse Event DLT dose-limiting toxicity EC 50 Median effective concentration SAE Serious Adverse Event TEAE Adverse events that occurred after administration of the study drug CR1 Human complement receptor 1

[0104] Example 1: In vitro pharmacodynamic studies Affinity of IBI302 for VEGF family and complement family cytokines Using Biacore T200, the affinity of IBI302 with related ligands, the affinity of IBI302 with the VEGF family, C3b, and C4b was examined; see Table 1.

[0105] The affinity of IBI302 to VEGF family cytokines was comparable to that of aflibercept injection and significantly stronger than that of bevacizumab injection. The affinity of IBI302 to C4b was comparable to that of CR1, and the affinity of IBI302 to C3b was slightly weaker than that of CR1, possibly because the CID terminus of IBI302 is part of the CR1 domain, but still reached the nM level.

[0106] [Table 1]

[0107] Inhibitory effect of IBI302 on VEGF-A-induced HUVEC proliferation After a series of gradient concentrations of IBI302 were reacted with a fixed concentration of VEGF-A165, HUVEC cells showed different proliferation abilities according to the amount of free VEGF-A165, and the inhibition efficiency of IBI302 on HUVEC cell proliferation was measured by measuring the number of HUVEC viable cells using a CCK-8 colorimetric kit. Aflibercept and bevacizumab injection were used as control drugs.

[0108] As shown in the results, the median effective concentration (EC 50 ) were 54.36ng / mL and 57.53ng / mL, which corresponded to 347pmol / L and 368pmol / L, respectively, and the EC 50 The EC value of bevacizumab injection was 41.02 ng / mL, which corresponds to 357 pmol / L. 50 was 87.07ng / mL, equivalent to 584pmol / L. IBI302 could significantly inhibit VEGF-stimulated HUVEC proliferation, with activity similar to aflibercept and slightly stronger than bevacizumab injection. See Table 2 and Figure 1.

[0109] [Table 2]

[0110] Inhibitory effect of IBI302 on the classical complement pathway Using a human serum complement-stimulated sensitized sheep red blood cell model, IBI302 was able to concentration-dependently inhibit the hemolysis of sensitized sheep red blood cells induced by human serum complement in the concentration range of 0.02 nM to 1080.26 nM, and the half maximal effective concentration (EC 50 The EC value for CR1 was 2.514 nM. 50 The value was 2.254 nM. It was suggested that IBI302 could significantly inhibit the classical complement pathway, similar to CR1. For details of the results, see Figure 2.

[0111] Inhibitory effect of IBI302 on the alternative complement pathway Using a human serum complement-stimulated rabbit red blood cell model, IBI302 was able to concentration-dependently inhibit the hemolysis of rabbit red blood cells induced by human serum complement in the concentration range of 1.50 nM to 383.39 nM, and had an EC 50 The EC value for CR1 was 14.59 nM. 50 The value was 15.30 nM. It was suggested that IBI302 could significantly inhibit the alternative complement pathway, similar to CR1. For details of the results, see Figure 3.

[0112] Effects of IBI302 on barrier function of hRPE cells oxidatively damaged by complement activation and its mechanism In the experiment, hRPE cells were used and divided into normal (nor), model (ctr), aflibercept (VEGF-Trap), CR1, and IBI302 groups. All groups except the normal group were added with t-BHP and 10% normal human serum, and the normal group was added with an equal volume of PBS. The drug treatment groups were further added with the corresponding drugs, with the final concentration of each drug being 1 μg / mL, and the normal and model groups were added with an equal volume of PBS. After 4 hours of culture, the barrier function of the hRPE monolayer cells was measured. After 4 hours of culture, VEGF, chemokine (CC motif) ligand 2 (CCL2), C3a, C5a, and MAC secreted by hRPE cells were measured by ELISA.

[0113] The transepithelial electrical resistance (TER) of hRPE oxidatively damaged by complement activation in the model group (ctr), aflibercept group, CR1 group and IBI302 group was 54.01%, 64.64%, 63.48% and 75.90% of that in the normal group (nor). The aflibercept group, CR1 group and IBI302 group all had significantly increased TER compared to the model group, and the IBI302 group had a significant difference compared to the aflibercept group and CR1 group. See Table 3.

[0114] [Table 3]

[0115] Compared with the model group, the aflibercept group, CR1 group and IBI302 group had a significant reduction in the concentration of VEGF secreted by hRPE. The IBI302 group had a significant reduction in the concentration of VEGF compared with the aflibercept group and CR1 group. The CR1 group and IBI302 group had a significant reduction in the CCL2 secreted by hRPE compared with the model group, and the aflibercept group had no statistically significant difference in the CLL2 secreted by hRPE compared with the model group. The IBI302 group had a significant reduction in the CCL2 concentration compared with the aflibercept group and CR1 group, see Tables 4 and 5.

[0116] [Table 4]

[0117] [Table 5]

[0118] The experimental results of the effect on hRPE complement activation show that, compared with the model group (ctr), the CR1 group and IBI302 group both significantly reduced the expression of complement active components C3a, C5a, and MAC. Compared with the CR1 group, the IBI302 group had no statistically significant inhibition of the expression of C3a, C5a, and MAC. Compared with the model group, the aflibercept group had no statistically significant effect on the production of complement active components C3a, C5a, and MAC, see Tables 6, 7, and 8.

[0119] [Table 6]

[0120] [Table 7]

[0121] [Table 8]

[0122] These experimental results indicate that IBI302 has a protective effect on the barrier function of hRPE cells oxidatively damaged by complement activation, and the mechanism behind this is thought to be that IBI302 simultaneously inhibits the expression of VEGF and the active complement components C3a, C5a, and MAC after complement activation, thereby further reducing CCL2 and VEGF secreted by hRPE.

[0123] Example 2: In vivo Pharmacodynamic Studies in Animals Effect and mechanism study of IBI302 on laser-induced choroidal neovascularization in mice In the experiment, C57BL / 6J mice were used, and laser photocoagulation was performed at four sites. The mice enrolled in the study were randomly divided into six groups, two mice per group (four eyes): a laser modeling group, a phosphate-buffered saline (PBS) treatment group, and IBI302 1μg / μL, 3μg / μL, 5μg / μL, and 10μg / μL dose groups. Immediately after laser photocoagulation, 1μL of each dose of IBI302 or PBS was injected into the vitreous cavity of both eyes of mice with choroidal neovascularization (CNV) in each group. Fluorescein isothiocyanate-dextran (FITC-Dextran) orbital sinus perfusion and ultrathin sectioning of the choroid were performed on the 7th day after laser photocoagulation to observe the effect of each dose of IBI302 on the area of ​​laser-induced CNV in mice.

[0124] In further experiments, the mice were divided into three groups: IBI302 group, aflibercept (VEGF-Trap) group, CR1 group, and PBS group. IBI302 and control drugs were both 10μg / μL, and 1μL of each group's sample was injected into the vitreous cavity of both eyes of the CNV mice in each group immediately after laser photocoagulation. Fundus angiography of the mice was performed 7 days after laser photocoagulation to observe the status of CNV. The mice were anesthetized with chloral hydrate and then dilated with tropicamide-phenylephrine hydrochloride. First, infrared fundus photographs were taken, and then FITC-Dextran, indocyanine green angiography (ICGA), and fluorescein fluorescent fundus angiography (FFA) were performed, respectively. Finally, the concentrations of VEGF, CCL2, TNF-α, and C3a and C5a proteins in the RPE-choroid were measured by ELISA.

[0125] Test Results: Inhibitory effect of different doses of IBI302 on CNV: Seven days after laser photocoagulation, ultrathin sections of the choroid were prepared by perfusion of mouse orbital sinus with FITC-Dextran, and it was confirmed that the neovascularization had a petal-like structure. The CNV area of ​​the laser modeling group was not statistically different from that of the PBS group. Compared with the PBS group, the CNV area of ​​the IBI302 1μg group, 3μg group, 5μg group, and 10μg group was reduced by 14.27%, 48.79%, 62.46%, and 68.83%, respectively, compared to the PBS group. When the CNV area of ​​the IBI302 10μg group was compared with the 1μg group, 3μg group, and 5μg group, there was a statistically significant difference in all cases. See Table 9 and Figure 4.

[0126] [Table 9]

[0127] Compared with the PBS control group, 10 μg / eye of IBI302, aflibercept and CR1 all inhibited the area and leakage of CNV. Compared with the aflibercept and CR1 groups, 10 μg / eye of IBI302 can significantly inhibit the area and leakage of CNV, see Table 10, Table 11 and Figure 5.

[0128] [Table 10]

[0129] [Table 11]

[0130] Inhibitory effect of IBI302 on VEGF production in laser-induced CNV mice: 3 days after laser photocoagulation, compared with the PBS group, 10 μg / eye of IBI302, aflibercept and CR1 can all inhibit VEGF production in laser-induced CNV mice.Compared with the aflibercept group and the CR1 group, the inhibitory effect of IBI302 on VEGF production is statistically significant, see Table 12.

