WO2021245539A9 - 약물 전달과 내재화 효율이 강화된 약물복합체 - Google Patents
약물 전달과 내재화 효율이 강화된 약물복합체 Download PDFInfo
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- WO2021245539A9 WO2021245539A9 PCT/IB2021/054774 IB2021054774W WO2021245539A9 WO 2021245539 A9 WO2021245539 A9 WO 2021245539A9 IB 2021054774 W IB2021054774 W IB 2021054774W WO 2021245539 A9 WO2021245539 A9 WO 2021245539A9
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Definitions
- the present invention relates to a drug complex with enhanced drug delivery and cell internalization efficiency. It relates to a unit drug complex, characterized in that a linking group capable of mutual bonding with other drug complexes is further linked to the drug complex.
- BACKGROUND ART Endocytosis is a general term defining the process by which cells absorb and/or excrete bound extracellular substances such as molecules, viruses, particles and microorganisms and deliver them to specific organs within the cytoplasm. Endocytosis is largely divided into phagocytosis and pinocytosis.
- the endocytosis is again macropinocytosis, clathrin-mediated endocytosis, and caveolin-mediated It can be divided into endocytosis, clathrin- and caveolin-independent endocytosis.
- the pathway of endocytosis may vary depending on the size of the endocytic vesicle, the nature of the cargo such as ligands, receptors and lipids, and the mechanism of vesicle formation (Conner SD et al. Nature 2003; 422:37- 44).
- macropyocytosis mainly delivers extracellular material into the cell by >1 ⁇ m plasma membrane entrapment
- clathrin-mediated endocytosis is ⁇ 120 nm
- caveolin-mediated endocytosis is ⁇ 60 nm
- clathrin-mediated endocytosis is ⁇ 60 nm.
- Trin- and caveolin-independent endocytosis introduces extracellular substances into cells with an intracellular vesicle size of ⁇ 90 nm.
- the endocytosis of extracellular substances is the internalization of drugs that can specifically bind to molecules (eg, receptors) widely expressed on cell membranes into target cells.
- a method for effectively internalizing a drug into a target cell it is effective by introducing a molecule (eg, a ligand) that can specifically bind to a molecule (eg, a receptor) widely expressed in a cell membrane (eg, a receptor). It can induce endocytosis (Marsh M. et al. Cell 2006; 124:729-40; Smith AE et al. Science 2004; 304:237-42). At this time, the drug-bound receptor is collected at the intrusion site by surface diffusion.
- Angiogenesis refers to the process in which new capillaries are formed from existing microvessels, and is known to play an important role in the normal physiological process, wound healing, and the female reproductive cycle.
- angiogenesis is not controlled autonomously and is caused by pathological growth.
- abnormally excessive angiogenesis is tumor or cancer growth and metastasis (metastasis), diabetic retinopathy (diabetic retinopathy), age-related macular degeneration. It is known to play a decisive role in diseases such as age-related macular degeneration, rheumatoid arthritis, endometriosis, psoriasis or chronic inflammation.
- Angiogenesis is also associated with coronary artery disease, stroke, myocardial infarction, ulcer or delayed wound healing.
- a tumor particularly a malignant tumor (cancer)
- cancer is a disease in which internal or external factors act on the cells of the body to divide irregularly, and the cells themselves grow out of control of the body and proliferate unintentionally. means Furthermore, it invades surrounding tissues, metastasizes to other organs through blood vessels and lymphatic vessels, and grows.
- angiogenesis is one of the important mechanisms of tumor.
- angiogenesis-related diseases exhibit serious conditions, and various therapeutic agents have been developed to treat them. If not, excessive therapeutic doses are repeatedly administered, and resistance to the therapeutic agent is likely to occur, and a clear therapeutic effect cannot be expected in many cases.
- target receptors that are the target of therapeutic agents for angiogenesis-related diseases exist in vascular endothelial cells, and thus target specific receptors due to blood pressure, blood flow, vascular permeability, etc. Since the binding between the targeting substance and the receptor can be dissociated and released within a short time, the therapeutic agent is repeatedly administered at a high dose for a long-term therapeutic effect, thereby causing various side effects.
- targeted cancer therapy which has recently been spotlighted, is a treatment method that targets a tumor-specific biomarker unlike existing treatment methods. photodynamic therapy, etc. Since drugs used for tumor-targeted therapy are delivered by targeting tumor-specific biomarkers, damage to normal cells is minimized and tumor cell death is induced.
- drugs used for these tumor-targeted therapies must have high selectivity and binding ability to tumor cells, as well as be effectively delivered to tumor cells through cell internalization.
- ligands including multimeric compounds capable of simultaneously binding to multiple target receptors have been developed (Wu Z. et al., J Nucl Med 2007; 48: 1536-1544.), but Due to positional specificity (blood pressure, blood flow, vascular permeability, etc.), there is a limitation in endocytosis in the body, and there is a disadvantage in that the effect of internalizing the drug into cells is low.
- the present inventors have focused on the fact that, in the case of a conventional drug complex used for the diagnosis or treatment of various diseases such as angiogenesis-related diseases, the internalization efficiency of the drug is very low due to the limitation of endocytosis in the body. It was expected that if the cell internalization of the drug was strengthened, the sensitivity and accuracy of diagnosis could be remarkably improved, and the targeted therapeutic efficacy of drugs could be greatly improved.
