KR20220147787A - Fusion protein comprising complement pathway inhibitor protein and use thereof - Google Patents

Abstract

The present invention provides a fusion protein comprising: a CRIg extracellular domain or a fragment thereof, and CD59 or a variant thereof; or a protein that specifically binds to VEGF. Also, the present invention provides a fusion protein comprising a protein that specifically binds to CD59 or a variant thereof and VEGF. The protein is not only effective for complement-related diseases, but also efficiently regulates angiogenesis, thereby being effectively used for the treatment and prevention of eye diseases, especially macular degeneration, and having high industrial potential.

Description

Fusion protein comprising complement pathway inhibitory protein and use thereof

The present invention relates to a fusion protein comprising a complement pathway inhibitory protein and a composition for treating eye diseases, specifically macular degeneration using the same.

Macular degeneration refers to a disease characterized by loss of central vision associated with abnormalities of Bruch's membrane, choroid, neural retina and/or retinal pigment epithelium. At the center of the retina is the macula, which is about 1/3 to 1/2 cm in diameter. Below the retina is the choroid, a collection of blood vessels embedded in fibrous tissue, and the pigment epithelium (PE) above the choroid layer. At this time, the choroidal blood vessels provide nutrition to the retina. The choroid and PE are found in the anterior chamber of the eye.

Age-related macular degeneration (AMD), one of the macular degenerations, is a disease associated with progressive loss of vision in the central part of the visual field, changes in color discrimination, and abnormal cancer adaptation and sensitivity. AMD is largely divided into dry or wet AMD. Dry AMD is associated with atrophic cell death in the central retina or macula required for fine vision used for activities such as reading, driving, or facial recognition. About 10-20% of the dry AMD patients progress to a type 2 of AMD known as wet AMD.

The most significant risk factors for both forms of development are age and deposition of drusen, an abnormal extracellular deposit behind the retinal pigment epithelium. Crystals are characteristic deposits associated with AMD. These crystals are known to contain complement activators, inhibitors, activation-specific complement fragments, and terminal pathway factors such as the cell membrane attack complex (MAC or C5b-9). In addition, wet AMD is associated with choroidal neovascularization (CNV). Although the pathogenesis of de novo choroidal angiogenesis is little known, factors such as inflammation, ischemia, and local production of angiogenic factors are thought to be important.

On the other hand, the complement system is a critical component of innate immunity against microbial infection and contains a group of proteins that normally exist in an inactive state in serum. The protein is activated through traditional pathways, lectin pathways and alternative pathways. Molecules on the surface of microorganisms can activate this pathway, resulting in the formation of a protease complex known as C3-converting enzyme.

Activation of the complement pathway involves biologically active fragments of complement proteins that mediate inflammatory responses in leukocyte chemotaxis, activation of macrophages, neutrophils, platelets, mast cells and endothelial cells, increased vascular permeability, cell lysis, and tissue damage. For example, it produces C3a, C4a and C5a hypertoxin (Anaphylatoxin) and C5b-9 cell membrane attack complex (MAC). In addition, it has been reported that some of the eye diseases are complement-related (Japanese Patent Application No. 2007-536964). However, even now, the need for drugs to effectively treat eye diseases, particularly macular degeneration, is increasing, and research on therapeutic agents for macular degeneration continues.

Japanese Patent Application 2007-536964

Accordingly, the present inventors completed the present invention by confirming that a fusion protein that blocks the complement-related pathway and the angiogenesis pathway can be utilized as a therapeutic agent for macular degeneration as a result of research to effectively treat and prevent eye diseases, particularly macular degeneration. .

In order to achieve the above object, the present invention provides an extracellular domain of CRIg or a fragment thereof; And it provides a fusion protein comprising an immunoglobulin fragment, a dimer thereof, and a pharmaceutical composition comprising the same as an active ingredient.

In addition, the present invention provides CD59 or a variant thereof; And it provides a fusion protein comprising an immunoglobulin fragment, a dimer thereof, and a pharmaceutical composition comprising the same as an active ingredient.

an extracellular domain of CRIg or a fragment thereof, which is a complement-related pathway inhibitory protein; and CD59 or a variant thereof; Alternatively, a fusion protein comprising a protein that specifically binds to VEGF can effectively inhibit complement-related mechanisms as well as angiogenesis. Accordingly, it is possible to effectively treat or prevent ocular diseases induced by the complement system and ocular diseases induced by angiogenesis. Therefore, the fusion protein can be effectively used to effectively treat macular degeneration, particularly, both dry macular degeneration and wet macular degeneration.

1 is a graph showing the binding affinity of PRO011 to C3b.
2 is a graph showing the binding affinity of PRO013 to C3b.
3 is a graph showing the binding affinity of PRO014 to C3b.
4 is a graph showing the binding affinity of PRO014 to VEGF165.
5 is a graph showing the binding affinity of PRO013 to C3b.
6 is a graph showing the binding affinity of PRO061 to C3b.
7 is a graph showing the binding ability of PRO014 to human C3b protein through enzyme-linked immunoprecipitation assay.
8a and 8b show PRO011, PRO013, PRO014, PRO017, PRO055, PRO056, PRO057, PRO058, PRO059, PRO060 and This study analyzed the inhibitory effects of PRO061 on the classical complement activation pathway and the alternative complement pathway.
9 shows a schematic diagram of the fusion protein: (left) CRIg-Fc (PRO011), (middle) CRIg-Fc-CD59 (PRO012, PRO013, PRO061), (right) CRIg-Fc-VEGF binder (PRO014).
10A and 10B are photographs and graphs comparing groups administered with test substances after induction of a choroidal neovascularization mouse model, immediately after induction, and 7 days after induction. 10A is a photograph confirming choroidal neovascularization through fluorescence fundus angiography, and FIG. 10B is a numerical representation of the presence or absence of choroidal neovascularization for each group.
11a and 11b are photographs and graphs comparing the number of cells in the outer granular layer, the area and the C3 expression level in the retina in the No AMD group, the Vehicle group and the PRO058 group after induction of the dry macular degeneration model.
12 is a graph showing the concentration in the vitreous humor after administration of 2,500 μg of PRO014 through intraocular injection in rabbits.
13 is a graph showing the concentration in the aqueous humor after administration of 2,500 μg of PRO014 through intraocular injection in rabbits.

Fusion protein containing CRIg extracellular domain

One aspect of the present invention, the extracellular domain of CRIg or a fragment thereof; And it provides a fusion protein comprising an immunoglobulin fragment.

In addition, the fusion protein is CD59 or a variant thereof; Or it may further include a protein that specifically binds to VEGF.

As used herein, the term “CRIg” refers to a complement receptor of the immunoglobulin family. As a receptor belonging to the type 4 complement receptor among the four types of complement receptors, it is expressed on the surface of macrophages, also called Kupffer cells, which phagocytose in the liver. CRIg is an Integral Membrane Protein bound to an extracellular region with an immunoglobulin domain. CRIg binds to C3b and iC3b, a fragment of complement, and is the most important receptor for phagocytic cells to recognize and eliminate bacteria that enter the human body or infectious bacteria in the blood.

In this case, the CRIg extracellular domain may be a portion excluding the transmembrane and cytoplasmic domain portions of the receptor. Specifically, human CRIg may have the amino acid sequence of SEQ ID NO: 29 or 30, and mouse CRIg may have the amino acid sequence of SEQ ID NO: 32. In addition, the human CRIg extracellular domain may have the amino acid sequence of SEQ ID NO: 15 or 48, and the mouse CRIg extracellular domain may have the amino acid sequence of SEQ ID NO: 16.

As used herein, the term “CD59” is a membrane-bound regulator that is a membrane binding inhibitor that reduces naturally occurring membrane attack complex (MAC) formation. In age-related macular degeneration (AMD), disease severity correlates with the formation of the membrane attack complex (MAC), a terminal step in the complement cascade, and reduced expression of CD59, a membrane-bound regulatory protein involved in MAC formation.

In this case, CD59 may have the amino acid sequence of SEQ ID NO: 19. In addition, some amino acids of the CD59 may be substituted with other amino acids. Specifically, the CD59 mutant may be one in which the 41st amino acid and/or the 44th amino acid of SEQ ID NO: 19 is substituted with another amino acid. More specifically, the CD59 variant may be in a form in which lysine (K), which is the 41st amino acid of SEQ ID NO: 19, is substituted with glutamine (Q). In this case, the CD59 variant may have the amino acid sequence of SEQ ID NO: 20. In addition, the CD59 variant may have a form in which histidine (H), which is the 44th amino acid of SEQ ID NO: 19, is substituted with glutamine (Q). In this case, the CD59 variant may have the amino acid sequence of SEQ ID NO: 21.

As used herein, the term “VEGF” is a vascular endothelial growth factor, which is produced by cells that stimulate blood vessel formation. It is an important signaling protein involved in angiogenesis. It is known that abnormal vascular proliferation in the retina is stimulated by VEGF in wet AMD.

As used herein, the term "a protein that specifically binds to VEGF" refers to an extracellular domain of an antibody or VEGF receptor that specifically binds to VEGF.

As used herein, the term "antibody that specifically binds to VEGF" refers to an antibody that specifically binds to VEGF to cause an antigen-antibody reaction.

As used herein, the term “VEGF receptor” refers to a receptor that binds to vascular endothelial growth factor (VEGF). In this case, the VEGF receptor may be any one selected from the group consisting of VEGF receptor 1 (VEGFR-1), VEGF receptor 2 (VEGFR-2), and VEGF receptor 3 (VEGFR-3). In this case, in one embodiment, the VEGF receptor may be VEGF receptor 1.

As used herein, the term "extracellular domain of the receptor of VEGF" refers to a fragment of a receptor that binds to vascular endothelial growth factor (VEGF). Specifically, it refers to a portion excluding the transmembrane region and the cytoplasmic region of the VEGF receptor. In addition, the extracellular domain of the receptor of VEGF may be a fragment of the extracellular domain of the receptor of VEGF as long as it binds to VEGF. In this case, one embodiment of the extracellular domain of the VEGF receptor may have the amino acid sequence of SEQ ID NO: 22.

In addition, the extracellular domain of CRIg or a fragment thereof and an immunoglobulin fragment may be linked through a linker. The linker connects two proteins. One embodiment of the linker may include 1 to 50 amino acids, albumin or a fragment thereof, or an Fc domain of an immunoglobulin. In this case, the Fc domain of the immunoglobulin includes the heavy chain constant region 2 (CH2) and the heavy chain constant region 3 (CH3) of the immunoglobulin, and includes the variable regions and the light chain constant region 1 (CH1) of the heavy and light chains of the immunoglobulin protein that does not The immunoglobulin may be IgG, IgA, IgE, IgD or IgM, preferably IgG1.

In addition, the fusion protein may be specifically composed of the following structural formula (I) or (II):

N'-X-[Linker(1)]n-Fc domain-[Linker(2)]m-Y-C'(I)

N'-Y-[Linker(1)]n-Fc domain-[Linker(2)]m-X-C'(II)

At this time, in the structural formulas (I) and (II),

The N' is the N-terminus of the fusion protein,

The C' is the C-terminus of the fusion protein,

wherein X is an extracellular domain of CRIg or a fragment thereof,

wherein Y is CD59 or a variant thereof; Or a protein that specifically binds to VEGF,

The linker (1) and linker (2) are peptide linkers,

Wherein n and m are each independently O or 1.

In this case, the aforementioned immunoglobulin fragment may be an Fc domain of an immunoglobulin. Specifically, the Fc domain may include the CH2 and CH3 regions of an immunoglobulin Fc heavy chain. In addition, the Fc domain of the immunoglobulin may be a wild-type Fc domain as well as an Fc domain variant. In addition, the term "Fc domain variant" as used herein is different from the glycosylation pattern of the wild-type Fc domain, increased sugar chains compared to the wild-type Fc domain, decreased sugar chains compared to the wild-type Fc domain, or the sugar chains are removed ( It may be in a deglycosylated form. It also includes an Aglycosylated Fc domain. The Fc domain or variant may have a number of sialic acid, fucosylation, and glycosylation adjusted through culture conditions or genetic manipulation of the host.

In addition, the sugar chain of the Fc domain of an immunoglobulin can be modified by a conventional method such as a chemical method, an enzymatic method, and a genetic engineering method using microorganisms. In addition, the Fc domain variant may be a mixed form of the immunoglobulin Fc region of IgG, IgA, IgE, IgD or IgM. In addition, the Fc domain variant may be a form in which some amino acids of the Fc domain are substituted with other amino acids. One embodiment of the Fc domain variant may be one having any one amino acid sequence selected from the group consisting of SEQ ID NOs: 7, 14, 17 and 18.

Preferably, the fusion protein may be of structural formula (I). The extracellular domain of the CRIg or a fragment thereof is as described above. In addition, the CD59 or a variant thereof; Alternatively, a protein that specifically binds to VEGF is as described above.

Specifically, the fusion protein may have the amino acid sequence of SEQ ID NO: 1, 2, 3, 4, 8, 9, 10 or 12. According to another embodiment, the fusion protein comprises 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity. In this case, identity, for example, percent homology, may be determined through homology comparison software such as BlastN software of the National Center of Biotechnology Information (NCBI).

said CD59 or a variant thereof; Alternatively, a peptide linker (1) may be included between the protein binding specifically to VEGF and the Fc domain. The peptide linker (1) may consist of 5 to 80 consecutive amino acids, 20 to 60 consecutive amino acids, or 25 to 50 consecutive amino acids, or 30 to 40 amino acids. In one embodiment, the peptide linker (1) may consist of 30 amino acids. In addition, the peptide linker (1) may include at least one cysteine. Specifically, it may contain one, two or three cysteines. In addition, the peptide linker (1) may be derived from the hinge of an immunoglobulin. In one embodiment, the peptide linker (1) may be a peptide linker consisting of the amino acid sequence of SEQ ID NO: 25 or 27.

The peptide linker (2) may consist of 1 to 50 consecutive amino acids, or 3 to 30 consecutive amino acids, or 5 to 15 amino acids. In one embodiment, the peptide linker (2) may be (G4S)n (in this case, n is an integer of 1 to 10). In this case, in (G4S)n, n may be 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. In one embodiment, the peptide linker (2) may be a peptide linker consisting of the amino acid sequence of SEQ ID NO: 26 or 28.

Another aspect of the present invention, the extracellular domain of the CRIg or a fragment thereof and the CD59 or a variant thereof; Alternatively, it provides a dimer to which two fusion proteins comprising a protein that specifically binds to VEGF are bound. The extracellular domain of the CRIg or a fragment thereof is as described above. In addition, the CD59 or a variant thereof; Alternatively, a protein that specifically binds to VEGF is as described above.

In this case, the bond between the fusion proteins constituting the dimer may be formed by a disulfide bond by a cysteine present in the linker, but is not limited thereto. The fusion proteins constituting the dimer may be the same, but may be different fusion proteins. Preferably, the dimer may be a homodimer. An embodiment of the fusion protein constituting the dimer may be a protein having the amino acid sequence of SEQ ID NO: 1, 2, 3, 4, 8, 9, 10 or 12.

Polynucleotide encoding a fusion protein comprising a CRIg extracellular domain

Another aspect of the present invention provides an extracellular domain of CRIg or a fragment thereof and CD59 or a variant thereof; Or it provides a polynucleotide encoding a fusion protein comprising a protein that specifically binds to VEGF.

The extracellular domain of the CRIg or a fragment thereof is as described above. In addition, the CD59 or a variant thereof; Alternatively, a protein that specifically binds to VEGF is as described above.

According to one embodiment, the polypeptide is at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 86 with SEQ ID NO: 1, 2, 3, 4, 8, 9, 10 or 12 %, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96 %, at least about 97%, at least about 98%, at least about 99%, or at least about 100% identity. According to one embodiment, it may include the nucleic acid sequence of SEQ ID NO: 33, 34, 35, 36, 40, 41, 42 or 44.

The polynucleotide may further include a nucleic acid encoding a signal sequence or a leader sequence. As used herein, the term “signal sequence” refers to a signal peptide that directs secretion of a target protein. The signal peptide is cleaved after translation in the host cell. Specifically, the signal sequence is an amino acid sequence that initiates the movement of the protein through the ER (Endoplasmic reticulum) membrane.

The signal sequence is well known in the art, and typically contains 16 to 30 amino acid residues, but may include more or fewer amino acid residues. A typical signal peptide consists of three regions: a basic N-terminal region, a central hydrophobic region, and a more polar C-terminal region. The central hydrophobic region contains 4 to 12 hydrophobic residues that anchor the signal sequence through the membrane lipid bilayer during migration of the immature polypeptide.

After initiation, the signal sequence is cleaved in the lumen of the ER by cellular enzymes commonly known as signal peptidases. In this case, the signal sequence may be a secretion signal sequence of tPa (Tissue Plasminogen Activation), HSV gDs (Signal sequence of Herpes simplex virus glycoprotein D), or growth hormone. Preferably, a secretion signal sequence used in higher eukaryotic cells including mammals and the like may be used. In addition, the signal sequence may be used by using a wild-type signal sequence, or by substituting a codon having a high expression frequency in a host cell.

A vector loaded with a polynucleotide encoding a fusion protein comprising the CRIg extracellular domain

Another aspect of the present invention provides a vector comprising the polynucleotide.

The vector can be introduced into a host cell, recombination and insertion into the host cell genome. or said vector is understood as a nucleic acid means comprising a polynucleotide sequence capable of spontaneously replicating as an episome. Such vectors include linear nucleic acids, plasmids, phagemids, cosmids, RNA vectors, viral vectors and analogs thereof. Examples of viral vectors include, but are not limited to, retroviruses, adenoviruses, and adeno-associated viruses.

Specifically, the vector may be plasmid DNA, phage DNA, etc., commercially developed plasmids (pUC18, pBAD, pIDTSAMRT-AMP, etc.), E. coli-derived plasmids (pYG601BR322, pBR325, pUC118, pUC119, etc.), Bacillus subtilis plasmids (pUB110, pTP5, etc.), yeast-derived plasmids (YEp13, YEp24, YCp50, etc.), phage DNA (Charon4A, Charon21A, EMBL3, EMBL4, λgt10, λgt11, λZAP, etc.), animal virus vectors (retroviruses) ), adenovirus, vaccinia virus, etc.), insect virus vectors (baculovirus, etc.). Since the vector exhibits different protein expression levels and modifications depending on the host cell, it is preferable to select and use the most suitable host cell for the purpose.

As used herein, the term "gene expression" or "expression" of a target protein is understood to mean transcription of a DNA sequence, translation of an mRNA transcript, and secretion of a fusion protein product or fragment thereof. A useful expression vector may be RcCMV (Invitrogen, Carlsbad) or a variant thereof. The expression vector includes a human CMV (Cytomegalovirus) promoter to promote continuous transcription of the target gene in mammalian cells, and a bovine growth hormone polyadenylation signal sequence to increase the stable-state level of RNA after transcription. can do.

Transformed cells expressing a fusion protein comprising the CRIg extracellular domain

Another aspect of the present invention provides a transformed cell into which the vector is introduced.

The host cell of the transformed cell may include, but is not limited to, a cell of prokaryotic, eukaryotic, mammalian, plant, insect, fungal or cellular origin. As an example of the prokaryotic cell, E. coli may be used. In addition, yeast may be used as an example of eukaryotic cells. In addition, CHO cells, F2N cells, CSO cells, BHK cells, Bowes melanoma cells, HeLa cells, 911 cells, AT1080 cells, A549 cells, HEK 293 cells or HEK293T cells may be used as the mammalian cells. , but is not limited thereto, and any cell that can be used as a mammalian host cell known to those skilled in the art is available.

In addition, when introducing the expression vector into the host cell, the CaCl ₂ precipitation method, the CaCl ₂ precipitation method using a reducing material called DMSO (Dimethyl sulfoxide) to increase the efficiency by the Hanahan method, electroporation (Electroporation), calcium phosphate precipitation method , protoplast fusion method, agitation method using silicon carbide fiber, agrobacterium mediated transformation method, transformation method using PEG, dextran sulfate, lipofectamine and drying/inhibition mediated transformation method can be used.

As described above, in order to optimize the properties of the fusion protein as a therapeutic agent or for other purposes, the glycosylation-related gene possessed by the host cell is manipulated through a method known to those skilled in the art, and the sugar chain pattern of the fusion protein (e.g., sialic acid, fucosylation, glycation) can be adjusted.

Method for producing fusion protein containing CRIg extracellular domain

Another aspect of the present invention, the extracellular domain of CRIg or a fragment thereof comprising the step of culturing the transformed cells; and CD59 or a variant thereof; Or it provides a method for producing a fusion protein comprising a protein that specifically binds to VEGF. Specifically, the production method comprises the steps of i) culturing the transformed cells to obtain a culture; and ii) recovering the fusion protein from the culture.

