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WO2018124582A1 - Composition pour la prévention et le traitement de maladies oculaires comprenant un anticorps anti-ang2 - Google Patents

Composition pour la prévention et le traitement de maladies oculaires comprenant un anticorps anti-ang2 Download PDF

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WO2018124582A1
WO2018124582A1 PCT/KR2017/014981 KR2017014981W WO2018124582A1 WO 2018124582 A1 WO2018124582 A1 WO 2018124582A1 KR 2017014981 W KR2017014981 W KR 2017014981W WO 2018124582 A1 WO2018124582 A1 WO 2018124582A1
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ang2
antibody
amino acid
seq
acid sequence
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PCT/KR2017/014981
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Korean (ko)
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고규영
김재령
박도영
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기초과학연구원
한국과학기술원
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Priority claimed from KR1020170174201A external-priority patent/KR102143132B1/ko
Application filed by 기초과학연구원, 한국과학기술원 filed Critical 기초과학연구원
Priority to US16/473,685 priority Critical patent/US10745472B2/en
Publication of WO2018124582A1 publication Critical patent/WO2018124582A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum

Definitions

  • the present invention relates to a composition for the prevention and treatment of eye diseases comprising an angiopoietin-2 (Anggiopoietin-2; Ang2) antibody or an antigen-binding fragment thereof, and more specifically, specifically binds to Ang2, And a novel use as an agent for preventing and treating ocular diseases, which binds to the Tie2 receptor and has improved affinity.
  • angiopoietin-2 Anggiopoietin-2; Ang2
  • Ang2 angiopoietin-2
  • Ang2 angiopoietin-2
  • ocular diseases which cause millions of blindness worldwide each year, are a major cause of angiogenesis.
  • representative examples of various eye diseases resulting from abnormal blood vessels include age-related macular degeneration, diabetic retinopathy, and glaucoma.
  • Age-related macular degeneration is a disease name that refers to the breakdown or destruction of the macula accompanying aging and occurs mainly in people over 50 years of age. This disease is caused by the accumulation of small waste products called drusen, which exude leaks from non-exudatives (dry type), which causes the macular atrophy to progress and loss of visual function, and abnormal neovascularization resulting from the accumulation of hypoxia and oxidative stress in the retina and choroid. As the macular edema is induced and this process is repeated, the visual and retinal pigment epithelial cells of the macula are permanently denatured and divided into exudatives (wet type) that cause vision loss.
  • wet type exudatives
  • wet macular degeneration mainly consists of antibody injection treatment for vascular endothelial growth factor, and other treatments such as laser photocoagulation, photodynamic therapy, and vitrectomy are known, but there is no complete treatment yet. to be.
  • Diabetic retinopathy is a diabetic retinopathy caused by diabetic peripheral circulatory disorders, which is a complication of the eye that causes a reduction in visual acuity due to disorders in the microcirculation of the retina. In early diabetic retinopathy, it can cause no symptoms or only mild vision problems, but can eventually lead to blindness. Diabetic retinopathy can develop in anyone with type 1 diabetes or type 2 diabetes.
  • Glaucoma is a chronic optic nerve disease, a severe intractable disease that causes progressive degeneration of the optic nerve, progressive loss of retinal ganglion cells and vision loss due to visual field defects. Risk factors for glaucoma include age, race, sex, and high blood pressure, but increased intraocular pressure is known as the most important cause of glaucoma, especially primary open angle glaucoma. Glaucoma is thought to be due to increased intraocular pressure due to increased resistance of the aqueous humoral outflow pathways through the Schlemm's canal and trabecular meshwork in the eye, but the molecular biological mechanisms that cause problems It has not been clear so far.
  • Angiopoietin-2 (Angiopoietin-2; Ang2) is an antagonistic ligand of receptor Tie2 present in vascular endothelial cells.
  • Angiopoietin-1 an agonist of Tie2. Inhibits signaling by Tie2 by competing for Ang1) and Tie2 binding.
  • Ang1 a ligand that activates the Tie2 receptor, acts as a major regulator of vascular stability by maintaining the barrier function of vascular endothelial cells. In the overexpression or inflammatory state of vascular endothelial growth factor, vascular endothelial cells are activated, and vascular permeability is increased.