- Patent Document 1 PCT/KR2011/003801
- Non-Patent Document 1 Conner S.D. et al. Nature 2003; 422:37-44;
- Non-Patent Document 2 Marsh M. et al., Cell 2006; 124: 729-40;
- Non-Patent Document 3 Smith A.E. et al. Science 2004; 304:237-42;
- Non-Patent Document 4 Wu Z. et al., J Nucl Med 2007; 48: 1536-1544.
- SUMMARY OF THE INVENTION It is an object of the present invention to provide a novel drug complex with improved drug delivery efficiency by remarkably increased internalization of cells.
- the present invention is characterized in that a binding group capable of mutual binding with another unit drug complex is further linked to a drug complex in which a drug and a targeting substance that specifically binds to a target cell are linked. Provides a unit drug complex.
- the present invention also provides the above-mentioned unit drug complex (first unit drug complex); And it provides a drug complex comprising the unit drug complex and another drug complex (second unit drug complex) that can be mutually bound through a bonding group.
- the present invention also provides a pharmaceutical composition for treating various diseases including the drug complex, preferably a pharmaceutical composition for treating angiogenesis-related diseases.
- the present invention also provides a composition for diagnosing various diseases, preferably a composition for diagnosing angiogenesis-related diseases, including the drug complex.
- the present invention also provides a pharmaceutical composition for diagnosing and treating various diseases including the drug complex, preferably a pharmaceutical composition for diagnosing and treating angiogenesis-related diseases.
- the present invention also provides a method for treating various diseases comprising administering the drug complex.
- the present invention also provides a variety of A method for diagnosing a disease is provided.
- the present invention also provides the use of the drug complex for the treatment of various diseases.
- the present invention also provides the use of the drug complex for the diagnosis of various diseases.
- the present invention also provides the use of the drug complex for the manufacture of a medicament for the treatment of various diseases.
- 1A is a schematic diagram showing the structure of the unit drug complex of the present invention.
- 1B is a schematic diagram briefly expressing the principle of operation of the present invention.
- 3A is a fluorescence imaging result confirming the effect of enhancing intracellular influx by the generation of cross-linkage between binders according to an embodiment of the present invention.
- 3B is a numerical result of fluorescence intensity of a fluorescence imaging result confirming the effect of enhancing intracellular influx by the generation of cross-linkage between binders according to an embodiment of the present invention.
- 3C is a Z-stack analysis result of a fluorescence image confirming the effect of promoting intracellular influx by the generation of cross-linkage between binders according to an embodiment of the present invention.
- 4 is an ex vivo biodistribution experimental result of the drug complex according to an embodiment of the present invention.
- 5 is a result confirming the difference in retention in the tumor according to the sequentially administered dose of the unit drug complex according to an embodiment of the present invention.
- the present invention is a unit characterized in that a binding group capable of mutual binding with another unit drug complex is further linked to a drug complex in which a drug and a targeting substance that specifically binds to a target cell are linked. It relates to drug complexes.
- the targeting material may be characterized in that it specifically binds to a target that is specifically expressed or overexpressed in a target cell, and the drug may be characterized as a therapeutic or diagnostic drug, It is not limited.
- the targeting material and the drug may be characterized in that they are connected by a linker, the targeting material and the drug may be directly connected without a linker.
- the bonding group may be characterized in that it is further linked to the linker, but may be coupled to other sites of the drug complex.
- the bonding group may be characterized in that at least one.
- the unit drug complex first unit drug complex
- it relates to a drug complex comprising the unit drug complex and another drug complex (second unit drug complex) that can be mutually bound through a bonding group.
- the bonding group included in the first unit drug complex is named as a first bonding group
- the bonding group included in the second unit drug complex is referred to as the second bonding group.
- the first unit drug complex and the second unit drug complex may be characterized in that the first bonding group and the second bonding group are mutually bonded.
- the targeting substance introduced into the first unit drug complex and the targeting substance introduced into the second unit drug complex may be the same or different from each other, but all of the targeting substances are specifically expressed or overexpressed in the same target cell It may be characterized in that it specifically binds to the target.
- the drug introduced into the first unit drug complex and the drug introduced into the second unit drug complex may be the same or different from each other.
- the present invention may also be a multi-drug complex in which a plurality of unit drug complexes can be multi-bonded by one or more linking group pairs.
- the present invention also provides the above-mentioned unit drug complex (first unit drug complex); and another drug complex (second unit drug complex) having a second bonding group capable of mutual bonding with the first bonding group of the first unit drug complex.
- the present invention also provides the above-mentioned unit drug complex (first unit drug complex); and another drug complex (second unit drug complex) having a second bonding group capable of mutual bonding with the first bonding group of the first unit drug complex.
- the second unit drug complex is a drug complex in which a second targeting material that specifically binds to a target specifically expressed or overexpressed in a target cell and a therapeutic or diagnostic drug are linked, the first unit of the drug complex It is characterized in that a second bonding group capable of mutual bonding with the bonding group is further connected.
- the present invention relates to a drug complex in which a second targeting substance that specifically binds to a target specifically expressed or overexpressed in a target cell and a therapeutic or diagnostic drug are linked, and the first binding group of the first unit drug complex is mutually It relates to a second unit drug complex, characterized in that a second bonding group capable of binding is further linked.
- the present invention relates to a drug complex in which the first unit drug complex and the second unit drug complex are formed by bonding a first bonding group and a second bonding group.
- first unit drug complex and/or the second unit drug complex according to the present invention rapid targeting to target cells, for example, cancer cells is possible. That is, when the existing anticancer drugs have slow tumor intake pharmacokinetics, high dose administration is inevitable because they inhibit normal cells and cause a decrease in drug efficacy due to rapid body metabolism, but the first unit drug complex and/or the second unit drug according to the present invention When using the complex, it has the advantage of being able to rapidly and selectively target tumor cell membrane proteins in an amount that is stable in blood and has little to no toxicity.