The method of culturing the transformed cells may be performed using a method well known in the art. Specifically, the culture may be continuously cultured in a batch process or in a fed batch or repeated fed batch process (Fed batch or Repeated fed batch process).

Use of a fusion protein comprising the CRIg extracellular domain or a dimer thereof

Another aspect of the present invention, a fusion protein comprising the extracellular domain of CRIg or a fragment thereof and an immunoglobulin fragment, or a fusion protein dimer to which two fusion proteins are bound, as an active ingredient, a pharmaceutical for treating or preventing eye disease A composition is provided. In this case, the fusion protein is CD59 or a variant thereof; Or it may further include a protein that specifically binds to VEGF.

The ocular diseases include age-related macular degeneration (AMD), map atrophy (GA), choroidal neovascularization (CNV), uveitis, diabetic and other ischemia-related retinopathy, diabetic macular edema, pathological myopia, von Hippel- It may be any one selected from the group consisting of Lindau disease, histoplasmosis of the eye, central retinal vein occlusion (CRVO), corneal neovascularization and retinal neovascularization.

The extracellular domain of the CRIg or a fragment thereof is as described above. In addition, the CD59 or a variant thereof; Alternatively, a protein that specifically binds to VEGF is as described above.

The preferred dosage of the pharmaceutical composition varies depending on the patient's condition and weight, the degree of disease, drug form, administration route and period, but may be appropriately selected by those skilled in the art. In the pharmaceutical composition for treating or preventing ocular diseases of the present invention, the active ingredient may exhibit ocular disease therapeutic activity, or, in particular, any amount ( effective amount), a typical effective amount will be determined within the range of 0.001% to 20.0% by weight based on the total weight of the composition. Herein, the term "effective amount" refers to an amount of an active ingredient capable of inducing an improvement or treatment effect of an eye disease, in particular an improvement or therapeutic effect of macular degeneration. Such effective amounts can be determined empirically within the ordinary ability of one of ordinary skill in the art.

As used herein, the term “treatment” may be used to include both therapeutic treatment and prophylactic treatment. In this case, prevention may be used in the sense of alleviating or reducing a pathological condition or disease of an individual. In one embodiment, the term "treatment" includes any form of administration or application for treating a disease in a mammal, including a human. The term also includes inhibiting or slowing the disease or its progression; restoring or repairing damaged or missing function, thereby partially or completely relieving the disease; or stimulate inefficient processes; It includes the meaning of alleviating serious diseases.

Pharmacokinetic parameters such as bioavailability and underlying parameters such as clearance rate may also affect efficacy. Thus, "enhanced efficacy" (eg, improvement in efficacy) can be attributed to improved pharmacokinetic parameters and improved efficacy, measured by comparing parameters such as clearance rate and ocular disease treatment or amelioration in a test animal or human subject. can be

Herein, the term "therapeutically effective amount" or "pharmaceutically effective amount" refers to an amount of a compound or composition effective for preventing or treating a target disease, which is sufficient to treat the disease at a reasonable benefit/risk ratio applicable to medical treatment, and It means an amount that does not cause side effects. The level of the effective amount is determined by the patient's health status, the type of disease, the severity, drug activity, sensitivity to the drug, administration method, administration time, administration route and excretion rate, treatment period, factors including the combination or concurrently used drugs; It may be determined according to factors well known in the medical field. In one embodiment, a therapeutically effective amount refers to an amount of a drug effective to treat an eye disease.

In this case, the pharmaceutical composition may further include a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may be any non-toxic material suitable for delivery to a patient. Distilled water, alcohol, fats, waxes and inert solids may be included as carriers. Pharmaceutically acceptable adjuvants (buffers, dispersants) may also be included in the pharmaceutical composition.

Specifically, the pharmaceutical composition may be prepared as a parenteral formulation according to the route of administration by a conventional method known in the art, including a pharmaceutically acceptable carrier in addition to the active ingredient. Here, "pharmaceutically acceptable" means that it does not inhibit the activity of an active ingredient and does not have toxicity beyond what the application (prescription) target can adapt.

When the pharmaceutical composition is prepared for parenteral use, it may be formulated in the form of injections, transdermal administrations, nasal inhalants and suppositories together with suitable carriers according to methods known in the art. When formulated as an injection, a suitable carrier may be sterile water, ethanol, polyol such as glycerol or propylene glycol, or a mixture thereof, preferably Ringer's solution, PBS (Phosphate Buffered Saline) containing triethanolamine or sterile for injection. Water, an isotonic solution such as 5% dextrose, etc. can be used. Formulation of pharmaceutical compositions is known in the art, and specifically, reference may be made to the literature [Remington's Pharmaceutical Sciences (19th ed., 1995)] and the like. This document is considered a part of this specification.

A preferred dosage of the pharmaceutical composition is in the range of 0.01 ug/kg to 10 g/kg, or 0.01 mg/kg to 1 g/kg per day, depending on the patient's condition, weight, sex, age, patient's severity, and administration route. can be Administration may be performed once a day or divided into several times. Such dosages should not be construed as limiting the scope of the invention in any respect.

Subjects to which the pharmaceutical composition can be applied (prescribed) are mammals and humans, particularly preferably humans. In addition to the active ingredient, the pharmaceutical composition of the present application may further include any compound or natural extract known to have an effect on treating eye diseases, particularly macular degeneration.

Fusion protein comprising CD59 or a variant thereof

Another aspect of the present invention is CD59 or a variant thereof; And it provides a fusion protein comprising an immunoglobulin fragment.

In this case, the above-described fusion protein may further include a protein that specifically binds to VEGF.

Specifically, the CD59 may be SEQ ID NO: 19. In addition, the CD59 variant may be one in which the 41st amino acid and/or the 44th amino acid of SEQ ID NO: 19 is substituted with another amino acid. In addition, the protein that specifically binds to VEGF may be an extracellular domain of an antibody or VEGF receptor that specifically binds to VEGF. said CD59 or a variant thereof; Alternatively, a protein that specifically binds to VEGF is as described above.

In addition, CD59 or a variant thereof and an immunoglobulin fragment may be linked via a linker.

The fusion protein may be specifically composed of the following structural formula (III) or (IV):

N'-V-[Linker(1)]p-Fc domain-[Linker(2)]q-(W)r-C'(III)

N'-(W)r-[Linker(1)]p-Fc domain-[Linker(2)]q-V-C'(IV)

In this case, in the structural formulas (III) and (IV),

The N' is the N-terminus of the fusion protein,

The C' is the C-terminus of the fusion protein,

wherein V is CD59 or a variant thereof,

Wherein W is a protein that specifically binds to VEGF,

The linker (1) and linker (2) are peptide linkers,

Wherein p, q and r are each independently O or 1.

In addition, the immunoglobulin fragment is as described above.

In this case, CD59 or a variant thereof, a protein that specifically binds to VEGF is as described above. Specifically, the fusion protein may have any one amino acid sequence selected from the group consisting of SEQ ID NOs: 5, 6 and 11.

Polynucleotide encoding a fusion protein comprising CD59 or a variant thereof

Another aspect of the present invention is CD59 or a variant thereof; And it provides a polynucleotide encoding a fusion protein comprising a protein that specifically binds to VEGF.

The CD59 or variant thereof and the protein specifically binding to VEGF are as described above.

According to one embodiment, the polypeptide is at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 86%, at least about 87%, at least about 88% with SEQ ID NO: 5, 6 or 11 %, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98 %, at least about 99%, or at least about 100% identity. According to one embodiment, it may include the nucleic acid sequence of SEQ ID NO: 37, 38 or 43.

A vector loaded with a polynucleotide encoding a fusion protein comprising CD59 or a variant thereof

Another aspect of the present invention provides a vector comprising the polynucleotide. The CD59 or variant thereof, VEGF receptor, etc. are as described above.

Transformed cells expressing a fusion protein comprising CD59 or a variant thereof

Another aspect of the present invention provides a transformed cell into which the vector is introduced. The CD59 or variant thereof, VEGF receptor, etc. are as described above.

Use of a fusion protein comprising CD59 or a variant thereof or a dimer thereof

Another aspect of the present invention provides a pharmaceutical composition for treating or preventing eye diseases, comprising a fusion protein comprising CD59 or a variant thereof and an immunoglobulin fragment or a fusion protein dimer to which two fusion proteins are bound as an active ingredient. . In this case, the fusion protein may additionally include a protein that specifically binds to VEGF.

In this case, the eye disease is age-related macular degeneration (AMD), map atrophy (GA), choroidal neovascularization (CNV), uveitis, diabetic and other ischemia-related retinopathy, diabetic macular edema, pathological myopia, von It may be any one selected from the group consisting of Hippel-Lindau disease, histoplasmosis of the eye, central retinal vein occlusion (CRVO), corneal neovascularization, and retinal neovascularization.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

Preparation Example 1. Preparation of fusion protein containing CRIg and fusion protein containing CD59

PROTEIN Format Description corresponding sequence PRO011 Fc-fusion hu CRIg-hu IgG1 Fc DANG seq1 (SEQ ID NO: 1) PRO012 Fc-fusion hu CRIg-hu IgG1 Fc DANG-hu CD59 (K41Q) seq2 (SEQ ID NO: 2) PRO013 Fc-fusion hu CRIg-hu IgG1 Fc DANG-hu CD59 (H44Q) seq3 (SEQ ID NO: 3) PRO014 Fc-fusion hu CRIg-hu IgG1 Fc DANG-VEGF binder seq4 (SEQ ID NO: 4) PRO015 Fc-fusion hu IgG1 Fc DANG-hu CD59 (K41Q) seq5 (SEQ ID NO: 5) PRO016 Fc-fusion hu IgG1 Fc DANG-hu CD59 (H44Q) seq6 (SEQ ID NO: 6) PRO017 Fc-fusion hu IgG1 Fc DANG seq7 (SEQ ID NO: 7) PRO061 Fc-fusion hu CRIg-hu IgG1 Fc DANG-hu CD59 without c-terminal propeptide seq8 (SEQ ID NO: 8) PR0055 Fc-fusion mu CRIg-mu IgG2a Fc DANG seq9 (SEQ ID NO: 9) PRO056 Fc-fusion mu CRIg-mu IgG2a Fc DANG-mu CD59a seq10 (SEQ ID NO: 10) PRO057 Fc-fusion mu IgG2a Fc DANG-mu CD59a seq11 (SEQ ID NO: 11) PRO058 Fc-fusion mu CRIg-mu IgG2a Fc DANG-VEGF binder seq12 (SEQ ID NO: 12) PRO059 Fc-fusion mu IgG2a Fc DANG-VEGF binder seq13 (SEQ ID NO: 13) PRO060 Fc-fusion mu IgG2a Fc DANG seq14 (SEQ ID NO: 14)

PRO011 (seq1) is composed of human IgG1 Fc with the effector function removed through the extracellular domain region (20-283) of human CRIg protein and linkers GGGGS and DANG mutations (D265A, N297G).

PRO012(seq2) mutated Lysine 41 (K) to Glutamine (Q) so that it was always activated with the extracellular domain region (20-283) of human CRIg protein, linker GGGGS, and the linker GGGGSGGGGS on the back of human IgG1 Fc DANG One CD59 (K41Q) was added.

PRO013 (seq3) is a human CRIg protein extracellular domain region (20-283), linker GGGGS, and linker GGGGSGGGGS on the back of human IgG1 Fc DANG, and histidine (H) 44 is mutated to Glutamine (Q) so that it is always active. One CD59 (H44Q) was added.

PRO014 (seq4) consists of the extracellular domain region (20-283) of the human CRIg protein, the linker GGGGS, the human IgG1 Fc DANG, the linker GGGGSGGGGS, and the VEGF binding site of Aflibercept.

PRO015 (seq5) is composed of human IgG1 Fc DANG, linker GGGGSGGGGS, and CD59 (K41Q) in which Lysine 41 (K) is mutated to Glutamine (Q) so that it is always activated.

PRO016 (seq6) consists of human IgG1 Fc DANG, linker GGGGSGGGGS, and CD59 (H44Q) in which Histidine (H) 44 is mutated to Glutamine (Q) to become an activated form.

PRO017(seq7) consists only of human IgG1 Fc DANG.

PRO061 (seq8) is a human CRIg protein extracellular domain region (20-283), linker GGGGS, and linker GGGGSGGGGS on the back of human IgG1 Fc DANG. Histidine (H) is mutated at No. 44 to Glutamine (Q) so that it is always active. The c-terminal propeptide (103-128) was removed from one CD59 (H44Q).

PRO055(seq9) is composed of mouse IgG2a Fc with effector function removed through extracellular domain region (20-187) of mouse CRIg protein and linker GGGGS and DANG mutations (D265A, N297G).

For PRO056 (seq10), the extracellular domain region (20-187) of the mouse CRIg protein, the linker GGGGS, and the linker GGGGSGGGGS and mouse CD59a were added to the rear of the mouse IgG2a Fc DANG.

PRO057(seq11) consists of mouse IgG2a Fc DANG, linker GGGGSGGGGS, and mouse CD59a.

PRO058 (seq12) is composed of the extracellular domain region (20-187) of the mouse CRIg protein, the linker GGGGS, the mouse IgG2a Fc DANG, the linker GGGGSGGGGS, and the VEGF binding site of Aflibercept.

PRO059(seq13) consists of mouse IgG2a Fc DANG, linker GGGGSGGGGS, and VEGF binding site of Aflibercept.

PRO060(seq14) consists only of mouse IgG2a Fc DANG.

[seq1] hu CRIg-hu IgG1 Fc DANG

RPILEVPESVTGPWKGDVNLPCTYDPLQGYTQVLVKWLVQRGSDPVTIFLRDSSGDHIQQAKYQGRLHVSHKVPGDVSLQLSTLEMDDRSHYTCEVTWQTPDGNQVVRDKITELRVQKLSVSKPTVTTGSGYGFTVPQGMRISLQCQARGSPPISYIWYKQQTNNQEPIKVATLSTLLFKPAVIADSGSYFCTAKGQVGSEQHSDIVKFVVKDSSKLLKTKTEAPTTMTYPLKATSTVKQSWDWTTDMDGYLGETSAGPGKSLP GGGGSDKTHTCPPCPAPELLGG P SVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[seq2] hu CRIg-hu IgG1 Fc DANG -hu CD59 (K41Q)

RPILEVPESVTGPWKGDVNLPCTYDPLQGYTQVLVKWLVQRGSDPVTIFLRDSSGDHIQQAKYQGRLHVSHKVPGDVSLQLSTLEMDDRSHYTCEVTWQTPDGNQVVRDKITELRVQKLSVSKPTVTTGSGYGFTVPQGMRISLQCQARGSPPISYIWYKQQTNNQEPIKVATLSTLLFKPAVIADSGSYFCTAKGQVGSEQHSDIVKFVVKDSSKLLKTKTEAPTTMTYPLKATSTVKQSWDWTTDMDGYLGETSAGPGKSLP GGGGSDKTHTCPPCPAPELLGGP SVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG GGGGSGGGG S LQCYNCPNPTADCKTAVNCSSDFDACLITKAGLQVYNKCW Q FEHCNFNDVTTRLRENELTYYCCKKDLCNFNEQLENGGTSLSEKTVLLLVTPFLAAAWSLHP

[seq3] hu CRIg-hu IgG1 Fc DANG -hu CD59 (H44Q)

RPILEVPESVTGPWKGDVNLPCTYDPLQGYTQVLVKWLVQRGSDPVTIFLRDSSGDHIQQAKYQGRLHVSHKVPGDVSLQLSTLEMDDRSHYTCEVTWQTPDGNQVVRDKITELRVQKLSVSKPTVTTGSGYGFTVPQGMRISLQCQARGSPPISYIWYKQQTNNQEPIKVATLSTLLFKPAVIADSGSYFCTAKGQVGSEQHSDIVKFVVKDSSKLLKTKTEAPTTMTYPLKATSTVKQSWDWTTDMDGYLGETSAGPGKSLP GGGGSDKTHTCPPCPAPELLGGP SVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG GGGGSGGGGS LQCYNCPNPTADCKTAVNCSSDFDACLITKAGLQVYNKCWKFE Q CNFNDVTTRLRENELTYYCCKKDLCNFNEQLENGGTSLSEKTVLLLVTPFLAAAWSLHP

[seq4] hu CRIg-hu IgG1 Fc DANG -VEGF binder

RPILEVPESVTGPWKGDVNLPCTYDPLQGYTQVLVKWLVQRGSDPVTIFLRDSSGDHIQQAKYQGRLHVSHKVPGDVSLQLSTLEMDDRSHYTCEVTWQTPDGNQVVRDKITELRVQKLSVSKPTVTTGSGYGFTVPQGMRISLQCQARGSPPISYIWYKQQTNNQEPIKVATLSTLLFKPAVIADSGSYFCTAKGQVGSEQHSDIVKFVVKDSSKLLKTKTEAPTTMTYPLKATSTVKQSWDWTTDMDGYLGETSAGPGKSLP GGGGSDKTHTCPPCPAPELLGGP SVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG GGGGSGGGGS SDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEK

[seq5] hu IgG1 Fc DANG -hu CD59 (K41Q)

DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG GGGGSGGGGS LQCYNCPNPTADCKTAVNCSSDFDACLITKAGLQVYNKCW Q FEHCNFNDVTTRLRENELTYYCCKKDLCNFNEQLENGGTSLSEKTVLLLVTPFLAAAWSLHP

[seq6] hu IgG1 Fc DANG -hu CD59 (H44Q)

DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG GGGGSGGGG SLQCYNCPNPTADCKTAVNCSSDFDACLITKAGLQVYNKCWKFE Q CNFNDVTTRLRENELTYYCCKKDLCNFNEQLENGGTSLSEKTVLLLVTPFLAAAWSLHP

[seq7] hu IgG1 Fc DANG

SVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSKLTSKSNGQPENNYVKSLSKSNGVLDSDPGFFQLSKLSKSNGQPENGNH

[seq8] hu CRIg- hu IgG1 Fc DANG -hu CD59 without c-terminal propeptide

RPILEVPESVTGPWKGDVNLPCTYDPLQGYTQVLVKWLVQRGSDPVTIFLRDSSGDHIQQAKYQGRLHVSHKVPGDVSLQLSTLEMDDRSHYTCEVTWQTPDGNQVVRDKITELRVQKLSVSKPTVTTGSGYGFTVPQGMRISLQCQARGSPPISYIWYKQQTNNQEPIKVATLSTLLFKPAVIADSGSYFCTAKGQVGSEQHSDIVKFVVKDSSKLLKTKTEAPTTMTYPLKATSTVKQSWDWTTDMDGYLGETSAGPGKSLPGGGGS DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG G GGGSGGGG S LQCYNCPNPTADCKTAVNCSSDFDACLITKAGLQVYNKCWKFEQCNFNDVTTRLRENELTYYCCKKDLCNFNEQLEN

[seq9] mu CRIg-mu IgG2a Fc DANG

HPTLKTPESVTGTWKGDVKIQCIYDPLRGYRQVLVKWLVRHGSDSVTIFLRDSTGDHIQQAKYRGRLKVSHKVPGDVSLQINTLQMDDRNHYTCEVTWQTPDGNQVIRDKIIELRVRKYNPPRINTEAPTTLHSSLEATTIMSSTSDLTTNGTGKLEETIAGSGRNLP GGGGSEPRGPTIKPCPPCKCP APNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVAVSEDDPDVQISWFVNNVEVHTAQTQTHREDYGSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK

[seq10] mu CRIg-mu IgG2a Fc DANG -mu CD59a

HPTLKTPESVTGTWKGDVKIQCIYDPLRGYRQVLVKWLVRHGSDSVTIFLRDSTGDHIQQAKYRGRLKVSHKVPGDVSLQINTLQMDDRNHYTCEVTWQTPDGNQVIRDKIIELRVRKYNPPRINTEAPTTLHSSLEATTIMSSTSDLTTNGTGKLEETIAGSGRNLPGGGGS EPRGPTIKPCPPCKCP APNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVAVSEDDPDVQISWFVNNVEVHTAQTQTHREDYGSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPG GGGGSGGGGS LTCYHCFQPVVSSCNMNSTCSPDQDSCLYAVAGMQVYQRCWKQSDCHGEIIMDQLEETKLKFRCCQFNLCNKS

[seq11] mu IgG2a Fc DANG -mu CD59a

EPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVAVSEDDPDVQISWFVNNVEVHTAQTQTHREDYGSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPG GGGGSGGGG SLTCYHCFQPVVSSCNMNSTCSPDQDSCLYAVAGMQVYQRCWKQSDCHGEIIMDQLEETKLKFRCCQFNLCNKS

[seq12] mu CRIg-mu IgG2a Fc DANG -VEGF binder

HPTLKTPESVTGTWKGDVKIQCIYDPLRGYRQVLVKWLVRHGSDSVTIFLRDSTGDHIQQAKYRGRLKVSHKVPGDVSLQINTLQMDDRNHYTCEVTWQTPDGNQVIRDKIIELRVRKYNPPRINTEAPTTLHSSLEATTIMSSTSDLTTNGTGKLEETIAGSGRNLP GGGGSEPRGPTIKPCPPCKCP APNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVAVSEDDPDVQISWFVNNVEVHTAQTQTHREDYGSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPG GGGGSGGGGS SDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEK

[seq13] mu IgG2a Fc DANG -VEGF binder

EPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVAVSEDDPDVQISWFVNNVEVHTAQTQTHREDYGSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPG GGGGSGGGGS SDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEK

[seq14] mu IgG2a Fc DANG

APNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVAVSEDDPDVQISWFVNNVEVHTAQTQTHREDYGSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEVERDIYKNTVEKRTNVKNHETKNHS

Preparation Example 2. Preparation of Human protein (PRO011-017)

Preparation Example 2.1. Vector construction and plasmid maxi-prep

Reagents and equipment used in Tables 2 and 3 below are described.

reagent manufacturing company Catalog# pTT5 chempartner In-Fusion HD cloning kit Clontech 639648 Accuprime pfx DNA polymerase Invitrogen 12344-04 Gel DNA fragment purification kit TaKaRa D823A FastDigest® BamHI Fermentas FD0055 FastDigest® EcoRI Fermentas FD0275

equipment and tools manufacturing company model name biosafety workbench NUAIRE LabGard class II centrifuge Eppendorf 5424 gel imaging system Tanon 2500R

The synthesized DNA fragment was amplified through PCR, and the PCR product was purified by gel. After cutting the pTT5 vector with restriction enzymes EcoRI and BamHI, the gel was purified. Each PCR product and the linear vector were ligated using the zin-Fusion Kit. The resulting vector was transformed into ECOS101 DH5α competent cells and cultured on 2xYT agar plates containing 100 μg/ml ampicillin. All manipulation procedures were performed according to the standard transformation protocol. Positive recombinants were confirmed by colony PCR, and sequence-verify sequencing was performed on the recombinant plasmid. A single colony was selected and the seed culture was inoculated into 5 mL 2xYT medium containing 100 μg/ml ampicillin. Incubated with shaking at 37°C for 8 hours.