  • Ang1 induces stabilization of vascular endothelial cells by promoting junctional integrity of vascular endothelial cells and decreases vascular permeability
  • increased Ang2 in activated vascular endothelial cells competes with Ang1 Inhibits endothelial cell stabilization. Therefore, Ang2 inhibits Ang1-Tie2 binding and signal transduction through maintaining stability of vascular endothelial cells, thereby promoting angiogenesis through dynamic rearrangement of blood vessels.
  • Overexpression of Ang2 has been reported in various solid and hematological cancers, and overexpression of Ang2 has also been reported in various diseases such as sepsis, bacterial infections, lung damage and kidney damage.
  • Korean Patent Publication No. 10-2015-0014077 specifically binds to angiopoietin-2 (Ang2), an angiogenesis inducer, binds to Tie2 receptor with Ang2, and humanizes it. And / or an anti-Ang2 antibody with improved affinity was identified and its use as an anticancer agent using this anti-Ang2 antibody (Korean Patent Publication No. 10-2015-0032075) and its use in sepsis (Korean Patent Publication No. 10- 2015-0028087) was confirmed. However, the therapeutic use of anti-ang2 antibodies in eye diseases has not been proved experimentally.
  • anti-ang2 antibody that specifically binds to Ang2 and binds to Tie2 receptor with Ang2 is a blood vessel leak and Inhibition of choroidal neovascularization, improvement of choroidal perfusion, improvement of vascular leakage and inhibition of macrophage infiltration in diabetic retinopathy animal model, by confirming the effect of improving Schlemm's tube homeostasis and IOP in glaucoma model, To complete.
  • the present invention relates to a novel use of an anti-ang2 antibody, and an object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of eye diseases comprising an anti-ang2 antibody or antigen-binding fragment thereof.
  • the present invention also provides a method for treating ocular disease comprising administering to a patient a pharmaceutical composition comprising an anti-ang2 antibody or antigen-binding fragment thereof, and an ocular disease of the pharmaceutical composition comprising the anti-ang2 antibody or antigen-binding fragment thereof. It is aimed at providing a therapeutic or prophylactic use.
  • the present invention provides a pharmaceutical composition for preventing or treating ocular disease, comprising an anti-Ang2 antibody or an antigen-binding fragment thereof, in order to achieve the above object.
  • the present invention also provides a pharmaceutical composition, wherein the ocular disease is selected from the group consisting of macular degeneration, diabetic retinopathy and glaucoma.
  • the present invention also provides a pharmaceutical composition wherein the glaucoma is primary open angle glaucoma.
  • the present invention also said anti Ang2 antibody,
  • CDR heavy chain complementarity determining region
  • a polypeptide comprising the amino acid sequence of SEQ ID NO: 4 (CDR-L1), a polypeptide comprising the amino acid sequence of SEQ ID NO: 5 (CDR-L2), and a polypeptide comprising the amino acid sequence of SEQ ID NO: 6 (CDR-L3) Provided is a pharmaceutical composition comprising a light chain complementarity determining region comprising one or more selected from the group consisting of or a light chain variable region comprising the one or more light chain complementarity determining regions.
  • the present invention also said anti Ang2 antibody,
  • composition comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8.
  • the present invention also provides a method for preventing or treating ocular disease, comprising administering to a patient a pharmaceutical composition comprising an anti Ang2 antibody or antigen-binding fragment thereof.
  • the present invention also provides a method of preventing or treating primary open angle glaucoma comprising administering to a patient a pharmaceutical composition comprising an anti Ang2 antibody or antigen binding fragment thereof.
  • the invention also provides the use of the treatment or prevention of ocular disease in a pharmaceutical composition comprising an anti Ang2 antibody or antigen binding fragment thereof.
  • the invention also provides for the use of the primary open angle glaucoma treatment or prevention of a pharmaceutical composition comprising an anti Ang2 antibody or antigen binding fragment thereof.
  • Figure 1 shows the inhibitory effect of vascular leakage and choroidal neovascularization in the prevention and treatment of anti-ang2 antibody administration in wet macular degeneration model.