- the first unit drug complex and or the second unit drug complex according to the present invention are used, there is an advantage in that the internalization of the drug into tumor cells can be enhanced. That is, the cancer cell internalization of existing anticancer drugs depends only on the natural intracellular uptake mechanism, but when using the first unit drug complex and/or the second unit drug complex according to the present invention, the desired target cell, for example, cancer
- the conjugates binding substances between the membrane protein and the target compound
- a cluster is formed, which accelerates the endocytosis and consequently enhances the internalization of the drug into the cell.
- the targeting substance (first targeting substance) introduced into the first unit drug complex and the targeting substance (second targeting substance) introduced into the second unit drug complex are specifically expressed or overexpressed in target cells.
- Any material capable of specifically binding to a target may be used without limitation.
- specific expression in target cells means that it is not expressed in normal cells but specifically expressed only in target cells, and overexpression in target cells means that it is abnormally expressed in a higher amount in target cells than in normal cells.
- the first targeting material and the second targeting material may target the same target or different targets, and may be different materials even when targeting the same target.
- both the first targeting material and the second targeting material targeting EGF receptor are EGF receptors may be an antibody to
- the first targeting material may be an antibody against EGF receptor
- the second targeting material may be EGF, which is a ligand for EGF receptor.
- both the first targeting material and the second targeting material are antibodies to the EGR receptor, (preferably monoclonal hieroglyphs), they may be antibodies having a different complementarity determining region (CDR) or variable region.
- CDR complementarity determining region
- Substances capable of specifically binding to a target specifically expressed in the target cell include an antibody, an aptamer, a peptide such as a ligand, a carbohydrate, and a low molecular weight compound ( small molecules), but is not limited thereto.
- an antibody includes not only a whole antibody form, but also an antigen-binding fragment of the antibody molecule.
- a complete antibody has a structure having two full-length light chains and two full-length heavy chains, and each light chain is linked to a heavy chain by a disulfide bond.
- the heavy chain constant region has gamma ( 7 ), mu ( ), alpha (a), delta (6) and epsilon ( £ ) types and subclasses gamma 1 ( y l ), gamma 2 ( 7 2 ), gamma 3 ( 7 3), gamma 4 ( 7 4), alpha 1 (al) and alpha 2 (a2).
- the constant region of the light chain has kappa (K) and lambda (X) types.
- Fab includes the variable regions of light and heavy chains and It has a structure with a constant region of the light chain and the first constant region (CH1) of the heavy chain, and has one antigen-binding site.
- Fab' is a hinge region comprising one or more cysteine residues at the C-terminus of the heavy chain CH1 domain ( hinge region) differs from Fab in that the F(ab')2 antibody is A cysteine residue is formed by forming a disulfide bond.
- Fv is a minimal antibody fragment having only a heavy chain variable region and a light chain variable region.
- a double chain Fv two-chain Fv
- the heavy chain variable region and the light chain variable region are connected by a non-covalent bond
- the single chain Fv (sin is e-chain Fv, scFv) is generally connected to the heavy chain variable region and the light chain through a peptide linker. Since the variable regions of are linked by a covalent bond or directly at the C-terminus, a dimer-like structure can be formed like a double-stranded Fv.
- Such antibody fragments can be obtained using proteolytic enzymes (for example, restriction digestion of the whole antibody with papain can give Fab and pepsin digestion to give F(ab')2 fragments), It can also be produced through genetic recombination technology.
- Fv fragment is an antibody fragment that contains a complete antibody recognition and binding site. This region consists of a dimer in which one heavy chain variable domain and one light chain variable domain are tightly and virtually covalently associated with, for example, an scFv.
- a “Fab” fragment contains the variable and constant domains of a light chain and the variable and first constant domains (CH1) of a heavy chain.
- F(ab')2 antibody fragments generally comprise a pair of Fab fragments covalently linked near their carboxy terminus by a hinge cysteine between them.
- a “single chain Fv” or “scFv” antibody fragment comprises the VH and VL domains of an antibody, which domains are present within a single polypeptide chain.
- the Fv polypeptide may further comprise a polypeptide linker between the VH and VL domains that enables the scFv to form the desired structure for antigen binding.
- the targeting material of the drug complex refers to a material capable of binding to a target that is specifically expressed or overexpressed in a target cell, for example, RGD (arginine(R)- glycine(G)-aspartic acid(D)) peptide, glutamate-urea-lysine (GUL) motif binding to prostate specific membrane antigen (PSMA), EGF binding to EGF receptor , VEGF-A or VEGF-B that binds to a vascular endothelial growth factor (VEGF) receptor, but is not limited thereto.
- RGD arginine(R)- glycine(G)-aspartic acid(D)
- GUL glutamate-urea-lysine motif binding to prostate specific membrane antigen
- PSMA prostate specific membrane antigen
- EGF binding to EGF receptor VEGF-A or VEGF-B that binds to a vascular endothelial growth factor (VEGF) receptor, but is not limited thereto.
- the target specifically expressed or overexpressed in the target cell means a protein that is specifically expressed in relation to a disease or overexpressed compared to a normal state as described above, for example, a receptor or a tumor-specific antigen and the like may be exemplified, but are not limited thereto.
