WO2016108587A1 - 리피바디 유도체-약물 복합체, 그 제조방법 및 용도 - Google Patents
리피바디 유도체-약물 복합체, 그 제조방법 및 용도 Download PDFInfo
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- WO2016108587A1 WO2016108587A1 PCT/KR2015/014423 KR2015014423W WO2016108587A1 WO 2016108587 A1 WO2016108587 A1 WO 2016108587A1 KR 2015014423 W KR2015014423 W KR 2015014423W WO 2016108587 A1 WO2016108587 A1 WO 2016108587A1
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- HDZZVAMISRMYHH-LITAXDCLSA-N tubercidin Chemical compound C1=CC=2C(N)=NC=NC=2N1[C@@H]1O[C@@H](CO)[C@H](O)[C@H]1O HDZZVAMISRMYHH-LITAXDCLSA-N 0.000 description 1
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- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
Definitions
- the present invention is a lipid body derivative-drug complex (Repebody Derivative-Drug)
- Conjugates are specifically linked to the variable region of the LRR structure at the variable lymphocyte receptor (VLR) at the N-terminus of the leucine-rich repeat (LRR) family protein, which has an alpha-helical capping motif.
- VLR variable lymphocyte receptor
- LRR leucine-rich repeat
- RDCs Repebody Derivative-Drug Conjugates
- lipid-bodied or lipid-derived protein backbones that exhibit substrate specificity to substances with activities such as drugs, toxins, ligands, and detection markers
- ADCs antibody-drug conjugates
- MMAE monomethyl auristatin E
- Adcetris blockedered ve (iotin) was developed by Seattle Genetics Inc. in the United States and received FDA approval in 2011 for relapsed AML (Acute Myeloid Lymphoma).
- Herceptin a therapeutic antibody that targets human epidermal growth factor receptor2
- Antibodies used in antibody therapies and ADCs have the advantage of high specific binding ability to target proteins, long half-life and low toxicity. However, they are expensive to produce in mammalian cell lines and are generally 150 kDa. It is a large protein with a molecular weight of 4, which results in poor tissue permeability and 4 polypeptides (2 light chains and 2 heavy chains) are linked by disulfide bonds, resulting in poor thermodynamic stability compared to other simple proteins. .
- Adnectin was developed by Adnexus, which is based on the 10th domain of type 3, and signed a technology transfer agreement with BMS for $ 4.3 million in 2007.
- Anticalin which targets Affibody and Lipocalin, which is based on B domain of Protein A. Atrimers have been developed using the plasma protein Tetranectin.
- DARPins developed by Molecular Partners and transferred to Roche for $ 1 billion in 2013
- Fynomers using the Fyn protein SH3 domain Fynomers using the Fyn protein SH3 domain
- Nanobody only developed by Ablynx
- Nanobody-pharmaceutical polymers have been developed.
- lipid bodies While continuing research to develop the complex, if you use a lipid body instead of an antibody in a conventional antibody-drug complex to make a lipid body-drug complex, the advantages of lipid bodies, namely soluble forms in E. coli easy to mass production at low cost, and the thermobody's T m is very thermodynamically stable above 85 C.
- Lipbodies have a molecular weight of 25-30 kDa for diagnostic and therapeutic proteins.
- the drug body complex which maintains a very high level of tissue penetrating force during development, is specifically designed to kill target cells by specifically binding to the target protein.
- -Drug Conjugate (RDC) to complete the present invention.
- the present invention relates to a new lipid which directly binds a drug to a protein (hereinafter referred to as a lipid body derivative) containing a lipid body or a lipid body as a basic backbone without using an enzyme or a black enzyme.
- a lipid body derivative containing a lipid body or a lipid body as a basic backbone without using an enzyme or a black enzyme.
- the libodibody is a microorganism-derived N-terminus of a Leucine rich repeat (LRR) protein with an alpha spiral capping motif. Fused to modified repeats of the variable lymphocyte receptor (VLR) protein and the C-terminus of the VLR protein, such that the iribody is, for example, specifically expressed or overexpressed only in cancer cells.
- VLR variable lymphocyte receptor
- the N-terminus of interleukin protein a constituent of Lipibody, can be selected from the N-terminus with high structural similarity according to the type of LRR family protein that can be fused, and the most stable amino acid can be selected through calculation of binding energy. Modifications of the amino acids of the mothers are possible.
- the lipid body derivative constituting the lipid body derivative-drug complex is the lipid body monomer of the above-mentioned known substance or the lipid body monomer composed of two or more lipid body monomers (hereinafter referred to as lipid body monomer).
- lipid body monomer the lipid body monomer composed of two or more lipid body monomers
- it may be a protein such as Fc protein or
- Organic / inorganic compounds such as polyethylene glycol (PEG) are introduced, each of which may additionally have an amino acid motif that the enzyme can recognize if necessary.
- PEG polyethylene glycol
- the lipid body is used in the monomer state as a lipid body derivative if it is within the object of the present invention.
- the molecular weight is 25-30 kDa.
- the rate of clearance can be high, and the blood half-life can also be short. Therefore, if it is necessary to slow the rate of discharge in the kidney or to make the blood half-life longer, the lipid body in the form of a multimer forms the threshold of kidney discharge.
- Fc protein ⁇ 50 kDa
- Fc neonatal receptor binding sites can increase blood half-life through the mechanism of binding to FcRn of vascular endothelial cells and endocytosis and release into the blood.
- the binding ability to the target protein can be improved, and in the case of multimers consisting of heterolipobody monomers, it is possible to simultaneously bind to two or more target proteins to develop a more effective therapeutic agent.
- Lipibodi monomers can be increased in blood half-life by incorporating PEG into the multimer (PEGylation).
- lipid body derivatives in which the lipid body monomers, the monomers, or the Fc protein or PEG are introduced into each of them, various kinds of proteins, specific amino acid sequences, organic / inorganic compounds, etc. may be obtained by methods well known in the art. It is possible to introduce and the resulting lipid body derivatives can also be used without limitation as long as they do not depart from the object of the present invention.
- a preferred form of the lipid body derivative-drug complex according to the present invention is a form in which a drug is bound to the lipid body derivative using an enzyme, and the lipid body derivative used in the preparation of the lipid body derivative-drug complex using the enzyme The enzyme must have an amino acid motif that the enzyme recognizes.
- Lipbodi derivatives according to the present invention-the drug complex may be obtained by directly binding the lipid body derivative and the drug without a specific enzyme, or may be obtained by binding using a specific enzyme.
- the drug when a drug is directly bound to the lipid body derivative without using an enzyme, the drug is bound to the drug through cysteine, lysine, or glycan present in the lipid body derivative, or artificially cysteine, selenocysteine, or unnaturally
- Unnatural amino acids can be substituted or added to other amino acids in the lipid body derivatives to bind the drug.
- lipid body derivative of the direct drug binding method since lipid body generally has four cysteine at C-terminus, it usually has two intramolecular disulfide bonds. Or by treating with a reducing agent such as TCEP to generate free thi groups and reacting linker-drugs with maleimide groups
- the thiol-maleimide bond can be used to make the RDC.
- DRR is averaged because problems such as shortening or hepatotoxicity can occur. It is advisable to set the reaction conditions so that 3 to 4 corrections are made and adjust the maximum DRR to less than 6 points.
- Another example of the direct drug binding method described above is that the specific amino acid of Lipibody is replaced by cysteine black or selenocysteine, or by inserting a cysteine or selenocysteine that did not exist originally by inserting it at a specific position, and then reducing the appropriate condition. Expose the thiol group and combine the drug using maleimide.
- Another direct drug-binding method is the replacement of lipid amino acids with unnatural amino acids with specific functional groups in addition to the 20 amino acids present in nature, or by insertion into lipid sites at thiol.
- One way to do this is to create a specific functional group other than an amine group and bind the drug to it.
- One way to do this is by using a technique to produce proteins in vitro without the use of cells, i.e. specific codons.
- a non-natural amino acid can be introduced at the desired position by inserting a tRNA capable of introducing an unnatural amino acid. Meanwhile, a cell line using non-natural amino acids can be developed to translate site-specific labeling.
- the cell line contains amber codon-recognizable tRNAs and unnatural amino acids that translate into stop codons. Recognized, it is engineered to express aminoacyl-tRNA synthase linked to this amber codon tRNA, and the lipid bodies produced from this cell line carry unnatural amino acids at specific positions.
- This non-natural amino acid can have specific functional groups. For example, if the non-natural amino acid is para-acetyl phenylalanine, the drug can be bound through the formation of an oxime bond. Depending on the functional group, the drug can be linked via click-chemistry.
- an amino acid motif that can be recognized by the enzyme must exist in the lipid body derivative, in which the enzyme is not limited but sortase and FGE (Formylglycine Generating Enzyme). , Transglutaminase or isoprenoids
- It may be an transferase (isoprenoid transferase).
- the sortase is a Gram-positive bacteria-derived enzyme.
- This pectidoglycan is immobilized, and this specificity is used to introduce an amino acid motif called LPXTG, which recognizes a sortase at the C-terminus of the light chain and / or the heavy chain of an antibody, and then attaches a tag with 3-5 glycine as sortase. can do.
- LPXTG amino acid motif
- FGE recognizes the amino acid motif CXPXR and converts cysteine in the sequence into formyl-glycine having an aldehyde group. Therefore, FGE is overexpressed after introducing the CXPXR sequence in the desired region of the lipid body.