  • Figure 2 shows the improvement of choroidal perfusion of anti-ang2 antibody administration in wet macular degeneration model.
  • Figure 3 shows the establishment and verification of the diabetic retinopathy model. Specifically, we established a diabetic retinopathy model by infusion of vascular endothelial growth factor (VEGF-A) and perivascular cell loss (DTAi ⁇ PC) (A). Significantly increased blood leakage was observed in manufactured diabetic retinopathy model mice. Observed (BC).
  • VEGF-A vascular endothelial growth factor
  • DTAi ⁇ PC perivascular cell loss
  • Figure 4 shows the effects of anti-ang2 antibody administration in the improvement of blood vessel leakage and macrophage infiltration in diabetic retinopathy model.
  • FIG. 5 shows the process of establishing and verifying a glaucoma model. Specifically, a glaucoma model that inhibits Ang-Tie2 signal was established (A), and it was confirmed that intraocular pressure increased significantly in the prepared glaucoma model mouse, which suppressed the formation of Schlemm's canal and maintained homeostasis.
  • Figure 6 shows the effect of anti-Ang2 antibody administration of Schlemm's tube homeostasis and lowering IOP in glaucoma model.
  • the anti-ang2 antibody or antigen-binding fragment thereof that specifically binds to Ang2 and binds to the Tie2 receptor together with Ang2 reduces the vascular leakage, choroidal neovascularization, and choroidal perfusion in macular degeneration.
  • blood vessel leakage was improved and macrophage infiltration was inhibited.
  • the present invention relates to a composition for preventing or treating ocular disease, including an anti Ang2 antibody or an antigen-binding fragment thereof.
  • the present invention relates to a method for preventing or treating ocular disease, comprising administering to a patient a pharmaceutical composition comprising an anti Ang2 antibody or antigen-binding fragment thereof.
  • the present invention relates to the use of the prophylaxis or treatment of ocular diseases of the pharmaceutical composition comprising an anti Ang2 antibody or antigen-binding fragment thereof.
  • Anti-ang2 antibody of the present invention is an antibody targeting the angiogenesis inducer Ang2, by binding specifically to Ang2 inhibits the function of Ang2 to inhibit neovascularization and reduce blood vessel density in cancer tissues,
  • Tie2 binds to induce activation of Tie2, thereby structurally and / or functionally normalizing blood vessels.
  • the anti-Ang2 antibody binds to the Tie2 receptor along with Ang2 and activates the Tie2 receptor with downregulation of Ang2 in diseases related to abnormal activation and dysfunction of blood vessels such as cancer, sepsis, and eye diseases. It has the effect of treating a disease by inducing functional normalization.
  • the anti Ang2 antibody of the present invention may specifically recognize Ang2 and bind to both Ang2 and Tie2 receptors.
  • the anti Ang2 antibody may be to induce the activation of the Tie2 receptor.
  • Such activation of the Tie2 receptor is one selected from the group consisting of increased phosphorylation of the Tie2 receptor and / or proteins associated with its underlying signaling pathways, such as Akt (NM_005163), eNOS (NM_000603), 42/44 (NM_002745), and the like. It can be induced by phosphorylation of more than one species.
  • the anti Ang2 antibody may be to induce internalization of the Tie2 receptor into the cell.
  • the anti-Ang2 antibody specifically binds to Ang2, unlike the conventional anti-Ang2 antibody, it does not inhibit the binding of Ang2 to the Tie2 receptor, thereby binding to the Tie2 receptor together with Ang2 to form a complex, Tie2 It may be to induce activation of the receptor.
  • the Ang2 protein which acts as an antigen of the anti-Ang2 antibody, is closely related to neovascularization and is a soluble ligand present in blood, and is widely used for angiogenesis, metastasis, cancer cell invasion, and the like. It works.
  • the Ang2 may be derived from mammals such as humans, primates such as monkeys, rodents such as mice, rats, and the like, for example, human Ang2 (NCBI Accession No. O15123, etc.), monkey Ang2 (NCBI Accession No. Q8MIK6, etc.). ), Mouse Ang2 (NCBI Accession No. O35608, etc.), rat Ang2 (NCBI Accession No. O35462, etc.) and the like, but is not limited thereto.