Then, the seed cells were diluted in 200 mL of selective 2xYT medium at a ratio of 1:1,000. Incubated with shaking at 37°C for 16 hours. Bacterial cells were harvested by centrifugation at 4°C and 4,700 rpm for 10 minutes. Resuspend the bacterial pellet in 12 mL of RES-EF solution. Thereafter, 12 mL of LYS-EF solution was added, and the sealed tube was vigorously inverted to thoroughly mix, followed by incubation at room temperature for 5 minutes. 12 mL of NEU-EF solution was added to the lysate and inverted vigorously to mix thoroughly.

Before injecting the lysate into the NucleoBond® Xtra Column filter, a homogeneous suspension of the precipitate was prepared by inverting the lysate tube 3 times to prevent clogging of the filter. Then, the NucleoBond® Xtra Column filter and NucleoBond® Xtra Column were washed with 10 mL of filter washing solution FIL-EF. Remove the NucleoBond® Xtra Column filter by pulling out the filter or inverting the column. Wash the NucleoBond® Xtra Column with 90 mL of wash solution ENDO.

The NucleoBond® Xtra Column was washed with 45 mL of wash solution WASH-EF. Plasmid DNA was eluted with 15 mL of elution solution ELU. The eluate was collected in a 50 mL centrifuge tube. 10.5 mL of room temperature isopropanol was added to precipitate the eluted plasmid DNA. After vortex, the mixture was left standing for 2 minutes.

Then, 5 mL of 70% ethanol was added to the pellet. The ethanol was carefully and completely removed from the tube using a pipette tip. The pellets were dried at room temperature (20-25° C.). Then, the DNA pellet was dissolved with 1,000 μl of H ₂ O.

Preparation Example 2.2. Cell transfection and protein expression

Materials and reagents used are described in Table 4 below.

Materials and reagents Manufacturer (Product #) 293F cells Invitrogen (R790-07) OPM 293 OPM (81075-001) Pluronic® F-68, 10% (100X) Gibco (24040-032) 1 mg/ml PEI Polyscience (23966) OPTI MEM I Gibco (31985088) Peptone (20x) FLUKA(P0521-1KG) shaker flask ISF1-X Incubator Shaker Kuhner shaker

The 293F seed strain containing the complete medium was maintained in an incubator shaker at 130 rpm, 37° C., and 8% CO ₂ . It was cultured at a density of 0.3-0.4x10 ⁶ cells/ml, and the medium was changed every 2-3 days. 24 hours before transfection, 293F cells in a new passage were prepared at 2.6x10 ⁶ cells/ml. The prepared cells were cultured in an incubator shaker at 130 rpm, 37° C., and 8% CO ₂ . On the day of transfection, cells were adjusted to a density of 5.0x10 ⁶ cells/ml using fresh medium. A total volume of 1 L was performed in a 3 L shaker flask. 0.4 mg HC and 0.6 mg LC plasmids were diluted with 50 ml OPTI MEM I and filtered through a 0.22 μm filter. Then, 2 mg PEI was diluted with 50 mL OPTI MEM I to prepare transfection reagent.

Diluted PEI was added to the DNA mixture and mixed immediately. Then incubated at room temperature for 15 minutes. A DNA-PEI mixture was added to 293F cells prepared at 2.6x10 ⁶ cells/ml. Thereafter, the cells were cultured continuously for 24 hours in an incubator shaker at 130 rpm, 37° C., and 8% CO ₂ . 24 hours after transfection, 10% peptone was added to 1/20 of the culture solution so that the final concentration was 0.5%. Thereafter, the cells were continuously cultured in an incubator shaker at 130 rpm, 37° C., and 8% CO ₂ . Cell density/viability was measured and recorded daily during the 2-5 day post-transfection period. Cells were harvested for purification 7 days after transfection or when cell viability was less than 70%.

Preparation Example 2.3. protein purification

Reagents, solutions, and equipment used for protein purification are described in Tables 5 to 7 below.

reagent manufacturing company Catalog# Mabselect SuRe GE Healthcare 11003493 Tris SIGMA 77-86-1 NaCl ACROS ORGANIVS 7647-14-5 sodium citrate Adamas-beta 76198B Citric acid GENERAL-Reagent G83162B Arginine VETEC V900343-500G succinic acid Sigma-Aldrich S9512-500G Triton X-100 ABCONE X10010-1L TRITON X-114 SIGMA-ALDRICH X114 Millex-GP Filter Unit 0.22 μm Sterile MILLIPORE SLGP033RS NaOH Merck B146369740

solution A 25 mM Tris, 150 mM NaCl, pH 8.0 solution B 25 mM Tris, 150 mM NaCl, 0.1% Triton X-100, 0.1% Triton X-114 pH 8.0 solution C 100 mM Sodium Citrate, 150 mM NaCl, pH 3.0 solution D 1M Arginine, 400 mM Succinic acid, pH 9.0 solution E 20mM PB pH 6.5, 1M (NH ₄ ) ₂ SO ₄ solution F 20 mM PB pH 6.5, 25% isopropyl alcohol final solution 20 mM HEPES, pH 7.5, 240 mM sucrose or 20 mM his acetate pH 5.5, 240 mM sucrose

device manufacturing company model name AKTA Pure GE Healthcare 29-0182-24 centrifuge Beckman J-26xp gel imaging system Tanon 2500R Sartopore 2 filter Sartorius 5445307H9-OO-A

Proteins were purified through Mabselect sure column. Specifically, the supernatant was harvested by centrifugation at 2,000xg and 4°C for 20 minutes. Then, the supernatant was filtered with a Sartopore 2 filter. The clarified supernatant was loaded onto a 5 ml MabSelect Sure column equilibrated with solution A. Then, the column was washed with solution A until the A280 absorbance reached the baseline. The column was washed with 10 CV solution B. The column was washed with 10 CV solution A. The bound protein was eluted with 6 CV solution C, and 1/6 volume of solution D was added to neutralize the eluted material. SDS-PAGE and SEC-HPLC analysis were performed.

Then, the protein was purified through HIC column. The protein was then dialyzed against solution E at 4° C. overnight. The supernatant was loaded onto the HIC column equilibrated with solution E. After that, the column was washed with solution E until the A280 absorbance reached baseline. The bound protein was eluted by gradient elution (10 CV solution F 0%-40%). The bound protein was eluted with 2 CV 100% solution F. SDS-PAGE analysis was performed.

After purifying the protein, the proteins were collected in one place, and then the protein was dialyzed against the final solution at 4°C overnight. Then, SDS-PAGE and SEC-HPLC analysis were performed.

Preparation Example 3. Preparation of Mouse Protein (PRO055-060) and Human Protein (PRO061)

Preparation 3.1. production of proteins

Materials and reagents used are shown in Table 8 below.

Materials and reagents manufacturing company Cat. # Expi293F™Cells Gibco A14527 Expi293™ Expression System Kit Gibco A14635 MabSelect SuRe GE Lifesciences 17543803 Superdex 200 increase 10/300 GE Lifesciences 28990944 MPC™Ceramic Hydroxyfluoroapatite Bio-rad 1570200

A DNA fragment corresponding to the protein sequence was synthesized in Genewiz (No. 80-383034849). The corresponding DNA fragment was amplified by PCR, and put into a linearized pcDNA3.3 expression vector. After verifying the construct through sequencing, a large-scale plasmid manufacturing process yielded a sufficient amount of DNA to perform cell transfection.

First, prepare 2.94x10 ⁶ cells/mL of Expi293F cells that have survived more than 95% in 2 L of cell culture medium. Plasmid DNA and ExpiFectamine™ 293 reagent were first diluted in Opti-MEM, mixed and added to the cell culture medium. Cell culture was performed on a platform shaker at a stirring speed of 150 rpm. The temperature was maintained at 37° C., and the CO ₂ concentration was maintained at 8%. 18-20 hours after transfection, Enhancer 1 and Enhancer 2 were added to the cell culture medium.

After 6 days of cell culture, the cells were centrifuged at 4,000 rpm at 25° C. for 10 minutes. The supernatant was collected for purification and gel electrophoresis. The supernatant was loaded onto an SDS-PAGE gel according to the instructions for NuPAGE™ 4-12% Bis-Tirs Protein Gels (ThermoFisher). A PageRuler™ Unstained Protein Ladder (ThermoFisher) was used with the protein sample to measure the molecular weight of the protein. The remaining supernatant of each protein was used for subsequent purification.

Protein purification was performed as follows. Specifically, the Protein A column was prepackaged with MabSelect Sure resin. Prior to loading the cell culture, the column was equilibrated with 0.1 M Tris, pH 7.0. After loading the cell culture, the column was washed with 0.1 M Tris, pH 7.0, and then eluted with 0.1 M glycine, pH 3.5. The eluted material was neutralized by adding 0.1 M Tris, pH 9.0. Then, the sample was dialyzed in PBS solution (Sangon Biotech, B548117-0500).

Before loading the sample, the SEC column (GE lifesciences, Superdex 200 increase 10/300) was equilibrated with PBS. After loading, samples were eluted with PBS and collected by chromatography. SDS-PAGE was performed to analyze each peak. Each sample was dialyzed against a formulation solution (10 mM Naphosphate, 0.3-0.4 M NaCl, pH 6.8).

The CHT column was prepackaged with CHT resin (Bio-rad, MPC™ Ceramic Hydroxyfluoroapatite), and equilibrated with solution A (10 mM Naphosphate, 30 mM NaCl, pH 6.8) before loading the sample. After loading, the column was eluted with 30% solution B (10 mM Naphosphate, 1 M NaCl, pH 6.8), followed by a linear gradient of 30%-90% solution B and a final 100% solution B. The eluate was characterized by SDS-PAGE, and the sample was dialyzed against the formulation solution (10 mM Naphosphate, 0.3-0.4 M NaCl, pH 6.8). The final protein was filtered through a 0.2 μm filter, and aseptically dispensed into 1.5 mL tubes in 0.5 mL each.

Preparation 3.1. Protein characterization

The protein concentration was measured at 280 nm using the Nano Drop. The purity of the protein was confirmed by SDS-PAGE and HPLC-SEC.

The SDS-PAGE sample was prepared by mixing 15 μL of purified protein and 5 μL of 4x loading buffer, and boiling for 5 minutes. 15 μL of the mixed sample was loaded on NuPAGE Bis-Tris Mini Gels 4-12% gel. For SEC-HPLC analysis, 80 μL of purified protein was loaded into TSKgel G3000SWxl column of HPLC system 1260 Infinity Ⅱ, pH 7.0, 50 mM sodium phosphate, 150 mM sodium chloride was used as a running buffer.

Experimental Example 1. Confirmation of binding force of fusion protein

Experimental Example 1.1. Biacore Surface Plasmon Resonance Analysis Techniques

The physical properties of the prepared fusion protein were analyzed using a Biacore 8K (GE Healthcare, 29129951) device. The reagents used at this time are described in Table 9.

reagent manufacturing company Cat # CM5 sensor chip GE Healthcare 29-1496-03 HBS-EP+ buffer (10 ×) GE Healthcare BR-1006-69 amine coupling kit GE Healthcare BR-1006-33 Human Antibody Capture Kit GE Healthcare 29234600 10 mM Glycine 1.5 GE Healthcare BR-1003-54 C3b Complement Technology A114

Experimental Example 1.2. Anti-human immunoglobulin G(Fc) antibody immobilization on CM5 sensor chip

1 L 1x HBS-EP+ buffer was prepared by mixing 100 mL 10x HBS-EP+ buffer with 900 mL Milli-Q water. After mixing 50 mM NHS and 200 mM EDC in a 1:1 ratio for 420 seconds, the CM5 chip was activated at a flow rate of 10 uL/min. Anti-human immunoglobulin G(Fc) antibody (25 ug/mL in Acetate pH 5.0) was injected at a rate of 10 uL/ml for 400 seconds to reach a fixation level of about 10,000 RU. The remaining activated ester groups were blocked by injecting 1 M ethanolamine (pH 8.5) for 420 s at a rate of 10 uL/min. To stabilize the baseline, the sensor chip was washed with 1xHBS-EP+ at a rate of 10 uL/min for 16 hours.

Experimental Example 1.3. Binding Kinetics Measurements

A startup cycle consisting of a sample step and a regeneration step was performed three times for baseline stabilization. Sample step: 1x HBS-EP+ buffer was injected into the flow cell at a flow rate of 30 uL/min for 120 seconds, followed by a cleavage phase for 120 seconds and a stabilization phase for 30 seconds. Regeneration step: 10 mM Glycine pH 1.5 was injected into the flow cell at a rate of 30 uL/min for 30 seconds followed by a 30 second stabilization step.

Thereafter, binding kinetics measurements were performed in the following manner:

C3b stock solution was diluted to 50 nM using 1x HBS-EP+ buffer. Human VEGF165 was diluted to 5 nM using 1x HBS-EP+ buffer. The 50 nM and 5 nM solutions were then diluted to 0.78125 nM and 0.078125 nM. In the sample step, the diluted antigens were injected into the flow cell at a rate of 30 uL/min. Two 0 nM antigens (1x HBS-EP+ buffer) were used to subtract from the reference signal. It had a binding time of 180 and a separation time of 400 seconds. After the separation time there was a stabilization phase for 60 seconds. In the regeneration step, 10 mM Glycine pH1.5 was injected into the flow cells at a rate of 30 uL/min for 30 seconds, followed by a stabilization step for 60 seconds.

Experimental Example 1.3. Analysis and results

After subtracting the reference and 0 nM values from the sample values, binding kinetics were calculated using Biacore Insight Evaluation Software (Version 2.0.15.12933) and 1:1 binding model for curved fitting.

Table 10 below shows the binding affinities of the test substances.

Capture 1 Solution Analyte 1 Solution ka (1/Ms) kd (1/s) KD (M) 0.5 ug/ml PRO011 C3b 3.47E+06 1.21E-02 3.47E-09 2 ug/ml PRO013 C3b 9.10E+06 4.66E-02 5.12E-09 2 ug/ml PRO014 C3b 3.66E+06 1.59E-02 4.34E-09 2 ug/ml PRO014 human VEGF165 3.94E+06 2.47E-04 6.28E-11

Capture 1 Solution Analyte 1 Solution ka (1/Ms) kd (1/s) KD (M) 2 ug/ml PRO013 C3b 2.71E+07 1.32E-01 4.85E-09 2 ug/ml PRO061 C3b 4.44E+05 3.48E-03 7.84E-09

Experimental Example 2. Confirmation of binding of fusion protein and C3b

Considering that the CRIg of the fusion protein must bind to C3b for its action, the binding between the C3b protein and the fusion protein was tested. Specifically, human C3b protein was immobilized on a plate and bound to PRO014 (CRIg-Fc-VEGF). Then, the anti-human immunoglobulin G antibody and the anti-mustard radish peroxidase (HRP) antibody were sequentially coupled. It was confirmed that PRO014 binds to human C3b in a concentration dependent manner ( FIG. 7 ).

Experimental Example 3. Analysis of classical complement pathway inhibitory effect through hemolysis (CH50, Classical pathway Hemolysis)

Reagent Vendor Factor B-Dpl serum Comptech Sheep RBC Yuduo biolody Hemolysin Yuduo biolody Gelatin Veronal Buffer (GVB; 5 mM Barbital) Boston bioproducts Assay plate Corning

In order to sensitize sheep's red blood cells using hemolysis, the experiment was conducted as follows. Sheep red blood cells were centrifuged in TBS at 400xg for 10 minutes, and this process was repeated twice. 1 mL 20% sheep red blood cells and hemolysin were incubated at 4°C for 30 min. Sheep red blood cells were washed with TBS using a centrifuge at 400xg for 10 minutes, and this process was repeated twice. Sheep red blood cells were washed with GVB++ buffer using a centrifuge at 400xg for 10 min. The sensitized sheep red blood cells were adjusted to a concentration of 1 x 10 ⁹ /mL using GVB++ buffer. The reagents used are shown in Table 10. To assay for CH50, 3% or 4.5% human Factor B-deficient serum was added to 96-well plates (50 μL/well). In addition, different concentrations of test substances were treated (50 μL/well). After incubation at 4°C for 30 min, sensitized sheep red blood cells were added (2.5 x 10 ⁶ /well, 50 uL/well). Incubated at 37° C. for 30 minutes. After centrifugation at 600xg for 10 minutes to collect 110 uL of the supernatant, the OD415 value was measured ( FIGS. 8A and 8B ).

Experimental Example 4. Analysis of Alternative Pathway Inhibition Effect through Hemolysis (AH50, Alternative Pathway Hemolysis)

Reagent Vendor C1q-depleted serum Comptech Rabbit RBC Yuduo biolody Gelatin Veronal Buffer (5 mM Barbital) Boston bioproducts Assay plate Corning

3 mL of rabbit red blood cells were washed with TBS using a centrifuge at 400xg for 10 min, and this process was repeated twice. Rabbit red blood cells were washed once again with GVB_EGTA buffer using a centrifuge at 400xg for 10 min. The concentration of rabbit red blood cells was adjusted to 1x10 ⁹ cells/mL using GVB_EGTA buffer. The reagents used are shown in Table 11. To assay for AH50, 9% human C1q-deficient serum was added to 96-well plates (50 uL/well). In addition, different concentrations of test substances were added (50 uL/well). After incubation at 4°C for 30 minutes, rabbit red blood cells were added (2x10 ⁶ /well, 50 uL/well). Incubated at 37° C. for 1.5 hours and centrifuged at 600×g for 10 minutes. After collecting 110 uL of the supernatant, the OD ₄₁₅ value was measured ( FIGS. 8A and 8B ).

Experimental Example 5. Efficacy evaluation using wet macular degeneration mouse animal model

Before induction of choroidal neovascularization, the presence of structural abnormalities was confirmed by spectral-area optical coherence tomography (Envisu R2200 SD-OCT System; Bioptigen, Inc., USA). Three choroidal neovascularizations were induced at Day 0 by penetrating Bruch's membrane in the right eye using a Dioudo laser (OcuLight TX - Green 532nm Laser; Iridex Corporate, USA). After induction of choroidal neovascularization, spectral domain optical coherence tomography and fluorescence fundus angiography (HRA2 FA system; Heidelberg Engineering GmbH, Germany) were used to confirm whether the model was induced normally. Immediately after laser use, PRO058 (350 μM; 48.3 μg/μl, 2 μl), aflibercept (Eylea; 350 μM; 40.0 μg/μl, 2 μl) or vehicle control (2 μl) was administered via intravitreal injection. injected.