- RDC can be prepared by attaching a tag with amine group to the libodied body having an aldehyde functional group obtained in the culture process and then adding a drug here.
- TG transglutaminase
- the native glutamine present in the lipid body is not recognized by TG in the arrangement of the amino acid sequences before and after, and the amino acid that TG recognizes in several parts of the lipid body is newly recognized.
- the motif LLQG can be introduced to bind the drug.
- the amino acid motifs that can be recognized by this enzyme are, but are not limited to, CAAX, XXCC, XCXC or CCXX, which are located at the C-terminus of the Lipbodi derivatives.
- Is cysteine, A is an aliphatic amino acid independently
- X is an amino acid that determines the substrate specificity of the enzyme, and when using FTase as an isoprenoid transferase as in the specific example of the present invention, there are various types of amino acid motifs. It is also possible to use -CVIM introduced in the C-terminal as a form that satisfies the conditions of the CAAX motif.
- the amino acid motifs recognized by the isoprenoid transferases can be linked to the C-terminus of the Lipbodies through spacers for the purpose of preserving the original structure of the protein and maximizing the response of the enzyme.
- the spacer is generally composed of amino acids, but the type and length thereof are not particularly limited, and as in one embodiment of the present invention, seven glycine may be used and a flexible (G4S) n spacer, That is, when four glycines and one serine are repeatedly arranged, black is a rigid alpha-helix spacer, that is, (EAAAK) n (where E is glutamate, A is alanine, K is lysine, and n is general) In the case of integers of 1 or more or G4S, various variants of glycine and serine may be available.) In order to introduce more hydrophilic properties in consideration of physical properties, DRDD (where D is aspartate and R is arginine) A variety of spacers
- the amino acid motif is not limited, but is CAAX, XXCC, XCXC or CCXX, C is cysteine, A is independently aliphatic amino acid, and X is The amino acid that determines that the motif is a substratase of the enzyme,
- It can be connected to the C-terminus of the lipid body via a spacer.
- the spacer is not particularly limited in type and length, and may preferably be composed of one or more amino acids or compounds, and most preferably, seven glycines may be used as in one embodiment of the present invention.
- the amino acid motif may be bound to the drug through one or more linkers, although not limited thereto.
- the linker may be combined with FPP-carbonyl analog, an analog of farnesyl pyrophosphate (FPP).
- the linker is an alkylene having 1 to 50 carbon atoms, and may satisfy at least one of the following (i) to ().
- the alkylene comprises at least one unsaturated bond
- the alkylene comprises at least one heteroarylene
- the carbon atom of the alkylene is substituted with one or more heteroatoms selected from nitrogen (N), oxygen (O) and sulfur (S),
- the alkylene is substituted with alkyl of 1 to 20 carbon atoms.
- the linker (L) may include at least one or more isoprenyl derivative units of the following Chemical Formula A, which may be recognized by an isoprenoid transferase.
- the linker (L) is a 1,3-dipolar cycloaddition reactions, hetero-diels reactions, nucleophilic substitution
- the binding unit may be formed by reaction of acetylene and azide, or reaction of an aldehyde or ketone group with hydrazine or hydroxylamine.
- the binding unit may be represented by the following Formula B, C or D.
- R u is hydrogen or alkyl of 1 to 10 carbon atoms
- 1 ⁇ 2 is alkylene having 1 to 30 carbon atoms.
- the linker (L) is a coupling unit represented by the formula E or F
- W is -0-, -S-, -NR 21- , -C (0) NR 22 -,-NR 23 C (0)-,-NR 24 S0 2 -or S0 2 NR 25- ;
- V is -0-, dC 8 alkylene or -NR 2 ";
- R 21 to R 25 are each independently hydrogen, dC 6 alkyl, -alkyl C 6 -C 2 ⁇ ryl or C r C
- r is an integer from 1 to 10;
- q is an integer from 0 to 10;
- p is an integer from 1 to 10;
- X is an integer from 1 to 10.
- the drug is not limited, but may be a drug, a toxin, an affinity ligand, a detection probe, or a combination thereof.
- Exemplary drugs include, but are not limited to, Aerotinib (TARCEVA;
- Fulvestrant (FASLODEX; AstraZeneca), Sutent (SU11248; Pfizer),
- 5-fluorouracil (5-FU, leucovorin), rapamycin (Sirolimus, RAPAMUNE;
- alkylating agents such as thiotepa and CYTOXAN cyclophosphamide
- alkylsulfonates for example, busulfan, impulsulfane and pifosulfan
- aziridine eg
- ethyleneimine and methylamine including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolomelamine Melamine
- acetogenins particularly bulataxin and bulataxinone
- Camptothecin (derives synthetic analogues of topotecan); bryostatin; calistatin;
- CC-1065 (including its adozelesin, kazelesin and bizelesin synthetic analogs);
- Cryptophycin especially cryptotopine 1 and cryptotopine 8
- dolastatin especially cryptotopine 1 and cryptotopine 8
- Duokamycin synthetic analogs, including KW-2189 and CB1-TM1
- eleuterobin synthetic analogs, including KW-2189 and CB1-TM1
- 5-fluorouracil 5-fluorouracil
- folic acid analogues for example denophtherine, methotrexate, pterotroperine, trimetrexate
- purine analogs for example fludarabine, 6-mercaptopurine , Thiamiprine and tiguanine
- pyrimidine analogues such as acitabine, azacytidine, 6-azauridine, chamopur, cytarabine, dideoxyuridine, doxyfluridine, enositabine and Phloxuridines
- androgens for example, calusosterone, dromostanolone propionate, epithiostanol, mephithiostane and testosterone
- anti-adrenal for example, aminoglutetimide, mitotan And trirostane
- folic acid supplements such as folic acid; aceglatone;
- Aldophosphamideglycoside aminolevulinic acid
- enyluracil aminolevulinic acid
- amsacrine aminolevulinic acid
- Bestrabucil Bisantrene; Edatraxate; Depopamine; Demecolsin; Diazicuone; Elponnitine; elliptinium acetate; epothilones; etogluside; gallium nitrate; Hydroxyurea; lentinan; ronidain; maitansinoids, for example, maitansine and ansamiin; mitoguazone; mitoxantrone; morphidanmol; nitraerin; pentostatin; Phenammet; pyrarubicin; loxazatron; 2-ethylhydrazide; procarbazine; PSK polysaccharide complexes (JHS Natural Products, Eugene, Oreg.); Lazoic acid; Lioxin; Shizopyran; Spirogermanium; Tenuazone acid; Trijikuon; 2,2 ', 2 "-trichlorotriethylamine; tricothecene (especially T-2 toxin,
- Formulations (American Pharmaceutical Partners, Schaumber, II 1.) and TAXOTERE docetaxel (Rhone-Poulenc Rorer, Antony, France); chloranbusil; gemcitabine;
- 6-thioguanine 6-thioguanine; mercaptopurine; platinum analogs such as cisplatin, carboplatin; Vinblastine; platinum; etoposide, phosphamide; miroxanthrone; vincristine;
- Additional drugs are not limited to this stone, but (i)
- Tamoxifen (including NOLVADEX [0117] tamoxifen), raloxifene, droxyfen,
- Hormone action on tumors such as anti-estrogen and selective estrogen receptor modulators (SERM), including 4-hydroxytamoxifen, trioxyphene, keoxyphene, LY117018, onapristone and FAREATON toremifene Anti-hormonal agent; (ii) aromatase, which regulates the production of estrogens in the adrenal glands Aromatase inhibitors that inhibit enzymes, for example 4 (5) -imidazole,
- cytokines may be used as pharmaceuticals.
- Proinsulin leracin; proleracin; glycoprotein hormones, such as vesicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), and luteinizing hormone (LH); liver growth factor fibroblast growth factor; prolactin; Placental lactogen; tumor necrosis factor - ⁇ and - ⁇ ;
- FSH vesicle stimulating hormone
- TSH thyroid stimulating hormone
- LH luteinizing hormone
- liver growth factor fibroblast growth factor prolactin
- Placental lactogen tumor necrosis factor - ⁇ and - ⁇ ;
- micegonadotropin-binding peptide inhibin; actibin; vascular endothelial growth factor; integrin; thrombopoierine (TPO); nerve growth factor, eg, NGF- ⁇ ; Platelet-growth factor; transforming growth factor (TGF), eg, TGF- ⁇ and TGF- ⁇ ; insulin-like growth factor-I and - ⁇ ; erythropoietin (EPO); osteoinductive factor; interferon, e.g. For example, interferon - ⁇ , - ⁇ and ⁇ ⁇ ; colony stimulating factor (CSF), e.g.
- CSF colony stimulating factor
- M-CSF Cells -CSF
- GM-CSF granulocytes-macrophages -CSF
- G-CSF granulocytes -CSF
- Interleukin (IL) eg, IL-1, IL-la, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9,
- cytokines also include recombinant cell cultures and biologically active equivalents of natural sequences or from base sequence cytokines.
- toxin refers to a toxic substance produced in living cells or organisms.
- Toxins may be small molecules, peptides or proteins that can cause disease upon contact with or by absorption of biological macromolecules, for example, body tissues that interact with enzymes or cell receptors.
- Toxins are plant toxins and animal toxins.
- animal toxins include, but are not limited to, diphtheria antitoxins, borium toxins, tetanus antitoxins, heterotoxins, cholera toxins, tetradodocin, brevetoxins, and guaroxine. , Including, but not limited to, lysine and AM-toxin.