- Targets specifically expressed in the target cells include integrins such as integrin avp3, prostate-specific membrane antigen (PSMA), CD3, CD4, CD6, CD1 la, CD 19, CD20, CD22, CD30, CD33, CD38, CD40, CD52 TNF receptors, including CD62, CD79b, CD80, CGRP, OX-40, CTLA4, 4-1BB, PD-1, EGF receptor, TNF (tumor necrosis factor)-a, catcher, folate receptor, GD2 , HER2, Her2/neu, HER3, HER4, VEGF receptor, interferon receptor, IgE receptor, IGF-1 receptor, interleukin 2 receptor, interleukin 5 receptor, interleukin 6 receptor, interleukin 17 receptor A, interleukin 31 receptor, interleukin 36 receptor, B7-H3 and CCR4 and the like may be exemplified, but are not limited thereto.
- PSMA prostate-specific membrane antigen
- CD3, CD4, CD6, CD1 la
- RGD Arginine(R)-ycine(G)-aspartic acid(D)
- RGD peptide that specifically binds to integrin avp3, glutamate-urea-lysine motif or antibody targeting PSMA, aptamer, small molecule compound , or a tumor-targeting peptide may be used, but is not limited thereto.
- the RGD peptide used as an aspect of the present invention is a targeting material that specifically binds to integrin avp3, a membrane protein involved in tumor neovascularization, and has three amino acids as basic structures: arginine-glycine-aspartic acid. and can be used as a targeting material for the diagnosis or treatment of tumors.
- the glutamate-urea-lysine motif that can be used in another embodiment may be a targeting material that targets PSMA, which is known as a biomarker of prostate cancer, but is not limited thereto.
- the target cell is a disease, preferably a cell that is a target for diagnosis or treatment of an angiogenesis-related disease, or a cell that is a target for diagnosis or treatment of prostate cancer, for example, a tumor cell, atherosclerosis. It may be a triggering cell, a myocardial infarction-inducing cell, etc.
- the drugs included in the first unit drug complex and the second unit drug complex may be the same drug or different drugs.
- the drug is a concept that includes both a diagnostic drug and a therapeutic drug, and the diagnostic drug may be characterized in that it is a fluorescence dye or a diagnostic gamma-ray/positron radioisotope, but is not limited thereto.
- the drug is a photosensitizer used in photodynamic therapy, a molecule containing the isotope boron (10B) used in boron neutron capture therapy, and a molecule used in nuclear medicine. It may be characterized in that it is selected from the group consisting of radioactive isotopes for alpha/beta-emitting therapy and anticancer agents used for anticancer chemotherapy, but is not limited thereto.
- the drug may be a low molecular weight compound, a synthetic drug, a peptide, a protein, or an antibody, but is not limited thereto.
- the drug is maytansinoid, auristatin, aminopterin, actinomycin, bleomycin, thalisomycin, camptothecin, N8-acetyl spermidine, 1-(2 chloroethyl)-1,2 -dimethyl sulfonylhydrazide, espiramicin, etoposide, 6-mercaptopurine, dolastatin, trichothecene, calicheamicin, taxol, taxane, paclitaxel, docetaxel, Methotrexate, vincristine, vinblastine, doxorubicin, melphalan, mitomycin A, mitomycin C, chlorambucil, duocarmycin, L-asparaginase, mercaptopurine, thioguanine
- the radioisotope may be an isotope that emits gamma rays or positrons to provide diagnostic acid or emits beta or alpha rays to provide therapeutic efficacy, for example, 11C, 18F, 99mTc, 188Re, 125/ 123/124/1311, 89Zr, 64/67Cu, 68Ga, 177Lu, 90Y, 225Ac, or 211At, but is not limited thereto.
- the fluorescent dye is fluorescein isothiocyanate (FITC), Tetramethylrhodamine (TRITC), alexa fluor series, or cyanine (Cy) may be a fluorescent dye, but is not limited thereto.
- FITC fluorescein isothiocyanate
- TRITC Tetramethylrhodamine
- alexa fluor series or cyanine (Cy)
- cyanine (Cy) may be a fluorescent dye, but is not limited thereto.
- the drugs included in the first unit drug complex and the second unit drug complex according to the present invention are different from each other. In this way, when the drugs included in the first unit drug complex and the second unit drug complex are different, there is an advantage that combination therapy can be implemented in a jumbo type through multi-drug loading and delivery. That is, the resistance of cancer to existing anticancer drugs shortens the cycle of use of anticancer drugs and eventually leads to discontinuation of treatment for patients.
- the first bonding group and the second bonding group may be used without limitation as long as they are bonding groups that can be bonded in the body, and the bonding group is a bonding group by a click reaction, a bonding group by a host-guest chemical action, or an avidin-biotin bonding group may be, but is not limited thereto.
- the binding may be characterized in that it is a binding by a click reaction, a binding by a host-guest interaction, or an avidin-biotin bond, but is not limited thereto, and the interaction between two or more unit drug complexes is It will be apparent to those skilled in the art that cross-linking can occur without limitation in the body to induce it.
- the bonding group is a bonding group using a click reaction.
- the click reaction without a copper catalyst is known to be a reaction in which a bond is formed in a short time even in an aqueous environment such as the body (Jewett JC et al. Chem. Soc. Rev. 2010;39: 1272-1279. ).
- the bonding group by the click reaction may be an azide-ADIBO (azadib enzocycl oocty ne) bonding group, TCO (trans cyclooctene)-tetrazine bonding group], or an alkynes-cyclopentadienones bonding group, but is not limited thereto.