[0131] [Table 12]

[0132] Inhibition of IBI302 on complement activation in laser-induced CNV mice: Three days after laser photocoagulation, ultrathin immunofluorescence sections of the choroid were prepared, and it was found that 10 μg / eye of IBI302 could significantly inhibit the deposition of MAC in the choroid, compared with the PBS group, the aflibercept group, and the CR1 group. 12 hours after laser photocoagulation, the expression levels of C3a and C5a in the RPE-choroid complex were measured by ELISA, and it was found that the expression of C3a and C5a was significantly reduced in the CR1 group and the IBI302 group, compared with the model group. There was no statistically significant difference in the concentrations of C3a and C5a between the IBI302 group and the CR1 group, and the concentrations of C3a and C5a were significantly reduced in the IBI302 group, compared with the aflibercept group, see Tables 13 and 14.

[0133] [Table 13]

[0134] [Table 14]

[0135] Inhibitory effect of IBI302 on inflammatory cytokines CCL2 and TNF-α in laser-induced CNV mice: 12 hours and 3 days after laser photocoagulation, the expression levels of inflammatory cytokines CCL2 and TNF-α in the RPE-choroid complex were measured by ELISA. Compared with the PBS group, the expression of inflammatory cytokines CCL2 and TNF-α was obviously reduced in the 10 μg / eye CR1 group and IBI302 group. The concentration of CCL2 and TNF-α in the IBI302 group was significantly reduced compared to the aflibercept group, see Tables 15 and 16.

[0136] [Table 15]

[0137] [Table 16]

[0138] Inhibitory effect of IBI302 on the aggregation of inflammatory cells in CNV mice induced by laser: On the first and third days after laser photocoagulation, ultrathin sections of the choroid were prepared and the aggregation of neutrophils and macrophages in the choroid was measured by immunofluorescence. IBI302 can obviously inhibit the deposition of neutrophils and macrophages in the choroid, and both were statistically significant compared with the PBS group and the aflibercept group. See Table 17, Table 18 and Figure 6.

[0139] [Table 17]

[0140] [Table 18]

[0141] The results showed that IBI302 could inhibit the formation and leakage of laser-induced CNV in mice, and the mechanism behind this may be through simultaneously inhibiting the expression of VEGF and the active components C3a, C5a, MAC, CCL2, and TNF-α after complement activation, and inhibiting the infiltration of macrophages and neutrophils, thereby inhibiting the secretion of VEGF and angiogenesis.

[0142] Inhibitory study of IBI302 on laser-induced choroidal neovascularization in rhesus monkeys In the experiment, a laser was used to perform photocoagulation around the fovea of ​​the fundus macula of rhesus monkeys to induce choroidal neovascularization in the fundus, thereby creating an animal model similar to human choroidal neovascularization. 25 monkeys (both male and female) that successfully modeled both eyes were selected and divided into 5 groups, namely, model control group, bevacizumab injection solution 1.25 mg / eye group, IBI302 0.25 mg / eye group, IBI302 0.5 mg / eye group, and IBI302 1.25 mg / eye group, with 5 monkeys per group, both male and female. For details, see Table 19. On the 21st day after photocoagulation, the monkeys in each group were given a single intravitreal injection of the corresponding drug at 50 μL / eye.

[0143] Color fundus photography and fluorescein fundus angiography were performed on the 14th and 28th days after administration, and optical coherence tomography (OCT) examinations were performed on the 11th and 25th days to observe the inhibition of choroidal neovascularization by the investigational drug sample. On the 29th, aqueous humor was extracted from both monkey eyes to measure VEGF, and histopathological examinations were performed on the left eyes, while CD31 and C5b-9 immunohistochemical staining examinations were performed on the right eyes.

[0144] [Table 19]

[0145] The results were as follows: Fluorescence angiography and OCT examination: In the model control group, the monkeys showed no obvious change in the degree of fluorescein leakage 14 and 28 days after administration, and the area of ​​the fluorescent spots did not show any obvious reduction. In some monkeys, the leakage of fluorescein in the eyes tended to increase over time. The number of grade 4 fluorescent spots did not show any obvious change compared to before administration. OCT examinations 11 and 25 days after administration showed no obvious decrease in retinal thickness, no repair of the local Bruch's membrane structure, choroidal neovascularization was still evident, and high-reflection spots were observed.

[0146] In the bevacizumab injection group, the leakage area was significantly smaller than before administration 14 and 28 days after administration, with a significant difference compared to the model control group (P<0.05), and the number of grade 4 fluorescent spots was significantly reduced compared to before administration. In OCT examinations 11 and 25 days after administration, the retinal thickness at the highest point of all ocular lesions was significantly reduced, approaching or reaching the level before modeling, and all were statistically significant compared to the control group (P<0.05).

[0147] In monkeys receiving IBI302 0.25 mg / eye, 0.5 mg / eye, and 1.25 mg / eye, the leakage area was significantly reduced from pre-administration on days 14 and 28, with significant differences compared to the model control group (P<0.05). Furthermore, the improvement in leakage area on day 28 was significantly greater than that of the positive control group (P<0.05). The number of grade 4 fluorescent spots was significantly reduced compared to pre-administration. In OCT examinations on days 11 and 25 after administration, the retinal thickness was significantly reduced, approaching or reaching the level before modeling, with statistically significant differences compared to the model control group (P<0.05), and no statistical differences were observed in any of the indexes compared to the positive control group (P>0.05).

[0148] The fluorescein leakage from the fundus laser spot, the number of fluorescent spots and the retinal thickness of the monkeys in each group before and after administration are shown in Tables 20, 21, 22 and FIG.

[0149] [Table 20]

[0150] [Table 21]

[0151] [Table 22]

[0152] VEGF measurement: 14 and 28 days after administration, serum VEGF concentrations were below the lower limit of quantification in one monkey in the bevacizumab injection 1.25 mg / eye group and the model control group, except for one monkey whose serum VEGF concentrations were near the lower limit of quantification at all other time points. 29 days after administration, the aqueous humor VEGF concentrations of monkeys in the bevacizumab injection 1.25 mg / eye group were decreased compared to the control group, with a statistically significant difference (P<0.05), and the aqueous humor VEGF concentrations of monkeys in each IBI302 group were all below the lower limit of quantification. For details of the results, see Table 23.

[0153] [Table 23]

[0154] Histopathology and immunohistochemistry: HE staining results showed that the model control group had mild to moderate focal retinal / choroidal fibrous tissue hyperplasia and mild to mild focal neuroepithelial detachment. The severity of the above lesions was less severe in each IBI302 group and bevacizumab injection 1.25 mg / eye group than in the model control group.

[0155] Masson's trichrome staining showed that the model control group had mild intraretinal focal collagen fiber hyperplasia positivity.Compared to the model control group, there was no obvious difference in the intensity of hyperplastic fiber tissue positivity in the bevacizumab injection 1.25 mg / eye group and each IBI302 group.The distribution of positivity was reduced in the positive control group and each IBI302 group compared to the model control group, and no positive staining was observed in one eye in the IBI302 1.25 mg / eye group.

[0156] The immunohistochemical results are as follows: Immunohistochemical staining results show that all IBI302 dose groups can reduce the expression of CD31 and C5b-9 in the choroid, and there is a certain dose-dependent relationship; bevacizumab injection has a significant inhibitory effect on the expression of CD31, but has no effect on the expression of C5b-9. For details of the results, please refer to Table 24, Table 25, Figure 8 and Figure 9.

[0157] [Table 24]

[0158] [Table 25]

[0159] The above study results showed that in a laser-induced choroidal neovascularization model in rhesus monkeys, IBI302 could significantly reduce fluorescein leakage, the area of ​​fluorescent spots and the number of fluorescent spots at the photocoagulation site, reduce the retinal thickness at the fluorescent spot lesions, restore the integrity and continuity of the pigment epithelium, reduce the VEGF level in the aqueous humor, alleviate the hyperplasia of fibrous tissue, and inhibit the expression of CD31 and C5b-9 in the choroid, and the efficacy of IBI302 was superior to that of clinical doses of bevacizumab.

[0160] Safety Pharmacology Studies Fifty rhesus monkeys were randomly divided into five groups: control group, IBI302 intravenous injection 8 mg / monkey group, IBI302 intravitreal injection 0.5 mg / eye group, IBI302 intravitreal injection 2 mg / eye group, and IBI302 intravitreal injection 4 mg / eye group. There were 10 animals per group, half of which were male and half were female. During the administration period and the recovery period, the general motor, mental, and respiratory conditions of the monkeys in each group were observed daily, and their body temperature was measured once a week. The respiratory conditions of the monkeys were observed and lead II electrocardiograms and blood pressure were measured at approximately 6, 24, 48, and 120 hours after the first administration, approximately 6 hours after the last administration, during the fourth week of the recovery period, and after the end of the recovery period.

[0161] The experimental results show that during the administration and recovery periods, the rhesus monkeys in each group were in good general condition, had normal spontaneous movement, and showed no drug-related behavioral abnormalities, and no abnormal body temperature was observed in the rhesus monkeys in each group during the study. At 6, 24, 48, and 120 hours after the first administration, approximately 6 hours after the last administration, during the fourth week of the recovery period, and at the end of the recovery period, the monkeys in each IBI302 group showed no drug-related abnormal changes in heart rate, electrocardiogram indices such as QT and corrected QT intervals, PR intervals, RR intervals, P wave duration, and QRS wave duration, systolic blood pressure, diastolic blood pressure, mean blood pressure, and macroscopic respiratory status. This suggests that intravitreal injection of IBI302 0.5 mg / eye, 2 mg / eye, or 4 mg / eye or intravenous injection of IBI302 8 mg / monkey to rhesus monkeys had no obvious effects on the central nervous system, respiratory system, or cardiovascular system.