- small molecule toxins include, but are not limited to, auristatin,
- Toxins include tubulin bonds, DNA bonds, Topoisomerase inhibitors may indicate cytotoxic and cell growth inhibitory activity.
- ligand refers to a molecule capable of forming a complex with a target biomolecule.
- a ligand is a molecule that binds to a predetermined position of a target protein and transmits a signal. It may be a substrate, inhibitor, stimulant, neurotransmitter or radioisotope.
- Detectable residues refer to compositions that can be detected by spectroscopy, photochemistry, biochemistry, immunochemistry, radioactivity or chemical means.
- useful labels are 32 P, 35 S, fluorescent dyes, Electron-dense reagents, enzymes (such as those commonly used in ELISA), biotin-streptavidin, dioxygenin, hapten and proteins available for antiserum or lipido, or nucleic acid molecules complementary to the target Detectable residues often detect measurable signals, such as radioactive, chromogenic or fluorescent signals, which can be used to quantify the amount of detectable residue bound in the sample.
- Quantification of the signal is achieved, for example, by scintillation counting, densitometry, flow cytometry, ELISA, or direct analysis by mass spectrometry of circular or subsequently digested peptides (one or more peptides may be tested).
- the skilled person is familiar with the techniques and means of detection for the labeled compounds of interest. These techniques and methods are common and are well known in the art.
- probe refers to a first term, such as fluorescence resonance energy transfer (FRET) by (i) providing a detectable signal or (ii) by mutually reacting a first or second probe. Or alter the detectable signal provided by the second probe, or (iii) stabilize the interaction with the antigen or ligand, or improve binding affinity.
- FRET fluorescence resonance energy transfer
- the target protein is a protein that is specific or overexpressed in cancer cells, and is a major indication of non-Hodgkin lymphoma.
- leukemia as the main sympathetic CD33 and CD43
- acute-lymphoid leukemia as the main sympathetic CD43
- multiple myeloma as the main sympathetic CD56, CD74, CD138 And endothelin B receptor
- head and neck cancer for EGFR
- pulmonary cancer for EGFR
- CD56, CD326, CRIPTO, FAP mesothelin, G2D, 5T4, and alpha v beta6.
- Predominantly glioblastoma EGFR, CD74, CD174, CD227 (MUC-1), CD326 (Epcam), CRIPTO, FAP, and ED-B, pancreatic cancer are the main indications for EGFR, EGFRvIII, and colorectal cancer.
- the main indications for prostate cancer are PSMA, STEAP-1, and TENB2, and kidney cancer for all major cases, CAIX, and TIM-1, mesothelioma.
- anti-EGFR lipid body derivative-antibody using a lipid body that binds to EGFR (endothelial growth factor receptor) was prepared and confirmed its efficacy. .
- the present invention provides a method for preparing a protein comprising: (a) preparing a protein to which an amino acid motif is linked to one or more C-terminus of a lipid body derivative; (b) reacting the protein prepared in step (a) with one or more substrates containing a first functional group to produce a functionalized protein; and (c) in step (b)
- the present invention relates to a method for producing a protein-drug complex, which comprises the step of producing a lipid body derivative-a drug complex by reacting a conjugated conjugate of the functionalized protein and the second functional group to the drug.
- the second functional group may be bound to the drug by one or more linkers, although not limited thereto.
- the reaction between the functionalized protein and the drug may be a reaction between acetylene and azide, or an aldehyde or ketone group and hydrazine or
- sequence variants of each of the bound forms are either a portion of the carboxy terminus removed, a new amino acid sequence added to the carboxy terminus, or a new amino acid sequence added after a portion of the carboxy terminus is removed.
- Amino acid sequences recognized by transferases can be combined.
- the C-terminal CAAX sequence which is a sequence recognized by the isoprenoid transferase (C is cysteinol, A is an aliphatic amino acid independently, and X is an amino acid which determines that the motif is a substratase of the enzyme).
- C cysteinol
- A is an aliphatic amino acid independently
- X is an amino acid which determines that the motif is a substratase of the enzyme.
- the present invention provides a method for preparing a protein comprising: (a) preparing a protein having an amino acid motif bound to at least one C-terminus of a lipid body derivative; (b) binding one or more drugs to the substrate of the enzyme to produce a conjugate; (c) a step of preparing a lipid body derivative-a drug complex by reacting the protein prepared in step (a) and the binder obtained in step (b) ; and a method for producing a protein-drug complex, comprising: will be.
- the present invention also relates to the diagnosis, prevention and prevention of diseases using lipido derivatives-drug complexes.
- the above-mentioned diseases may include, but are not limited to, all known diseases, for example, digestive diseases, respiratory diseases, cardiovascular diseases, kidney diseases, endocrine diseases, immune diseases, Blood diseases, hereditary diseases, congenital metabolic disorders, sexually transmitted diseases, cancer, psychiatric disorders, addictions or diseases related to surgical diseases, etc.
- brain cancer leukemia, stomach cancer, colon cancer, colorectal cancer, liver cancer, lung cancer, Infectious diseases such as cold, pneumonia, tuberculosis, AIDS, black death, prion disease, including esophageal cancer, prostate cancer, breast cancer, skin cancer, uterine cancer, ⁇ hepatitis, arteriosclerosis, hernia, natural head, anemia, polio And other diseases such as allergy, asthma, diabetes, arteriosclerosis, kidney disease, stroke, Alzheimer's disease and obesity.
- Infectious diseases such as cold, pneumonia, tuberculosis, AIDS, black death, prion disease, including esophageal cancer, prostate cancer, breast cancer, skin cancer, uterine cancer, ⁇ hepatitis, arteriosclerosis, hernia, natural head, anemia, polio And other diseases such as allergy, asthma, diabetes, arteriosclerosis, kidney disease, stroke, Alzheimer's disease and obesity.
- the dosage form of the pharmaceutical composition may be, but is not limited to, an oral dosage form selected from the group consisting of powders, granules, tablets, capsules, suspensions, emulsions, and syrups.
- the amount of lipid body derivative-drug complex among the above compositions is not limited.
- the composition may be added to 0.01 to 95% by weight of the total composition.
- the composition is not limited but may be oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, and sterilized injections. It may also be used in the form of a solution.
- the composition may further include, but is not limited to, carriers, excipients and diluents, preferably lactose, dextrose,
- Stearates and mineral oils can be used.
- composition When the composition is prepared, it is usually prepared by using a diluent or excipient such as a layering agent, an extender, a binder, a humectant, a disintegrant, and an interfacial drug.
- a diluent or excipient such as a layering agent, an extender, a binder, a humectant, a disintegrant, and an interfacial drug.
- Solid preparations for oral administration may include tablets, pills, powders, granules, capsules, and the like, and at least one excipient such as starch, calcium carbonate, etc. in the above composition.
- excipients such as starch, calcium carbonate, etc.
- lubricants such as magnesium stearate and talc can also be used.
- Liquid oral agents for oral use include suspensions, solvents, emulsions, syrups, etc.
- Other excipients for example, wetting agents, liquid paraffin, and other excipients, such as wetting agents, sweeteners, fragrances, preservatives, etc., which are commonly used in the preparation of simple diluents, may be used for parenteral administration. Lyophilized preparations and suppositories are included.
- Non-aqueous solvents and suspending agents include vegetable oils such as propylene glycol, polyethylene glycol and olive oil. Injectable esters such as acrylate may be used. Examples of suppositories may include witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, and the like. Toxicities and side effects are rare, so they can be used with confidence even for long-term use for preventive or therapeutic purposes.
- composition is an essential component of the indicated ratio and contains the composition.
- Other ingredients are not restricted and may contain various flavors or natural carbohydrates as additional ingredients.
- natural carbohydrates described above include monosaccharides such as glucose and fructose; disaccharides such as horses Toss, sucrose, and the like; and conventional sugars such as polysaccharides, e.g., dextrins, cyclotextins, and sugar alcohols such as xylol, sorbitan, and erythritol. Martin), stevia extracts (e.g. Rebaudioside A, glycyrzin, etc.) and synthetic flavoring agents (saccharin, aspartame) can be used advantageously.
- the ratio of natural carbohydrates is lipibody derivative of the present invention.
- the composition of the present invention is composed of various nutrients, vitamins, minerals (electrolytes), synthetic flavors and Flavors such as natural flavors, coloring and neutralizing agents (cheese, chocolate), pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloid thickeners, pH regulators, stabilizers, preservatives, glycerin, alcohols, carbonic acid Carbonate used in beverages may be contained.
- the proportion of such additives is not limited but is preferably selected in the range of 0 to about 20 parts by weight per 100 parts by weight of the composition of the present invention.
- composition using the lipid body derivative-drug complex is
- Substances on biochips prepared to directly administer the composition to a subject for information on disease diagnosis, or to detect genes, proteins, cells, etc., known as disease-specific targets. To diagnose diseases with high accuracy and reliability by attaching them to and detecting the genes, proteins, or cells at the same time.
- the present invention also relates to polynucleotides encoding the above lipid body derivatives.
- the present invention also relates to a recombinant vector comprising said polynucleotide.
- the type of the vector may be selected and used without being limited in the range normally used.
- the present invention also relates to microorganisms transformed with the above recombinant vector.
- the microorganism for transformation is not particularly limited, but may be optionally selected and used microorganisms capable of overexpression of the recombinant vector, preferably genetically engineered and widely known E. coli (E « ⁇ en ' c /» i coli) can be used.