In vivo imaging was performed immediately after induction of choroidal neovascularization (Day 0) and 7 days after induction (Day 7) using spectral domain optical coherence tomography and fluorescence fundus angiography. For each choroidal neovascularization in the fluorescein angiography photograph, 1 point was given if there was a vascular leak and 0 if not, and the lesion probability was calculated (eg, 100% = vascular leak was seen in three choroidal neovascularizations). ).

As a result, when comparing the groups administered with the test substances after induction of the choroidal neovascularization mouse model, the PRO058 group showed a similar protective effect as the aflibercept group 7 days after administration, and it was confirmed that there was a significant protective effect compared to the vehicle group (Fig. 10a). and Figure 10b).

Experimental Example 6. Efficacy evaluation using a dry macular degeneration mouse animal model

A mouse animal model of dry macular degeneration was induced by administering 20 mg/kg sodium iodate (NaIO ₃ ) to C57BL/6 mice at week 8 via tail vein injection. After model induction, PRO058 (260 μM; 36.1 μg/μl, 1.5 μl) or vehicle control (1.5 μl) was administered on Day 0 and Day 7 by intraocular injection. Two weeks after induction of the model, the test animals were euthanized, and the eyes were enucleated and fixed in Davidson's solution at 4°C for 24 hours. Thereafter, it was stored at 4° C. in 30% sucrose solution for 3 days. After freezing the samples in OCT compound (Cat #4583, Sakura), they were cut to a thickness of 20 μm. The excised tissues were stained with C3 (Cat #MA1-40046, Thermofisher) protein using immunofluorescence, and outer nuclear layer (ONL) stained with Daffy (Cat #H-1200, Vector Laboratories) staining method. Stained samples were analyzed using a confocal microscope (LSM700; Zeiss, Germany).

As a result, when the number and area of the outer granular layer were measured, it was confirmed that the PRO058 group significantly inhibited retinal degeneration compared to the vehicle group (FIG. 11a). In addition, it was confirmed that C3 expression was significantly increased in the vehicle group compared to the Non-AMD group, and it was confirmed that it was significantly decreased in the PRO058 group (FIG. 11b).

Experimental Example 7. Analysis of the pharmacodynamic profile of PRO014

Eighteen New Zealand White rabbits were divided into six groups (G01 to G06), three per group. After grouping, 2,500 μg PRO014 (50 μl/eye) was administered via intraocular injection. Sample collection was performed as described in Table 14 below.

Group Animal Number Dose Route Sample and Tissue Collection Time Points (Days) 1 hour 24 hours 3 days 7 days 14 days 28 days G01 RB1001, RB1002, RB1003 intravitreal injection Vitreous humor, Aqueous humor, Plasma G02 RB2001, RB2002, RB2003 Vitreous humor, Aqueous humor, Plasma G03 RB3001, RB3002, RB3003 Vitreous humor, Aqueous humor, Plasma G04 RB4001, RB4002, RB4003 Vitreous humor, Aqueous humor, Plasma G05 RB5001, RB5002, RB5003 Vitreous humor, Aqueous humor, Plasma G06 RB6001, RB6002, RB6003 Vitreous humor, Aqueous humor, Plasma

At each hour, 0.5 ml of blood was collected intravenously from rabbits. After plasma separation from the collected blood samples, they were stored frozen at -60°C. In addition, vitreous humor (0.2 ml) and aqueous humor (0.2 ml) were collected for each hour and stored frozen at -60°C. Concentrations of PRO014 were determined in plasma, vitreous humor and aqueous humor using an enzyme immunoassay (ELISA). Pharmacokinetic parameters were obtained by performing non-compartmental pharmacokinetic analysis with the measured values.

The pharmacokinetic parameters analyzed after administration of 2,500 μg/ml PRO014 are shown in Table 15, the concentration in the vitreous fluid is shown in Tables 16 and 12, and the concentration in the aqueous humor is shown in Tables 17 and 13 below. In, the plasma concentrations are summarized in Table 18, respectively.

Matrix Aqueous humor Vitreous humor PK parameters Mean Mean C _max (ng/mL) 103705 3204272 T _max (h) 1.00 1.00 T _1/2 (h) 114 226 T _last (h) 168 336 AUC _0-last (ng.h/mL) 10206790 545028800 AUC _0-inf (ng.h/mL) 15572980 851153000 MRT _0-last (h) 70.6 146 MRT _0-inf (h) 161 332 AUC _Extra (%) 34.5 36.0 AUMC _Extra (%) 71.2 71.8

Time (h) RBn001* RBn002 RBn003 Mean SD CV (%) n=1 One 2789070 3594376 3229369 3204272 403239 12.6 n=2 24 1561470 1336610 2160474 1686185 425856 25.3 n=3 1638252 2031203 2506814 2058756 434936 21.1 n=4 168 1659880 1767054 1783308 1736747 67064 3.86 n=5 336 1206629 1286796 317153 936859 538176 57.4 n=6 672 BQL** BQL BQL ND*** ND ND

* RB# represents the animal number.

** BQL is below the quantifiable limit.

*** ND is not determined.

Time (h) RBn001* RBn002 RBn003 Mean SD CV (%) n=1 One 1542 4803 304769 103705 174135 168 n=2 24 84982 54751 85448 75061 17590 23.4 n=3 38192 78324 90493 69003 27368 39.7 n=4 168 30505 37937 29392 32612 4646 14.2 n=5 336 BQL** BQL BQL ND*** ND ND n=6 672 BQL BQL BQL ND ND ND

* RB# represents the animal number.

** BQL is below the quantifiable limit.

*** ND is not determined.

Time (h) RBn001* RBn002 RBn003 Mean SD CV (%) n=1 One BQL** BQL BQL ND*** ND ND n=2 24 BQL BQL BQL ND ND ND n=3 BQL BQL BQL ND ND ND n=4 168 BQL BQL BQL ND ND ND n=5 336 BQL BQL BQL ND ND ND n=6 672 BQL BQL BQL ND ND ND

* RB# represents the animal number.