[0162] conclusion Conclusions of the Pharmacodynamic Study IBI302, on the one hand, can specifically bind to the VEGF family via its VID terminus and inhibit VEGF-A-induced HUVEC proliferation, and on the other hand, can specifically bind to C3b and C4b via its CID terminus and inhibit hemolysis mediated by the alternative complement pathway and classical pathway, indicating that IBI302 is a dual-targeting specific monoclonal antibody with a clear target and mechanism of action.

[0163] IBI302 exerted protective effects on hRPE cells by inhibiting the release of VEGF-A, CCL2, C3a, C5a and MAC from hRPE cells stimulated by t-BHP through dual blocking of VEGF-A and complement-mediated signaling pathways. It inhibited the expression of VEGF, CCL2, TNF-α, C3a, C5a and MAC in laser-induced choroidal neovascularization mice, and reduced choroidal neovascularization. It inhibited the expression of VEGF, CD31 and C5-b9 in laser-induced choroidal neovascularization rhesus monkeys, reduced choroidal neovascularization and neovascular leakage, reduced retinal thickness and protected pigment epithelium, demonstrating the efficacy of IBI302.

[0164] Pharmacodynamic characteristics and implications (1) Dual targeting: IBI302 specifically binds to VEGF-A165, VEGF-A121 and PIGF via its VID terminus on the one hand, and specifically binds to C3b and C4b via its CID terminus on the other hand. It is a dual targeting drug with distinct targets.

[0165] (2) Clear mechanism of action: The CID of IBI302 specifically binds to C3b and C4b, thereby inhibiting the activation of the classical and alternative complement pathways and reducing inflammatory responses mediated by complement activation; the VID terminus binds to the VEGF family and blocks the signal transduction pathway mediated by VEGF, thereby inhibiting the survival and proliferation of vascular endothelial cells, thereby inhibiting angiogenesis, reducing vascular permeability, and decreasing vascular leakage.

[0166] (3) Clear efficacy: In the t-BHP-induced hRPE oxidative stress model, IBI302 was shown to have a significant protective effect on hRPE, and in the laser-induced choroidal neovascularization models in mice and rhesus monkeys, IBI302 was able to produce obvious anti-angiogenic and anti-leakage effects, suggesting that IBI302 has excellent clinical efficacy.

[0167] (4) Better efficacy than commercially available anti-VEGF drugs: IBI302 was more effective than aflibercept or bevacizumab in both the t-BHP-induced hRPE oxidative stress model and the laser-induced mouse and rhesus monkey choroidal neovascularization models, suggesting that IBI302 may be more effective than commercially available anti-VEGF drugs alone.

[0168] (5) Clinical indications: Based on the preclinical pharmacological activity of IBI302 to date and the clinical uses of similar drugs, IBI302 is intended for the clinical treatment of wet age-related macular degeneration (AMD).

[0169] Example 3: Pharmacokinetic studies absorption In vivo pharmacokinetic study of IBI302 in rhesus monkeys In a pharmacokinetic study of a single intravenous or intravitreal injection of IBI302 in rhesus monkeys, 27 rhesus monkeys were randomly assigned to intravenous and intravitreal injection groups, with 21 animals (11 females, 10 males) in the intravitreal injection group and 6 animals (3 females, 3 males) in the intravenous injection group. Blood was collected from the 6 animals in the intravenous and intravitreal injection groups before and 0.5, 1, 2, 4, 10, 24, 48, 72, 96, 144, 192, 240, 336, and 504 hours after administration, respectively, and serum was separated. For the intravitreal injection group, aqueous humor, vitreous humor, lens, cornea, iris, retina, choroid, sclera, optic nerve, and serum were collected at 4, 24, 72, 168, 336, and 504 hours after administration. See Table 26 for details of the experimental design.

[0170] [Table 26]

[0171] The results showed that the drug half-life T 1 / 2 The drug concentration in the eye was significantly higher than that in the serum, and the risk of systemic toxicity was relatively small. The drug distribution in the eye tissues was mainly in the vitreous, retina, and choroid, and the terminal elimination half-life T 1 / 2 Judging from both the mean residence time (MRT) and the mean residence time (MRT), the drug remained in the retina and choroid for a relatively long time and played a role.

[0172] For pharmacokinetic results in serum see Table 27 and Figure 10, and for pharmacokinetic results in ocular tissues see Table 28, Figure 11 and Figure 12.

[0173] [Table 27]

[0174] [Table 28]

[0175] Toxicokinetic study of repeated administration of IBI302 In a 4-week repeated dose toxicity study of intravitreal injection of IBI302 in rhesus monkeys, 50 rhesus monkeys were randomly divided into 5 groups: control group, IBI302 8mg / mouse intravenous injection group, IBI302 0.5mg / eye intravitreal injection group, IBI302 2mg / eye intravitreal injection group, and IBI302 4mg / eye intravitreal injection group. The monkeys were administered once every 2 weeks for 3 consecutive doses, with 10 animals per group, half male and half female. Blood samples were taken from the control group before the first and last doses and 24 hours after each dose, and serum was prepared. Blood samples were taken from the IBI302 8mg / mouse intravenous injection group before the first and last doses and 5 minutes, 1 hour, 4 hours, 8 hours, 24 hours, 48 ​​hours, 72 hours, 120 hours, 168 hours, and 336 hours after each dose, and serum was prepared. For the IBI302 intravitreal injection group, blood was collected before the first and last administration, and 1 hour, 4 hours, 8 hours, 24 hours, 48 ​​hours, 72 hours, 120 hours, and 168 hours after administration, and serum was prepared. IBI302 concentrations in serum were measured using an established ELISA method. See Table 29 for details of the experimental design.

[0176] [Table 29]

[0177] The results showed that the accumulation ratio was 0.7 after repeated intravenous injections of IBI302 in rhesus monkeys. Repeated intravitreal injections of IBI302 at 0.5 mg / eye, 2 mg / eye, and 4 mg / eye in rhesus monkeys showed a significant increase in C max and AUC (0~t) The ratios of C were 1:4.4:5.5 and 1:6.3:13.4, respectively, and showed a certain dose-dependent relationship. After the last dose, max and AUC (0~t)The ratios of IBI302 were 1:2.3:7.9 and 1:15.7:54.6, respectively. The accumulation rates of IBI302 at each dose were NA (cannot be calculated because the drug was not detected in a very small number of animals at the final dose), 0.3, and 0.4, respectively. For details of the results, please refer to Tables 30 and 31 and Figures 13 and 14.

[0178] [Table 30]

[0179] [Table 31]

[0180] The above results showed that repeated intravitreal injections of IBI302 in rhesus monkeys increased the drug exposure and maximum concentration with increasing dose, with a certain dose correlation. The drug exposure in serum after the last injection was reduced, albeit to a lesser extent, compared with the exposure after the first injection. Combined with the immunogenicity results, this showed that antibodies were produced in some animals and did not accumulate after repeated administration.

[0181] distribution See Example 1 for an in vivo pharmacokinetic study of IBI302 in rhesus monkeys. metabolism According to "ICH S6 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals" and "General Principles for Preclinical Safety Technical Evaluation of Therapeutic Biological Products", IBI302 is an antibody drug and metabolism testing is not required, so no studies related to the metabolism of IBI302 were conducted.

[0182] According to these drug metabolism rules, the metabolic products of IBI302 are predicted to be peptide fragments or amino acids.

[0183] excretion No relevant studies were conducted.

[0184] conclusion Pharmacokinetic Study Conclusions After intravitreal injection of IBI302 in rhesus monkeys, the metabolic rate of IBI302 in the local (ocular) range was significantly lower than that in the whole body, the local drug concentration in the eye was significantly higher than that in the serum, and most of the drug was restricted to the eye, so there was a small risk of systemic toxicity. The ocular exposure of the drug showed that the drug was most effectively distributed in the vitreous humor, retina, and choroid. When intravitreal injection of IBI302 was repeated in rhesus monkeys, the drug exposure and maximum concentration increased with increasing dose, with a certain dose correlation, and the drug exposure in the serum after the last injection was reduced, although to a greater or lesser extent, compared to the exposure after the first injection. Combined with the immunogenicity results, it was shown that antibodies were produced in some animals, and that they did not accumulate after repeated administration.

[0185] Pharmacokinetic characteristics and implications (1) Tissue distribution: After intravitreal injection of IBI302, most of the drug was restricted to the eye, and the local drug concentration in the eye was significantly higher than that in the serum, suggesting that IBI302 exerts its pharmacological activity mainly in the eye and has a low risk of systemic toxicity. In addition, the drug was distributed most frequently in the vitreous humor, retina, and choroid, which is consistent with the design objective of the drug acting mainly on the retina and choroid.