  • the Tie2 receptor (TEK tyrosine kinase) of the present invention is an Ang1 receptor, expressed in various mammalian endothelial cells such as mice (NM_013690; NP_038718), rats, humans (NM_000459; NP_000450), and various downstream signals. It is involved in downstream signaling.
  • Anti Ang2 antibody of the present invention binds Ang2 specifically but does not inhibit the binding of Ang2 and Tie2 receptor, and the antibody complexed with Ang2 and Tie2 receptor (antibody / Ang2 / Tie2), dimerization of antibody ), Thereby effectively clustering the Tie2 receptor complexed thereto, thereby inducing the activation of the Tie2 receptor and its downstream signaling. Due to this mechanism of action, the antibody of the present invention binds to Ang2, induces intracellular migration and degradation, thereby inhibiting Ang2 function and lowers circulating Ang2 levels, and binds to Tie2 receptors with Ang2 to bind Tie2 like Ang1.
  • vascular endothelial cells By having a dual function that activates the receptors to induce stabilization of vascular endothelial cells, it can be useful in the treatment of diseases caused by Ang2 overexpression as well as decreased stabilization of vascular endothelial cells, ie increased vascular permeability. have.
  • the anti-Ang2 antibody may be exposed to all or a portion of a human Ang2 (hAng2; SEQ ID NO: 9; Accession # O15123) from 417 to 434 amino acids in loop 1 SEQ ID NO: 9 (eg, exposed to the outside in a loop).
  • hAng2 human Ang2
  • SEQ ID NO: 9 human Ang2
  • An amino acid sequence region comprising 2 to 10 or 2 to 5 amino acids may be recognized as an epitope or specifically bound to this region.
  • Table 1 shows the Ang2 sequence of SEQ ID NO.
  • the anti Ang2 antibody is a contiguous or noncontiguous 2 comprising amino acid residues in combination with Q418, P419, Q418 and P419, located in loop 1 of SEQ ID NO: 9, or in combination with Q418, P419, Q418 and P419 in SEQ ID NO: 9.
  • An amino acid sequence region comprising from 20 to 2, 2 to 15, 2 to 10, or 2 to 5 amino acids may be recognized as an epitope or specifically bound to this site.
  • the anti-Ang2 antibody may recognize amino acid residues of Q418 and P419 of SEQ ID NO: 9 as epitopes or specifically bind to this portion.
  • Q418, P419, or an amino acid site including the specific binding site of the anti-Ang2 antibody is an exposed amino acid residue located at loop 1 of the three-dimensional structure of Ang2, and is directly involved in binding between Ang2 and Tie2 receptors. It is considered to be a site controlling this.
  • Q418, P419, or an amino acid site including the same “non-contiguous amino acids” are adjacent to each other on the secondary or tertiary structure of the protein, but are not contiguous on the amino acid sequence. It may mean an amino acid that does not.
  • “contiguous or non-contiguous amino acid residues” herein may mean contiguous amino acid residues on the primary, secondary or tertiary structure of a protein.
  • the anti Ang2 antibodies include not only complete antibody forms, but also antigen binding fragments of the antibody molecules.
  • a complete antibody is a structure having two full length light chains and two full length heavy chains, each of which is linked by heavy and disulfide bonds.
  • the heavy chain constant region has gamma ( ⁇ ), mu ( ⁇ ), alpha ( ⁇ ), delta ( ⁇ ) and epsilon ( ⁇ ) types and subclasses gamma 1 ( ⁇ 1), gamma 2 ( ⁇ 2), and gamma 3 ( ⁇ 3). ), Gamma 4 ( ⁇ 4), alpha 1 ( ⁇ 1) and alpha 2 ( ⁇ 2).
  • the constant regions of the light chains have kappa ( ⁇ ) and lambda ( ⁇ ) types.
  • the basic four-chain antibody unit is a heterodimeric glycoprotein consisting of two identical light chains (L) and two identical heavy chains (H).
  • the light chain has a variable region (VL) at the N-terminus, followed by a constant region at its other end.
  • the heavy chain has a variable region (VH) at the N-terminus, followed by three constant regions (CH) for the ⁇ and ⁇ chains and four CH regions for the ⁇ and ⁇ isotypes, respectively.