** BQL is below the quantifiable limit.

*** ND is not determined.

<110> Kanaph Therapeutics Inc. <120> FUSION PROTEIN COMPRISING COMPLEMENT PATHWAY INHIBITOR PROTEIN AND USE THEREOF <130> SPD21-039_KNP <160> 48 <170> KoPatentIn 3.0 <210> 1 <211> 496 <212> PRT <213> Artificial Sequence <220> <223> hu CRIg-hu IgG1 Fc DANG <400> 1 Arg Pro Ile Leu Glu Val Pro Glu Ser Val Thr Gly Pro Trp Lys Gly 1 5 10 15 Asp Val Asn Leu Pro Cys Thr Tyr Asp Pro Leu Gln Gly Tyr Thr Gln 20 25 30 Val Leu Val Lys Trp Leu Val Gln Arg Gly Ser Asp Pro Val Thr Ile 35 40 45 Phe Leu Arg Asp Ser Ser Gly Asp His Ile Gln Gln Ala Lys Tyr Gln 50 55 60 Gly Arg Leu His Val Ser His Lys Val Pro Gly Asp Val Ser Leu Gln 65 70 75 80 Leu Ser Thr Leu Glu Met Asp Asp Arg Ser His Tyr Thr Cys Glu Val 85 90 95 Thr Trp Gln Thr Pro Asp Gly Asn Gln Val Val Arg Asp Lys Ile Thr 100 105 110 Glu Leu Arg Val Gln Lys Leu Ser Val Ser Lys Pro Thr Val Thr Thr 115 120 125 Gly Ser Gly Tyr Gly Phe Thr Val Pro Gln Gly Met Arg Ile Ser Leu 130 135 140 Gln Cys Gln Ala Arg Gly Ser Pro Pro Ile Ser Tyr Ile Trp Tyr Lys 145 150 155 160 Gln Gln Thr Asn Asn Gln Glu Pro Ile Lys Val Ala Thr Leu Ser Thr 165 170 175 Leu Leu Phe Lys Pro Ala Val Ile Ala Asp Ser Gly Ser Tyr Phe Cys 180 185 190 Thr Ala Lys Gly Gln Val Gly Ser Glu Gln His Ser Asp Ile Val Lys 195 200 205 Phe Val Val Lys Asp Ser Ser Lys Leu Leu Lys Thr Lys Thr Glu Ala 210 215 220 Pro Thr Thr Met Thr Tyr Pro Leu Lys Ala Thr Ser Thr Val Lys Gln 225 230 235 240 Ser Trp Asp Trp Thr Thr Asp Met Asp Gly Tyr Leu Gly Glu Thr Ser 245 250 255 Ala Gly Pro Gly Lys Ser Leu Pro Gly Gly Gly Gly Ser Asp Lys Thr 260 265 270 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 275 280 285 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 290 295 300 Thr Pro Glu Val Thr Cys Val Val Val Ala Val Ser His Glu Asp Pro 305 310 315 320 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 325 330 335 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Val Val 340 345 350 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 355 360 365 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 370 375 380 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 385 390 395 400 Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 405 410 415 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 420 425 430 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 435 440 445 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 450 455 460 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 465 470 475 480 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 485 490 495 <210> 2 <211> 608 <212> PRT <213> Artificial Sequence <220> <223> hu CRIg-hu IgG1 Fc DANG-hu CD59 (K41Q) <400> 2 Arg Pro Ile Leu Glu Val Pro Glu Ser Val Thr Gly Pro Trp Lys Gly 1 5 10 15 Asp Val Asn Leu Pro Cys Thr Tyr Asp Pro Leu Gln Gly Tyr Thr Gln 20 25 30 Val Leu Val Lys Trp Leu Val Gln Arg Gly Ser Asp Pro Val Thr Ile 35 40 45 Phe Leu Arg Asp Ser Ser Gly Asp His Ile Gln Gln Ala Lys Tyr Gln 50 55 60 Gly Arg Leu His Val Ser His Lys Val Pro Gly Asp Val Ser Leu Gln 65 70 75 80 Leu Ser Thr Leu Glu Met Asp Asp Arg Ser His Tyr Thr Cys Glu Val 85 90 95 Thr Trp Gln Thr Pro Asp Gly Asn Gln Val Val Arg Asp Lys Ile Thr 100 105 110 Glu Leu Arg Val Gln Lys Leu Ser Val Ser Lys Pro Thr Val Thr Thr 115 120 125 Gly Ser Gly Tyr Gly Phe Thr Val Pro Gln Gly Met Arg Ile Ser Leu 130 135 140 Gln Cys Gln Ala Arg Gly Ser Pro Pro Ile Ser Tyr Ile Trp Tyr Lys 145 150 155 160 Gln Gln Thr Asn Asn Gln Glu Pro Ile Lys Val Ala Thr Leu Ser Thr 165 170 175 Leu Leu Phe Lys Pro Ala Val Ile Ala Asp Ser Gly Ser Tyr Phe Cys 180 185 190 Thr Ala Lys Gly Gln Val Gly Ser Glu Gln His Ser Asp Ile Val Lys 195 200 205 Phe Val Val Lys Asp Ser Ser Lys Leu Leu Lys Thr Lys Thr Glu Ala 210 215 220 Pro Thr Thr Met Thr Tyr Pro Leu Lys Ala Thr Ser Thr Val Lys Gln 225 230 235 240 Ser Trp Asp Trp Thr Thr Asp Met Asp Gly Tyr Leu Gly Glu Thr Ser 245 250 255 Ala Gly Pro Gly Lys Ser Leu Pro Gly Gly Gly Gly Ser Asp Lys Thr 260 265 270 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 275 280 285 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 290 295 300 Thr Pro Glu Val Thr Cys Val Val Val Ala Val Ser His Glu Asp Pro 305 310 315 320 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 325 330 335 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Val Val 340 345 350 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 355 360 365 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 370 375 380 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 385 390 395 400 Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 405 410 415 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 420 425 430 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 435 440 445 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 450 455 460 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 465 470 475 480 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly 485 490 495 Gly Gly Gly Ser Gly Gly Gly Gly Ser Leu Gln Cys Tyr Asn Cys Pro 500 505 510 Asn Pro Thr Ala Asp Cys Lys Thr Ala Val Asn Cys Ser Ser Asp Phe 515 520 525 Asp Ala Cys Leu Ile Thr Lys Ala Gly Leu Gln Val Tyr Asn Lys Cys 530 535 540 Trp Gln Phe Glu His Cys Asn Phe Asn Asp Val Thr Thr Arg Leu Arg 545 550 555 560 Glu Asn Glu Leu Thr Tyr Tyr Cys Cys Lys Lys Asp Leu Cys Asn Phe 565 570 575 Asn Glu Gln Leu Glu Asn Gly Gly Thr Ser Leu Ser Glu Lys Thr Val 580 585 590 Leu Leu Leu Val Thr Pro Phe Leu Ala Ala Ala Trp Ser Leu His Pro 595 600 605 <210> 3 <211> 608 <212> PRT <213> Artificial Sequence <220> <223> hu CRIg-hu IgG1 Fc DANG-hu CD59 (H44Q) <400> 3 Arg Pro Ile Leu Glu Val Pro Glu Ser Val Thr Gly Pro Trp Lys Gly 1 5 10 15 Asp Val Asn Leu Pro Cys Thr Tyr Asp Pro Leu Gln Gly Tyr Thr Gln 20 25 30 Val Leu Val Lys Trp Leu Val Gln Arg Gly Ser Asp Pro Val Thr Ile 35 40 45 Phe Leu Arg Asp Ser Ser Gly Asp His Ile Gln Gln Ala Lys Tyr Gln 50 55 60 Gly Arg Leu His Val Ser His Lys Val Pro Gly Asp Val Ser Leu Gln 65 70 75 80 Leu Ser Thr Leu Glu Met Asp Asp Arg Ser His Tyr Thr Cys Glu Val 85 90 95 Thr Trp Gln Thr Pro Asp Gly Asn Gln Val Val Arg Asp Lys Ile Thr 100 105 110 Glu Leu Arg Val Gln Lys Leu Ser Val Ser Lys Pro Thr Val Thr Thr 115 120 125 Gly Ser Gly Tyr Gly Phe Thr Val Pro Gln Gly Met Arg Ile Ser Leu 130 135 140 Gln Cys Gln Ala Arg Gly Ser Pro Pro Ile Ser Tyr Ile Trp Tyr Lys 145 150 155 160 Gln Gln Thr Asn Asn Gln Glu Pro Ile Lys Val Ala Thr Leu Ser Thr 165 170 175 Leu Leu Phe Lys Pro Ala Val Ile Ala Asp Ser Gly Ser Tyr Phe Cys 180 185 190 Thr Ala Lys Gly Gln Val Gly Ser Glu Gln His Ser Asp Ile Val Lys 195 200 205 Phe Val Val Lys Asp Ser Ser Lys Leu Leu Lys Thr Lys Thr Glu Ala 210 215 220 Pro Thr Thr Met Thr Tyr Pro Leu Lys Ala Thr Ser Thr Val Lys Gln 225 230 235 240 Ser Trp Asp Trp Thr Thr Asp Met Asp Gly Tyr Leu Gly Glu Thr Ser 245 250 255 Ala Gly Pro Gly Lys Ser Leu Pro Gly Gly Gly Gly Ser Asp Lys Thr 260 265 270 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 275 280 285 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 290 295 300 Thr Pro Glu Val Thr Cys Val Val Val Ala Val Ser His Glu Asp Pro 305 310 315 320 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 325 330 335 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Val Val 340 345 350 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 355 360 365 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 370 375 380 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 385 390 395 400 Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 405 410 415 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 420 425 430 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 435 440 445 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 450 455 460 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 465 470 475 480 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly 485 490 495 Gly Gly Gly Ser Gly Gly Gly Gly Ser Leu Gln Cys Tyr Asn Cys Pro 500 505 510 Asn Pro Thr Ala Asp Cys Lys Thr Ala Val Asn Cys Ser Ser Asp Phe 515 520 525 Asp Ala Cys Leu Ile Thr Lys Ala Gly Leu Gln Val Tyr Asn Lys Cys 530 535 540 Trp Lys Phe Glu Gln Cys Asn Phe Asn Asp Val Thr Thr Arg Leu Arg 545 550 555 560 Glu Asn Glu Leu Thr Tyr Tyr Cys Cys Lys Lys Asp Leu Cys Asn Phe 565 570 575 Asn Glu Gln Leu Glu Asn Gly Gly Thr Ser Leu Ser Glu Lys Thr Val 580 585 590 Leu Leu Leu Val Thr Pro Phe Leu Ala Ala Ala Trp Ser Leu His Pro 595 600 605 <210> 4 <211> 710 <212> PRT <213> Artificial Sequence <220> <223> hu CRIg-hu IgG1 Fc DANG-VEGF binder <400> 4 Arg Pro Ile Leu Glu Val Pro Glu Ser Val Thr Gly Pro Trp Lys Gly 1 5 10 15 Asp Val Asn Leu Pro Cys Thr Tyr Asp Pro Leu Gln Gly Tyr Thr Gln 20 25 30 Val Leu Val Lys Trp Leu Val Gln Arg Gly Ser Asp Pro Val Thr Ile 35 40 45 Phe Leu Arg Asp Ser Ser Gly Asp His Ile Gln Gln Ala Lys Tyr Gln 50 55 60 Gly Arg Leu His Val Ser His Lys Val Pro Gly Asp Val Ser Leu Gln 65 70 75 80 Leu Ser Thr Leu Glu Met Asp Asp Arg Ser His Tyr Thr Cys Glu Val 85 90 95 Thr Trp Gln Thr Pro Asp Gly Asn Gln Val Val Arg Asp Lys Ile Thr 100 105 110 Glu Leu Arg Val Gln Lys Leu Ser Val Ser Lys Pro Thr Val Thr Thr 115 120 125 Gly Ser Gly Tyr Gly Phe Thr Val Pro Gln Gly Met Arg Ile Ser Leu 130 135 140 Gln Cys Gln Ala Arg Gly Ser Pro Pro Ile Ser Tyr Ile Trp Tyr Lys 145 150 155 160 Gln Gln Thr Asn Asn Gln Glu Pro Ile Lys Val Ala Thr Leu Ser Thr 165 170 175 Leu Leu Phe Lys Pro Ala Val Ile Ala Asp Ser Gly Ser Tyr Phe Cys 180 185 190 Thr Ala Lys Gly Gln Val Gly Ser Glu Gln His Ser Asp Ile Val Lys 195 200 205 Phe Val Val Lys Asp Ser Ser Lys Leu Leu Lys Thr Lys Thr Glu Ala 210 215 220 Pro Thr Thr Met Thr Tyr Pro Leu Lys Ala Thr Ser Thr Val Lys Gln 225 230 235 240 Ser Trp Asp Trp Thr Thr Asp Met Asp Gly Tyr Leu Gly Glu Thr Ser 245 250 255 Ala Gly Pro Gly Lys Ser Leu Pro Gly Gly Gly Gly Ser Asp Lys Thr 260 265 270 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 275 280 285 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 290 295 300 Thr Pro Glu Val Thr Cys Val Val Val Ala Val Ser His Glu Asp Pro 305 310 315 320 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 325 330 335 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Val Val 340 345 350 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 355 360 365 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 370 375 380 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 385 390 395 400 Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 405 410 415 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 420 425 430 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 435 440 445 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 450 455 460 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 465 470 475 480 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly 485 490 495 Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Asp Thr Gly Arg Pro Phe 500 505 510 Val Glu Met Tyr Ser Glu Ile Pro Glu Ile Ile His Met Thr Glu Gly 515 520 525 Arg Glu Leu Val Ile Pro Cys Arg Val Thr Ser Pro Asn Ile Thr Val 530 535 540 Thr Leu Lys Lys Phe Pro Leu Asp Thr Leu Ile Pro Asp Gly Lys Arg 545 550 555 560 Ile Ile Trp Asp Ser Arg Lys Gly Phe Ile Ile Ser Asn Ala Thr Tyr 565 570 575 Lys Glu Ile Gly Leu Leu Thr Cys Glu Ala Thr Val Asn Gly His Leu 580 585 590 Tyr Lys Thr Asn Tyr Leu Thr His Arg Gln Thr Asn Thr Ile Ile Asp 595 600 605 Val Val Leu Ser Pro Ser His Gly Ile Glu Leu Ser Val Gly Glu Lys 610 615 620 Leu Val Leu Asn Cys Thr Ala Arg Thr Glu Leu Asn Val Gly Ile Asp 625 630 635 640 Phe Asn Trp Glu Tyr Pro Ser Ser Lys His Gln His Lys Lys Leu Val 645 650 655 Asn Arg Asp Leu Lys Thr Gln Ser Gly Ser Glu Met Lys Lys Phe Leu 660 665 670 Ser Thr Leu Thr Ile Asp Gly Val Thr Arg Ser Asp Gln Gly Leu Tyr 675 680 685 Thr Cys Ala Ala Ser Ser Ser Gly Leu Met Thr Lys Lys Asn Ser Thr Phe 690 695 700 Val Arg Val His Glu Lys 705 710 <210> 5 <211> 339 <212> PRT <213> Artificial Sequence <220> <223> hu IgG1 Fc DANG-hu CD59 (K41Q) <400> 5 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Ala Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Leu Gln Cys Tyr 225 230 235 240 Asn Cys Pro Asn Pro Thr Ala Asp Cys Lys Thr Ala Val Asn Cys Ser 245 250 255 Ser Asp Phe Asp Ala Cys Leu Ile Thr Lys Ala Gly Leu Gln Val Tyr 260 265 270 Asn Lys Cys Trp Gin Phe Glu His Cys Asn Phe Asn Asp Val Thr Thr 275 280 285 Arg Leu Arg Glu Asn Glu Leu Thr Tyr Tyr Cys Cys Lys Lys Asp Leu 290 295 300 Cys Asn Phe Asn Glu Gln Leu Glu Asn Gly Gly Thr Ser Leu Ser Glu 305 310 315 320 Lys Thr Val Leu Leu Leu Leu Val Thr Pro Phe Leu Ala Ala Ala Trp Ser 325 330 335 Leu His Pro <210> 6 <211> 339 <212> PRT <213> Artificial Sequence <220> <223> hu IgG1 Fc DANG-hu CD59 (H44Q) <400> 6 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Ala Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Leu Gln Cys Tyr 225 230 235 240 Asn Cys Pro Asn Pro Thr Ala Asp Cys Lys Thr Ala Val Asn Cys Ser 245 250 255 Ser Asp Phe Asp Ala Cys Leu Ile Thr Lys Ala Gly Leu Gln Val Tyr 260 265 270 Asn Lys Cys Trp Lys Phe Glu Gln Cys Asn Phe Asn Asp Val Thr Thr 275 280 285 Arg Leu Arg Glu Asn Glu Leu Thr Tyr Tyr Cys Cys Lys Lys Asp Leu 290 295 300 Cys Asn Phe Asn Glu Gln Leu Glu Asn Gly Gly Thr Ser Leu Ser Glu 305 310 315 320 Lys Thr Val Leu Leu Leu Leu Val Thr Pro Phe Leu Ala Ala Ala Trp Ser 325 330 335 Leu His Pro <210> 7 <211> 208 <212> PRT <213> Artificial Sequence <220> <223> hu IgG1 Fc DANG <400> 7 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 1 5 10 15 Arg Thr Pro Glu Val Thr Cys Val Val Val Ala Val Ser His Glu Asp 20 25 30 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 35 40 45 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Val 50 55 60 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 65 70 75 80 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 85 90 95 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 100 105 110 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 115 120 125 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 130 135 140 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 145 150 155 160 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 165 170 175 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 180 185 190 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 195 200 205 <210> 8 <211> 582 <212> PRT <213> Artificial Sequence <220> <223> hu CRIg-hu IgG1 Fc DANG-hu CD59 without c-terminal propeptide <400> 8 Arg Pro Ile Leu Glu Val Pro Glu Ser Val Thr Gly Pro Trp Lys Gly 1 5 10 15 Asp Val Asn Leu Pro Cys Thr Tyr Asp Pro Leu Gln Gly Tyr Thr Gln 20 25 30 Val Leu Val Lys Trp Leu Val Gln Arg Gly Ser Asp Pro Val Thr Ile 35 40 45 Phe Leu Arg Asp Ser Ser Gly Asp His Ile Gln Gln Ala Lys Tyr Gln 50 55 60 Gly Arg Leu His Val Ser His Lys Val Pro Gly Asp Val Ser Leu Gln 65 70 75 80 Leu Ser Thr Leu Glu Met Asp Asp Arg Ser His Tyr Thr Cys Glu Val 85 90 95 Thr Trp Gln Thr Pro Asp Gly Asn Gln Val Val Arg Asp Lys Ile Thr 100 105 110 Glu Leu Arg Val Gln Lys Leu Ser Val Ser Lys Pro Thr Val Thr Thr 115 120 125 Gly Ser Gly Tyr Gly Phe Thr Val Pro Gln Gly Met Arg Ile Ser Leu 130 135 140 Gln Cys Gln Ala Arg Gly Ser Pro Pro Ile Ser Tyr Ile Trp Tyr Lys 145 150 155 160 Gln Gln Thr Asn Asn Gln Glu Pro Ile Lys Val Ala Thr Leu Ser Thr 165 170 175 Leu Leu Phe Lys Pro Ala Val Ile Ala Asp Ser Gly Ser Tyr Phe Cys 180 185 190 Thr Ala Lys Gly Gln Val Gly Ser Glu Gln His Ser Asp Ile Val Lys 195 200 205 Phe Val Val Lys Asp Ser Ser Lys Leu Leu Lys Thr Lys Thr Glu Ala 210 215 220 Pro Thr Thr Met Thr Tyr Pro Leu Lys Ala Thr Ser Thr Val Lys Gln 225 230 235 240 Ser Trp Asp Trp Thr Thr Asp Met Asp Gly Tyr Leu Gly Glu Thr Ser 245 250 255 Ala Gly Pro Gly Lys Ser Leu Pro Gly Gly Gly Gly Ser Asp Lys Thr 260 265 270 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 275 280 285 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 290 295 300 Thr Pro Glu Val Thr Cys Val Val Val Ala Val Ser His Glu Asp Pro 305 310 315 320 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 325 330 335 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Val Val 340 345 350 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 355 360 365 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 370 375 380 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 385 390 395 400 Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys 405 410 415 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 420 425 430 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 435 440 445 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 450 455 460 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 465 470 475 480 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly 485 490 495 Gly Gly Gly Ser Gly Gly Gly Gly Ser Leu Gln Cys Tyr Asn Cys Pro 500 505 510 Asn Pro Thr Ala Asp Cys Lys Thr Ala Val Asn Cys Ser Ser Asp Phe 515 520 525 Asp Ala Cys Leu Ile Thr Lys Ala Gly Leu Gln Val Tyr Asn Lys Cys 530 535 540 Trp Lys Phe Glu Gln Cys Asn Phe Asn Asp Val Thr Thr Arg Leu Arg 545 550 555 560 Glu Asn Glu Leu Thr Tyr Tyr Cys Cys Lys Lys Asp Leu Cys Asn Phe 565 570 575 Asn Glu Gln Leu Glu Asn 580 <210> 9 <211> 406 <212> PRT <213> Artificial Sequence <220> <223> mu CRIg-mu IgG2a Fc DANG <400> 9 His Pro Thr Leu Lys Thr Pro Glu Ser Val Thr Gly Thr Trp Lys Gly 1 5 10 15 Asp Val Lys Ile Gln Cys Ile Tyr Asp Pro Leu Arg Gly Tyr Arg Gln 20 25 30 Val Leu Val Lys Trp Leu Val Arg His Gly Ser Asp Ser Val Thr Ile 35 40 45 Phe Leu Arg Asp Ser Thr Gly Asp His Ile Gln Gln Ala Lys Tyr Arg 50 55 60 Gly Arg Leu Lys Val Ser His Lys Val Pro Gly Asp Val Ser Leu Gln 65 70 75 80 Ile Asn Thr Leu Gln Met Asp Asp Arg Asn His Tyr Thr Cys Glu Val 85 90 95 Thr Trp Gln Thr Pro Asp Gly Asn Gln Val Ile Arg Asp Lys Ile Ile 100 105 110 Glu Leu Arg Val Arg Lys Tyr Asn Pro Pro Arg Ile Asn Thr Glu Ala 115 120 125 Pro Thr Thr Leu His Ser Ser Leu Glu Ala Thr Thr Ile Met Ser Ser 130 135 140 Thr Ser Asp Leu Thr Thr Asn Gly Thr Gly Lys Leu Glu Glu Thr Ile 145 150 155 160 Ala Gly Ser Gly Arg Asn Leu Pro Gly Gly Gly Gly Ser Glu Pro Arg 165 170 175 Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn 180 185 190 Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp 195 200 205 Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val Val Val Ala 210 215 220 Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn 225 230 235 240 Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Gly 245 250 255 Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp 260 265 270 Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro 275 280 285 Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala 290 295 300 Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys 305 310 315 320 Gln Val Thr Leu Thr Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile 325 330 335 Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn 340 345 350 Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys 355 360 365 Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys 370 375 380 Ser Val Val His Glu Gly Leu His Asn His His Thr Thr Lys Ser Phe 385 390 395 400 Ser Arg Thr Pro Gly Lys 405 <210> 10 <211> 488 <212> PRT <213> Artificial Sequence <220> <223> mu CRIg-mu IgG2a Fc DANG-mu CD59a <400> 10 His Pro Thr Leu Lys Thr Pro Glu Ser Val Thr Gly Thr Trp Lys Gly 1 5 10 15 Asp Val Lys Ile Gln Cys Ile Tyr Asp Pro Leu Arg Gly Tyr Arg Gln 20 25 30 Val Leu Val Lys Trp Leu Val Arg His Gly Ser Asp Ser Val Thr Ile 35 40 45 Phe Leu Arg Asp Ser Thr Gly Asp His Ile Gln Gln Ala Lys Tyr Arg 50 55 60 Gly Arg Leu Lys Val Ser His Lys Val Pro Gly Asp Val Ser Leu Gln 65 70 75 80 Ile Asn Thr Leu Gln Met Asp Asp Arg Asn His Tyr Thr Cys Glu Val 85 90 95 Thr Trp Gln Thr Pro Asp Gly Asn Gln Val Ile Arg Asp Lys Ile Ile 100 105 110 Glu Leu Arg Val Arg Lys Tyr Asn Pro Pro Arg Ile Asn Thr Glu Ala 115 120 125 Pro Thr Thr Leu His Ser Ser Leu Glu Ala Thr Thr Ile Met Ser Ser 130 135 140 Thr Ser Asp Leu Thr Thr Asn Gly Thr Gly Lys Leu Glu Glu Thr Ile 145 150 155 160 Ala Gly Ser Gly Arg Asn Leu Pro Gly Gly Gly Gly Ser Glu Pro Arg 165 170 175 Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn 180 185 190 Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp 195 200 205 Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val Val Val Ala 210 215 220 Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn 225 230 235 240 Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Gly 245 250 255 Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp 260 265 270 Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro 275 280 285 Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala 290 295 300 Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys 305 310 315 320 Gln Val Thr Leu Thr Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile 325 330 335 Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn 340 345 350 Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys 355 360 365 Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys 370 375 380 Ser Val Val His Glu Gly Leu His Asn His His Thr Thr Lys Ser Phe 385 390 395 400 Ser Arg Thr Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Leu 405 410 415 Thr Cys Tyr His Cys Phe Gln Pro Val Val Ser Ser Cys Asn Met Asn 420 425 430 Ser Thr Cys Ser Pro Asp Gln Asp Ser Cys Leu Tyr Ala Val Ala Gly 435 440 445 Met Gln Val Tyr Gln Arg Cys Trp Lys Gln Ser Asp Cys His Gly Glu 450 455 460 Ile Ile Met Asp Gln Leu Glu Glu Thr Lys Leu Lys Phe Arg Cys Cys 465 470 475 480 Gln Phe Asn Leu Cys Asn Lys Ser 485 <210> 11 <211> 315 <212> PRT <213> Artificial Sequence <220> <223> mu IgG2a Fc DANG-mu CD59a <400> 11 Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro 1 5 10 15 Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys 20 25 30 Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val 35 40 45 Val Val Ala Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe 50 55 60 Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu 65 70 75 80 Asp Tyr Gly Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His 85 90 95 Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys 100 105 110 Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser 115 120 125 Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Glu Glu Glu Met 130 135 140 Thr Lys Lys Gln Val Thr Leu Thr Cys Met Val Thr Asp Phe Met Pro 145 150 155 160 Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn 165 170 175 Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met 180 185 190 Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser 195 200 205 Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His His Thr Thr 210 215 220 Lys Ser Phe Ser Arg Thr Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Leu Thr Cys Tyr His Cys Phe Gln Pro Val Val Ser Ser Cys 245 250 255 Asn Met Asn Ser Thr Cys Ser Pro Asp Gln Asp Ser Cys Leu Tyr Ala 260 265 270 Val Ala Gly Met Gln Val Tyr Gln Arg Cys Trp Lys Gln Ser Asp Cys 275 280 285 His Gly Glu Ile Ile Met Asp Gln Leu Glu Glu Thr Lys Leu Lys Phe 290 295 300 Arg Cys Cys Gln Phe Asn Leu Cys Asn Lys Ser 305 310 315 <210> 12 <211> 620 <212> PRT <213> Artificial Sequence <220> <223> mu CRIg-mu IgG2a Fc DANG-VEGF binder <400> 12 His Pro Thr Leu Lys Thr Pro Glu Ser Val Thr Gly Thr Trp Lys Gly 1 5 10 15 Asp Val Lys Ile Gln Cys Ile Tyr Asp Pro Leu Arg Gly Tyr Arg Gln 20 25 30 Val Leu Val Lys Trp Leu Val Arg His Gly Ser Asp Ser Val