- the lipid body derivative-drug complex (RDC) according to the present invention is a combination of high substrate specificity and excellent tissue and tumor penetrating ability provided by the lipid body, and biologically active drug, when used as a lipid body alone. Compared with conventional antibodies, it has the advantage of minimizing toxicity by having a superior effect compared to that used as a compound alone and having specific selectivity for target cells.
- Existing antibody which is expressed in soluble form can be mass produced easily at low cost, is very thermodynamically stable, has very good tissue penetrability, and kills target cells by specific binding to the target protein.
- the advantages of drug complexes provide new types of drug complexes that have survived.
- Figure 1 is MCF7 (EGFR low expression breast cancer cell line), A431 (EGFR overexpressing epidermal cancer
- HCC827 EGFR and expressing lung cancer cell line
- FIG. 2 is a conceptual diagram of the structure of a lipid body derivative-drug complex
- FIG. 3 shows the results of HIC-HPLC peak identification of the intermediate step (B), which is activated by Farnesyl analog from the lipid body derivative (A), and the step of processing the body body derivative-drug complex (C).
- Figure 4 is prepared using the anti-EGFR lipid body derivative Erep-Vl
- FIG. 5 shows the anti-EGFR lipid body derivative Erep-Vl and the lipid body derivatives Erep-V2 and Erep-V3 which have improved binding ability to EGFR based on the parent compound ERDC-Vl.
- the results of in vitro cytotoxicity on A431 of ERDC-V2 and ERDC-V3 were measured.
- the drug was administered six times daily.
- Figure 10 is Lipibodi derivative-drug complex ERDC-Vl, ERDC-V2, ERDC-V3 and
- Lipbodies having a polypeptide sequence of SEQ ID NO: 1 (KR2014-0062391, hereinafter)
- RP-E1V1 overexpressed OrigamiB (DE3) (Novagen, USA) with 0.5 mM IPTG as host cells and purified the protein via affinity and gel permeation chromatography.
- MCF7 EGFR low expression breast cancer cell line
- A431 EGFR overexpression epidermal cancer cell line
- HCC827 EGFR over expression lung cancer cell line
- RP-E1V1 was labeled and treated with each cancer cell at a concentration of 1 g / mL for about 3 hours, confocal microscopy was used to observe fluorescence bound to the cells.
- Cysteine-valine-isoleucine-methionine are connected in turn to induce the derivative of Lipibody of SEQ ID NO: 2 (hereinafter referred to as Erep-Vl).
- IPTG As inoculated with ampicillin-LB medium, incubated at 37 ° C, IPTG to reach a final concentration of 0.5 mM when OD 600 reaches 0.5
- Erep-Vl was used as a parent to bind EGFR.
- the target compound A was prepared according to the method described in US Patent Publication No. US2012-0308584 A1.
- Prenylation of lipidi was carried out using Faraesyl analog (Compound A) and FTase (# 3 4 41 4 5, Calbiochem, USA). Prenylation reaction was performed with 5 mM MgCl 2 , 10 M ZnCl 2 and 5. 50 mM Tris-HC1 (pH 7.4) buffer solution containing mM DTT was performed at 30 ° C for 12 hours. After completion of the reaction, desalting was performed using a PD-10 desalting column (GE Lifescience). Concentrated with Vivaspin 2 and replaced the buffer with PBS. The protein was then quantified by Nanodrop and BCA methods.
- Lipibody was prepared using Compound A and FTase according to the method described above.
- Prenylated The material prepared as above was named prenylated lipidbody derivative.
- Prenylated Lipbodi derivatives obtained by prenylating Erep-Vl, Erep-V2, Erep-V3, and Erep-NV with Compound A are Compound B for Erep-Vl, Compound C for Erep-V2, and Erep-V3, respectively.
- Erep-NV is called compound E.
- the structure of these compounds is as follows.
- Triphenylphosphine (16.9 g, 64.6 mmol) and compound lb (10.3 g, 58.7 mmol) dissolved in dichloromethane (100 mL) were added and the mixture was added. The phases were stirred at for 13 hours. After completion of the reaction, dichloromethane (300 mL) and distilled water (300 mL) were added, followed by extraction. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
- Compound 10 was dissolved in DMSO to prepare a 10 mM solution and mixed at a ratio of 1:15 for oxime binding of the prenylated lipidi derivatives and toxin. After completion of the reaction, desalination was performed using PD-10 column, concentrated with Vivaspin 2, and protein quantification was performed using Nanodrop and BCA methods.
- a commercially available A431 cells (EGFR overexpressing squamous cell carcinoma cell line), MCF-7 cells (EGFR low expression breast cancer cell line), and HCC-827 cells (EGFR overexpressing non-small cell lung cancer cell line) were used together with cell lines with commercially available cell lines. Cultures were in accordance with the recommended specification provided.
- ERDC Anti-EGFR Lipbody Body-Drug Conjugates
- Anti-EGFR Lipbody Anti-EGFR Lipbody
- MMAF used to prepare ERDC were used.
- In vitro activity of ERDC was measured using the cell line described above (anti-EGFR lipidobody and lysine MMAF used in the preparation of ERDC were used as a control).
- A431 and MCF7 cells were plated on 96-well culture plates with 4 lxlOs per well and HCC827 cells 5xl0 3 . After 24 hours of incubation, Lipbodies, drugs and conjugates were added at various concentrations. The number of viable cells after 72 hours was counted using SRB dye. Absorbance was measured at 540 nm using SpectraMax 190 (Molecular Devices, USA).
- Erep-V2 and Erep-V3 lipid body derivatives were prepared using Erep-Vl as a parent, and the anti-EGFR lipid body derivative-drug complex ERDC-V1, ERDC-V2 and ERDC-V3 were made and their efficacy was compared by in vitro cytotoxicity test. It was confirmed that ERDC-V3 showed the best cell death effect in A431 cells (FIG. 5).
- the superior cytotoxicity of ERDC-V3 is another cell line that overexpresses EGFR.
- HCC-827 cell line 5 ⁇ 10 6/200 fiL was administered per Balb / C nude mouse and 6 mice with a tumor size of 130 mm 3 were divided into groups of PBS, Cetuximab (10 mg / day). kg), Erep-V3 (10 mg / kg), ERDC-V3 (1 mg / kg), ERDC-V3 (10 mg kg) once daily for 6 days and once every 3 days for 20 days of tumor size ((length X width) 2/2), the body weight was observed in the population.
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Abstract
본 발명은 리피바디(repebody) 유도체를 이용한 약물 복합체 및 그 제조방법에 관한 것으로, 상세하게는 알파 나선형 캡핑 모티프(capping motif)를 가지는 LRR(leucine-rich repeat) 패밀리 단백질의 N-말단에 VLR(variable lymphocyte receptor)에서 기인한 LRR 구조가 가변부위로 연결되어 기질특이성을 나타내는 리피바디에 약물, 독소, 리간드 및 탐지 표지와 같은 활성을 갖는 물질이 접합된 리피바디 유도체 -약물 복합체(Repebody derivative Drug Conjugate, RDC)와 이를 제조하는 방법에 관한 것이다. 본 발명에 따른 RDC는 리피바디가 제공하는 높은 기질특이성과 우수한 조직 및 종양 침투력과, 생물학적 활성을 지닌 화합물이 결합한 것으로써, 리피바디 단독으로 사용하는 경우에 비해 월등한 효능을 지니고, 화합물 단독으로 사용하는 경우에 비해 특이적 선택성을 지니는 장점을 가지고 있으며, 이를 활용하여 암세포에 과발현되는 단백질에 특이적으로 결합하는 리피바디에, 세포를 사멸시키는 독소를 결합시켜 암세포만을 선택적으로 사멸시킴으로써 종양 치료에 활용될 수 있을 것으로 기대된다.
Description
명세서
발명의명칭:리피바디유도체 -약물복합체,그제조방법및용도 기술분야
[1] 본발명은리피바디유도체 -약물복합체 (Repebody Derivative-Drug
Conjugates)에관한것으로ᅳ상세하게는알파나선형캡핑모티프 (capping motif)를가지는 LRR(leucine-rich repeat)패밀리단백질의 N-말단에 VLR(variable lymphocyte receptor)에서기인한 LRR구조가가변부위로연결되어
기질특이성을나타내는리피바디또는리피바디를기본골격으로갖는단백질 유도체에약물,독소,리간드및탐지표지와같은활성을갖는물질이접합된 리피바디유도체 -약물복합체 (Repebody Derivative-Drug Conjugates, RDC),그 제조방법및용도에관한것이다.
배경기술
[2] 1975년 Kohler및 Milstein에의해하이브리도마세포 (hybridoma cell)로부터 단일클론항체를만들어내는기술이개발된이후,이를치료용항체로개발하기 위한노력이지속되어왔다.
[3]
[4] 그러나항체자체로는암세포를사멸시키는효능이크지않아항체에독소를 결합시킨항체 -약물복합체 (antibody-drug conjugates, ADC)가연구되어온바, CD30을표적으로하는항체에 MMAE (monomethyl auristatin E)를결합시킨 Adcetris(brentuximab ve(iotin)가미국의 Seattle Genetics사에의해개발되어 재발성급성골수성백혈병 (relapsed AML, Acute Myeloid Lymphoma)을 적웅증으로 2011년 FDA의승인을받았고, 2013년엔 HER2 (Human Epidermal growth factor Receptor2)를표적으로하는치료용항체인 Herceptin에
maytansinoid계열의독소인 DM1을결합시킨 Kadcyla(ado-trastuzumab emtansine)가스위스의 Roche사에의해개발되어허셉틴 (herceptin)에내성을 보이는 HER2-양성전이성유방암환자를대상으로 FDA의승인을취득하였다.