[0186] (2) Long-lasting efficacy: After intravitreal injection of IBI302, the terminal elimination half-life T 1 / 2 In terms of both the mean residence time (MRT) and the mean residence time (MRT), the drug remained in the retina and choroid for a long time, helping it to perform its role.

[0187] (3) Accumulation: When IBI302 was repeatedly injected intravenously or intravitreously into rhesus monkeys, the drug exposure after the final injection was lower than that after the first injection, showing no accumulation.

[0188] (4) Immunogenicity: When IBI302 was repeatedly injected intravenously or intravitreously into rhesus monkeys, the drug exposure in the serum after the final injection was reduced, although to varying degrees, compared to the exposure after the first injection, suggesting that antibodies against IBI302 were produced in some animals.

[0189] Example 4: Toxicological studies Single-dose toxicity IBI302 was administered once via intravitreal injection to rhesus monkeys at a dose of 2 mg / eye or 4 mg / eye and observed for 14 days. No obvious toxic reactions were observed in any of the monkeys, indicating that a single administration of IBI302 via intravitreal injection to rhesus monkeys at a dose of 2 mg / eye or 4 mg / eye was well tolerated.

[0190] Repeated Dose Toxicity Fifty rhesus monkeys were randomly assigned to five groups: control, IBI302 8 mg / monkey intravenous injection, IBI302 0.5 mg / eye intravitreal injection, IBI302 2 mg / eye intravitreal injection, and IBI302 4 mg / eye intravitreal injection. There were 10 animals per group, half male and half female. The control and IBI302 4 mg / eye groups received intravitreal injections of 0.9% sodium chloride injection and 40 mg / mL IBI302 in a volume of 100 μL / eye, respectively, and the IBI302 0.5 mg / eye and 2 mg / eye groups received intravitreal injections of 10 mg / mL and 40 mg / mL IBI302 in a volume of 50 μL / eye, respectively, in both eyes. The study was administered once every 2 weeks for three consecutive doses, with a recovery period of 74 days. See Table 32 for details of the study design.

[0191] [Table 32]

[0192] The results were as follows: No abnormal changes were observed in the body weight, body temperature, food intake, hematology, blood biochemistry, urinalysis index, bone marrow-related index, electrocardiogram, blood pressure, organ weight and organ index, or histopathological examination of each organ other than the eyeball and optic nerve in the rhesus monkeys in the intravenous group and each intravitreal injection group.

[0193] Intravitreal injection of IBI302 at each dose induced intraocular inflammation in rhesus monkeys, although to varying degrees, with the main findings being as follows:

[0194] 0.5 mg / eye group: During the treatment period, in 1 / 10 rhesus monkeys (right eye from 3 days after the first dose, left eye from 7 days after the second dose), indirect ophthalmoscopy revealed severe vitreous opacity / refractive media opacity, blindness of the fundus or whitening of retinal venules, hemorrhagic foci, and vitreous opacity, slit-lamp examination revealed anterior chamber exudation, reduction in intraocular pressure, vitreous opacity, unclear iris details, aqueous humor flare, cells, corneal edema or opacity or anterior chamber exudation, AR, and vitreous opacity, intraocular pressure was clearly reduced, and white blood cell count (WBC), monocytes (MONO), neutrophils, and percentages (NEU, NEU%) were clearly increased, and pathological examination revealed inflammatory cell infiltration and vitreous degeneration.

[0195] During the fourth week of the recovery period, whitening of the retinal branch vessels was found in one-quarter of the eyes, and by the sixth week of the recovery period, the condition had almost completely recovered. Pathological examination revealed mild inflammatory cell infiltration in only a small number of eyes.

[0196] 2 mg / eye group: During the treatment period, 1 / 10 monkeys (left eye from 3 days after the second dose and right eye from 3 days after the third dose) showed anterior chamber exudation, severe vitreous opacification, no fundus or perivascular whitening of retinal veins with perivascular hemorrhage by indirect ophthalmoscopy, anterior chamber exudation, difficult pupil dilation, bulbar chemosis, conjunctival and ciliary congestion, corneal opacification, aqueous humor flare, iris detail obscuration, edema or iris detail obscuration, edema by slit lamp examination, obvious reduction in intraocular pressure, obvious increase in WBC, MONO, NEU, NEU%, and gross dissection showed grayish white in the anterior chamber pupillary region of both eyes. Another monkey showed a blood clot in the vitreous (possibly related to the injection) 1 day after the third dose, vitreous opacification and no fundus by 6 days after the third dose. Ocular electrophysiological (ERG) testing revealed that female monkeys had reduced b-wave amplitude under light adaptation 3.0 (Cone-R) after treatment was discontinued, and pathological examination revealed ocular monocytic infiltration, neutrophil infiltration, vitreous degeneration, retinal / iris edema, and minor optic nerve monocytic infiltration.

[0197] During the fourth week of the recovery period, whitening of the retinal branch vessels was found in 2 / 4 of the monkeys, which had almost completely recovered by the sixth week of the recovery period. During the fourth and seventh weeks of the recovery period, female monkeys were found to have reduced b-wave amplitude under light adaptation of 3.0 (Cone-R), and pathological examination revealed slight optic nerve, ciliary body, or retinal monocytic infiltration in only a small number of eyes.

[0198] 4 mg / eye group: During the treatment period, 1 / 10 monkey (both eyes, 6 days after the third dose) had vitreous opacity in both eyes detected by indirect ophthalmoscopy, and anterior chamber exudation and vitreous opacity detected by slit-lamp examination. One monkey developed anterior chamber exudation in the left eye 1 day after the first dose. After the end of treatment, the female monkey had reduced amplitudes of b-wave under light adaptation 3.0 (Cone-R) and a-wave under dark adaptation 3.0 (Max-R). Pathological examination revealed monocyte infiltration in the eye, vitreous degeneration, retinal edema, and slight monocyte infiltration in the optic nerve.

[0199] At the 4th week of recovery, indirect ophthalmoscopy revealed white lines around the retinal branch vessels in 3 / 4 monkeys, which had almost completely recovered by the 10th week of recovery. Slit-lamp examination revealed vitreous opacities in both eyes in one monkey (1 / 4) at the 5th week, which had returned to normal by the 6th week of recovery. At the 4th and 7th weeks of recovery, the female monkey had reduced b-wave amplitude under light adaptation 3.0 (Cone-R), and no findings were noted at the 10th week of recovery. At the 4th week of recovery, binocular OCT scans of 2 / 4 monkeys showed obvious edema and thickening of the retina around the retinal vessels, increased retinal vascular reflections, and dark shadows were noted on the corresponding histological scans below. At the 7th week of recovery, no findings were noted. Pathological examination revealed only minor optic nerve, ciliary body, or retinal monocytic infiltration in only a few eyes.

[0200] In summary, IBI302 was administered to rhesus monkeys via intravitreal injection at doses of 0.5 mg / eye, 2 mg / eye, or 4 mg / eye, or intravenously at a dose of 8 mg / animal, once every 2 weeks for three consecutive doses, with a recovery period of 74 days. No systemic toxicity was observed at each dose, and only a small number of animals were found to have intraocular inflammation. After the recovery period, ophthalmologic examination of each group showed that intraocular inflammation had almost completely resolved, and histopathological changes in the eyes had obviously resolved.

[0201] Genotoxicity According to "ICH S6 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals" and "General Principles for Preclinical Safety Technical Evaluation of Therapeutic Biological Products", IBI302 is an antibody drug and its metabolic products are peptide fragments or amino acids, neither of which have any effect on DNA and other genetic materials, making genotoxicity studies unnecessary, so no studies related to the genotoxicity of IBI302 were conducted.

[0202] Carcinogenicity Because this product is administered by intravitreal injection, has low systemic exposure, and is targeted to an indication population aged 50 years or older, no carcinogenicity studies were conducted.

[0203] Reproductive toxicity Because this product is administered by intravitreal injection, has low systemic exposure, is targeted at an intended population of 50 years or older, and poses a low risk of reproductive toxicity, no reproductive toxicity studies were conducted.

[0204] Local tolerance IBI302 was administered by eye drop administration to Japanese white rabbits once a week for four consecutive weeks at a dose of 0.5 mg / eye or 2 mg / eye (concentrations of 10 mg / mL or 40 mg / mL, respectively), and no irritation was observed in the rabbit eyes.

[0205] Other Toxicological Tests immunogenicity Fifty rhesus monkeys were randomly assigned to five groups: control, 8 mg IBI302 intravenous injection / monkey, 0.5 mg IBI302 intravitreal injection / eye, 2 mg IBI302 intravitreal injection / eye, and 4 mg IBI302 intravitreal injection / eye. There were 10 animals per group, half male and half female. Treatment was once every 2 weeks for three consecutive doses, with a recovery period of 74 days.

[0206] The results of the immunogenicity study showed that after the last dose, circulating immune complexes (CICs) increased in female and male monkeys in the 2mg / eye and 4mg / eye intravitreal injection groups, and during the fourth week of recovery, CICs tended to increase in female and male monkeys in the 4mg / eye intravitreal injection group as well. Anti-drug antibodies were produced in some animals in each dose group, and analysis by biological activity assay showed that some of the anti-drug antibodies may be neutralizing antibodies, indicating that IBI302 has a certain degree of immunogenicity.