  • Variables indicate that certain portions of the variable region differ greatly in sequence between antibodies.
  • the V region mediates antigen binding and defines the specificity of a particular antibody for that particular antigen. Variability is concentrated in three segments called hypervariable regions (HVRs), or CDRs, in both the light and heavy chain variable regions.
  • HVRs hypervariable regions
  • CDRs framework regions
  • the heavy and light chain variable regions have the structures FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4 from the N-terminus to the C-terminus.
  • variable chain refers to a variable region domain VH comprising an amino acid sequence having sufficient variable region sequence to confer specificity to an antigen and a full length heavy chain comprising three constant region domains CH1, CH2 and CH3 And fragments thereof.
  • light chain refers to a full-length light chain and fragment thereof comprising a variable region domain VL and a constant region domain CL comprising an amino acid sequence having sufficient variable region sequence to confer specificity to the antigen. All means.
  • the antigen binding fragment or antibody fragment of an antibody means the fragment which has antigen binding function, and includes Fab, F (ab ') 2, Fv, etc.
  • Fv fragments are antibody fragments containing complete antibody recognition and binding sites. This region consists of a dimer in which one heavy chain variable domain and one light chain variable domain are tightly and covalently associated, for example, with scFv.
  • Fab fragments contain the variable and constant domains of the light chain and the variable and first constant domains (CH1) of the heavy chain.
  • F (ab ') 2 antibody fragments generally comprise a pair of Fab fragments covalently linked near their carboxy termini by hinge cysteines between them.
  • Single-chain Fv or “scFv” antibody fragments comprise the VH and VL domains of an antibody, which domains are present in a single polypeptide chain.
  • the Fv polypeptide may further comprise a polypeptide linker between the VH domain and the VL domain that allows the scFv to form the desired structure for antigen binding.
  • the anti Ang2 antibody In the present invention, the anti Ang2 antibody,
  • CDR heavy chain complementarity determining region
  • the anti Ang2 antibody Preferably, the anti Ang2 antibody,
  • a polypeptide comprising the amino acid sequence of SEQ ID NO: 1 (CDR-H1), a polypeptide comprising the amino acid sequence of SEQ ID NO: 2 (CDR-H2), and a polypeptide comprising the amino acid sequence of SEQ ID NO: 3 (CDR-H3) A heavy chain complementarity determining site comprising: or a heavy chain variable region comprising the heavy chain complementarity determining site;
  • a polypeptide comprising the amino acid sequence of SEQ ID NO: 4 (CDR-L1), a polypeptide comprising the amino acid sequence of SEQ ID NO: 5 (CDR-L2), and a polypeptide comprising the amino acid sequence of SEQ ID NO: 6 (CDR-L3) ) May include light chain complementarity determining regions, or light chain variable regions comprising the light chain complementarity determining regions.
  • the heavy chain complementarity determining site and the light chain complementarity determining site of the anti Ang2 antibody may be those having the amino acid sequences shown in Table 2 below.
  • the heavy chain variable region of the antibody may comprise the amino acid sequence of SEQ ID NO: 7 in Table 3 below
  • the light chain of the antibody may include the amino acid sequence of SEQ ID NO: 8 in Table 3 below .
  • the anti-Ang2 antibody may include a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7, a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8, or a combination of the heavy chain variable region and the light chain variable region.
  • the anti Ang2 antibody may comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8.
  • Antibodies in the present invention include all animal-derived antibodies, chimeric antibodies, humanized antibodies and human antibodies.
  • Animal-derived antibodies that are produced by immunizing a desired antigen with an immunized animal are generally capable of immunorejection upon administration to humans for therapeutic purposes, and chimeric antibodies have been developed to suppress such rejection.
  • Chimeric antibodies are obtained by replacing the constant region of an animal-derived antibody causing an anti-isotype reaction with the constant region of a human antibody using genetic engineering methods. Chimeric antibodies have been significantly improved in anti-isotype responses compared to animal derived antibodies, but still contain adverse effects on potential anti-idiotypic responses due to the presence of animal derived amino acids in the variable region. Doing. Humanized antibodies have been developed to ameliorate these side effects. It is produced by implanting a region of complementarity determining regions (CDRs) that play an important role in binding of antigens in the variable regions of chimeric antibodies to the human antibody framework.