[5]
[6] 한편항체치료제나 ADC에이용되는항체는표적단백질에대해특이적으로 높은결합능을보이며혈중반감기가길고독성이적다는장점이있으나, 포유동물세포주에서생산해야하므로생산비가비싸고,일반적으로 150 kDa의 분자량을지닌큰단백질이기에조직투과능이떨어지며, 4개의폴리펩타이드 (경쇄 2개,중쇄 2개)가이황화결합 (disulfide bond)으로연결되어있어다른 간단한단백질들에비해열역학적안정성이떨어진다는단점도있다.
[7]
[8] 이러한단점들을극복하고자최근항체를대체하여,특정표적단백질에
특이적으로결합할수있고,대장균등미생물에서저렴한비용으로간편하게
생산가능하며,열역학적으로매우안정한새로운단백질골격에대한연구가 활발히수행되어온바,수십여개의신규형태단백질구조들이등장하였다 (Urlich et al., Cancer Genomics Proteomics, 2013).대표적인예들로파이브로넥틴 타입 3의열번째도메인을기본골격으로하는 Adnectin이 Adnexus사에의해 개발되어 2007년 430만불규모로 BMS와기술이전계약을맺었고, Protein A의 B도메인을기본골격으로하는 Affibody, Lipocalin을골격으로하는 Anticalin, 혈장단백질인 Tetranectin을웅용한 Atrimers등이개발되었고,다양한
막수용체의 A-도메인을이용한 Avimers는 Avidia사에의해개발되어 2006년 Amgen사에 380만불규모로기술이전되었다.
[9]
[10] 또한 FN3 domain을이용한 Centrin, Ankyrin repeat motif를근간으로한
DARPins (Molecular Partner사에의해개발되어 2013년 10억불규모로 Roche에 기술이전됨), Fyn단백질의 SH3도메인을이용한 Fynomers,낙타항체의가변 부위만을따온 Nanobody (Ablynx사가개발하여 Spircgen사와함께
Nanobody-약물중합체를개발하기로함)등도활발히연구되고있다.
발명의상세한설명
기술적과제
[11] 상기와같은연구흐름에따라본발명자들도보다효과적인단백질 -약물
복합체를개발하기위하여연구를계속하던중,종래의항체 -약물형태의 복합체에서항체대신리피바디를이용하여리피바디 -약물형태의복합체를 만들경우,리피바디의장점들,즉대장균에서수용성형태 (soluble form)로 발현되어저렴한비용으로쉽게대량생산이가능한점과,리피바디의 Tm이 85 C이상으로열역학적으로매우안정되어있다는점,리피바디는그분자량이 25-30 kDa로진단및치료용단백질로개발시조직침투력이매우우수한점 둥을유지하면서도,표적단백질에특이적으로결합함으로써표적세포를 사멸시키는약물복합체로서치료효능을충분히발휘할수있는새로운형태의 약물복합체인리피바디유도체 -약물복합체 (Repebody derivative-Drug Conjugate, RDC)를창안하기에이르러본발명을완성하였다.
과제해결수단
[12] 본발명은리피바디또는리피바디를기본골격으로포함하는단백질 (이하, 리피바디유도체라한다)에약물을효소등을이용하여결합시키거나흑은 효소를이용하지않고직접결합시킨새로운리피바디유도체 -약물복합체를 제공한다.
[13]
[14] 리피바디란,인터날린단백질의 N-말단및 LRR(Leucine rich repeat)패밀리
단백질이융합된수용성융합폴리펩타이드및이를기본구조로하여
부분적으로변형된폴리펩타이드를의미하는데,한국 KAIST의김학성교수팀에
의해최초로개발되어리피바디 (Repebody)로명명된것 (대한민국공개특허공보 10-2011-0099600 A1,대한민국등록특허공보 1356075,국제공개특허공보 WO2013-129852 A1및리피바디관련논문 Proc Natl Acad Sci U S A. 2012 Feb 28;109(9):3299-304참조)이다.보다구체적으로는,상기리피바디는미생물 유래이고알파나선형캡핑모티프 (capping motif)를가지는 LRR(Leucine rich repeat)패밀리단백질의 N-말단, VLR(variable lymphocyte receptor)단백질의 변형된반복모들및 VLR단백질의 C-말단이융합된것으로서,이리피바디는, 예컨대,암세포에서만특이적으로발현되거나과다하게발현되는
수용체 (receptor)와같은특정의표적단백질에특이적으로결합하는특성이 있으며,반복모들을갖는 LRR패밀리에속하는모든단백질및이의생물학적 성질을향상시킨모든융합 LRR패밀리단백질올포함할수있다.또한상기 리피바디의구성성분인인터날린단백질의 N-말단은융합될수있는 LRR 패밀리단백질의종류에따라높은구조유사도를갖는 N-말단이선택될수 있고,결합에너지등의계산을통해가장안정적인아미노산을선택하여해당 모들의아미노산의변이가가능하다.
[15]
[16] 본발명에서리피바디유도체 -약물복합체를구성하는리피바디유도체는, 전술한공지의리피바디단량체이거나 , 2이상의리피바디단량체로이루어진 리피바디다량체 (이하,리피바디다량체라한다)일수있고,또한,이들리피바디 단량체나리피바디다량체에 Fc단백질과같은단백질또는
폴리에틸렌글리콜 (PEG)과같은유기 /무기화합물이도입된것으로서,이들 각각은필요한경우에효소가인식할수있는아미노산모티프를추가적으로 지닐수있다.
[17]
[18] 즉,본발명의목적범위내에서라면리피바디유도체로서리피바디를단량체 상태로사용하더라도문제되지않는다.다만,리피바디단량체의경우,분자량이 25-30 kDa로서,신장에서배출 (renal clearance)되는속도가빠를수있고,또한 혈중반감기도짧을수있다.따라서신장에서의배출속도를늦추거나혈중 반감기를보다길게만들필요가있는경우에는,리피바디를다량체형태로 만들어신장배출의임계치 (threshold)인 ~60 kDa이상의분자량을갖게하거나, 리피바디단량체또는리피바디다량체에 Fc단백질 (~50 kDa)올연결시킴으로 분자량을크게하여신장배출속도를느리게하는동시에, Fc단백질내에 존재하는 FcRn (Fc neonatal receptor)결합부위가혈관내피세포의 FcRn에 결합하여 endocytosis되고다시혈중으로방출되는기전을통해혈중반감기를 늘릴수있으며,특히,동종의리피바디단량체로구성된다량체의경우표적 단백질에대한결합능을향상시킬수있고,이종리피바디단량체로구성된 다량체의경우두개이상의표적단백질에동시에결합하여보다효과적인 치료제로서의개발이가능할수있다.또한, PEGylation의경우예전부터크기가
작아혈중반감기가짧은단백질에결합시킴으로서분자량을크게하여 반감기를늘리는시도돌이수행되어성공적인케이스들이많이보고된 바 (대표적인예: interferon alpha 2a에 PEG를연결시킨 C-형간염치료제 Pegasys),같은방법으로리피바디단량체흑은다량체에 PEG를도입하여 (PEGylation)혈중반감기를늘릴수있다.
리피바디단량체나다량체,또는이들각각에 Fc단백질이나 PEG가도입된 전술한리피바디유도체외에도,본발명의분야에서잘알려져있는방법에 의하여다양한종류의단백질이나특정의아미노산서열및유기 /무기화합물 등을도입하는것이가능하고,그결과얻어진리피바디유도체들도본발명의 목적을벗어나지않는범위내에서라면제한없이사용될수있다.
또한,본발명에따른리피바디유도체-약물복합체의바람직한형태증하나는 효소를이용하여리피바디유도체에약물을결합시킨형태인데,효소를이용한 리피바디유도체 -약물복합체의제조에이용되는리피바디유도체는해당 효소가인식할수있는아미노산모티프를갖도록하여야한다. 본발명에따른리피바디유도체 -약물복합체는리피바디유도체와약물을 특정의효소없이직접결합시켜얻어진것일수도있고,특정의효소를 이용하여결합시킴으로써얻어진것일수있다. 본발명에서리피바디유도체에약물을효소를사용하지않고직접결합시키는 경우는리피바디유도체에존재하는 cysteine, lysine,혹은 glycan올통해약물을 결합시키거나,인위적으로 cysteine이나 selenocysteine,혹은비자연적인
(unnatural)아미노산을해당리피바디유도체내다른아미노산과치환하거나 추가하여약물을결합시킬수도있다.
상기한직접적인약물결합방법중리피바디유도체내존재하는 cysteine에 직접약물을결합시키고자할경우,리피바디는일반적으로 C-말단부위에 4개의 cysteine이존재하여평소엔두개의 intramolecular disulfide bond를이루고 있기에, DTT나 TCEP과같은 reducing agent로처리하여 free thi이기를생성해 내고여기에 maleimide group을가지고있는 linker-drug을반응시켜
thiol-maleimide결합올통해 RDC를만들수있다.