[0207] immunotoxicity Fifty rhesus monkeys were randomly assigned to five groups: control, 8 mg IBI302 intravenous injection / monkey, 0.5 mg IBI302 intravitreal injection / eye, 2 mg IBI302 intravitreal injection / eye, and 4 mg IBI302 intravitreal injection / eye. There were 10 animals per group, half male and half female. Treatment was once every 2 weeks for three consecutive doses, with a recovery period of 74 days.

[0208] During the immunotoxicity study, the experimental results showed that no abnormal changes were observed in other immune indices of immunoglobulins IgG, IgA, IgM and T lymphocyte subsets CD3+, CD4+, CD8+ in female and male monkeys in each IBI302 group. After the end of administration and the end of the recovery period, no abnormal changes were observed in the absolute weights and organ indexes of the spleen and thymus of the monkeys in each IBI302 group, and no abnormal changes were observed in the pathological examination, indicating that IBI302 has no immunotoxicity.

[0209] Other Tests Tissue cross-reactivity The immunological cross-reactivity of IBI302 with healthy human and cynomolgus monkey tissues was examined using a conventional immunohistochemical method (one-step method). The experimental results showed that (1) at concentrations of 2 μg / mL and 20 μg / mL, biotinylated IBI302 (Biotin-IBI302) and biotinylated aflibercept (Biotin-ZALTRAP) showed specific staining in recombinant human VEGF-A165 protein smears. Biotin-IBI302 showed specific staining in human complement C4b protein smears, while Biotin-ZALTRAP showed no specific staining in human complement C4b protein smears. In the negative control group, no specific staining was observed for Biotin-IBI302 or Biotin-ZALTRAP, and no staining was observed in any protein smears in any reagent control group (IBI302 placebo), indicating that the experimental system was established. (2) At concentrations of 2 μg / mL and 20 μg / mL, no specific staining was observed in immunohistochemical staining of IBI302 and aflibercept in healthy human and cynomolgus monkey tissues.

[0210] conclusion Conclusions of the toxicological study IBI302 was administered to rhesus monkeys by intravitreal injection at a dose of 2 mg / eye or 4 mg / eye once every 2 weeks for three consecutive doses at a dose of 0.5 mg / eye, 2 mg / eye, or 4 mg / eye, or intravenously at a dose of 8 mg / mouse, with a recovery period of 74 days. The results showed that no obvious systemic toxicity was observed, and intravitreal injection of IBI302 at each dose was able to cause intraocular inflammation in monkeys, although to varying degrees, and inflammatory pathological changes in the eye and optic nerve were observed. After the recovery period, ophthalmic examination of each group showed that intraocular inflammation had almost recovered, and histopathological changes in the eye had obviously recovered. Anti-drug antibodies were produced in all intravenous and intravitreal groups, and some of the anti-drug antibodies were neutralizing antibodies, which were not completely resolved by 10 weeks of recovery. Intraocular inflammation may be related to the production of anti-drug antibodies and the formation of immune complexes, and is unlikely to occur in clinical studies, so the risk is small. In addition, IBI302 was administered by instillation at a dose of 0.5 mg / eye or 2 mg / eye once a week for 4 consecutive weeks to Japanese white rabbits, and no irritation was observed in the rabbit eyes. IBI302 had no obvious tissue cross-reactivity with either healthy human tissue or cynomolgus monkey tissue.

[0211] Characteristics and implications of toxicological studies (1) Single-dose administration: When IBI302 was administered to rhesus monkeys by intravitreal injection at a dose of 2 mg / eye or 4 mg / eye, no obvious toxic reactions were observed, and there was no obvious effect on the central nervous system, respiratory system, or cardiovascular system. This suggests that a single intravitreal injection of IBI302 is highly safe.

[0212] (2) Multiple administration: Rhesus monkeys were administered IBI302 by intravitreal injection at doses of 0.5 mg / eye, 2 mg / eye, or 4 mg / eye, once every 2 weeks, for three consecutive doses, or intravenously at a dose of 8 mg / mouse, with a recovery period of 74 days. No obvious systemic toxicity was observed. The main symptoms were intraocular inflammation, although to varying degrees, in the intravitreal injection group, and inflammatory pathological changes in the eye and optic nerve. After the recovery period, ophthalmologic examination of each group showed that intraocular inflammation had almost completely recovered, and histopathological changes in the eye had clearly recovered. The toxic reaction of IBI302 occurred only locally in the eye and was reversible, suggesting high safety.

[0213] (3) Immunotoxicity and immunogenicity: Repeated intravitreal injections of IBI302 in rhesus monkeys did not result in any immunotoxicity. Anti-drug antibodies were produced at a high incidence in all IBI302 dose groups. It was suggested that IBI302 has a certain degree of immunogenicity in rhesus monkeys, but caution is still recommended in clinical studies.

[0214] (4) Endophthalmitis: The intraocular inflammation that occurs after intravitreal injection of IBI302 is related to the production of anti-drug antibodies and the formation of immune complexes. Considering that IBI302 is a fully human monoclonal antibody and the occurrence of anti-drug antibodies and immune complexes is unlikely in clinical practice, the risk of endophthalmitis is small; however, caution should still be exercised in clinical studies.

[0215] (5) Local irritation experiment: IBI302 was administered by dropwise administration at a dose of 0.5 mg / eye or 2 mg / eye to Japanese white rabbits once a week for 4 consecutive weeks. No irritation was observed in the rabbits' eyes. This suggests that IBI302 does not irritate the eyes.

[0216] (6) Tissue specificity: IBI302 had no significant cross-reactivity with either healthy human tissues or cynomolgus monkey tissues, suggesting that IBI302 has no significant interactions with healthy human tissues and very low target-related toxicity.

[0217] Example 5: A Phase I Dose-Escalation Clinical Study of the Tolerability and Safety of a Single Dose in Patients with Wet Age-Related Macular Degeneration (AMD) Research purpose To evaluate the safety, tolerability, bioactivity, and efficacy of a single intravitreal injection of IBI302 in patients with wet AMD.

[0218] Drugs It is IBI302 and the specifications are 0.2mL:2mg, 0.2mL:8mg. The 0.5 mg / eye, 2 mg / eye, and 4 mg / eye doses can be extracted directly from the investigational drug in conventional specifications.

[0219] The other doses were prepared by the following steps. A fixed volume of study drug is extracted from the vial with a syringe. Pour into a solvent bottle of corresponding volume. The syringe is removed and the vehicle and investigational drug are mixed homogeneously. Extract 50 µL from the homogeneously mixed solvent bottle with a new syringe and perform the intraocular injection. The volumes of drug to be extracted and the corresponding solvent volumes for each dosage group are as follows:

[0220] [Table 33]

[0221] research design The study is designed as a multicenter, open-label, dose-escalation study, and patients with active subfoveal choroidal neovascularization (CNV) secondary to wet AMD can be enrolled in the clinical study. Each subject cannot have both eyes as study subjects. Eligible subjects received an intravitreal injection of the investigational drug on the first day (D1) of the study. After administration, subjects will undergo safety monitoring at the study site until D2, and will be allowed to leave the study site once there are no clinically significant abnormal conditions. Subjects will be required to return to the hospital for follow-up on D3-D6, D8, D15, D29, and D43. See the dose escalation schematic in Figure 15.

[0222] This study had six dose groups: 0.05 mg / eye, 0.15 mg / eye, 0.5 mg / eye, 1 mg / eye, 2 mg / eye, and 4 mg / eye. A 3+3 dose escalation design was used. Dose-limiting toxicity (DLT) was observed within 14 days of dosing (i.e., from dosing on D1 to completion of testing on D15) as evidence of dose escalation. PK, PD, and immunogenicity studies were conducted in the 0.15 mg / eye to 4 mg / eye dose groups, and the 0.5 mg / eye to 4 mg / eye dose groups should be increased to 6 subjects after the dose escalation study is completed and before the maximum tolerated dose (MTD) is reached. See the schematic diagram of the study flow in Figure 16.

[0223] Dose-limiting toxicity is defined as any of the following adverse events (AEs) related to IBI302 occurring within the DLT observation period: Mild or severe intraocular inflammation (see Appendix 2), A sustained increase in intraocular pressure of 10 mmHg or more for more than 60 minutes after administration Acute visual loss unrelated to mild or more severe intraocular inflammation (see Appendix 2), Moderate or severe intravitreal hemorrhage (see Appendix 2), Intracranial hemorrhage or other clinically significant bleeding elsewhere outside the eye, Serious adverse events (SAEs) considered by the investigator to be related to the study drug.

[0224] [Table 34]

[0225] [Table 35]

[0226] See Hogan et al. (Hogan MJ, Kimura SJ, Thygeson P.) Am J. Ophthalmol 1959;47:155-70 for grading criteria for anterior uveitis and signs and symptoms of uveitis, the entire contents of which are incorporated herein by reference.

[0227] [Table 36]

[0228] Research Subjects Be male or female aged 50 or older.

[0229] Active subfoveal CNV secondary to wet AMD in the study eye, with lesion size ≤12 optic disc diameters.

[0230] The Early Treatment of Diabetic Retinopathy Trial Group had best corrected visual acuity (BCVA) in the study eye, measured using the ETDRS eye chart, ranging from 10 to 73 letters.