  • CDRs complementarity determining regions
  • CDR grafting technology for producing humanized antibody is to select an optimized human antibody that can best accept the CDR region of an animal-derived antibody.
  • structure analysis and molecular modeling techniques are used to select an optimized human antibody that can best accept the CDR region of an animal-derived antibody.
  • amino acids that are located in the skeleton of an animal-derived antibody and affect antigen binding.
  • additional antibody engineering techniques to restore antigen binding capacity is essential.
  • the antibody may be a mouse derived antibody, mouse-human chimeric antibody, humanized antibody, or human antibody.
  • the anti-ang2 antibody or antigen-binding fragment thereof of the present invention has a function of inhibiting abnormal angiogenesis by inhibiting the function of Ang2, eye diseases accompanying vascular abnormalities such as macular degeneration, diabetic retinopathy, and glaucoma It can be used for prevention and / or treatment.
  • Prevention means any action that inhibits or delays the progression of an ocular disease by administration of a composition according to the present invention
  • treatment means inhibiting, alleviating or eliminating the development of ocular disease.
  • macular degeneration is a condition in which new blood vessels grow abnormally and the macula is damaged to affect vision. Macular degeneration occurs mainly in people over 50 years of age and is divided into non-exudative (dry type) or exudative (wet type). In particular, wet macular degeneration can lead to blindness, the cause of which is unknown, but the risk factor is age, and environmental factors include smoking, hypertension, obesity, genetic predisposition, and excessive UV exposure. And low blood antioxidant levels.
  • diabetes retinopathy is a peripheral circulatory disorder caused by diabetes, which is a complication of the eye that causes a decrease in vision due to a disorder in the microcirculation of the retina, which initially causes no symptoms or only mild vision. It can cause problems, but ultimately blindness. Diabetic retinopathy can develop in anyone with type 1 diabetes or type 2 diabetes.
  • glaucoma is a chronic optic nerve lesion, a severe refractory disease that causes progressive degeneration of the optic nerve, progressive loss of retinal ganglionic cells, and vision loss due to visual field defects.
  • Risk factors for glaucoma include age, race, sex, and hypertension, but increased intraocular pressure is known as the most important cause of glaucoma, especially primary open angle glaucoma. Accordingly, the present invention can be used to prevent and / or treat primary open angle glaucoma.
  • the pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable carrier, which is commonly used in the formulation of drugs, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, Calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, minerals It may be one or more selected from the group consisting of oils, but is not limited thereto.
  • a pharmaceutically acceptable carrier which is commonly used in the formulation of drugs, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, Calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate,
  • the pharmaceutical composition may further include one or more selected from the group consisting of diluents, excipients, lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives, and the like, which are conventionally used for preparing pharmaceutical compositions.
  • the pharmaceutical composition, or pharmaceutically effective amount of the antibody may be administered orally or parenterally.
  • parenteral administration it can be administered by intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, endothelial administration, topical administration, intranasal administration, pulmonary administration and rectal administration.
  • the protein or peptide is digested so that the oral composition can be formulated to coat the active agent or protect it from degradation in the stomach.
  • the composition may be administered by any device in which the active substance may migrate to the target cell.
  • the content of anti Ang2 antibody in the pharmaceutical composition varies depending on factors such as formulation method, mode of administration, age, weight, sex, morbidity, food, time of administration, interval of administration, route of administration, rate of excretion and reaction sensitivity of the patient. Can be prescribed.
  • the daily dosage of the anti Ang2 antibody may range from 0.001 to 1000 mg / kg, specifically 0.01 to 100 mg / kg, more specifically 0.1 to 50 mg / kg, but is not limited thereto.
  • the daily dosage may be formulated into one formulation in unit dosage form, may be formulated in appropriate quantities or may be prepared within a multi-dose container.
  • the "pharmaceutical effective amount” may refer to the amount or dosage of an active ingredient that may exhibit a desired pharmacological effect, and may include a formulation method, a mode of administration, a patient's age, weight, sex, morbidity, food, and time of administration. It can be determined variously by factors such as the administration interval, the route of administration, the rate of excretion, and the reaction sensitivity.