또한상기한직접적인약물결합방법중리피바디유도체내존재하는 lysine에 직접약물을결합시키고자할경우,리피바디는통상 18-19개의 lysine이 존재하며,이중반정도가 solvent-accessible하다고가정할때 (참고로항체의 경우통상 80-90개의 lysine이존재하며이중절반정도가 solvent-accessible 하다고알려져있음),대략 10개의 lysine에 amide bond형성을통해약물을 결합시킬수있는데,한개의리피바디에대하여결합되는약물의개수 (DRR (Drug-Repebody Ratio))가통상 6개이상으로높으면 RDC의반감기가
짧아지거나간독성을유발하는등의문제가발생할수있으므로 DRR은평균
3~4개정 가되도록반웅조건을수립하고,최대 DRR이 6개미만이되도록 조절하는것이좋다.
[27] 상기한직접적인약물결합방법의또다른예는리피바디의특정아미노산을 cysteine흑은 selenocysteine으로치환하거나,특정위치에삽입함으로원래 존재하지않던 cysteine혹은 selenocysteine을도입한후,적당한조건으로 환원시켜 thiol기를노출시키고여기에 maleimide등을이용하여약물을 결합시키는방법이다.
[28] 또다른직접적인약물결합방법으로,리피바디의특정아미노산을자연계에 존재하는 20여개의아미노산외에특별한작용기를가진비자연적아미노산 (unnatural amino acid)으로치환하거나,리피바디특정위치에삽입하여 thiol 이나 amine기외의특정작용기를만들어내고여기에약물을결합시키는 방법을들수있다.이를위한한방법으로세포를이용하지않고시험관에서 단백질을생산하는기술을들수있다.즉,특정코돈 (codon)을단백질로번역시, 비자연적아미노산을도입할수있는 tRNA를넣어줌으로써원하는위치에 원하는작용기를가진비자연적아미노산의도입이가능하다.한편비자연적 아미노산을사용하고번역할수있는세포주를개발하여 site-specific labeling을 수행할수도있다.이기술에서해당세포주는 stop codon으로번역되는 amber codon올인식할수있는 tRNA와비자연적아미노산을인식하여 ,이 amber codon tRNA에연결되는 aminoacyl-tRNA synthase를발현시킬수있도록조작하여,이 세포주로부터생산되는리피바디는특정위치에비자연적아미노산올지니게 된다.이비자연적아미노산은특정작용기를지닐수있기에이를통해약물을 결합시킬수있는데,일례로비자연적아미노산이 para-acetyl phenylalanine일 경우, oxime bond형성을통해약물올결합시킬수있다.또한작용기에따라 click-chemistry를통한약물결합도물론가능하다.
[29]
[30] 한편,효소를이용하여약물을결합시키는경우,리피바디유도체에효소에 의하여인식될수있는아미노산모티프가존재해야하는데,이때효소는 제한되지는않으나소르타제 (sortase), FGE (Formylglycine Generating Enzyme), 트랜스글루타미나제 (transglutaminase)또는이소프레노이드
트랜스퍼라제 (isoprenoid transferase)일수있다.
[31]
[32] 상기효소들중 sortase는그람 -양성박테리아유래의효소로단백질올
peptidoglycan에고정시키는역할을하는데,이러한특이성을이용하여항체의 경쇄또는 /및중쇄의 C-말단에 sortase가인식할수있는 LPXTG라는아미노산 모티프를도입한후, 3-5개의 glycine을가진 tag을 sortase로부착할수있다.
[33] 상기효소들중 FGE는아미노산모티프 CXPXR올인식하여해당서열내의 cysteine을 aldehyde기를가진 formyl-glycine으로전환시키므로,리피바디의 원하는부위에 CXPXR서열을도입한후 FGE가과발현되는세포주를이용하여
리피바디생산세포주를구축한후배양공정과정에서얻어진 aldehyde작용기를 지니는리피바디에 amine기가붙은 tag을붙이고여기에다시 drug을붙여 RDC를제조할수있다.
[34] 상기효소들증 transglutaminase(TG)는 free primary amine을 glutamine의
sidechain acyl그룹에연결하는반옹을촉매한다.리피바디내존재하는 native glutamine은전후아미노산서열의배열에있어 TG에의해인식되지않는다는 점을기반으로하여,리피바디내여러부분에새로이 TG가인식하는아미노산 모티프인 LLQG를도입하여약물올결합시킬수있다.
[35]
[36] 이하에서는효소로서미국공개특허공보 US2012-0308584 A1에개시되어있는 이소프레노이드트랜스퍼라제를사용하여얻어진리피바디유도체 -약물 복합체를대표적으로예시하여상세히설명하지만,본발명에따른리피바디 유도체 -약물복합체는이에국한되지않음은전술한바와같다.
[37]
[38] 상기효소들증이소프레노이드트랜스퍼라제를사용하는경우,이효소가 인식할수있는아미노산모티프는제한되지는않으나리피바디유도체의 C-말단에위치하는 CAAX, XXCC, XCXC또는 CCXX이다.여기서, C는 시스테인을, A는독립적으로지방족아미노산을, X는효소의기질특이성을 결정하는아미노산이며,본발명의구체적인예에서와같이이소프레노이드 트랜스퍼라제로서 FTase를사용하는경우아미노산모티프는다양한종류를 사용할수있으며,상기 CAAX모티프의조건을만족하는하나의형태로서 C-말단에도입된 -CVIM을사용할수있다.
[39]
[40] 상기이소프레노이드트랜스퍼라제가인식하는아미노산모티프는단백질의 본래구조를은전히보존하며효소의반웅성을최대화시킬수있도록하는 목적으로스페이서 (spacer)를통하여리피바디의 C-말단에연결될수있다. 여기서스페이서는일반적으로아미노산으로구성되지만,그종류와길이가 특별히제한되는것은아니며,본발명의하나의실시예에서와같이 7개의 glycine을사용할수도있고, flexable한성질을가진 (G4S)n spacer,즉, glycine 4개와 serine 1개가반복적으로배열된경우,흑은 rigid한성질을가진 alpha-helix spacer,즉 (EAAAK)n (여기서 E는 glutamate, A는 alanine, K는 lysine이며,상기 n 은일반적으로 1이상정수이나 G4S의경우 glycine과 serine의숫자및배열이 다양한변형체도가능하다)도가능하며,물성을고려하여보다 hydrophilic한 성질을도입하기위해 DRDD (여기서 D는 aspartate, R은 arginine)둥의 charged 아미노산이포함된다양한 spacer들도이용될수있다.
[41]
[42] 본발명에서상기아미노산모티프는제한되지는않으나 CAAX, XXCC, XCXC 또는 CCXX이며 , C는시스테인을, A는독립적으로지방족아미노산을, X는
모티프가효소의서브스트레이트임을결정하는아미노산이며,
스페이서 (spacer)를통하여리피바디의 C-말단에연결될수있다.상기
스페이서는그종류와길이가특별히제한되는것은아니며 ,바람직하게는 1개 이상의아미노산,화합물로구성될수있고,가장바람직하게는본발명의 하나의실시예에서와같이 7개의 glycine을사용할수있다.
[43]
[44] 본발명에서상기아미노산모티프는제한되지는않으나하나이상의링커를 통하여약물에결합될수있으며,바람직하게는상기링커는 FPP(farnesyl pyrophosphate)의아날로그 (analog)인 FPP-carbonyl analog와결합될수있다.
[45]
[46] 본발명에서상기링커는탄소수 1내지 50의알킬렌으로,하기 (i)내지 ( )중 적어도하나를만족할수있다.
[47] (i)상기알킬렌은적어도하나의불포화결합을포함하고,
[48] (ii)상기알킬렌은적어도하나의헤테로아릴렌을포함하고,
[49] (iii)상기알킬렌의탄소원자는질소 (N),산소 (O)및황 (S)으로부터선택되는 하나이상의헤테로원자로치환되고,
[50] (iv)상기알킬렌은탄소수 1내지 20의알킬로더치환된다.
[51] 본발명에서상기링커 (L)는이소프레노이드트랜스퍼라제에의하여인식될 수있는하기화학식 A의이소프레닐유도체유닛을적어도하나이상포함할수 있다.
[52] [화학식 A]
[53]
[54] 본발명에서상기링커 (L)는 1,3-양극성고리첨가반웅 (1,3-dipolar cycloaddition reactions),헤테로-디엘스반응 (hetero-diels reactions),친핵성치환
반웅 (nucleophilic substitution reactions),논 -알돌형?]"보닐반웅 (non-aldol type carbonyl reactions),탄소 -탄소다중결합에대한첨가 (additions to carbon-carbon . multiple bonds),산화반웅 (oxidation reactions)또는클릭반응 (dick reaction)에 의하여형성된결합유닛을더포함할수있다.본발명에서상기결합유닛은 아세틸렌과아지드와의반응,또는알데히드또는케톤그룹과하이드라진또는 하이드록실아민과의반응으로형성될수있다.본발명에서상기결합유닛은 하기화학식 B, C또는 D로표시될수있다.
[61] 상기!^은단일결합또는탄소수 1내지 30의알킬렌이고;
[62] Ru은수소또는탄소수 1내지 10의알킬이고;
[63] 1^2는탄소수 1내지 30의알킬렌이다.
[64] 본발명에서,상기링커 (L)는화학식 E또는 F로표시되는연결유닛을더
포함할수있다.