[0231] Central foveal thickness of 250 μm or greater as measured by optical coherence tomography (OCT) scanning.

[0232] The center of the eye and the lens are not clouded, allowing clear stereoscopic fundus photographs to be obtained.

[0233] Female subjects of reproductive age or male subjects married to a female of reproductive age who agree to use effective contraception from the start of the screening period until 3 months after the end of treatment.

[0234] Willingly sign written informed consent and be able to comply with visits and related procedures as outlined in the plan.

[0235] Dosage regimen Subjects will receive a single intraocular injection of IBI302 at doses of 0.05 mg / eye, 0.15 mg / eye, 0.5 mg / eye, 1 mg / eye, 2 mg / eye, or 4 mg / eye, depending on the order of enrollment.

[0236] Evaluation Metrics Safety indicators: Status of BCVA decline, Change in intraocular pressure after administration relative to baseline Incidence and severity of intraocular inflammation, Changes in vital signs, physical examination results, and laboratory test results after treatment compared to baseline; Incidence, correlation with study drug, and severity of all adverse events (AEs), treatment-emergent adverse events (TEAEs), and serious adverse events (SAEs).

[0237] Efficacy evaluation indicators: Changes in central foveal thickness from baseline by ophthalmic OCT examination at D8, D15, D29, and D43; Characteristics of CNV and change in CNV area from baseline by fluorescein angiography (FA) at D43 Changes versus baseline in BCVA at D2, D4, D6, D8, D15, D29, and D43.

[0238] Immunogenicity evaluation index: Anti-drug antibody (ADA) and neutralizing antibody (NAb) positivity rate.

[0239] PK metrics: The PK parameter was the area under the drug-time curve from time 0 to time t (AUC 0~t ), the area under the drug-time curve from time 0 to infinity (AUC 0~∞ ), maximum concentration (C max ), time to reach maximum concentration (T max ), clearance (CL), apparent volume of distribution (V), half-life (t 1 / 2 ), mean residence time (MRT), and the like.

[0240] PD evaluation index: Free VEGF concentration, total VEGF concentration, complement-related indicators (C3, C4, C5 and their fragments) and inflammation-related indicators (IL-1b, IL-6).

[0241] statistical methods Sample amount:

[0242] The study will have six dose groups and will evaluate the six dose levels using a 3+3 dose escalation design, with the 0.5 mg / eye, 1 mg / eye, 2 mg / eye, and 4 mg / eye dose groups requiring an increase to six subjects per designated dose group prior to the MTD after completion of the dose escalation study, for a total of approximately 30 to 36 patients with wet AMD.

[0243] Statistical analysis method: Descriptive statistics were primarily used, and in principle no comparisons were made between groups. Safety indicators, PK / PD parameters, immunogenicity, and efficacy indicators of a single intravitreal injection of IBI302 in patients with wet AMD were summarized by dose group.

[0244] Continuous variables will be described by number of cases, mean, standard deviation, median, minimum and maximum, categorical variables will be described by frequency and percentage, and for efficacy endpoints, 95% confidence intervals of the endpoint means across different dose groups will be provided.

[0245] Experimental Results Preliminary efficacy data for the treatment of nAMD with IBI302 are derived from the Phase I single-agent dose-escalation study CIBI302A101, designed as a multicenter, open-label, dose-escalation study with six dose arms: 0.05 mg / eye, 0.15 mg / eye, 0.5 mg / eye, 1 mg / eye, 2 mg / eye, and 4 mg / eye. Eligible subjects received an intravitreal injection of the study drug on the first day (D1) of the study. Using a 3+3 dose-escalation design, the 0.5 mg / eye to 4 mg / eye dose arms require escalation to six subjects in the designated dose arms after the dose-escalation study is completed and before the maximum tolerated dose. In total, 31 nAMD subjects were enrolled and received the study drug.

[0246] 1. Safety and tolerance Haematology, blood chemistry, liver function, and urine routine laboratory tests were unremarkable.

[0247] No abnormalities were observed in vital signs or physical examinations. Only one subject (1 / 15) experienced a decrease in BCVA of more than 5 letters after administration, which returned to baseline levels by day 6 after administration. No SAEs, such as endophthalmitis, arterial embolic events, retinal detachment, or retinal pigment epithelium tears, occurred. The most common AE was bulbar subconjunctival hemorrhage (6 / 15, 40%, self-limited, not affecting vision). Two subjects experienced intraocular pressure (IOP) exceeding 21 mmHg (upper limit of normal) after administration, which was self-limited and returned to normal within 24 hours.

[0248] 2.Best corrected visual acuity (BCVA) The visual acuity of the subjects in a sitting position was measured at a distance of 4 meters using the ETDRS visual acuity chart. The number of correctly identified letters was observed, and the results showed that the number of correctly identified letters tended to increase, and the initial test results are shown in Figure 17. In the figure, the BCVA value is the number of correctly identified letters, and ΔBCVA% is AVERVGE (number of correctly identified letters at this follow-up - number of correctly identified letters at the first follow-up) x 100%. In the figure, the average value of each dosage group is shown.

[0249] During the study period, on days 2, 4, 6, 8, 15, 29, and 43 (i.e., days 1, 3, 5, 7, 14, 28, and 42 after administration), the mean best-corrected visual acuity (BCVA) in the study eye of all subjects improved by 2.1 ± 3.87 letters, 2.8 ± 4.49 letters, 3.8 ± 4.69 letters, 5.5 ± 6.19 letters, 5.9 ± 6.86 letters, 6.0 ± 8.15 letters, and 6.1 ± 7.47 letters compared to baseline, respectively.

[0250] For BCVA in the target eye, 83.9%, 74.2%, 87.1%, 83.9%, 87.1%, 77.4%, and 71.0% of subjects, respectively, improved from baseline on D2, 4, 6, 8, 15, 29, and 43, 19.4%, 29.0%, 32.3%, 48.4%, 54.8%, 48.4%, and 48.4% of subjects, respectively, improved by ≥5 letters, 6.5%, 3.2%, 16.1%, 22.6%, 25.8%, 25.8%, and 22.6% of subjects, respectively, improved by ≥10 letters, and the percentages of subjects improving by ≥15 letters were 0, 3.2%, 3.2%, 9.7%, 12.9%, 19.4%, and 12.9%, respectively. All BCVA test results in the target eye at each visit were improved from baseline in all dose groups. For the trends of change over time in the test results and the trends of change over time in the test results relative to the baseline, see Figures 19 and 20, respectively. In the figures, the average values ​​for each dosage group are shown.

[0251] 3. Optical Coherence Tomography (OCT) After discharge, OCT examinations were performed at follow-up on D8, D15, D29, and D43. After administration, all subjects showed intraretinal fluid (IRF) and subretinal fluid (SRF) absorption, although to varying degrees, and the degree and rate of absorption showed a certain dose-dependent relationship.

[0252] 4. Foveal retinal thickness (CST) After discharge, the central retinal thickness was measured at follow-up on D8, D15, D29 and D43. After administration, all subjects experienced a decrease in central retinal thickness, and the decrease in thickness showed a certain dose-dependent relationship. The initial results of the change trend of central retinal thickness (CST) and comparison with baseline are shown in Figure 18. In the figure, the average value of each dose group is shown.

[0253] During the study period, on days D8, 15, 29, and 43, i.e., 7, 14, 28, and 42 after administration, the CST of the control eyes of all subjects was reduced by an average of 100 ± 80.62 μm, 122.8 ± 100.48 μm, 141.2 ± 153.66 μm, and 66.1 ± 205.05 μm, respectively.

[0254] After administration, the CST decreased in the OCT examination of the target eyes of each dose group, and the degree of decrease in thickness was maximum on the 28th day after administration. The decrease in thickness was significantly greater in the 0.5 mg and above dose groups than in the 0.05 mg and 0.15 mg dose groups. The decrease in thickness was maximum in the 4 mg dose group on D29, reaching 328.5 μm. See Figure 21 for the change in the CST test results over time of the target eyes of each dose group, and see Figure 22 for the change in the CST test results over time from the baseline of the target eyes of each dose group. The average values ​​of each dose group are shown in the figure.

[0255] Specifically, the improvement of retinal thickness in the macular region was observed as a mean central retinal thickness (CST) of 1 mm measured by OCT. All dose groups showed a decrease in CST on the 7th day after administration. On the 7th day after administration (i.e., D8), each dose group (0.05 mg, 0.15 mg, 0.5 mg, 1 mg, 2 mg, and 4 mg) showed a decrease of 21.3 ± 29.69 μm, 8.3 ± 90.47 μm, 136.8 ± 89.87 μm, 142 ± 100.97 μm, 90.6 ± 41.94 μm, and 117.5 ± 44.70 μm, respectively, compared to baseline, and the percentage decrease compared to baseline was 5%, 2%, 22%, 29%, 17%, and 23%, respectively. Among these, the degree of CST improvement in the 0.5 mg and above dose groups was significantly higher than that of the 0.05 mg and 0.15 mg dose groups. On the 28th day after administration (i.e., D29), the dose groups (0.05 mg, 0.15 mg, 0.5 mg, 1 mg, 2 mg, and 4 mg) had a decrease of 8.0 ± 67.64 μm, 23.7 ± 79.53 μm, 171.8 ± 131.88 μm, 203.7 ± 159.66 μm, 115.3 ± 154.06 μm, and 328.5 ± 191.63 μm, respectively, with the percentage decrease from baseline being 1.7%, 4.4%, 27.4%, 41.1%, 22.0%, and 63.3%, respectively. Among these, the dose groups of 0.5 mg and above had a significantly higher degree of CST improvement than the 0.05 mg and 0.15 mg dose groups. The CST improvement effect continued until the end of the study.