  • compositions may be in the form of solutions, suspensions, syrups or emulsions in oils or aqueous media or may be formulated in the form of extracts, powders, powders, granules, tablets or capsules, etc. It may further include a topic.
  • the pharmaceutical composition comprising the anti Ang2 antibody or antigen-binding fragment thereof comprises an antibody and thus may be formulated into an immune liposome.
  • Liposomes comprising the antibody can be prepared according to methods well known in the art.
  • the immune liposomes can be prepared by reverse phase evaporation as a lipid composition comprising phosphatidylcholine, cholesterol and polyethyleneglycol-derivatized phosphatidylethanolamine.
  • Fab 'fragments of antibodies can be conjugated to liposomes via disulfide-replacement reactions.
  • the pupils of an 8-week-old mouse were dilated by the use of a Shandong agent, and then the laser was irradiated to four locations for each mouse eye while observing the retina using a slit lamp microscope. Induced. At this time, only the lesions located at the location where the Bruch's membrane was found to be ruptured were included in the analysis, and bleeding was excluded from the analysis.
  • anti-ang2 antibodies comprising the heavy chain CDRs of SEQ ID NOs: 1 to 3 and the light chain CDRs of SEQ ID NOs: 4 to 6 listed in Table 2 are effective in inhibiting vascular leakage and choroidal neovascularization.
  • the evaluation was divided into categories. In order to compare the therapeutic effect with the anti-vascular endothelial growth factor antibody, the most widely used drug, experiments were conducted in three groups (placebo-administered group, anti-ang2 antibody-administered group and anti-vascular endothelial growth factor-administered group). Proceeded.
  • the anti-Ang2 antibody-treated group had vascular leakage (prevention: 63.1%; treatment: 66.4%) and the volume of choroidal neovascularization (prevention: 61.3%; treatment: 50.1). %) was significantly reduced, and compared with the anti-vascular endothelial growth factor antibody administration group showed a similar degree of vascular leakage inhibition and choroidal neovascular volume reduction effect (Fig. 1).
  • Anti-vascular endothelial growth factor treatment which has been widely used for the treatment of wet macular degeneration, requires only periodic repetitive injection treatment for a long period of time because it temporarily reduces the volume of CNV and suppresses vascular leakage.
  • the retinal and choroidal hypoxia and oxidative stress intensify the retinal neovascularization.
  • time series of angiography using light coherence tomography showed that the choroids at the periphery of the laser-induced choroidal neovascularization in the anti-vascular endothelial growth factor antibody-administered group.
  • the size of the avascular site increased (35.9%, 28.3%, and 47.5%) during the follow-up period, while the anti-ang2 antibody-treated group gradually decreased (27.3%, 43.1%, and 45.5%). 2).
  • anti-Ang2 antibody has similar inhibitory effect of vascular leakage and choroidal neovascularization compared with conventional anti-vascular endothelial growth factor treatment, resulting in an immediate therapeutic effect as well as reducing the size of choroidal avascular region.
  • hypoxia and oxidative stress it has been shown to fundamentally inhibit the recurrence of choroidal neovascularization and not to induce side effects such as degeneration of retinal pigment epithelium and optic nerve cells.
  • the first vascular changes in diabetic retinopathy are known to be thickening of the retinal capillary basement membrane and loss of perivascular cells. As these changes occur and over time, extensive capillary non-perfusion occurs and excessive regeneration of vascular endothelial growth factors from the ischemic retina results in retinal neovascularization causing complications such as bleeding and inflammation.
  • the diabetic retinopathy model was newly prepared in the mouse, considering that the early changes in diabetic retinopathy caused loss of perivascular cells and that excessively produced vascular endothelial growth factor was important for the progression of diabetic retinopathy.
  • PDGF-receptor-beta platelet-derived growth factor receptor
  • tamoxifen to produce diphtheria toxin. It was.
  • vascular endothelial growth factor was injected into the eye of the mammary gland engineered mouse and compared with the retina of the control eyeball, it was observed that the leakage of blood vessels was significantly increased in the genetically engineered mouse (FIG. 3). This produced an animal model based on the mechanism of development of diabetic retinopathy and showing an vascular disease similar to diabetic retinopathy.