Thr Ile 35 40 45 Phe Leu Arg Asp Ser Thr Gly Asp His Ile Gln Gln Ala Lys Tyr Arg 50 55 60 Gly Arg Leu Lys Val Ser His Lys Val Pro Gly Asp Val Ser Leu Gln 65 70 75 80 Ile Asn Thr Leu Gln Met Asp Asp Arg Asn His Tyr Thr Cys Glu Val 85 90 95 Thr Trp Gln Thr Pro Asp Gly Asn Gln Val Ile Arg Asp Lys Ile Ile 100 105 110 Glu Leu Arg Val Arg Lys Tyr Asn Pro Pro Arg Ile Asn Thr Glu Ala 115 120 125 Pro Thr Thr Leu His Ser Ser Leu Glu Ala Thr Thr Ile Met Ser Ser 130 135 140 Thr Ser Asp Leu Thr Thr Asn Gly Thr Gly Lys Leu Glu Glu Thr Ile 145 150 155 160 Ala Gly Ser Gly Arg Asn Leu Pro Gly Gly Gly Gly Ser Glu Pro Arg 165 170 175 Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn 180 185 190 Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp 195 200 205 Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val Val Val Ala 210 215 220 Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn 225 230 235 240 Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Gly 245 250 255 Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp 260 265 270 Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro 275 280 285 Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala 290 295 300 Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys 305 310 315 320 Gln Val Thr Leu Thr Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile 325 330 335 Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn 340 345 350 Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys 355 360 365 Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys 370 375 380 Ser Val Val His Glu Gly Leu His Asn His His Thr Thr Lys Ser Phe 385 390 395 400 Ser Arg Thr Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Gly Ser Ser 405 410 415 Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu Ile 420 425 430 Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val Thr 435 440 445 Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr Leu 450 455 460 Ile Pro Asp Gly Lys Arg Ile Ile Ile Trp Asp Ser Arg Lys Gly Phe Ile 465 470 475 480 Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu Ala 485 490 495 Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg Gln 500 505 510 Thr Asn Thr Ile Ile Asp Val Val Leu Ser Pro Ser His Gly Ile Glu 515 520 525 Leu Ser Val Gly Glu Lys Leu Val Leu Asn Cys Thr Ala Arg Thr Glu 530 535 540 Leu Asn Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro Ser Ser Lys His 545 550 555 560 Gln His Lys Lys Leu Val Asn Arg Asp Leu Lys Thr Gln Ser Gly Ser 565 570 575 Glu Met Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp Gly Val Thr Arg 580 585 590 Ser Asp Gln Gly Leu Tyr Thr Cys Ala Ala Ser Ser Gly Leu Met Thr 595 600 605 Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys 610 615 620 <210> 13 <211> 447 <212> PRT <213> Artificial Sequence <220> <223> mu IgG2a Fc DANG-VEGF binder <400> 13 Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro 1 5 10 15 Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys 20 25 30 Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val 35 40 45 Val Val Ala Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe 50 55 60 Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu 65 70 75 80 Asp Tyr Gly Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His 85 90 95 Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys 100 105 110 Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser 115 120 125 Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Glu Glu Glu Met 130 135 140 Thr Lys Lys Gln Val Thr Leu Thr Cys Met Val Thr Asp Phe Met Pro 145 150 155 160 Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn 165 170 175 Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met 180 185 190 Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser 195 200 205 Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His His Thr Thr 210 215 220 Lys Ser Phe Ser Arg Thr Pro Gly Gly Gly Gly Gly Ser Gly Gly Gly 225 230 235 240 Gly Ser Ser Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile 245 250 255 Pro Glu Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys 260 265 270 Arg Val Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu 275 280 285 Asp Thr Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys 290 295 300 Gly Phe Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr 305 310 315 320 Cys Glu Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr 325 330 335 His Arg Gln Thr Asn Thr Ile Ile Asp Val Val Leu Ser Pro Ser His 340 345 350 Gly Ile Glu Leu Ser Val Gly Glu Lys Leu Val Leu Asn Cys Thr Ala 355 360 365 Arg Thr Glu Leu Asn Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro Ser 370 375 380 Ser Lys His Gln His Lys Lys Leu Val Asn Arg Asp Leu Lys Thr Gln 385 390 395 400 Ser Gly Ser Glu Met Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp Gly 405 410 415 Val Thr Arg Ser Asp Gln Gly Leu Tyr Thr Cys Ala Ala Ser Ser Gly 420 425 430 Leu Met Thr Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys 435 440 445 <210> 14 <211> 217 <212> PRT <213> Artificial Sequence <220> <223> mu IgG2a Fc DANG <400> 14 Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys 1 5 10 15 Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val 20 25 30 Val Val Ala Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe 35 40 45 Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu 50 55 60 Asp Tyr Gly Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His 65 70 75 80 Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys 85 90 95 Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser 100 105 110 Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Glu Glu Glu Met 115 120 125 Thr Lys Lys Gln Val Thr Leu Thr Cys Met Val Thr Asp Phe Met Pro 130 135 140 Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn 145 150 155 160 Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met 165 170 175 Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser 180 185 190 Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His His Thr Thr 195 200 205 Lys Ser Phe Ser Arg Thr Pro Gly Lys 210 215 <210> 15 <211> 264 <212> PRT <213> Artificial Sequence <220> <223> Human CRIg extracellular domain <400> 15 Arg Pro Ile Leu Glu Val Pro Glu Ser Val Thr Gly Pro Trp Lys Gly 1 5 10 15 Asp Val Asn Leu Pro Cys Thr Tyr Asp Pro Leu Gln Gly Tyr Thr Gln 20 25 30 Val Leu Val Lys Trp Leu Val Gln Arg Gly Ser Asp Pro Val Thr Ile 35 40 45 Phe Leu Arg Asp Ser Ser Gly Asp His Ile Gln Gln Ala Lys Tyr Gln 50 55 60 Gly Arg Leu His Val Ser His Lys Val Pro Gly Asp Val Ser Leu Gln 65 70 75 80 Leu Ser Thr Leu Glu Met Asp Asp Arg Ser His Tyr Thr Cys Glu Val 85 90 95 Thr Trp Gln Thr Pro Asp Gly Asn Gln Val Val Arg Asp Lys Ile Thr 100 105 110 Glu Leu Arg Val Gln Lys Leu Ser Val Ser Lys Pro Thr Val Thr Thr 115 120 125 Gly Ser Gly Tyr Gly Phe Thr Val Pro Gln Gly Met Arg Ile Ser Leu 130 135 140 Gln Cys Gln Ala Arg Gly Ser Pro Pro Ile Ser Tyr Ile Trp Tyr Lys 145 150 155 160 Gln Gln Thr Asn Asn Gln Glu Pro Ile Lys Val Ala Thr Leu Ser Thr 165 170 175 Leu Leu Phe Lys Pro Ala Val Ile Ala Asp Ser Gly Ser Tyr Phe Cys 180 185 190 Thr Ala Lys Gly Gln Val Gly Ser Glu Gln His Ser Asp Ile Val Lys 195 200 205 Phe Val Val Lys Asp Ser Ser Lys Leu Leu Lys Thr Lys Thr Glu Ala 210 215 220 Pro Thr Thr Met Thr Tyr Pro Leu Lys Ala Thr Ser Thr Val Lys Gln 225 230 235 240 Ser Trp Asp Trp Thr Thr Asp Met Asp Gly Tyr Leu Gly Glu Thr Ser 245 250 255 Ala Gly Pro Gly Lys Ser Leu Pro 260 <210> 16 <211> 168 <212> PRT <213> Artificial Sequence <220> <223> Mouse CRIg extracellular domain <400> 16 His Pro Thr Leu Lys Thr Pro Glu Ser Val Thr Gly Thr Trp Lys Gly 1 5 10 15 Asp Val Lys Ile Gln Cys Ile Tyr Asp Pro Leu Arg Gly Tyr Arg Gln 20 25 30 Val Leu Val Lys Trp Leu Val Arg His Gly Ser Asp Ser Val Thr Ile 35 40 45 Phe Leu Arg Asp Ser Thr Gly Asp His Ile Gln Gln Ala Lys Tyr Arg 50 55 60 Gly Arg Leu Lys Val Ser His Lys Val Pro Gly Asp Val Ser Leu Gln 65 70 75 80 Ile Asn Thr Leu Gln Met Asp Asp Arg Asn His Tyr Thr Cys Glu Val 85 90 95 Thr Trp Gln Thr Pro Asp Gly Asn Gln Val Ile Arg Asp Lys Ile Ile 100 105 110 Glu Leu Arg Val Arg Lys Tyr Asn Pro Pro Arg Ile Asn Thr Glu Ala 115 120 125 Pro Thr Thr Leu His Ser Ser Leu Glu Ala Thr Thr Ile Met Ser Ser 130 135 140 Thr Ser Asp Leu Thr Thr Asn Gly Thr Gly Lys Leu Glu Glu Thr Ile 145 150 155 160 Ala Gly Ser Gly Arg Asn Leu Pro 165 <210> 17 <211> 209 <212> PRT <213> Artificial Sequence <220> <223> Human IgG1 Fc DANG-K <400> 17 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 1 5 10 15 Arg Thr Pro Glu Val Thr Cys Val Val Val Ala Val Ser His Glu Asp 20 25 30 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 35 40 45 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Val 50 55 60 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 65 70 75 80 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 85 90 95 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 100 105 110 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 115 120 125 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 130 135 140 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 145 150 155 160 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 165 170 175 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 180 185 190 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 195 200 205 Lys <210> 18 <211> 216 <212> PRT <213> Artificial Sequence <220> <223> Mouse IgG2a Fc DANG <400> 18 Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys 1 5 10 15 Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val 20 25 30 Val Val Ala Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe 35 40 45 Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu 50 55 60 Asp Tyr Gly Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His 65 70 75 80 Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys 85 90 95 Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser 100 105 110 Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Glu Glu Glu Met 115 120 125 Thr Lys Lys Gln Val Thr Leu Thr Cys Met Val Thr Asp Phe Met Pro 130 135 140 Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn 145 150 155 160 Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met 165 170 175 Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser 180 185 190 Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His His Thr Thr 195 200 205 Lys Ser Phe Ser Arg Thr Pro Gly 210 215 <210> 19 <211> 103 <212> PRT <213> Artificial Sequence <220> <223> Human CD59-Origin <400> 19 Leu Gln Cys Tyr Asn Cys Pro Asn Pro Thr Ala Asp Cys Lys Thr Ala 1 5 10 15 Val Asn Cys Ser Ser Asp Phe Asp Ala Cys Leu Ile Thr Lys Ala Gly 20 25 30 Leu Gln Val Tyr Asn Lys Cys Trp Lys Phe Glu His Cys Asn Phe Asn 35 40 45 Asp Val Thr Thr Arg Leu Arg Glu Asn Glu Leu Thr Tyr Tyr Cys Cys 50 55 60 Lys Lys Asp Leu Cys Asn Phe Asn Glu Gln Leu Glu Asn Gly Gly Thr 65 70 75 80 Ser Leu Ser Glu Lys Thr Val Leu Leu Leu Val Thr Pro Phe Leu Ala 85 90 95 Ala Ala Trp Ser Leu His Pro 100 <210> 20 <211> 103 <212> PRT <213> Artificial Sequence <220> <223> Human CD59-K41Q <400> 20 Leu Gln Cys Tyr Asn Cys Pro Asn Pro Thr Ala Asp Cys Lys Thr Ala 1 5 10 15 Val Asn Cys Ser Ser Asp Phe Asp Ala Cys Leu Ile Thr Lys Ala Gly 20 25 30 Leu Gln Val Tyr Asn Lys Cys Trp Gln Phe Glu His Cys Asn Phe Asn 35 40 45 Asp Val Thr Thr Arg Leu Arg Glu Asn Glu Leu Thr Tyr Tyr Cys Cys 50 55 60 Lys Lys Asp Leu Cys Asn Phe Asn Glu Gln Leu Glu Asn Gly Gly Thr 65 70 75 80 Ser Leu Ser Glu Lys Thr Val Leu Leu Leu Val Thr Pro Phe Leu Ala 85 90 95 Ala Ala Trp Ser Leu His Pro 100 <210> 21 <211> 103 <212> PRT <213> Artificial Sequence <220> <223> Human CD59-H44Q <400> 21 Leu Gln Cys Tyr Asn Cys Pro Asn Pro Thr Ala Asp Cys Lys Thr Ala 1 5 10 15 Val Asn Cys Ser Ser Asp Phe Asp Ala Cys Leu Ile Thr Lys Ala Gly 20 25 30 Leu Gln Val Tyr Asn Lys Cys Trp Lys Phe Glu Gln Cys Asn Phe Asn 35 40 45 Asp Val Thr Thr Arg Leu Arg Glu Asn Glu Leu Thr Tyr Tyr Cys Cys 50 55 60 Lys Lys Asp Leu Cys Asn Phe Asn Glu Gln Leu Glu Asn Gly Gly Thr 65 70 75 80 Ser Leu Ser Glu Lys Thr Val Leu Leu Leu Val Thr Pro Phe Leu Ala 85 90 95 Ala Ala Trp Ser Leu His Pro 100 <210> 22 <211> 205 <212> PRT <213> Artificial Sequence <220> <223> VEGF binder (VEGFR1 D2-VEGFR2 D3) <400> 22 Ser Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu 1 5 10 15 Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val 20 25 30 Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr 35 40 45 Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe 50 55 60 Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu 65 70 75 80 Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg 85 90 95 Gln Thr Asn Thr Ile Ile Asp Val Val Leu Ser Pro Ser His Gly Ile 100 105 110 Glu Leu Ser Val Gly Glu Lys Leu Val Leu Asn Cys Thr Ala Arg Thr 115 120 125 Glu Leu Asn Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro Ser Ser Lys 130 135 140 His Gln His Lys Lys Leu Val Asn Arg Asp Leu Lys Thr Gln Ser Gly 145 150 155 160 Ser Glu Met Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp Gly Val Thr 165 170 175 Arg Ser Asp Gln Gly Leu Tyr Thr Cys Ala Ala Ser Ser Gly Leu Met 180 185 190 Thr Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys 195 200 205 <210> 23 <211> 77 <212> PRT <213> Artificial Sequence <220> <223> Human CD59 without c-terminal propeptide <400> 23 Leu Gln Cys Tyr Asn Cys Pro Asn Pro Thr Ala Asp Cys Lys Thr Ala 1 5 10 15 Val Asn Cys Ser Ser Asp Phe Asp Ala Cys Leu Ile Thr Lys Ala Gly 20 25 30 Leu Gln Val Tyr Asn Lys Cys Trp Lys Phe Glu Gln Cys Asn Phe Asn 35 40 45 Asp Val Thr Thr Arg Leu Arg Glu Asn Glu Leu Thr Tyr Tyr Cys Cys 50 55 60 Lys Lys Asp Leu Cys Asn Phe Asn Glu Gln Leu Glu Asn 65 70 75 <210> 24 <211> 73 <212> PRT <213> Artificial Sequence <220> <223> Mouse CD59a <400> 24 Leu Thr Cys Tyr His Cys Phe Gln Pro Val Val Ser Ser Cys Asn Met 1 5 10 15 Asn Ser Thr Cys Ser Pro Asp Gln Asp Ser Cys Leu Tyr Ala Val Ala 20 25 30 Gly Met Gln Val Tyr Gln Arg Cys Trp Lys Gln Ser Asp Cys His Gly 35 40 45 Glu Ile Ile Met Asp Gln Leu Glu Glu Thr Lys Leu Lys Phe Arg Cys 50 55 60 Cys Gln Phe Asn Leu Cys Asn Lys Ser 65 70 <210> 25 <211> 23 <212> PRT <213> Artificial Sequence <220> <223> human Linker-1 <400> 25 Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala 1 5 10 15 Pro Glu Leu Leu Gly Gly Pro 20 <210> 26 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> human Linker-2 <400> 26 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1 5 10 <210> 27 <211> 21 <212> PRT <213> Artificial Sequence <220> <223> mouse Linker-1 <400> 27 Gly Gly Gly Gly Ser Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro 1 5 10 15 Pro Cys Lys Cys Pro 20 <210> 28 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> mouse Linker-2 <400> 28 Gly Gly Gly Gly Ser 1 5 <210> 29 <211> 399 <212> PRT <213> Artificial Sequence <220> <223> Human CRIg-Whole <400> 29 Met Gly Ile Leu Leu Gly Leu Leu Leu Leu Leu Gly His Leu Thr Val Asp 1 5 10 15 Thr Tyr Gly Arg Pro Ile Leu Glu Val Pro Glu Ser Val Thr Gly Pro 20 25 30 Trp Lys Gly Asp Val Asn Leu Pro Cys Thr Tyr Asp Pro Leu Gln Gly 35 40 45 Tyr Thr Gln Val Leu Val Lys Trp Leu Val Gln Arg Gly Ser Asp Pro 50 55 60 Val Thr Ile Phe Leu Arg Asp Ser Ser Gly Asp His Ile Gln Gln Ala 65 70 75 80 Lys Tyr Gln Gly Arg Leu His Val Ser His Lys Val Pro Gly Asp Val 85 90 95 Ser Leu Gln Leu Ser Thr Leu Glu Met Asp Asp Arg Ser His Tyr Thr 100 105 110 Cys Glu Val Thr Trp Gln Thr Pro Asp Gly Asn Gln Val Val Arg Asp 115 120 125 Lys Ile Thr Glu Leu Arg Val Gln Lys Leu Ser Val Ser Lys Pro Thr 130 135 140 Val Thr Thr Gly Ser Gly Tyr Gly Phe Thr Val Pro Gln Gly Met Arg 145 150 155 160 Ile Ser Leu Gln Cys Gln Ala Arg Gly Ser Pro Pro Ile Ser Tyr Ile 165 170 175 Trp Tyr Lys Gln Gln Thr Asn Asn Gln Glu Pro Ile Lys Val Ala Thr 180 185 190 Leu Ser Thr Leu Leu Phe Lys Pro Ala Val Ile Ala Asp Ser Gly Ser 195 200 205 Tyr Phe Cys Thr Ala Lys Gly Gln Val Gly Ser Glu Gln His Ser Asp 210 215 220 Ile Val Lys Phe Val Val Lys Asp Ser Ser Lys Leu Leu Lys Thr Lys 225 230 235 240 Thr Glu Ala Pro Thr Thr Met Thr Tyr Pro Leu Lys Ala Thr Ser Thr 245 250 255 Val Lys Gln Ser Trp Asp Trp Thr Thr Asp Met Asp Gly Tyr Leu Gly 260 265 270 Glu Thr Ser Ala Gly Pro Gly Lys Ser Leu Pro Val Phe Ala Ile Ile 275 280 285 Leu Ile Ile Ser Leu Cys Cys Met Val Val Phe Thr Met Ala Tyr Ile 290 295 300 Met Leu Cys Arg Lys Thr Ser Gln Gln Glu His Val Tyr Glu Ala Ala 305 310 315 320 Arg Ala His Ala Arg Glu Ala Asn Asp Ser Gly Glu Thr Met Arg Val 325 330 335 Ala Ile Phe Ala Ser Gly Cys Ser Ser Asp Glu Pro Thr Ser Gln Asn 340 345 350 Leu Gly Asn Asn Tyr Ser Asp Glu Pro Cys Ile Gly Gln Glu Tyr Gln 355 360 365 Ile Ile Ala Gln Ile Asn Gly Asn Tyr Ala Arg Leu Leu Asp Thr Val 370 375 380 Pro Leu Asp Tyr Glu Phe Leu Ala Thr Glu Gly Lys Ser Val Cys 385 390 395 <210> 30 <211> 305 <212> PRT <213> Artificial Sequence <220> <223> human CRIg (VSIG4) isoform 3 <400> 30 Met Gly Ile Leu Leu Gly Leu Leu Leu Leu Leu Gly His Leu Thr Val Asp 1 5 10 15 Thr Tyr Gly Arg Pro Ile Leu Glu Val Pro Glu Ser Val Thr Gly Pro 20 25 30 Trp Lys Gly Asp Val Asn Leu Pro Cys Thr Tyr Asp Pro Leu Gln Gly 35 40 45 Tyr Thr Gln Val Leu Val Lys Trp Leu Val Gln Arg Gly Ser Asp Pro 50 55 60 Val Thr Ile Phe Leu Arg Asp Ser Ser Gly Asp His Ile Gln Gln Ala 65 70 75 80 Lys Tyr Gln Gly Arg Leu His Val Ser His Lys Val Pro Gly Asp Val 85 90 95 Ser Leu Gln Leu Ser Thr Leu Glu Met Asp Asp Arg Ser His Tyr Thr 100 105 110 Cys Glu Val Thr Trp Gln Thr Pro Asp Gly Asn Gln Val Val Arg Asp 115 120 125 Lys Ile Thr Glu Leu Arg Val Gln Lys His Ser Ser Lys Leu Leu Lys 130 135 140 Thr Lys Thr Glu Ala Pro Thr Thr Met Thr Tyr Pro Leu Lys Ala Thr 145 150 155 160 Ser Thr Val Lys Gln Ser Trp Asp Trp Thr Thr Asp Met Asp Gly Tyr 165 170 175 Leu Gly Glu Thr Ser Ala Gly Pro Gly Lys Ser Leu Pro Val Phe Ala 180 185 190 Ile Ile Leu Ile Ile Ser Leu Cys Cys Met Val Val Phe Thr Met Ala 195 200 205 Tyr Ile Met Leu Cys Arg Lys Thr Ser Gln Gln Glu His Val Tyr Glu 210 215 220 Ala Ala Arg Ala His Ala Arg Glu Ala Asn Asp Ser Gly Glu Thr Met 225 230 235 240 Arg Val Ala Ile Phe Ala Ser Gly Cys Ser Ser Asp Glu Pro Thr Ser 245 250 255 Gln Asn Leu Gly Asn Asn Tyr Ser Asp Glu Pro Cys Ile Gly Gln Glu 260 265 270 Tyr Gln Ile Ile Ala Gln Ile Asn Gly Asn Tyr Ala Arg Leu Leu Asp 275 280 285 Thr Val Pro Leu Asp Tyr Glu Phe Leu Ala Thr Glu Gly Lys Ser Val 290 295 300 Cys 305 <210> 31 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> human Ig V domain <400> 31 Pro Ile Leu Glu Val Pro Glu Ser Val Thr Gly Pro Trp Lys Gly Asp 1 5 10 15 Val Asn Leu Pro Cys Thr Tyr Asp Pro Leu Gln Gly Tyr Thr Gln Val 20 25 30 Leu Val Lys Trp Leu Val Gln Arg Gly Ser Asp Pro Val Thr Ile Phe 35 40 45 Leu Arg Asp Ser Ser Gly Asp His Ile Gln Gln Ala Lys Tyr Gln Gly 50 55 60 Arg Leu His Val Ser His Lys Val Pro Gly Asp Val Ser Leu Gln Leu 65 70 75 80 Ser Thr Leu Glu Met Asp Asp Arg Ser His Tyr Thr Cys Glu Val Thr 85 90 95 Trp Gln Thr Pro Asp Gly Asn Gln Val Val Arg Asp Lys Ile Thr 100 105 110 <210> 32 <211> 280 <212> PRT <213> Artificial Sequence <220> <223> Mouse CRIg-Whole <400> 32 Met Glu Ile Ser Ser Gly Leu Leu Leu Phe Leu Gly His Leu Ile Val Leu 1 5 10 15 Thr Tyr Gly His Pro Thr Leu Lys Thr Pro Glu Ser Val Thr Gly Thr 20 25 30 Trp Lys Gly Asp Val Lys Ile Gln Cys Ile Tyr Asp Pro Leu Arg Gly 35 40 45 Tyr Arg Gln Val Leu Val Lys Trp Leu Val Arg His Gly Ser Asp Ser 50 55 60 Val Thr Ile Phe Leu Arg Asp Ser Thr Gly Asp His Ile Gln Gln Ala 65 70 75 80 Lys Tyr Arg Gly Arg Leu Lys Val Ser His Lys Val Pro Gly Asp Val 85 90 95 Ser Leu Gln Ile Asn Thr Leu Gln Met Asp Asp Arg Asn His Tyr Thr 100 105 110 Cys Glu Val Thr Trp Gln Thr Pro Asp Gly Asn Gln Val Ile Arg Asp 115 120 125 Lys Ile Ile Glu Leu Arg Val Arg Lys Tyr Asn Pro Pro Arg Ile Asn 130 135 140 Thr Glu Ala Pro Thr Thr Leu His Ser Ser Leu Glu Ala Thr Thr Ile 145 150 155 160 Met Ser Ser Thr Ser Asp Leu Thr Thr Asn Gly Thr Gly Lys Leu Glu 165 170 175 Glu Thr Ile Ala Gly Ser Gly Arg Asn Leu Pro Ile Phe Ala Ile Ile 180 185 190 Phe Ile Ile Ser Leu Cys Cys Ile Val Ala Val Thr Ile Pro Tyr Ile 195 200 205 Leu Phe Arg Cys Arg Thr Phe Gln Gln Glu Tyr Val Tyr Gly Val Ser 210 215 220 Arg Val Phe Ala Arg Lys Thr Ser Asn Ser Glu Glu Thr Thr Arg Val 225 230 235 240 Thr Thr Ile Ala Thr Asp Glu Pro Asp Ser Gln Ala Leu Ile Ser Asp 245 250 255 Tyr Ser Asp Asp Pro Cys Leu Ser Gln Glu Tyr Gln Ile Thr Ile Arg 260 265 270 Ser Thr Met Ser Ile Pro Ala Cys 275 280 <210> 33 <211> 1488 <212> DNA <213> Artificial Sequence <220> <223> hu CRIg-hu IgG1 Fc DANG sequence <400> 33 cggcctatcc tggaggtgcc agagtccgtg accggaccat ggaagggcga cgtgaacctg 60 ccctgcacct acgatcctct gcagggctat acacaggtgc tggtgaagtg gctggtgcag 120 aggggcagcg accctgtgac catcttcctg cgcgacagct ccggcgatca catccagcag 180 gccaagtacc agggcaggct gcacgtgtct cacaaggtgc ctggcgatgt gagcctgcag 240 ctgtccaccc tggagatgga cgatcgcagc cactatacat gtgaggtgac ctggcagaca 300 ccagacggca atcaggtggt gcgggataag atcaccgagc tgagagtgca gaagctgtcc 360 gtgtctaagc caaccgtgac cacaggcagc ggctacggct tcacagtgcc ccagggcatg 420 aggatctccc tgcagtgcca ggcaaggggc tctccaccta tcagctacat ctggtataag 480 cagcagacca acaatcagga gcctatcaag gtggccaccc tgtccacact gctgttcaag 540 ccagccgtga tcgccgacag cggctcctat ttttgtacag caaagggaca agtgggctcc 600 gagcagcact ctgacatcgt gaagtttgtg gtgaaggatt ctagcaagct gctgaagacc 660 aagacagagg cccctaccac aatgacctac ccactgaagg ccaccagcac agtgaagcag 720 tcctgggact ggaccacaga catggatggc tatctgggcg agacatctgc cggaccaggc 780 aagagcctgc caggaggagg cggcagcgat aagacccaca catgcccacc ctgtcctgca 840 ccagagctgc tgggaggacc atccgtgttc ctgtttcctc caaagcctaa ggacaccctg 900 atgatctctc ggaccccaga ggtgacatgc gtggtggtgg ccgtgagcca cgaggacccc 960 gaggtgaagt ttaactggta cgtggatggc gtggaggtgc acaatgccaa gaccaagccc 1020 cgggaggagc agtacggctc cacctataga gtggtgtctg tgctgacagt gctgcaccag 1080 gattggctga acggcaagga gtataagtgc aaggtgtcca ataaggccct gcccgcccct 1140 atcgagaaga ccatctctaa ggcaaaggga cagccaaggg agccacaggt gtacacactg 1200 cccccttcca gagacgagct gaccaagaac caggtgtctc tgacatgtct ggtgaagggc 1260 ttctatccct ctgatatcgc cgtggagtgg gagagcaatg gccagcctga gaacaattac 1320 aagaccacac cacccgtgct ggactccgat ggctctttct ttctgtatag caagctgacc 1380 gtggataagt ccagatggca gcagggcaac gtgttttctt gtagcgtgat gcacgaggcc 1440 ctgcacaatc actacacaca gaagtccctg tctctgagcc ccggcaag 1488 <210> 34 <211> 1824 <212> DNA <213> Artificial Sequence <220> <223> hu CRIg-hu IgG1 Fc DANG-hu CD59 (K41Q) sequence <400> 34 cggcccatcc tggaggtgcc tgagtccgtg accggacctt ggaagggcga cgtgaacctg 60 ccatgcacat acgatcccct gcagggctat acccaggtgc tggtgaagtg gctggtgcag 120 aggggcagcg acccagtgac catcttcctg aagacagct ccggcgatca catccagcag 180 gccaagtacc agggccggct gcacgtgtct cacaaggtgc caggcgacgt gagcctgcag 240 ctgtctacac tggagatgga cgatagaagc cactatacct gtgaggtgac ctggcagaca 300 cccgacggca atcaggtggt gagggataag atcaccgagc tgcgcgtgca gaagctgagc 360 gtgtccaagc ccacagtgac cacaggcagc ggctacggct tcaccgtgcc tcagggcatg 420 cggatctccc tgcagtgcca ggcaagaggc agcccaccta tctcctacat ctggtataag 480 cagcagacaa acaatcagga gccaatcaag gtggccaccc tgtccacact gctgttcaag 540 cccgccgtga tcgccgactc tggcagctac ttttgtaccg caaagggaca agtgggctct 600 gagcagcaca gcgacatcgt gaagtttgtg gtgaaggatt ctagcaagct gctgaagacc 660 aagacagagg cccccaccac aatgacatac cctctgaagg ccacctccac agtgaagcag 720 tcttgggact ggaccacaga catggatggc tatctgggag agacctctgc cggacctggc 780 aagagcctgc caggaggagg cggcagcgat aagacccaca catgcccacc atgtcctgca 