[0256] 5. Measurement of the area of ​​choroidal neovascularization (CNV) by FA During the study period, on the 42nd day after administration, the mean CNV area measured by FA in the target eye of all subjects was 0.524 ± 3.7806 mm 2 All dose groups, except for the 2 mg dose group, showed a reduction in CNV area 42 days after administration. The mean CNV area in the contralateral eye was 0.352 ± 1.7891 mm 2 Among these, on the 42nd day after administration, the 0.05 mg dose group had a decrease of 0.980 ± 0.4857 mm compared to baseline. 2 The 0.15 mg dose group showed a decrease of 4.963 ± 9.9122 mm compared to baseline. 2 The 0.5 mg dose group showed a decrease of 0.365 ± 1.7140 mm compared to baseline. 2 The 1 mg dose group showed a decrease of 0.820 ± 1.7530 mm compared to baseline. 2 The 4 mg dose group showed a decrease of 0.327 ± 0.4206 mm compared to baseline. 2 The baseline for the above data is the last non-missing value before the first administration of the investigational drug (including data from the screening period). Change = Measured value - Baseline value.

Claims

1. A method of preventing or treating age-related macular degeneration (AMD) in an individual comprising administering to the individual a fusion protein that inhibits the VEGF pathway and the complement pathway.

2. The method of claim 1 , wherein the fusion protein comprises the sequence of SEQ ID NO:

1.

3. The method of claim 1 , wherein the sequence of the fusion protein is the sequence shown in SEQ ID NO:

1.

4. The method according to any one of claims 1 to 3, wherein the AMD is wet AMD.

5. 5. The method of claim 4, wherein the wet AMD has one or more symptoms and signs of reduced vision, metamorphopsia, central scotoma, dyslexia, macular edema, fundus hemorrhage, neovascularization, cicatricial fibrosis, geographic atrophy, or any combination thereof.

6. 5. The method of claim 4, wherein the wet AMD comprises choroidal neovascularization (CNV).

7. 5. The method of claim 4, wherein the wet AMD is an AMD having the following characteristics: (1) Active subfoveal CNV secondary to wet AMD in the target eye; and / or (2) central foveal thickness of 250 μm or more as measured by optical coherence tomography (OCT) scanning;

8. 10. The method according to any one of the preceding claims, wherein the individual is a human individual and has a disease, condition and / or characteristic according to any one of the preceding claims.

9. 2. The method of any one of the above claims, wherein the individual is a human individual and is a patient with wet AMD accompanied by geographic atrophy.

10. 2. The method of any one of the above claims, wherein the individual is affected with wet AMD having the following characteristics: (1) Active subfoveal CNV secondary to wet AMD in the target eye; and / or (2) central foveal thickness of 250 μm or more as measured by optical coherence tomography (OCT) scanning;

11. 2. The method of any one of the above claims, wherein said treatment achieves one or more of the following effects in said individual: 1) A decrease in central foveal thickness compared to baseline, 2) reduction in the area of ​​choroidal neovascularization (CNV); 3) improvement in best corrected visual acuity (BCVA) compared to baseline; 4) delaying the onset of geographic atrophy in patients with wet AMD; and / or 5) Delayed onset of geographic atrophy in patients with wet AMD.

12. 2. The method of any one of the above claims, wherein said treatment achieves one or more of the following effects in said individual: 1) improving best corrected visual acuity (BCVA); and / or 2) reducing central foveal thickness, and / or 3) Reducing the area of ​​choroidal neovascularization (CNV).

13. 2. The method of any one of the above claims, wherein said treatment achieves one or more of the following effects in said individual: 1) Best corrected visual acuity (BCVA) is improved by at least one letter on the ETDRS chart compared to a baseline level, preferably by at least 5 letters on the ETDRS chart, more preferably by 5 to 35 letters on the ETDRS chart, for example, by 5 to 25 letters on the ETDRS chart, for example, by 5 to 10 letters, 5 to 15 letters, 5 to 20 letters, 10 to 15 letters, 10 to 20 letters, 10 to 20 letters, improved by 5 characters, 15 to 20 characters, or 15 to 25 characters, for example, improved by 5 characters, 6 characters, 7 characters, 8 characters, 9 characters, 10 characters, 11 characters, 12 characters, 13 characters, 14 characters, 15 characters, 16 characters, 17 characters, 18 characters, 19 characters, 20 characters, 21 characters, 22 characters, 23 characters, 24 characters, 25 characters, 26 characters, 27 characters, 28 characters, 29 characters, 30 characters, 31 characters, 32 characters, 33 characters, 34 characters, or 35 characters; and / or 2) Best corrected visual acuity (BCVA) is improved by 5% or more compared to the baseline level, preferably by 10% or more, for example, 10% to 200%, preferably 10% to 150%, more preferably 10% to 100%, even more preferably 20% to 100%, even more preferably 50% to 100%, 60% to 100%, 20% to 80%, or 30% to 70%, even more preferably 50% to 70%. 0%, more preferably 60% to 70%, for example 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190% or 200% improved; and / or 3) Central foveal thickness (CST) is reduced by 25 μm or more compared to baseline levels, e.g., by 25 μm to 350 μm, preferably by 50 μm to 300 μm, more preferably by 50 μm to 200 μm, e.g., by 25 μm, 50 μm, 75 μm, 100 μm, 125 μm, 150 μm, 175 μm, 200 μm, 225 μm, 250 μm, 275 μm, 300 μm, 325 μm a decrease of 300 μm, 350 μm, or a decrease of 5% or more compared to baseline levels, for example a decrease of 10% to 70%, preferably a decrease of 10% to 60%, more preferably a decrease of 30% to 50%, even more preferably a decrease of 40% to 50%, for example a decrease of 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65% or 70%; and / or 4) The area of ​​choroidal neovascularization (CNV) is reduced by 0.1 mm compared to the baseline level ２ For example, the decrease is 0.1 mm or more. ２ ~20mm ２ , preferably 0.2 mm ２ ~5mm ２ , more preferably 0.3 mm ２ ~2mm ２ It decreases, for example, by 0.1 mm. ２ , 0.2 mm ２ , 0.3 mm ２ , 0.4 mm ２ , 0.5 mm ２ , 0.6 mm ２ , 0.7 mm ２ , 0.8 mm ２ , 0.9 mm ２ , 1 mm ２ , 1.1 mm ２ , 1.2 mm ２ , 1.3 mm ２ , 1.4 mm ２ , 1.5 mm ２ , 1.6 mm ２ , 1.7 mm ２ , 1.8 mm ２ , 1.9 mm ２ , 2 mm ２ , 2.1 mm ２ , 2.2 mm ２ , 2.3 mm ２ , 2.4 mm ２ , 2.5 mm ２ 、2.6mm ２ 、2.7mm ２ 、2.8mm ２ 、2.9mm ２ 、3mm ２ 、3.1mm ２ 、3.2mm ２ 、3.3mm ２ 、3.4mm ２ 、3.5mm ２ 、3.6mm ２ 、3.7mm ２ 、3.8mm ２ 、3.9mm ２ 、4mm ２ 、4.1mm ２ 、4.2mm ２ 、4.3mm ２ 、4.4mm ２ 、4.5mm ２ 、4.6mm ２ 、4.7mm ２ 、4.8mm ２ 、4.9mm ２ 、5mm ２ 、5.5mm ２ 、6mm ２ 、6.5mm ２ 、7mm ２ 、7.5mm ２ 、8mm ２ 、8.5mm ２ 、9mm ２ 、9.5mm ２ 、10mm ２ 、10.5mm ２ 、11mm ２ 、11.5mm ２ 、12mm ２ 、12.5mm ２ 、13mm ２ 、13.5mm ２ 、14mm ２ 、14.5mm ２ 、15mm ２ 、15.5mm ２ 、16mm ２ 、16.5mm ２ 、17mm ２ 、17.5mm ２ 、18mm ２ 、18.5mm ２ 、19mm ２, 19.5mm ２ Or 20mm ２ A decrease or a decrease of 5% or more compared to baseline levels, for example, a 10% to 70%, preferably a 10% to 60%, more preferably a 30% to 50%, even more preferably a 40% to 50%, for example, a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65% or 70% decrease.