  • Diabetic retinopathy model mice show vascular leakage and macrophage infiltration.
  • Intraperitoneal administration of an anti-Ang2 antibody comprising the heavy chain CDRs of SEQ ID NOS: 1 to 3 and the light chain CDRs of SEQ ID NOs: 4 to 6 described in Table 2 results in diabetic retinopathy model mice. Tran blood vessel leakage was reduced, macrophage infiltration was confirmed to decrease (Fig. 4).
  • Glaucoma is known to occur due to an increase in intraocular pressure due to an increase in the resistance of the waterproof outflow path through the Schlemm's canal and trabecular meshwork in the eye.
  • Ang-Tie2 signaling regulates angiogenesis and remodeling of blood vessels
  • Ubiquitin-Cre; Ang1 & Ang2 double floxed mouse inhibits Ang-Tie2 signaling by inhibiting Ang1 and Ang2 expression overall.
  • the prepared glaucoma model mice were found to significantly increase intraocular pressure by inhibiting formation of Schlemm's canal and maintaining homeostasis (FIG. 5).
  • an anti-Ang2 antibody comprising the heavy chain CDRs of SEQ ID NOS: 1 to 3 and the light chain CDRs of SEQ ID NOs: 4 to 6 shown in Table 2 having a Tie2 activation action is released from the mouse together with recombinant Ang2.
  • changes in intraocular pressure, regions of the Schlemm's canal and expression levels of the transcription factors Prox1 and Tie2 receptors were compared.
  • the present invention provides a therapeutic use of an anti-ang2 antibody that inhibits Ang2 and simultaneously activates a Tie2 receptor to promote downstream signal transduction, thereby making it useful for developing macular degeneration, diabetic retinopathy, and glaucoma therapeutic agents. have.

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  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)

Abstract

La présente invention concerne une composition qui est destinée à prévenir et à traiter des maladies oculaires et comprend un anticorps anti-angiopoïétine-2 (Ang2) et, plus spécifiquement, une nouvelle utilisation d'un anticorps anti-Ang2 en tant qu'agent pour prévenir ou traiter des maladies oculaires, l'anticorps anti-Ang2 étant spécifiquement couplé à l'Ang2, étant couplé à un récepteur de Tie2 avec l'Ang2, et ayant une affinité améliorée. La composition selon la présente invention peut être utilisée utilement pour développer un agent de traitement pour la dégénérescence maculaire, la rétinopathie diabétique et le glaucome.
PCT/KR2017/014981 2016-12-26 2017-12-19 Composition pour la prévention et le traitement de maladies oculaires comprenant un anticorps anti-ang2 WO2018124582A1 (fr)

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KR20160179099 2016-12-26
KR10-2016-0179099 2016-12-26
KR1020170174201A KR102143132B1 (ko) 2016-12-26 2017-12-18 항 Ang2 항체를 포함하는 안구질환 예방 및 치료용 조성물
KR10-2017-0174201 2017-12-18

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WO2020223209A1 (fr) * 2019-04-29 2020-11-05 Aerpio Pharmaceuticals, Inc. Activateurs de tie -2 ciblant le canal de schlemm
CN113728004A (zh) * 2019-02-25 2021-11-30 药物抗体公司 抗Ang2抗体及其用途

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113728004A (zh) * 2019-02-25 2021-11-30 药物抗体公司 抗Ang2抗体及其用途
WO2020223209A1 (fr) * 2019-04-29 2020-11-05 Aerpio Pharmaceuticals, Inc. Activateurs de tie -2 ciblant le canal de schlemm
US11253502B2 (en) 2019-04-29 2022-02-22 EyePoint Pharmaceuticals, Inc. Tie-2 activators targeting the Schlemm's canal
CN114269341A (zh) * 2019-04-29 2022-04-01 视点制药公司 靶向施莱姆管的Tie-2激活剂
US12064420B2 (en) 2019-04-29 2024-08-20 EyePoint Pharmaceuticals, Inc. Tie-2 activators targeting the Schlemm's canal

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