[65] [화학식 E]
[66] -(CH2)r(W(CH2)q)p-
[67] [화학식 F]
[68] -(CH2CH2V)X -
[69] 상기 W는 -0-, -S-, -NR21 -, -C(0)NR22-,-NR23C(0)-,-NR24S02-또는 S02NR25 -이고;
[7이 V는 -0-, d-C8알킬렌또는 -NR2「이고;
[71] R21내지 R25는각각독립적으로수소, d-C6알킬, - 알킬 C6-C2^릴또는 CrC
6알킬 C3-C20헤테로아릴이고;
[72] r은 1내지 10의정수이고;
[73] q는 0내지 10의정수이고;
[74] p는 1내지 10의정수이고;및
[75] X는 1내지 10의정수이다.
[76]
[77] 본발명에서상기약물은제한되지않으나약물,독소,친화성리간드,검출 탐침또는이들의조합일수있다.
[78] 예시적인약물은,이들로제한되지는않지만,어로티니브 (TARCEVA;
Genentech/OSI Pharm.),보어테조미브 (VELCADE; MilleniumPharm.),
풀베스트란트 (FASLODEX; AstraZeneca),수텐트 (SU11248; Pfizer),
레트로졸 (FEMARA; Novartis),이마티니브메실레이트 (GLEEVEC; Novartis), PTK787/ZK 222584(Novartis),옥살리플라틴 (Eloxatin; Sanofi),
5-플루오로우라실 (5-FU, leucovorin),라파마이신 (Sirolimus, RAPAMUNE;
Wyeth),라파티니브 (TYKERB, GSK572016; GlaxoSmith line),로나파니브 (SCH 66336),소라페니브 (BAY43-9006; Bayer Labs.),게피티니브 (IRESSA;
Astrazeneca), AG1478, AG1571(SU 5271; Sugen),알킬화제,예를들면,티오테파 및 CYTOXAN 사이클로포스파미드;알킬설포네이트,예를들면,부설판, 임프로설판및피포설판;아지리딘,예를들면,벤조도파,카보쿠온,메투레도파 및우레도파;알트레타민,트리에틸렌멜라민,트리에틸렌포스포라미드, 트리에틸렌티오포스포라미드및트리메틸올로멜라민을포함하는에틸렌이민 및메틸아멜라민;아세토게닌스 (특히불라탁신및불라탁시논);
캄프토테신 (합성유사체토포테칸을유도);브리오스타틴;칼리스타틴;
CC-1065(이의아도젤레신,카젤레신및비젤레신합성유사체를포함);
크립토파이신 (특히크립토파이신 1및크립토파이신 8);돌라스타틴;
두오카마이신 (합성유사체, KW-2189및 CB1-TM1포함);엘레우테로빈;
판크라티스타틴;사코딕틴;스폰기스타틴;질소머스타드,예를들면, 클로람부실,클로르나파진,클로로포스파미드,에스트라무스틴,이포스파미드, 메클로레타민,메클로레타민옥사이드하이드로클로라이드,멜팔란,노뱀비킨, 페네스터린,프레드니무스틴,트로포스파미드,우라실머스타드;아질산우레아, 예를들면,카무스틴,클로로조톡신,포테무스틴,로무스틴,니무스틴및 라님누스틴;항생물질,예를들면,에네디인항생물질 (예:칼리케아마이신,특히 칼리케아마이신감마 II및칼리케아마이신오메가 11(예를들면,참조: Agnew, Chem Intl ed Engl., 33: 183-186 (1994))및다인미신 A를유도하는다인미신; 비스포스포네이트,예를들면,클로드로네이트;에스페라미신,
니오카지노스타틴발색단및관련크로모단백질에넨디인항생발색단, 아클라시노마이신,악티노마이신,안트라마이신,아자세린,블레오마이신, 칵티노마이신,카라비신,카니노마이신,카지노필린,크로모마이신,
닥티노마이신,다우노루비신,데토루부신, 6-디아조 -5-옥소 -L-노르류신, ADRLIMYCIN 독소루비신 (모르폴리노-독소루비신,
시아노모르폴리노-독소루비신, 2-피를리노-독소루비신,리포솜독소루비신및 데옥시독소루비신포함),에피루비신,에소루비신,마셀로마이신,미토마이신, 예를들면,미토마이신 C,마이코페놀산,노갈라마이신,을리보마이신,
페플로마이신,포트피로마이신,푸로마이신,쿠엘라마이신,로두루비신, 스트렙토미그린,스트랩토조신,투베르시딘,우베니멕스,지노스타틴및 조루비신;항 -대사산물,예를들면, 5-플루오로우라실 (5-FU);폴산유사체,예를 들면,데노프테린,메토트렉세이트,프테로프테린,트리메트렉세이트;푸린 유사체,예를들면,플루다라빈, 6-머캅토푸린,티아미프린및티구아닌;피리미딘 유사체,예를들면,아시타빈,아자시티딘, 6-아자우리딘,카모푸르,사이타라빈, 디데옥시우리딘,독시플루리딘,에노시타빈및플록수리딘;안드로겐,예를 들면,칼루스테론,드로모스타놀론프로피오네이트,에피티오스타놀, 메피티오스탄및테스토락톤;항 -아드레날,예를들면,아미노글루테티미드, 미토탄및트리로스탄;폴산보충제,예를들면,폴린산;아세글라톤;
알도포스파미드글리코사이드;아미노레불린산;에닐우라실;암사크린;
베스트라부실;비산트렌;에다트락세이트;데포파민;데메콜신;디아지쿠온; 엘포르니틴;엘립티늄아세테이트;에포틸론;에토글루시드;갈륨니트레이트; 하이드록시우레아;렌티난;로니다이닌;마이탄시노이드,예를들면,마이탄신 및안사미특신;미토구아존;미톡산트론;모피단몰;니트라에린;펜토스타틴; 페나메트;피라루비신;로속사트론; 2-에틸하이드라지드;프로카바진; PSK 다당류착체 (JHS Natural Products, Eugene, Oreg.);라족산;리족신;시조피란; 스피로게르마늄;테누아존산;트리아지쿠온 ; 2,2',2"-트리클로로트리에틸아민; 트리코테센 (특히 T-2독소,베라쿠린 A,로리딘 A및안구이딘);우레탄;빈데신; 다카바진;만노무스틴;미토브로니톨;미토락롤;피포브로만;가시토신;
아라비노시드 ('Ara-C');사이클로포스파미드;티오테파;탁소이드,예를들면, TAXOL 파클리탁샐 (Bristol-Myers Squibb Oncology, Princeton, N. J.)
ABRAXANE™크레모포부재,파클리탁셀의알부민가공나노입자
제형 (American Pharmaceutical Partners, Schaumber, II 1.)및 TAXOTERE 독세탁셀 (Rhone-Poulenc Rorer, Antony, France);클로란부실;겜시타빈;
6-티오구아닌;머캅토푸린;백금유사체,예를들면,시스플라틴,카보플라틴; 빈블라스틴;백금;에토포시드,이포스파미드;미록산트론;빈크리스틴;
NAVELBINE 비노텔빈;노반트론;테니포시드;데아트렉세이트;다우노마이신; 아미노프테린;젤로다;이반드로네이트; CPT-11;토포이소머라제억제제 RFS 2000;디플루오로메틸로르니틴 (DFMO);레티노이드,예를들면,레틴산;
카페시타빈;및약제학적으로허용되는이의염,용매화물,산또는유도체를 포함한다.
추가의약물은이돌로제한되지는않지만, (i)예를들면,
타목시펜 (NOLVADEX[0117] 타목시펜포함),라록시펜,드로록시펜,
4-하이드록시타목시펜,트리옥시펜,케옥시펜, LY117018,오나프리스톤및 FAREATON 토레미펜을포함하는,항 -에스트로겐및선택적에스트로겐 수용체조절제 (SERM)와같은종양에대한호르몬작용올조절하거나억제하는 작용을하는항 -호르몬제; (ii)부신내에스트로겐생성을조절하는,아로마타제
효소를억제하는아로마타제억제제,예를들면, 4(5)-이미다졸,
아미노글루테티미드, MEGASE 메게스트를아세테이트, AROMASIN 엑세메스탄, FEMARA 레트로졸및 ARIMIDEX 아나스트로졸; (iii) 항 -안드로겐,예를들면,플루타미드,닐루타미드,비칼루타미드,레우프를리드 및고세텔린;뿐만아니라트록사시타빈 (1,3-디옥솔란뉴클레오시드시토신 유사체); (iv)아로마타제억제제; (V)단백질키나제억제제; (vi)지질키나제 억제제; (vii)안티센스올리고뉴클레오티드,특히부착세포에연관된시그널링 통로내유전자발현을억제하는것,예를들면, PKC-알파, Raf, H-Ras; (viii) 리보자임,예를들면, VEGF억제계,예를들면, ANGIOZYME리보자임및 HER2 발현억제제; (ix)백신,예를들면,유전자치료백신; ALLOVECTIN 백신, LEUVECTIN백신및 VAXID백신; PROLEUKIN rlL-2; LURTOTECAN 토포이소머라제 1억제제; ABARELIX rmRH; (x)항-맥관발생제,예를들면, 베박시주마브 (AVASTIN, Genentech);및 (xi)약제학적으로허용되는이의염, 용매화물,산또는유도체를포함한다ᅳ
[80] 일부양태에서,시토카인이약제로서사용될수있다.시토카인은다수의
세포에의하여분비되는소세포-시그널링단백질분자이고,세포내정보교환에 광범위하게사용되는시그널링분자의범주이다.이는모노카인,림포카인, 전통적인폴리펩티드호르몬등을포함한다.시토카인의예는,이들로 제한되지는않지만,성장호르몬,예를들면,사람성장호르몬, N-메티오닐사람 성장호르몬및보바인성장호르몬;부갑상선호르몬;티록신;인슐린;
프로인술린;레락신;프로레락신;당단백질호르몬,예를들면,소포자극 호르몬 (FSH),갑상선자극호르몬 (TSH)및황체형성호르몬 (LH);간성장인자 섬유아세포성장인자;프로락틴;태반락토겐;종양괴사인자 -α및 -β;
물러 -억제물질;마우스고나도트로핀결합펩티드;인히빈;악티빈;혈관내피 성장인자;인테그린;트롬보포이에린 (TPO);신경성장인자,예를들면, NGF-β; 혈소판 -성장인자;변환성장인자 (TGF),예를들면, TGF-α및 TGF-β;인술린 유사성장인자 -I및 -Π;에리트로포이에틴 (EPO);골유도인자;인터페론,예를 들면,인터페론 -α, -β및ᅳ γ;집락자극인자 (CSF),예를들면,대식
세포 -CSF(M-CSF);과립구 -대식세포 -CSF(GM-CSF);및과립구 -CSF(G-CSF); 인터류킨 (IL),예를들면, IL-1, IL-la, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9,
IL-10, IL-11, IL-12;종양괴사인자,예를들면, TNF-a및 TNF-β;및 LIF및키트 리간드 (KL)를포함하는기타폴리펩티드인자를포함한다.본원에서사용된 바와같이,용어시토카인은또한천연공급원으로부터또는기본서열 시토카인의재조합세포배양물및생물학적활성동등물을포함한다.