840 ccagagctgc tgggaggacc atccgtgttc ctgtttcctc caaagcccaa ggacaccctg 900 atgatctcta ggaccccaga ggtgacatgc gtggtggtgg ccgtgagcca cgaggaccct 960 gaggtgaagt tcaactggta cgtggatggc gtggaggtgc acaatgccaa gaccaagccc 1020 agggaggagc agtacggctc cacatatcgc gtggtgtctg tgctgaccgt gctgcaccag 1080 gattggctga acggcaagga gtataagtgc aaggtgtcca ataaggccct gcccgcccct 1140 atcgagaaga caatctctaa ggccaagggc cagcctaggg agccacaggt gtacaccctg 1200 ccaccttcca gggacgagct gacaaagaac caggtgtctc tgacctgtct ggtgaagggc 1260 ttctatcctt ctgatatcgc cgtggagtgg gagagcaatg gccagccaga gaacaattac 1320 aagaccacac cacccgtgct ggactctgat ggcagcttct ttctgtatag caagctgaca 1380 gtggacaagt cccgctggca gcagggcaac gtgttttcct gctctgtgat gcacgaggcc 1440 ctgcacaatc actacaccca gaaaagcctg tccctgtctc ctggaggagg aggaggcagc 1500 ggcggaggag gctccctgca gtgctataac tgtccaaatc ccaccgccga ttgcaagaca 1560 gccgtgaact gttcctctga ctttgatgcc tgcctgatca caaaggccgg cctgcaggtg 1620 tacaataagt gctggcagtt cgagcactgt aactttaatg acgtgaccac acggctgaga 1680 gagaacgagc tgacctacta ttgctgtaag aaggacctgt gcaacttcaa tgagcagctg 1740 gagaatggcg gcaccagcct gtccgagaag acagtgctgc tgctggtgac cccttttctg 1800 gcagcagcat ggagcctgca ccca 1824 <210> 35 <211> 1824 <212> DNA <213> Artificial Sequence <220> <223> hu CRIg-hu IgG1 Fc DANG-hu CD59 (H44Q) sequence <400> 35 cggcccatcc tggaggtgcc tgagtccgtg accggacctt ggaagggcga cgtgaacctg 60 ccatgcacat acgatcccct gcagggctat acccaggtgc tggtgaagtg gctggtgcag 120 aggggcagcg acccagtgac catcttcctg aagacagct ccggcgatca catccagcag 180 gccaagtacc agggccggct gcacgtgtct cacaaggtgc caggcgacgt gagcctgcag 240 ctgtctacac tggagatgga cgatagaagc cactatacct gtgaggtgac ctggcagaca 300 cccgacggca atcaggtggt gagggataag atcaccgagc tgcgcgtgca gaagctgagc 360 gtgtccaagc ccacagtgac cacaggcagc ggctacggct tcaccgtgcc tcagggcatg 420 cggatctccc tgcagtgcca ggcaagaggc agcccaccta tctcctacat ctggtataag 480 cagcagacaa acaatcagga gccaatcaag gtggccaccc tgtccacact gctgttcaag 540 cccgccgtga tcgccgactc tggcagctac ttttgtaccg caaagggaca agtgggctct 600 gagcagcaca gcgacatcgt gaagtttgtg gtgaaggatt ctagcaagct gctgaagacc 660 aagacagagg cccccaccac aatgacatac cctctgaagg ccacctccac agtgaagcag 720 tcttgggact ggaccacaga catggatggc tatctgggag agacctctgc cggacctggc 780 aagagcctgc caggaggagg cggcagcgat aagacccaca catgcccacc atgtcctgca 840 ccagagctgc tgggaggacc atccgtgttc ctgtttcctc caaagcccaa ggacaccctg 900 atgatctcta ggaccccaga ggtgacatgc gtggtggtgg ccgtgagcca cgaggaccct 960 gaggtgaagt tcaactggta cgtggatggc gtggaggtgc acaatgccaa gaccaagccc 1020 agggaggagc agtacggctc cacatatcgc gtggtgtctg tgctgaccgt gctgcaccag 1080 gattggctga acggcaagga gtataagtgc aaggtgtcca ataaggccct gcccgcccct 1140 atcgagaaga caatctctaa ggccaagggc cagcctaggg agccacaggt gtacaccctg 1200 ccaccttcca gggacgagct gacaaagaac caggtgtctc tgacctgtct ggtgaagggc 1260 ttctatcctt ctgatatcgc cgtggagtgg gagagcaatg gccagccaga gaacaattac 1320 aagaccacac cacccgtgct ggactctgat ggcagcttct ttctgtatag caagctgaca 1380 gtggacaagt cccgctggca gcagggcaac gtgttttcct gctctgtgat gcacgaggcc 1440 ctgcacaatc actacaccca gaaaagcctg tccctgtctc ctggaggagg aggaggcagc 1500 ggcggaggag gctccctgca gtgctataac tgtccaaatc ccaccgccga ttgcaagaca 1560 gccgtgaact gttcctctga ctttgatgcc tgcctgatca caaaggccgg cctgcaggtg 1620 tacaataagt gctggaagtt cgagcagtgt aactttaatg acgtgaccac acggctgaga 1680 gagaacgagc tgacctacta ttgctgtaag aaggacctgt gcaacttcaa tgagcagctg 1740 gagaatggcg gcaccagcct gtccgagaag acagtgctgc tgctggtgac cccttttctg 1800 gcagcagcat ggagcctgca ccca 1824 <210> 36 <211> 2130 <212> DNA <213> Artificial Sequence <220> <223> hu CRIg-hu IgG1 Fc DANG-VEGF binder sequence <400> 36 cgccctatcc tggaggtgcc agagtccgtg accggaccat ggaagggcga cgtgaacctg 60 ccctgcacct acgatcctct gcagggctat acacaggtgc tggtgaagtg gctggtgcag 120 aggggcagcg accctgtgac catcttcctg cgcgacagct ccggcgatca catccagcag 180 gccaagtacc agggcaggct gcacgtgtcc cacaaggtgc ctggcgacgt gagcctgcag 240 ctgtctaccc tggagatgga cgatcgcagc cactatacat gtgaggtgac ctggcagaca 300 ccagacggca atcaggtggt gagggataag atcaccgagc tgcgcgtgca gaagctgtcc 360 gtgtctaagc caaccgtgac cacaggctct ggctacggct tcacagtgcc ccagggcatg 420 aggatcagcc tgcagtgcca ggcaaggggc agcccaccta tctcctacat ctggtataag 480 cagcagacca acaatcagga gcctatcaag gtggccaccc tgtccacact gctgttcaag 540 ccagccgtga tcgccgacag cggctcctac ttttgtacag ccaagggcca agtgggctct 600 gagcagcaca gcgacatcgt gaagtttgtg gtgaaggatt ctagcaagct gctgaagacc 660 aagacagagg cccctaccac aatgacctac ccactgaagg ccacctccac agtgaagcag 720 tcttgggact ggaccacaga catggatggc tatctgggag agacaagcgc cggacctggc 780 aagtccctgc caggaggcgg cggctccgat aagacccaca catgcccacc atgtcctgca 840 ccagagctgc tgggaggacc tagcgtgttc ctgtttcctc caaagccaaa ggacaccctg 900 atgatctccc ggaccccaga ggtgacatgc gtggtggtgg ccgtgtctca cgaggacccc 960 gaggtgaagt tcaactggta cgtggatggc gtggaggtgc acaatgccaa gaccaagccc 1020 cgggaggagc agtacggctc tacctataga gtggtgagcg tgctgacagt gctgcaccag 1080 gattggctga acggcaagga gtataagtgc aaggtgagca ataaggccct gcccgcccct 1140 atcgagaaga ccatctccaa ggcaaaggga cagccaaggg agccacaggt gtacacactg 1200 cccccttcca gagacgagct gaccaagaac caggtgtctc tgacatgtct ggtgaagggc 1260 ttttatccct ctgatatcgc cgtggagtgg gagagcaatg gccagcctga gaacaattac 1320 aagaccacac cacccgtgct ggactctgat ggcagcttct ttctgtattc caagctgacc 1380 gtggacaagt ctagatggca gcagggcaac gtgttctctt gcagcgtgat gcacgaggcc 1440 ctgcacaatc actacaccca gaagtccctg tctctgagcc caggaggagg aggaggctct 1500 ggaggaggag gctcctctga tacaggcagg ccctttgtgg agatgtatag cgagatccct 1560 gagatcatcc acatgaccga gggaagggag ctggtcatcc catgtagagt gacatcccct 1620 aacatcaccg tgacactgaa gaagttccca ctggacaccc tgatccccga tggcaagcgg 1680 atcatctggg acagcagaaa gggctttatc atctccaatg ccacatacaa ggagatcggc 1740 ctgctgacct gcgaggccac agtgaacggc cacctgtaca agaccaatta tctgacacac 1800 cgccagacca acacaatcat cgatgtggtg ctgtccccat ctcacggcat cgagctgagc 1860 gtgggcgaga agctggtgct gaattgtacc gcccggacag agctgaacgt gggcatcgac 1920 ttcaattggg agtaccctag ctccaagcac cagcacaaga agctggtcaa ccgggatctg 1980 aagacccaga gcggctccga gatgaagaag tttctgagca ccctgacaat cgacggcgtg 2040 accagatccg atcagggcct gtatacatgt gccgcctcta gcggcctgat gaccaagaag 2100 aatagcacat ttgtgagggt gcacgagaag 2130 <210> 37 <211> 1017 <212> DNA <213> Artificial Sequence <220> <223> hu IgG1 Fc DANG-hu CD59 (K41Q) sequence <400> 37 gacaagaccc acacatgccc accttgtcca gcaccagagc tgctgggagg accttccgtg 60 ttcctgtttc cacccaagcc aaaggatacc ctgatgatca gcaggacccc tgaggtgaca 120 tgcgtggtgg tggccgtgtc ccacgaggac ccagaggtga agttcaactg gtacgtggat 180 ggcgtggagg tgcacaatgc caagaccaag cccagggagg agcagtacgg ctccacatat 240 cgcgtggtgt ctgtgctgac cgtgctgcac caggactggc tgaacggcaa ggagtataag 300 tgcaaggtgt ctaataaggc cctgcctgcc ccaatcgaga agacaatcag caaggcaaag 360 ggacagccaa gggagccaca ggtgtacacc ctgcctccat ccagagacga gctgacaaag 420 aaccaggtgt ctctgacctg tctggtgaag ggcttctatc catctgatat cgccgtggag 480 tgggagagca atggccagcc cgagaacaat tacaagacca caccccctgt gctggacagc 540 gatggctcct tctttctgta tagcaagctg acagtggaca agtccagatg gcagcagggc 600 aacgtgtttt cttgtagcgt gatgcacgag gccctgcaca atcactacac ccagaagtcc 660 ctgtctctga gccctggagg aggaggaggc tctggaggag gaggcagcct gcagtgctat 720 aactgtccca atcctaccgc cgattgcaag acagccgtga actgtagctc cgactttgat 780 gcctgcctga tcacaaaggc cggcctgcag gtgtacaata agtgctggca gttcgagcac 840 tgtaacttta atgacgtgac cacacggctg agagagaacg agctgaccta ctattgctgt 900 aagaaggacc tgtgcaactt caatgagcag ctggagaatg gcggcacctc cctgtctgag 960 aagacagtgc tgctgctggt gacccccttt ctggcagcag catggagcct gcaccct 1017 <210> 38 <211> 1017 <212> DNA <213> Artificial Sequence <220> <223> hu IgG1 Fc DANG-hu CD59 (H44Q) sequence <400> 38 gacaagaccc acacatgccc accttgtcca gcaccagagc tgctgggagg accttccgtg 60 ttcctgtttc cacccaagcc aaaggatacc ctgatgatca gcaggacccc tgaggtgaca 120 tgcgtggtgg tggccgtgtc ccacgaggac ccagaggtga agttcaactg gtacgtggat 180 ggcgtggagg tgcacaatgc caagaccaag cccagggagg agcagtacgg ctccacatat 240 cgcgtggtgt ctgtgctgac cgtgctgcac caggactggc tgaacggcaa ggagtataag 300 tgcaaggtgt ctaataaggc cctgcctgcc ccaatcgaga agacaatcag caaggcaaag 360 ggacagccaa gggagccaca ggtgtacacc ctgcctccat ccagagacga gctgacaaag 420 aaccaggtgt ctctgacctg tctggtgaag ggcttctatc catctgatat cgccgtggag 480 tgggagagca atggccagcc cgagaacaat tacaagacca caccccctgt gctggacagc 540 gatggctcct tctttctgta tagcaagctg acagtggaca agtccagatg gcagcagggc 600 aacgtgtttt cttgtagcgt gatgcacgag gccctgcaca atcactacac ccagaagtcc 660 ctgtctctga gccctggagg aggaggaggc tctggaggag gaggcagcct gcagtgctat 720 aactgtccca atcctaccgc cgattgcaag acagccgtga actgtagctc cgactttgat 780 gcctgcctga tcacaaaggc cggcctgcag gtgtacaata agtgctggaa gttcgagcag 840 tgtaacttta atgacgtgac cacacggctg agagagaacg agctgaccta ctattgctgt 900 aagaaggacc tgtgcaactt caatgagcag ctggagaatg gcggcacctc cctgtctgag 960 aagacagtgc tgctgctggt gacccccttt ctggcagcag catggagcct gcaccct 1017 <210> 39 <211> 678 <212> DNA <213> Artificial Sequence <220> <223> hu IgG1 Fc DANG sequence <400> 39 gacaagaccc accatgccc accttgtcca gcaccagagc tgctgggagg accatccgtg 60 ttcctgtttc cacccaagcc caaggatacc ctgatgatca gcaggacccc agaggtgaca 120 tgcgtggtgg tggccgtgtc ccacgaggac cctgaggtga agttcaactg gtacgtggat 180 ggcgtggagg tgcacaatgc caagaccaag ccacgggagg agcagtacgg ctccacctat 240 agagtggtgt ctgtgctgac agtgctgcac caggactggc tgaacggcaa ggagtataag 300 tgcaaggtgt ctaataaggc cctgcctgcc ccaatcgaga agaccatcag caaggcaaag 360 ggacagccaa gggagcctca ggtgtacaca ctgcctccat cccgcgacga gctgaccaag 420 aaccaggtgt ctctgacatg tctggtgaag ggcttctatc cttctgatat cgccgtggag 480 tgggagagca atggccagcc agagaacaat tacaagacca caccccctgt gctggactct 540 gatggcagct tctttctgta tagcaagctg accgtggata agtccaggtg gcagcagggc 600 aacgtgttta gctgttccgt gatgcacgag gccctgcaca atcactacac acagaagtct 660 ctgagcctgt cccctggc 678 <210> 40 <211> 1749 <212> DNA <213> Artificial Sequence <220> <223> hu CRIg-hu IgG1 Fc DANG-hu CD59 without propeptide sequence <400> 40 aggcctattc tcgaggtgcc cgagagcgtg accggacctt ggaagggaga cgtgaatctg 60 ccttgcacct acgaccctct gcaaggctac acccaagtgc tcgtgaagtg gctggtgcag 120 agaggatccg atcccgtgac catctttctg agagattcca gcggagacca catccagcaa 180 gctaagtacc aaggaagact gcatgtgagc cacaaggtgc ccggcgatgt gtctctgcag 240 ctgagcacac tggagatgga tgatagatcc cactacacat gcgaagtgac atggcaaacc 300 cccgatggca accaagtggt gagagacaag attaccgagc tcagagtcca gaagctgagc 360 gtgagcaaac ccacagtgac caccggaagc ggatatggct ttaccgtgcc ccaaggcatg 420 agaatctctc tgcaatgcca agccagaggc tcccctccta tcagctacat ttggtacaag 480 cagcaaacca acaaccaaga gcccatcaaa gtggctacac tgtccacact gctcttcaag 540 cccgccgtga tcgctgacag cggcagctac ttttgcaccg ctaagggaca agtgggatcc 600 gagcagcact ccgacattgt caagttcgtc gtcaaggact ccagcaagct gctgaagaca 660 aagaccgagg cccccacaac catgacctac cctctgaaag ctaccagcac agtgaagcag 720 agctgggact ggacaaccga catggatgga tacctcggcg agaccagcgc tggccccggc 780 aagtctctgc ccggcggcgg aggctccgac aagacacata catgccctcc ttgccccgcc 840 cccgagctcc tcggaggccc ttccgtgttt ctgtttcccc ccaagcccaa ggacacactc 900 atgatctcca gaacccccga ggtgacatgc gtggtggtgg ccgtcagcca tgaggacccc 960 gaagtgaagt tcaactggta cgtcgacggc gtggaggtcc acaatgccaa gacaaagcct 1020 agggaggagc aatatggcag cacatacaga gtggtcagcg tgctcacagt gctccaccaa 1080 gactggctga acggcaagga gtataagtgc aaggtgtcca acaaagccct ccccgccccc 1140 atcgagaaga ccatcagcaa ggccaaaggc cagcctaggg agccccaagt gtatacactg 1200 cccccttcca gagacgagct gaccaagaac caagtgtctc tgacatgtct ggtgaaggga 1260 ttctacccca gcgacatcgc tgtcgagtgg gaaagcaacg gacagcccga gaacaactac 1320 aagaccaccc ctcccgtgct ggattccgac ggaagcttct tcctctacag caagctgacc 1380 gtggacaagt ccagatggca gcaaggcaat gtgttcagct gctccgtgat gcacgaagct 1440 ctgcacaacc actacacaca gaagtctctg tctctgtccc ccggcggagg aggcggaagc 1500 ggaggcggcg gatctctgca gtgctacaat tgccctaacc ccaccgctga ctgcaagacc 1560 gctgtgaact gctccagcga ttttgacgct tgtctgatta ccaaggctgg actgcaagtg 1620 tacaacaagt gctggaaatt cgaacaatgc aacttcaatg acgtcaccac cagactgaga 1680 gagaatgagc tgacatacta ctgctgcaaa aaagatctgt gcaatttcaa cgaacagctg 1740 gagaactga 1749 <210> 41 <211> 1221 <212> DNA <213> Artificial Sequence <220> <223> mu CRIg-mu IgG2a Fc DANG sequence <400> 41 caccctacac tgaagacacc cgagtccgtc accggcacat ggaagggaga cgtcaagatc 60 cagtgcatct acgaccccct cagaggctat agacaagtgc tcgtcaaatg gctcgtgaga 120 cacggctccg atagcgtgac catctttctg agagacagca ccggcgacca tatccagcaa 180 gccaagtata gaggcagact gaaggtgagc cacaaggtgc ccggcgatgt gtctctgcag 240 atcaacacac tgcagatgga tgatagaaac cactatacat gcgaggtcac atggcagacc 300 cccgatggaa accaagtgat tagagacaag atcatcgagc tgagggtgag gaagtacaac 360 ccccctagga tcaacaccga ggctcctacc acactgcaca gctctctgga ggccacaaca 420 atcatgtcca gcaccagcga tctgacaacc aacggaaccg gcaagctgga agagaccatc 480 gccggcagcg gaaggaatct gcccggcgga ggaggcagcg agcctagagg acccacaatt 540 aagccttgcc ccccttgcaa atgtcccgcc cctaatctgc tcggcggccc cagcgtgttc 600 atcttccccc ccaagattaa ggacgtgctg atgatctctc tgtcccccat tgtgacatgc 660 gtggtcgtgg ctgtctccga ggacgacccc gacgtccaga tcagctggtt cgtcaacaat 720 gtggaggtcc ataccgccca gacacagacc catagagagg attacggcag cacactgaga 780 gtggtcagcg ctctgcccat ccaacaccaa gactggatga gcggcaagga gttcaagtgt 840 aaagtgaaca acaaggatct gcccgccccc attgagagga ccatctccaa acctaagggc 900 agcgtgaggg ctcctcaagt gtatgtgctc cccccccccg aggaggaaat gaccaagaag 960 caagtgacac tgacatgcat ggtcaccgac ttcatgcccg aggacatcta cgtggagtgg 1020 accaacaacg gcaagaccga gctgaattac aagaacaccg aacccgtgct ggatagcgat 1080 ggctcctact tcatgtacag caagctgaga gtggagaaaa agaactgggt cgagaggaac 1140 agctacagct gctccgtcgt gcatgagggc ctccacaacc accatacaac caagagcttc 1200 tctaggacac ccggcaaatg a 1221 <210> 42 <211> 1467 <212> DNA <213> Artificial Sequence <220> <223> mu CRIg-mu IgG2a Fc DANG-mu CD59a sequence <400> 42 caccctacac tgaagacccc cgagagcgtc accggcacat ggaagggcga tgtgaagatc 60 cagtgcatct acgaccctct gagaggctat agacaagtgc tcgtgaagtg gctggtgaga 120 cacggatccg acagcgtcac catctttctg agagacagca ccggcgacca catccagcaa 180 gccaagtata gaggaagact gaaagtgtcc cataaggtgc ccggagatgt gtctctgcag 240 attaacaccc tccagatgga cgatagaaac cactacacat gcgaagtgac atggcaaacc 300 cccgacggca accaagtgat tagagataag atcatcgagc tgagggtgag aaagtacaat 360 ccccctagaa tcaacacaga agctcccacc acactgcata gctctctgga ggctaccacc 420 atcatgtcct ccacatccga tctgaccacc aacggcaccg gaaaactgga agagaccatc 480 gctggaagcg gaagaaatct gcccggcgga ggaggctccg aacctagggg acctaccatc 540 aagccttgcc ccccttgcaa atgtcccgcc cccaatctgc tgggaggccc ttccgtgttc 600 atcttccccc ccaagatcaa ggatgtgctg atgatctctc tgtcccctat tgtgacatgc 660 gtggtcgtgg ctgtgtccga ggatgacccc gacgtccaga tcagctggtt cgtcaacaac 720 gtggaagtcc acacagccca gacacaaaca catagagaag actacggctc cacactgagg 780 gtggtgagcg ctctccctat ccagcatcaa gactggatgt ccggcaagga attcaaatgc 840 aaggtgaaca acaaggatct ccccgctccc attgagagga ccatttccaa gcccaaggga 900 agcgtgagag ctccccaagt gtatgtcctc cctccccccg aggaggagat gacaaagaag 960 caagtgacac tgacatgcat ggtgacagac tttatgcccg aggacattta cgtggagtgg 1020 accaataacg gcaagacaga gctgaattac aagaacaccg agcccgtgct ggatagcgac 1080 ggcagctact tcatgtacag caagctgaga gtcgagaaga agaactgggt cgagagaaac 1140 tcctacagct gcagcgtcgt gcacgaagga ctgcacaatc accacaccac caagagcttc 1200 tctaggacac ccggcggagg cggaggatcc ggaggaggag gatctctgac atgctaccat 1260 tgcttccaac ccgtcgtgag cagctgcaat atgaacagca catgctcccc cgaccaagac 1320 agctgcctct acgccgtggc cggcatgcaa gtgtaccaaa ggtgctggaa acagtccgac 1380 tgtcacggag agatcatcat ggatcagctg gaggagacca agctgaagtt tagatgctgc 1440 cagttcaatc tgtgcaacaa gagctga 1467 <210> 43 <211> 948 <212> DNA <213> Artificial Sequence <220> <223> mu IgG2a Fc DANG-mu CD59a sequence <400> 43 gaacctaggg gacctaccat caagccttgc cccccttgca aatgtcccgc ccccaatctg 60 ctgggaggcc cttccgtgtt catcttcccc cccaagatca aggatgtgct gatgatctct 120 ctgtccccta ttgtgacatg cgtggtcgtg gctgtgtccg aggatgaccc cgacgtccag 180 atcagctggt tcgtcaacaa cgtggaagtc cacacagccc agacacaaac acatagagaa 240 gactacggct ccacactgag ggtggtgagc gctctcccta tccagcatca agactggatg 300 tccggcaagg aattcaaatg caaggtgaac aacaaggatc tccccgctcc cattgagagg 360 accatttcca agcccaaggg aagcgtgaga gctccccaag tgtatgtcct ccctcccccc 420 gaggaggaga tgacaaagaa gcaagtgaca ctgacatgca tggtgacaga ctttatgccc 480 gaggacattt acgtggagtg gaccaataac ggcaagacag agctgaatta caagaacacc 540 gagcccgtgc tggatagcga cggcagctac ttcatgtaca gcaagctgag agtcgagaag 600 aagaactggg tcgagagaaa ctcctacagc tgcagcgtcg tgcacgaagg actgcacaat 660 caccacacca ccaagagctt ctctaggaca cccggcggag gcggaggatc cggaggagga 720 ggatctctga catgctacca ttgcttccaa cccgtcgtga gcagctgcaa tatgaacagc 780 acagctccc ccgaccaaga cagctgcctc tacgccgtgg ccggcatgca agtgtaccaa 840 aggtgctgga aacagtccga ctgtcacgga gagatcatca tggatcagct ggaggagacc 900 aagctgaagt tagatgctg ccagttcaat ctgtgcaaca agagctga 948 <210> 44 <211> 1863 <212> DNA <213> Artificial Sequence <220> <223> mu CRIg-mu IgG2a Fc DANG-VEGF binder sequence <400> 44 caccctacac tgaagacacc cgagtccgtc accggcacat ggaagggaga cgtcaagatc 60 cagtgcatct acgaccccct cagaggctat agacaagtgc tcgtcaaatg gctcgtgaga 120 cacggctccg atagcgtgac catctttctg agagacagca ccggcgacca tatccagcaa 180 gccaagtata gaggcagact gaaggtgagc cacaaggtgc ccggcgatgt gtctctgcag 240 atcaacacac tgcagatgga tgatagaaac cactatacat gcgaggtcac atggcagacc 300 cccgatggaa accaagtgat tagagacaag atcatcgagc tgagggtgag gaagtacaac 360 ccccctagga tcaacaccga ggctcctacc acactgcaca gctctctgga ggccacaaca 420 atcatgtcca gcaccagcga tctgacaacc aacggaaccg gcaagctgga agagaccatc 480 gccggcagcg gaaggaatct gcccggcgga ggaggcagcg agcctagagg acccacaatt 540 aagccttgcc ccccttgcaa atgtcccgcc cctaatctgc tcggcggccc cagcgtgttc 600 atcttccccc ccaagattaa ggacgtgctg atgatctctc tgtcccccat tgtgacatgc 660 gtggtcgtgg ctgtctccga ggacgacccc gacgtccaga tcagctggtt cgtcaacaat 720 gtggaggtcc ataccgccca gacacagacc catagagagg attacggcag cacactgaga 780 gtggtcagcg ctctgcccat ccaacaccaa gactggatga gcggcaagga gttcaagtgt 840 aaagtgaaca acaaggatct gcccgccccc attgagagga ccatctccaa acctaagggc 900 agcgtgaggg ctcctcaagt gtatgtgctc cccccccccg aggaggaaat gaccaagaag 960 caagtgacac tgacatgcat ggtcaccgac ttcatgcccg aggacatcta cgtggagtgg 1020 accaacaacg gcaagaccga gctgaattac aagaacaccg aacccgtgct ggatagcgat 1080 ggctcctact tcatgtacag caagctgaga gtggagaaaa agaactgggt cgagaggaac 1140 agctacagct gctccgtcgt gcatgagggc ctccacaacc accatacaac caagagcttc 1200 tctaggacac ccggcggcgg aggcggatcc ggaggaggcg gcagctccga taccggaaga 1260 cctttcgtgg agatgtattc cgagattccc gagatcatcc acatgaccga gggaagagag 1320 ctggtcatcc cttgtagagt cacaagcccc aacattaccg tgaccctcaa gaagttccct 1380 ctggacacac tgattcccga cggcaagagg attatctggg actctaggaa gggcttcatc 1440 atcagcaacg ccacctataa agagatcgga ctgctgacat gcgaggccac agtgaatggc 1500 cacctctaca agaccaacta tctgacccat agacaaacca acaccattat cgacgtggtg 1560 ctgagcccta gccacggcat cgaactcagc gtgggagaga aactggtgct gaattgcacc 1620 gctaggaccg aactcaacgt gggaatcgac ttcaactggg agtacccctc cagcaagcac 1680 cagcacaaga agctcgtgaa tagagatctg aagacccaga gcggaagcga gatgaagaaa 1740 ttcctctcca cactgaccat cgatggcgtg acaaggagcg accaaggact gtacacatgc 1800 gctgcttcca gcggactgat gacaaagaag aacagcacct tcgtgagggt ccacgaaaaa 1860 tga 1863 <210> 45 <211> 1344 <212> DNA <213> Artificial Sequence <220> <223> mu IgG2a Fc DANG-VEGF binder sequence <400> 45 gagcctagag gacccacaat taagccttgc cccccttgca aatgtcccgc ccctaatctg 60 ctcggcggcc ccagcgtgtt catcttcccc cccaagatta aggacgtgct gatgatctct 120 ctgtccccca ttgtgacatg cgtggtcgtg gctgtctccg aggacgaccc cgacgtccag 180 atcagctggt tcgtcaacaa tgtggaggtc cataccgccc agacacagac ccatagagag 240 gattacggca gcacactgag agtggtcagc gctctgccca tccaacacca agactggatg 300 agcggcaagg agttcaagtg taaagtgaac aacaaggatc tgcccgcccc cattgagagg 360 accatctcca aacctaaggg cagcgtgagg gctcctcaag tgtatgtgct cccccccccc 420 gaggaggaaa tgaccaagaa gcaagtgaca ctgacatgca tggtcaccga cttcatgccc 480 gaggacatct acgtggagtg gaccaacaac ggcaagaccg agctgaatta caagaacacc 540 gaacccgtgc tggatagcga tggctcctac ttcatgtaca gcaagctgag agtggagaaa 600 aagaactggg tcgagaggaa cagctacagc tgctccgtcg tgcatgaggg cctccacaac 660 caccatacaa ccaagagctt ctctaggaca cccggcggcg gaggcggatc cggaggaggc 720 ggcagctccg ataccggaag acctttcgtg gagatgtatt ccgagattcc cgagatcatc 780 cacatgaccg agggaagaga gctggtcatc ccttgtagag tcacaagccc caacattacc 840 gtgaccctca agaagttccc tctggacaca ctgattcccg acggcaagag gattatctgg 900 gactctagga agggcttcat catcagcaac gccacctata aagagatcgg actgctgaca 960 tgcgaggcca cagtgaatgg ccacctctac aagaccaact atctgaccca tagacaaacc 1020 aacaccatta tcgacgtggt gctgagccct agccacggca tcgaactcag cgtgggagag 1080 aaactggtgc tgaattgcac cgctaggacc gaactcaacg tgggaatcga cttcaactgg 1140 gagtacccct ccagcaagca ccagcacaag aagctcgtga atagagatct gaagacccag 1200 agcggaagcg agatgaagaa attcctctcc acactgacca tcgatggcgt gacaaggagc 1260 gaccaaggac tgtacacatg cgctgcttcc agcggactga tgacaaagaa gaacagcacc 1320 ttcgtgaggg tccacgaaaa atga 1344 <210> 46 <211> 654 <212> DNA <213> Artificial Sequence <220> <223> mu IgG2a Fc DANG sequence <400> 46 gcccccaatc tgctgggagg cccttccgtc ttcatcttcc cccccaagat caaggacgtg 60 ctgatgatct ctctgagccc catcgtgaca tgcgtggtgg tggccgtgag cgaggacgat 120 cccgacgtgc agatcagctg gttcgtcaac aacgtggagg tgcataccgc ccaaacacag 180 acccatagag aggactacgg ctccacactg agagtggtgt ccgctctgcc catccagcat 240 caagactgga tgagcggcaa ggagttcaag tgcaaggtga acaacaagga tctgcccgcc 300 cctatcgaga ggaccatctc caagcccaaa ggctccgtga gagctcccca agtgtatgtg 360 ctgcctcccc ccgaggagga gatgaccaag aagcaagtga cactgacatg catggtgacc 420 gatttcatgc ccgaagacat ctacgtggag tggaccaaca acggcaagac cgagctcaac 480 tacaagaaca ccgagcccgt gctcgacagc gacggcagct acttcatgta cagcaagctg 540 agggtcgaga agaaaaactg ggtggagagg aacagctaca gctgtagcgt ggtgcaggag 600 ggactgcaca accaccatac caccaagagc ttctccagaa cacccggcaa gtga 654 <210> 47 <211> 702 <212> DNA <213> Artificial Sequence <220> <223> mu IgG2a Fc DANG including hinge sequence <400> 47 gagcccagag gccccacaat caagccttgc cccccttgca aatgtcccgc ccccaatctg 60 ctgggaggcc cttccgtctt catcttcccc cccaagatca aggacgtgct gatgatctct 120 ctgagcccca tcgtgacatg cgtggtggtg gccgtgagcg aggacgatcc cgacgtgcag 180 atcagctggt tcgtcaacaa cgtggaggtg cataccgccc aaacacagac ccatagagag 240 gactacggct ccacactgag agtggtgtcc gctctgccca tccagcatca agactggatg 300 agcggcaagg agttcaagtg caaggtgaac aacaaggatc tgcccgcccc tatcgagagg 360 accatctcca agcccaaagg ctccgtgaga gctccccaag tgtatgtgct gcctcccccc 420 gaggaggaga tgaccaagaa gcaagtgaca ctgacatgca tggtgaccga tttcatgccc 480 gaagacatct acgtggagtg gaccaacaac ggcaagaccg agctcaacta caagaacacc 540 gagcccgtgc tcgacagcga cggcagctac ttcatgtaca gcaagctgag ggtcgagaag 600 aaaaactggg tggagaggaa cagctacagc tgtagcgtgg tgcacgaggg actgcacaac 660 caccatacca ccaagagctt ctccagaaca cccggcaagt ga 702 <210> 48 <211> 170 <212> PRT <213> Artificial Sequence <220> <223> human CRIg (VSIG4) isoform 3 extracellular domain <400> 48 Arg Pro Ile Leu Glu Val Pro Glu Ser Val Thr Gly Pro Trp Lys Gly 1 5 10 15 Asp Val Asn Leu Pro Cys Thr Tyr Asp Pro Leu Gln Gly Tyr Thr Gln 20 25 30 Val Leu Val Lys Trp Leu Val Gln Arg Gly Ser Asp Pro Val Thr Ile 35 40 45 Phe Leu Arg Asp Ser Ser Gly Asp His Ile Gln Gln Ala Lys Tyr Gln 50 55 60 Gly Arg Leu His Val Ser His Lys Val Pro Gly Asp Val Ser Leu Gln 65 70 75 80 Leu Ser Thr Leu Glu Met Asp Asp Arg Ser His Tyr Thr Cys Glu Val 85 90 95 Thr Trp Gln Thr Pro Asp Gly Asn Gln Val Val Arg Asp Lys Ile Thr 100 105 110 Glu Leu Arg Val Gln Lys His Ser Ser Lys Leu Leu Lys Thr Lys Thr 115 120 125 Glu Ala Pro Thr Thr Met Thr Tyr Pro Leu Lys Ala Thr Ser Thr Val 130 135 140 Lys Gln Ser Trp Asp Trp Thr Thr Asp Met Asp Gly Tyr Leu Gly Glu 145 150 155 160 Thr Ser Ala Gly Pro Gly Lys Ser Leu Pro 165 170