- the host-guest interaction is a host compound and It is an interaction that shows high avidity in the form of a non-covalent bond between guest compounds (Yu G. et al, Theranostics. 2019;9:3047-3074.). In particular, it is applicable to the present invention because it shows a high binding force between the compounds even in an environment similar to the body.
- the linking group may be characterized as a cucurbituril-adamantane, cyclodextrin-amino acid bonding group, but is not limited thereto.
- the linking group may use an avidin-biotin interaction.
- the avidin-biotin interaction is one of the strong non-covalent bonds that exist in nature and is a selective bond, and above all, has the advantage of having a stronger binding force than antibody-antigen binding (Jain A. et al. J Control Release. 2017; 245: 27- 40).
- the first targeting substance and drug contained in the first unit drug complex and/or the second targeting substance and drug contained in the second unit drug complex are linked by a linker or may be directly linked without a linker.
- first targeting substance and the first linking group included in the first unit drug complex and / or the second targeting substance and the second binding group included in the second unit drug complex are linked by a linker or can be directly linked without a linker.
- first targeting substance, drug, and first linking group included in the first unit drug complex are linked by a linker (linking group) having three or more functional groups as shown in FIG. Tae, but is not limited thereto.
- the first targeting agent, the drug, and the first binding group may each be linked by a linker or may be directly linked.
- the linker may be an amino acid, hydrocarbon or PEG chain, but is not limited thereto.
- the linker may be used without limitation as long as it is a material known in the art having an atomic or molecular group and other functional groups suitable for linking the targeting substance and the drug, and further linking a binding group thereto.
- the unit drug complex (first unit drug complex) And it relates to a drug complex comprising the unit drug complex and another drug complex (second unit drug complex) that can be mutually bound through linkages (first linkage group and second linkage group).
- the mutual bond may be characterized as a bond by a click reaction, a bond by a host-guest interaction, or an avidin-biotin bond, but is not limited thereto.
- the bond by the click reaction may be characterized as an azide-ADIBO bond, a TCO-tetrazine bond, or an alkynes-cyclopentadienones bond, but is not limited thereto.
- the host-guest bond by chemical action may be characterized as a cucurbituril-adamantane bond or a cyclodextrin-amino acid bond, but is not limited thereto.
- the present invention relates to a pharmaceutical composition for the treatment of angiogenesis-related diseases comprising the unit drug complex.
- the pharmaceutical composition may include two or more different unit drug complexes.
- the different two or more unit drug complexes may mean that the linking groups that function to allow the drug complexes constituting each unit drug complex to interact are different in the two or more unit drug complexes. Also, it may mean that each drug bound to a plurality of unit drug complexes constituting two or more unit drug complexes is different from each other.
- the first unit drug complex and the second unit drug complex may be administered at the same time, preferably, it may be characterized in that it is administered sequentially.
- the first unit drug complex is administered prior to the second unit drug complex, and after the first unit drug complex reaches and binds to the target of the target cell, the second unit drug complex is It is preferably administered.
- the second unit drug complex is administered from 1 minute to 600 minutes, preferably from 5 minutes to 480 hours, more preferably from 10 minutes to 300 minutes, most preferably from 30 minutes to after administration of the first unit drug complex. It is preferably administered after 240 minutes have elapsed.
- the second unit drug complex may be used in the same amount as the first unit drug complex.
- one or more unit drug complexes may be used per first unit drug complex, for example, 1 to 10 types of unit drug complexes administered per first unit drug complex, preferably 1 to 5 types may be used.
- the present invention is not limited thereto.
- the angiogenesis-related disease is benign tumor, malignant tumor (cancer), diabetic retinopathy, age-related macular degeneration, rheumatoid arthritis, endometriosis, psoriasis, chronic inflammation, coronary artery disease, atherosclerosis, It may be characterized as selected from the group consisting of stroke, ulcer and myocardial infarction, but is not limited thereto.
- the present invention relates to a composition for diagnosing angiogenesis-related diseases comprising the unit drug complex.
- the angiogenesis-related disease is benign tumor, malignant tumor (cancer), diabetic retinopathy, age-related macular degeneration, rheumatoid arthritis, endometriosis, psoriasis, chronic inflammation, coronary artery disease, atherosclerosis, It may be characterized as selected from the group consisting of stroke, ulcer and myocardial infarction, but is not limited thereto.
- the present invention relates to a composition for diagnosing and treating angiogenesis-related diseases, including the unit drug complex, so that diagnosis and treatment can be performed simultaneously.
- the first unit drug complex is administered prior to the second unit drug complex, the drug contained in the first unit drug complex is a diagnostic drug, and the drug contained in the second unit drug complex is for treatment characterized as a drug can do.
- the first unit drug complex is administered prior to the second unit drug complex, the drug contained in the first unit drug complex is a therapeutic drug, and the drug contained in the second unit drug complex is for diagnosis It may be characterized as a drug.
- the angiogenesis-related disease is benign tumor, malignant tumor (cancer), diabetic retinopathy, age-related macular degeneration, rheumatoid arthritis, endometriosis, psoriasis, chronic inflammation, coronary artery disease, atherosclerosis, It may be characterized as selected from the group consisting of stroke, ulcer and myocardial infarction, but is not limited thereto.
- the pharmaceutical composition is any one selected from the group consisting of injections, oral preparations, patches, solutions, capsules, granules, tablets, powders, sprays, ointments, gels, mucosal administration preparations and suppositories It may be characterized in that it is formulated in a dosage form, but is not limited thereto.