14. The method comprises administering the fusion protein intravitreally or intravenously to the individual at a single dose of about 0.01 mg / eye to 10 mg / eye, preferably 0.05 mg / eye to 8 mg / eye, more preferably 0.05 mg / eye to 6 mg / eye, even more preferably 0.5 mg / eye to 5 mg / eye, even more preferably 1 mg / eye to 5 mg / eye, even more preferably 2 mg / eye to 5 mg / eye, once per day, once every two days, twice per week, once per week, once every two weeks, once per four weeks, once per five weeks, or once per six weeks, wherein the individual's foveal retinal thickness level is reduced by 25 μm or more, for example, by 25 μm to 5 μm, 6 or 8 weeks after administration, compared to the individual's pre-administration level of the foveal retinal thickness level. 350μm, preferably 50μm to 300μm, more preferably 50μm to 200μm, for example 25μm, 50μm, 75μm, 100μm, 125μm, 150μm, 175μm, 200μm, 225μm, 250μm, 275μm, 300μm, 325μm, 350μm, or a decrease of 5% or more compared to pre-administration levels, for example 10% to 70%, preferably 10% to 60%, more preferably 30% to 50%, even more preferably 40% to 50%, for example 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65% or 70%.

15. The method comprises administering the fusion protein intravitreally or intravenously to the individual at a single dose of about 0.01 mg / eye to 10 mg / eye, preferably 0.05 mg / eye to 8 mg / eye, more preferably 0.05 mg / eye to 6 mg / eye, even more preferably 0.5 mg / eye to 5 mg / eye, even more preferably 1 mg / eye to 5 mg / eye, even more preferably 2 mg / eye to 5 mg / eye, once per day, once every two days, twice per week, once per week, once every two weeks, once per four weeks, once per five weeks, or once per six weeks, wherein the area of ​​choroidal neovascularization (CNV) of the individual is reduced by 0.1 mm 6 or 8 weeks after administration compared to a pre-administration level of the area of ​​CNV of the individual. ２ For example, the decrease is 0.1 mm or more. ２ ~20mm ２ , preferably 0.2 mm ２ ~5mm ２ , more preferably 0.3 mm ２ ~2mm ２ It decreases, for example, by 0.1 mm. ２ , 0.2 mm ２ , 0.3 mm ２ , 0.4 mm ２ , 0.5 mm ２ , 0.6 mm ２ , 0.7 mm ２ , 0.8 mm ２ , 0.9 mm ２ , 1 mm ２ , 1.1 mm ２ , 1.2 mm ２ , 1.3 mm ２ , 1.4 mm ２ , 1.5 mm ２ , 1.6 mm ２ , 1.7 mm ２ , 1.8 mm ２ , 1.9 mm ２ , 2 mm ２ , 2.1 mm ２ , 2.2 mm ２ , 2.3 mm ２ , 2.4 mm ２ , 2.5 mm ２ , 2.6 mm ２ , 2.7 mm ２ , 2.8 mm ２ , 2.9 mm ２ , 3 mm ２ , 3.1 mm ２ , 3.2 mm ２ , 3.3 mm ２ , 3.4 mm ２ , 3.5 mm ２ , 3.6 mm ２ , 3.7 mm ２ , 3.8 mm ２ , 3.9 mm ２ , 4 mm ２ , 4.1 mm ２ , 4.2 mm ２ , 4.3 mm ２ , 4.4 mm ２ , 4.5 mm ２ , 4.6 mm ２ , 4.7 mm ２ , 4.8 mm ２ , 4.9 mm ２ , 5 mm ２ , 5.5 mm ２ , 6 mm ２ , 6.5 mm ２ , 7 mm ２ , 7.5 mm ２ , 8 mm ２ , 8.5 mm ２ , 9 mm ２ , 9.5 mm ２ , 10 mm ２ , 10.5 mm ２ , 11 mm ２ , 11.5 mm ２ , 12 mm ２ , 12.5 mm ２ , 13 mm ２ , 13.5 mm ２ , 14 mm ２ , 14.5 mm ２ , 15 mm ２ , 15.5 mm ２ , 16 mm ２ , 16.5 mm ２ , 17 mm ２ , 17.5 mm ２ , 18 mm ２ , 18.5 mm ２ , 19 mm ２ , 19.5 mm ２ or 20 mm ２10. The method of any one of the above claims, wherein the level of IL-1 is decreased or is decreased by more than 5% compared to pre-administration levels, for example by 10% to 70%, preferably by 10% to 60%, more preferably by 30% to 50%, even more preferably by 40% to 50%, for example by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65% or 70%.

16. the fusion protein is administered intravitreally or intravenously to the individual at a single dose of about 0.01 mg / eye to 10 mg / eye, preferably 0.05 mg / eye to 8 mg / eye, more preferably 0.05 mg / eye to 6 mg / eye, even more preferably 0.5 mg / eye to 5 mg / eye, even more preferably 1 mg / eye to 5 mg / eye, even more preferably 2 mg / eye to 5 mg / eye once per day, once every two days, twice per week, once per week, once every two weeks, once per four weeks, once per five weeks, or once per six weeks, to achieve a pre-treatment level of best corrected visual acuity (BCVA) in the individual. In comparison, 6 or 8 weeks after administration, the individual's best corrected visual acuity (BCVA) is improved by at least 1 letter on the ETDRS chart, preferably by at least 5 letters on the ETDRS chart, more preferably by 5 to 35 letters on the ETDRS chart, for example by 5 to 25 letters on the ETDRS chart, for example by 5 to 10 letters, 5 to 15 letters, 5 to 20 letters, 10 to 15 letters, 10 to 20 letters, 10 to 25 letters, 15 to 20 letters or 15 to 25 letters, for example, ... 10 to 2 Improved by 5% or more, preferably 10% or more, for example, 10% to 200%, preferably 10% to 150%, more preferably 10% to 100%, and even more preferably 20% to 300%, more preferably 20% to 400%, more preferably 20% to 50%, more preferably 20% to 60%, more preferably 20% to 70%, more preferably 20% to 80%, more preferably 20% to 90%, more preferably 20% to 100%, and even more preferably 20% to 300%, more preferably 20% to 400%, more preferably 20% to 50%, more preferably 20% to 50%, more preferably 20% to 60%, and even more preferably 20% to 70%, and even more preferably 20% to 80%, and even more preferably 20% to 90%, and even more preferably 20% to 10 ...

5. The method of any one of the above claims, wherein the method is improved by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190% or 200%.

17. 1. Use of a fusion protein that inhibits the VEGF pathway and the complement pathway in the manufacture of a medicament for preventing or treating age-related macular degeneration (AMD) in an individual, comprising: The fusion protein comprises the sequence of SEQ ID NO:

1. use.

18. The use according to claim 17, wherein the sequence of the fusion protein is the sequence shown in SEQ ID NO:

1.

19. The use according to claim 17 or 18, wherein the AMD is as defined in any one of claims 4 to 7.

20. The use according to any one of claims 17 to 19, wherein the individual is as defined in any one of claims 8 to 10.

21. comprising a fusion protein that inhibits the VEGF pathway and the complement pathway, The fusion protein comprises the sequence of SEQ ID NO:

1. Single drug dose unit.

22. 22. The single drug dose unit of claim 21, wherein the sequence of the fusion protein is the sequence shown in SEQ ID NO:

1.

23. 0.01 mg to 10 mg, preferably 0.05 mg to 8 mg, more preferably 0.05 mg to 6 mg, even more preferably 0.5 mg to 5 mg, even more preferably 1 mg to 5 mg, even more preferably 2 mg to 5 mg, for example, 0.5 mg to 2 mg, 1 mg to 3 mg, 2 mg to 4 mg, 2 mg to 3 mg or 3 mg to 5 mg, for example, 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0. 35mg, 0.4mg, 0.45mg, 0.5mg, 0.55mg, 0.6mg, 0.65mg, 0.7mg, 0.75mg, 0.8mg, 0.85mg, 0.9mg, 0.95mg, 1mg, 1.1mg, 1. 2mg, 1.3mg, 1.4mg, 1.5mg, 1.6mg, 1.7mg, 1.8mg, 1.9mg, 2mg, 2.1mg, 2.2mg, 2.3mg, 2.4mg, 2.5mg, 2.6mg, 2.7mg, 2.8 mg, 2.9mg, 3mg, 3.1mg, 3.2mg, 3.3mg, 3.4mg, 3.5mg, 3.6mg, 3.7mg, 3.8mg, 3.9mg, 4mg, 4.1mg, 4.2mg, 4.3mg, 4.4mg, 4.5mg, 4.6mg, 4.7mg, 4.8mg, 4.9mg, 5mg, 5.1mg, 5.2mg, 5.3mg, 5.4mg, 5.5mg, 5.6mg, 5.7mg, 5.8mg, 5.9mg, 6mg, 6.1 23. A single drug dosage unit according to claim 21 or 22, comprising a dose of the fusion protein of: 6.2 mg, 6.3 mg, 6.4 mg, 6.5 mg, 6.6 mg, 6.7 mg, 6.8 mg, 6.9 mg, 7 mg, 7.1 mg, 7.2 mg, 7.3 mg, 7.4 mg, 7.5 mg, 7.6 mg, 7.7 mg, 7.8 mg, 7.9 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, preferably 2 mg or 4 mg.

24. A drug kit comprising the fusion protein according to any one of claims 21 to 23.

25. Use of a single drug dosage unit according to any one of claims 21 to 23 or a drug kit according to claim 24 in the manufacture of a medicament for preventing or treating age-related macular degeneration (AMD).

26. A single drug dosage unit according to any one of claims 21 to 23 or a drug kit according to claim 24 for preventing or treating age-related macular degeneration (AMD).

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