Claims (24)

an extracellular domain of CRIg or a fragment thereof; and a fusion protein comprising an immunoglobulin fragment. According to claim 1,
CD59 or a variant thereof; Or a fusion protein that additionally comprises a protein that specifically binds to VEGF. 3. The method of claim 2,
The CD59 is SEQ ID NO: 19, the fusion protein. 3. The method of claim 2,
The CD59 variant is a fusion protein wherein the 41st amino acid and/or the 44th amino acid of SEQ ID NO: 19 is substituted with another amino acid. 3. The method of claim 2,
The protein that specifically binds to VEGF is an extracellular domain of an antibody or VEGF receptor that specifically binds to VEGF, a fusion protein. According to claim 1,
The extracellular domain of CRIg or a fragment thereof and an immunoglobulin fragment are linked through a linker, the fusion protein. 3. The method of claim 2,
The fusion protein is of the following structural formula (I) or (II), the fusion protein:
N'-X-[Linker(1)]n-Fc domain-[Linker(2)]mYC'(I)
N'-Y-[Linker(1)]n-Fc domain-[Linker(2)]mXC'(II)
At this time, in the structural formulas (I) and (II),
The N' is the N-terminus of the fusion protein,
The C' is the C-terminus of the fusion protein,
wherein X is an extracellular domain of CRIg or a fragment thereof,
wherein Y is CD59 or a variant thereof; Or a protein that specifically binds to VEGF,
The linker (1) and linker (2) are peptide linkers,
Wherein n and m are each independently O or 1. According to claim 1,
The fusion protein will have any one amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 2, 3, 4, 8, 9, 10 and 12, the fusion protein. According to claim 1,
The immunoglobulin fragment comprises a DANG mutation, the fusion protein. CD59 or a variant thereof; and a fusion protein comprising an immunoglobulin fragment. 11. The method of claim 10,
A fusion protein that additionally comprises a protein that specifically binds to VEGF. 11. The method of claim 10,
The CD59 is SEQ ID NO: 19, the fusion protein. 11. The method of claim 10,
The CD59 variant is a fusion protein wherein the 41st amino acid and/or the 44th amino acid of SEQ ID NO: 19 is substituted with another amino acid. 12. The method of claim 11,
The protein that specifically binds to VEGF is an extracellular domain of an antibody or VEGF receptor that specifically binds to VEGF, a fusion protein. 11. The method of claim 10,
A fusion protein, wherein CD59 or a variant thereof and an immunoglobulin fragment are linked through a linker. 12. The method of claim 11,
The fusion protein is of the following structural formula (III) or (IV), the fusion protein:
N'-V-[Linker(1)]p-Fc domain-[Linker(2)]q-(W)rC'(III)
N'-(W)r-[Linker(1)]p-Fc domain-[Linker(2)]qVC'(IV)
In this case, in the structural formulas (III) and (IV),
The N' is the N-terminus of the fusion protein,
The C' is the C-terminus of the fusion protein,
wherein V is CD59 or a variant thereof,
Wherein W is a protein that specifically binds to VEGF,
The linker (1) and linker (2) are peptide linkers,
Wherein p, q and r are each independently O or 1. 11. The method of claim 10,
The fusion protein will have any one amino acid sequence selected from the group consisting of SEQ ID NOs: 5, 6 and 11, the fusion protein. 12. The method of claim 11,
The immunoglobulin fragment comprises a DANG mutation, the fusion protein. A dimer to which two of the fusion proteins of claims 1 to 9 are bound. A pharmaceutical composition for treating or preventing eye disease comprising the dimer of claim 19 as an active ingredient. 21. The method of claim 20,
The ocular diseases include age-related macular degeneration (AMD), map atrophy (GA), choroidal neovascularization (CNV), uveitis, diabetic and other ischemia-related retinopathy, diabetic macular edema, pathological myopia, von Hippel- Lindau disease, histoplasmosis of the eye, central retinal vein occlusion (CRVO), corneal neovascularization, and any one selected from the group consisting of retinal neovascularization, a pharmaceutical composition for the treatment or prevention of eye diseases. A dimer to which two of the fusion proteins of claims 10 to 18 are bound. A pharmaceutical composition for treating or preventing eye disease comprising the dimer of claim 22 as an active ingredient. 24. The method of claim 23,
The ocular diseases include age-related macular degeneration (AMD), map atrophy (GA), choroidal neovascularization (CNV), uveitis, diabetic and other ischemia-related retinopathy, diabetic macular edema, pathological myopia, von Hippel- Lindau disease, histoplasmosis of the eye, central retinal vein occlusion (CRVO), corneal neovascularization, and any one selected from the group consisting of retinal neovascularization, a pharmaceutical composition for the treatment or prevention of eye diseases.

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