- These formulations can be prepared by conventional methods used for formulation in the art or by methods disclosed in Remington's Pharmaceutical Science (latest edition), Mack Publishing Company, Easton PA, and are formulated into various formulations according to each disease or component. can be However, the above description is exemplary, and the formulation to which the present invention is applicable is not limited thereto.
- the pharmaceutical composition may be characterized in that it further contains acceptable excipients, and the adjuvant may be, for example, a carrier.
- a pharmaceutically acceptable carrier may be used in a mixture of saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, and one or more of these components, and if necessary, antioxidant
- Other conventional additives such as agents, buffers, and bacteriostats may be added.
- composition of the present invention may be administered parenterally (eg, intravenously, subcutaneously, orally, (term) intraperitoneally or topically) according to a desired method, and the dosage may vary depending on the patient's weight, age, sex The range varies according to , health status, diet, administration time, administration method, excretion rate and severity of disease.
- the dosage regimen and dosage will vary according to the age, weight and response of the individual patient. Appropriate dosage regimens and dosages should be determined by one of ordinary skill in the art taking these factors into account.
- the composition of the unit drug complex is divided into a targeting substance, a binding group, a drug, and a linker as shown in FIG. la, and the roles of each component are summarized below.
- Targeting substance refers to a substance capable of binding to a target that is specifically expressed or overexpressed in a target cell, for example, a ligand that specifically binds to an integrin receptor involved in tumor angiogenesis, a receptor related to PSMA It means a ligand that binds to, a ligand that binds to an EGF receptor, a ligand that binds to a vascular endothelial growth factor (VEGF) receptor, and the like, but is not limited thereto.
- VEGF vascular endothelial growth factor
- Linking group A linking group is a functional group that induces cross-linking in the body between different unit drug complexes, and may spontaneously covalently or non-covalently bond when positioned close to each other, for example, binding by click reaction, host-guest interaction binding or avidin-biotin binding.
- the bonding group used for bonding by the click reaction may be characterized as azide-ADIBO, TCO-tetrazine, or alkynes-cyclopentadienones, but is not limited thereto.
- the bonding group used for host-guest chemistry may be cucurbituril-adamatane or cyclodextrin-amino acid, but is not limited thereto.
- the avidin-biotin bonding group may be characterized as avidin-biotin, However, the present invention is not limited thereto. Modes in which a plurality of unit drug complexes are mutually bound through a bonding group are very diverse, and some aspects will be described in detail as follows.
- One or a plurality of second unit drug complexes may be bound to the first unit drug complex according to the present invention. When one second unit drug complex is bound to the first unit drug complex, binding by a click reaction between bonding groups for cross-linking in the body, binding by host-guest interaction, or avidin-biotin bond may be used.
- each of the unit drug complexes may contain one A and a.
- the linking group structure of the first unit drug complex may be more diverse than the structure in which one second unit drug complex is bound.
- the bonding groups introduced into the unit drug complex in the bonding method selected for cross-linking in the body can be expressed as A and a.
- the first unit drug complex may include one or more A as a linking group, and this unit drug complex may be combined with a plurality of second unit drug complexes including a.
- a included in the unit drug complex may be connected to the unit drug complex in various forms, specifically, as shown below, may be connected in the form of a linear, cyclic, branched, etc., but limited thereto it doesn't happen
- A means a bonding group capable of interaction, as described in the above-described bonding group, and specific examples include azide-ADIBO, TCO-tetrazine, alkynes-cyclopentadienones, cucurbituril-adamantane, cyclodextrin-amino acid, avidin-biotin, etc., and may have 1 to 30 linking groups.
- _ is a linker and _ is a linking group.
- the following is an exemplary representation of a partial, linear, cyclic, or branched structure, but the present invention is not limited thereto.
- a drug is a concept including both a diagnostic drug and a therapeutic drug.
- the diagnostic drug may be characterized as a fluorescence dye or a diagnostic gamma-ray/positron emitting radioisotope, but is not limited thereto, and the therapeutic drug is a photosensitizer used in photodynamic therapy.
- photosensitizer a molecule containing the isotope boron ( 10 B) used for boron neutron capture therapy, a radioisotope for alpha/beta emission therapy used for nuclear medicine treatment, and chemotherapy for chemotherapy It may be characterized in that it is selected from the group consisting of the anticancer agents used, but is not limited thereto.
- the linker refers to a substance having an atomic or molecular group and other functional groups that further link a targeting substance, a drug, and a bonding group.
- the linker may be an amino acid, hydrocarbon or PEG chain, but is not limited thereto. Specifically, amino acids having carboxylic acid and amine as functional groups as functional groups connecting each component, amine (-NH2), carboxylic acid (-COOH), sulfonic acid (-SH), alcohol (-OH) at least one or more residues ), a hydrocarbon or PEG chain having a halogen group (-Br, Cl, I, etc.).
- the present invention relates to a kit for diagnosing angiogenesis-related disease or a kit for treating angiogenesis-related disease containing one or two or more of the above unit drug complexes.
- the present invention relates to the use of the drug complex for use in the treatment of angiogenesis-related diseases.
- the present invention relates to the use of the drug complex for the manufacture of a medicament for the treatment of angiogenesis-related diseases.
- it relates to the use of the drug complex for use in the diagnosis of angiogenesis-related diseases.
- the present invention relates to the use of the drug complex for preparing a reagent for the diagnosis of angiogenesis-related diseases.
- the present invention relates to the use of the drug complex for use in the treatment and diagnosis of angiogenesis-related diseases.
- the present invention relates to the use of the drug complex for the manufacture of a medicament for the treatment and diagnosis of angiogenesis-related diseases.
- the unit drug complex according to the present invention is fluorescence image-guided surgery, nuclear imaging, photodynamic therapy (PDT), boron neutron capture therapy (BNCT) , can be used in various diagnostic and treatment methods such as radioimmunotherapy and targeted chemotherapy.
- the present invention relates to a method for treating an angiogenesis-related disease comprising the following steps:
- the present invention relates to a method for diagnosing angiogenesis-related diseases comprising the following steps:
- the present invention relates to a method for diagnosing and treating angiogenesis-related diseases comprising the following steps:
- the drug complex according to the present invention has the following characteristics.
- the unit drug complex according to the present invention can rapidly target cells on which the unit drug complex acts. In general, if it does not specifically bind to a target cell or the pharmacokinetics of uptake into the target cell is slow, it inhibits the function of normal cells other than the target cell and reduces the drug efficacy due to metabolism in the body. This causes a problem in that the dosage is increased.
- the drug complex according to the present invention introduces a targeting material that specifically binds to a target cell, thereby exhibiting a high therapeutic effect with a small dose, thereby preventing toxicity or side effects caused by high dose administration.
- the drug complex according to the present invention enhances cell internalization. If the cell internalization of the conventional tumor cell-targeted therapeutic agent depends only on the natural intracellular uptake mechanism, the unit drug complex according to the present invention induces the mutual binding of the unit drug complex in the body by introducing a linking group that induces cross-linking in the body. do.
- the sequential administration method of first administering a unit drug complex having such a binding group and then administering other unit drug complexes capable of mutually binding to the binding group is a targeting substance in which each unit drug complex specifically binds to a target cell. It specifically binds to the target on the target cell.
- a plurality of unit drug complexes bound to these target cells are cross-linked in the body, and a colony is formed by induced cross-linking in the body between the formed conjugates, and this cluster accelerates endocytosis and promotes internalization of the drug
- drugs can be effectively delivered to target cells even with low dose administration.
- a group may be formed by inducing cross-linking in the body between three or more different unit drug complexes by combining the unit drug complexes introduced with different bonding groups with other unit drug complexes that interact with each other, and the drugs included therein They may be different drugs.
- multi-purpose treatment and combination treatment can be customized through the present invention.
- a plurality of unit drug complexes may have different bonding groups and different drugs, and a plurality of different unit drug complexes may contain as many different drugs as possible, so it is very useful for multi-purpose treatment and combination treatment. can be utilized.
- one unit drug complex of the present invention contains a drug for diagnosis, and the other unit drug complex contains a drug for treatment. If drugs are included, diagnosis and treatment may proceed simultaneously.
- the present invention will be described in more detail through examples. These examples are only for illustrating the present invention in more detail, and it will be apparent to those of ordinary skill in the art that the scope of the present invention is not to be construed as being limited by these examples.
- Example 1 Preparation of drug complex
- the targeting substance selected as an embodiment of the present invention is an RGD peptide that binds to the integrin otvp3 of tumor angiogenesis, and the structure is as follows.
- Peptide A Correction paper (Rule 91) ISA/KR Specifically, peptide A is D-[c(RGDfK)] 2 by linking two cyclicRGDfECs with aspartic acid (D), and peptide B is Dc ( RGDyK)-c(RGDfK).
- the targeting material is described in BC Lee et al., RSC Advances 2013; 3:782-792.> Synthesized as a basis.
- the unit drug complex used in the present invention is as follows.
- Each unit drug complex has a form in which a targeting substance, drug, and bonding group are connected through a linker, and various methods of connecting each component with a linker are widely known in the art, but in this embodiment, the amide bond ( Each drug complex was prepared using an amide bond).
- Unit drug complex 1
- Targeting substance peptide B
- drug FITC
- binding group tetrazine unit drug complex 4 Correction Form (Rule 91)
- ISA/KR ISA/KR
- Targeting substance RGD peptide A
- drug radioactive isotope iodine ( 123 1 or 125 1)
- binding group azide unit drug complex 6 g _ - X target _ freighter _ Correction paper (Rule 91)
- ISA/KR ISA/KR
- linking group ADIBO correction paper (Rule 91) ISA/KR
- Drug complex 3-4 combination of unit drug complexes 3 and 4
- Drug complex 5-6 combination of unit drug complexes 5 and 6
- a unit drug complex targeting PSMA was prepared.
- the selected targeting material is a GUL (glutamate-urea-lysine)-based motif that binds to PSMA, and the structure is as follows.
- the targeting material was synthesized based on the literature (Maresca KP et al, J Med Chem 2009;52:347-357.).
- Peptide C is a GUL (glutamate-urea-lysine)-based motif that binds to PSMA, and the structure is as follows.
- the targeting material was synthesized based on the literature (Maresca KP et al, J Med Chem 2009;52:347-357.).
- Target material peptide C
- drug FITC
- binding group azide unit drug complex 14 Correction Form (Rule 91) ISA/KR
- the fluorescence resonance energy transfer (FRET) method is an analysis method that can check the interaction between two compounds by measuring the fluorescence resonance energy between two fluorescent dyes occurring between 1 - 10 nm.
- the FRET method was used to measure the effect of mutual binding and cell internalization between the unit drug complexes.
- the conditions of the FRET experiment for comparing and confirming the cell internalization effect were designed as described in Table 1 below, and the unit drug complexes used in this experiment are unit drug complexes 1 and 2 and unit drug complexes 3 and 4, respectively.
- the post-conjugation targeting described in Table 1 below refers to a form in which each unit drug complex is cross-linked in advance before in vitro or in vitro experiments.
- it refers to drug complex 1-2 in which the binding between azide, the binding group of unit drug complex 1, and ADIBO, the binding group of unit drug complex 2, has already been completed before targeting.
- Post-targeting conjugation refers to the technique according to the present invention, and if unit drug complexes 1 and 2 are described as an example, unit drug complex 1 is targeted and bound to a target cell, and then to the same target cell
- unit drug complex 2 is targeted and bound, and in this case, the unit drug complex 1 and the unit drug complex 2, which are a pair of unit drug complexes, form a cross-linkage through each bonding group.
- FIGS. 3A and 3B The results of the fluorescence imaging according to the experimental conditions described in Table 1 are shown in FIGS. 3A and 3B, the fluorescence imaging photograph is shown in FIG. 3A, and the fluorescence imaging result is shown as a numerical graph according to the fluorescence intensity in FIG. 3B.
- the result of treating each drug complex 1 or 2 alone, which can check the tumor cell uptake ability of each drug complex shows that the FITC channel and TRITC channel, which can read the wavelength of each fluorescent dye of the unit drug complex, are applied to the target cells, respectively. It shows that the unit drug complex is ingested.
- unit drug complexes 1 and 2 were mixed with ethanol and After dissolving and performing a binding reaction at room temperature for 40 minutes to synthesize and isolate the drug complex 1-2, the post-conjugation target, it was treated with cells. 2 were sequentially processed.
- fluorescence wavelength analysis was performed on the FITC channel and TRITC channel that can read the wavelength of each fluorescent dye of the unit drug complex, and the FRET channel that can read the wavelength when the unit drug complex binds.
- the analysis results are as shown in FIGS. 3a and 3b, and the drug complex as the post-conjugation target In the case of 1-2, the intensity of fluorescence was measured to be quite low in the results of the FRET channel, whereas in the case of sequential administration of unit drug complex 2 after administration of unit drug complex 1 (ie, target conjugation), drug complex 1 In the case of -2 treatment (i.e., post-conjugated target), the fluorescence intensity was confirmed to be 4 times stronger than that of the post-conjugated target.
- the principle of maximizing the cell internalization effect by sequentially introducing the unit drug complex into the cell is applicable to different types of drugs included in the drug complex.
- it is particularly advantageous for combination therapy in which various drugs must be administered together, and each drug used for treatment of major diseases and complications can be treated together to increase intracellular influx, so it can be applied to multi-purpose treatment.
- Example 4. Verification of target cell binding capacity, stability, and internalization efficacy of the unit drug complex
- the unit drug complex used in this experiment is a drug complex 5, in which the unit drug complex 5 labeled with iodine, a radioactive isotope, unit drug complex 6 not labeled with a radioactive isotope, and drug complexes 5 and 6 are combined.
- 6 is The stability experiments of the unit drug complex 5 and drug complex 5-6 were measured using Radio-TLC. Centrifugation from human blood at 3500 rpm for 5 minutes The obtained serum was used. The radioisotope-labeled compound unit drug complex 5 and drug complex 5-6 (3.7 MBq) were treated in 0.5 mL of serum.
- the unit drug complex used in this experiment is a unit drug complex 7 incorporating non-radioactive iodine and a drug complex 6-7 in which the unit drug complexes 6 and 7 are combined.
- the target cell binding capacity of the unit drug complex 7 and the drug complex 6-7 was performed using U-87MG cells (Korea Cell Line Bank), which are known to have high integrin avp3 expression.
- the cells were treated with 125 Ic(RGDyV) (0.037 MBq), known as a competitive inhibitor for the cells, and each of the unit drug complex 7 and drug complex 6-7 was treated at different concentrations (0 to 5 nM) and cultured for 1 hour.
- the tumor uptake remained at least 60% for 2 hours regardless of the administration amount of the unit drug complex 6.
- the smallest amount, 0.18 mg/kg of unit drug complex 6 was sequentially treated, more than 95% of the tumor intake was maintained up to 2 hours, and the tumor retention effect was most prominent.
- Example 4-4 Comparison of retention enhancement effect in tumor cells for 24 hours in tumor model mice
- the effect of enhancing retention in the tumor for a short time according to sequential treatment of the unit drug complex was confirmed, and this was observed for a longer period of time.
- the drug complex according to the present invention can act on tumor cells for a long time after internalization into tumor cells.
- the drug complex according to the present invention contains a targeting material that specifically binds to a target cell, enabling rapid targeting to the target cell.
- each Linking groups that can interact with the drug complex are additionally introduced, so when each drug complex is sequentially injected, the linkers combine with each other in the body, and cross-linking between the conjugates (different drug complexes bound to the target cell) Inducing the drug complex to form a kind of cluster.
- Clustering on the target cell surface of such a drug complex artificially enhances the effect of internalization of cells by endocytosis, so it is possible to exert maximized therapeutic and/or diagnostic effects even with a small amount of administration, and to avoid side effects caused by high-dose administration.
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CA3180590A CA3180590A1 (en) | 2020-06-01 | 2021-06-01 | Drug conjugate having enhanced drug delivery and internalization efficiency |
US17/928,879 US20230226201A1 (en) | 2020-06-01 | 2021-06-01 | Drug conjugate having enhanced drug delivery and internalization efficiency |
AU2021284541A AU2021284541A1 (en) | 2020-06-01 | 2021-06-01 | Drug conjugate having enhanced drug delivery and internalization efficiency |
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