[81] 용어 "독소''는살아있는세포또는유기체내에서생성되는독성물질을
말한다 독소는생물학적거대분자,예를들면,효소또는세포수용체와상호 작용하는체조직과접촉또는이에의하여흡수시질환을유발할수있는 소분자,펩티드또는단백질일수있다.독소는식물독소및동물독소를
포함한다.동물독소의예는,이들로제한되지는않지만,디프테리아항독소, 보를리움독소,파상풍항독소,이질독소,콜레라독소,테트로도특신, 브레베특신,시구아록신을포함한다.식물독소의예는,이들로제한되지는 않지만,리신및 AM-독소를포함한다.
[82] 소분자독소의예는,이들로제한되지는않지만,아우리스타틴,
겔다나마이신 (Kerr et al., [0120] 1997, Bioconjugate Chem. 8(6):781-784), 마이타시노이드 (EP 1391213, ACR 2008, 41, 98- 107),칼리케아마이신 (US
2009105461, Cancer Res. 1993, 53, 3336-3342),다우노마이신,독소루비신, 메토트렉세이트,빈데신, SG2285(Cancer Res. 2010, 70(17), 6849-6858), 돌라스타틴,돌라스타틴유사체의아우리스타틴 (US563548603),크립토파이신, 캄프토테신,리족신유도체, CC-1065유사체또는유도체,두오카마이신,엔디인 항생물질,에스페라미신,에포틸론및록소이드를포함한다.독소는튜불린 결합, DNA결합,토포이소머라제억제둥에의하여세포독성및세포성장억제 활성을나타낼수있다.
[83] 용어 "리간드''는표적생체분자와착체를형성할수있는분자를말한다.
리간드의예는표적단백질의소정위치에결합하여신호를전송하는분자이다. 이는기질,억제제,자극제,신경전달물질또는방사성동위원소일수있다.
[84] "검출가능한잔기 "또는 "표지 "는분광,광화학,생화학,면역화학,방사성또는 화학적수단에의하여검출가능한조성물을말한다.예를들면,유용한표지는 32 P, 35S,형광성염료,전자 -밀집시약,효소 (예: ELISA에통상적으로사용되는것), 비오틴-스트렙타비딘,디옥시게닌,합텐및항혈청또는리피바디가사용가능한 단백질,또는표적에상보적인서열올갖는핵산분자를포함한다.검출가능한 잔기는종종샘플내결합된검출가능한잔기의양을정량하는데사용될수 있는,측정가능한신호,예를들면,방사성,발색성또는형광신호를
발생시킨다.신호의정량은예를들면,신틸레이션카운팅,밀도계,유동 세포분석, ELISA또는원형또는후속적으로다이제스트된펩티드의질량 분광법에의한직접분석 (하나이상의펩티드가검정될수있다)에의하여 달성된다.당업자는관심있는표지화합물에대한기술및검출수단에 친숙하다.이러한기술및방법은통상적이고당해기술분야에익히공지되어 있다.
[85] 본원에서사용된바와같은용어 "탐침 "은 (i)검출가능한신호를제공하거나, (ii)제 1탐침또는제 2탐침올상호반웅시켜형광공명에너지전달 (FRET)과 같은,제 1또는제 2탐침에의하여제공된검출가능한신호를변경시키거나, (iii) 항원또는리간드와의상호작용을안정화시키거나결합친화도를
증가시키거나, (iv)전하,소수성등과같은물리적파라미터에의하여전기 이동도또는세포-침입작용에영향올미치거나, (V)리간드친화도,항원 -항체 결합또는이온착체형성을조절할수있는물질을말한다.
[86]
[87] 본발명에서리피바디유도체 -약물복합체를항암치료제로서개발할경우, 제한되지는않으나그표적단백질은암세포에서특이적혹은과발현되는 단백질로서 ,비호지킨림프종 (non-Hodgkin lymphoma)을주된적응증으로할 경우 CD19, CD20, CD21, CD22, CD37, CD70, CD72, CD79a/b,그리고 CD180등이 될수있으며,호지킨림프종 (non-Hodgkin lymphoma)을주된적응증으로할 경우 CD30,급성골수성백혈병 (acute-myeloid leukemia)을주된적웅증으로할 경우 CD33과 CD43,급성림프구성백혈병 (acute-lymphoid leukemia)을주된 적웅증으로할경우 CD43,다발성골수종 (multiple myeloma)을주된적웅증으로 할경우 CD56, CD74, CD138,그리고 endothelin B receptor,두경부암 (head and neck cancer)을주된적응증으로할경우 EGFR,폐암을주된적응증으로할경우 EGFR, CD56, CD326, CRIPTO, FAP, mesothelin, G2D, 5T4,그리고 alpha v beta6, 교모세포종 (glioblastoma)을주된적응증으로할경우 EGFR, EGFRvIII, 대장 /직장암을주된적옹증으로할경우 EGFR, CD74, CD174, CD227 (MUC-1), CD326 (Epcam), CRIPTO, FAP,그리고 ED-B,췌장암을주된적응증으로할경우 CD74, CD227 (MUC-1), nectin-4 (ASG-22ME),그리고 alpha v beta6,유방암을 주된적응증으로할경우 HER2, CD 174, GPNMB, CRIPTO, nectin-4 (ASG-22ME), 그리고 LIV1A,난소암을주된적웅증으로할경우 MUC16 (CA125), TIM-1, 그리고 mesothelin,흑색종 (melanoma)을주된적응증으로할경우 GD2, GPNMB, ED-B, PMEL 17,그리고 endothelin B receptor,전립선암을주된적응증으로할 경우 PSMA, STEAP-1,그리고 TENB2,신장암올주된적웅증으로할경우 CAIX, 그리고 TIM-1,중피종 (mesothelioma)을주된적응증으로할경우 mesothelin 둥이될수있다.
[88] 상기열거한적웅증과표적단백질은반드시일치해야할필요는없으며,특히
EGFR과 HER2의경우다양한암에서과발현되는경우들이많아적웅증을 국한시킬필요는없다.
[89] 본발명에서는하나의실시예로 EGFR (내피세포성장인자수용체)에결합하는 리피바디를이용한항 -EGFR리피바디유도체 -약물 (anti-EGFR RDC, ERDC)을 제조하여그효능을확인하였다.
[90]
[91] 또한본발명은 (a)리피바디유도체의 C-말단하나이상에효소가인식할수 있는아미노산모티프가결합된단백질을제조하는단계; (b)상기 (a)단계에서 제조된단백질을효소를사용하여제 1작용기를포함하는하나이상의기질과 반웅시켜기능단화된단백질을제조하는단계;및 (c)상기 (b)단계의
기능단화된단백질과제 2작용기를약물에결합시킨결합체를반웅시켜 리피바디유도체 -약물복합체를제조하는단계;를포함하는것을특징으로하는 단백질 -약물복합체제조방법에관한것이다.
[92] 본발명에서상기제 2작용기는제한되지는않으나하나이상의링커에의해 약물에결합될수있다.
[93] 본발명에서상기기능단화된단백질과약물사이의반웅은아세틸렌과 아지드와의반웅,또는알데히드또는케톤그룹과하이드라진또는
하이드록실아민과의반웅으로형성될수있다.
[94] 상기리피바디단량체및이들로구성된다량체,여기에 Fc단백질, PEG가
결합된형태들각각의서열변이체는,그카르복시말단의일부가제거되거나, 카르복시말단에신규아미노산서열이첨가되거나,카르복시말단의일부가 제거된후신규아미노산서열이첨가된다음에이소프레노이드
트랜스퍼라아제가인식할수있는아미노산서열이결합될수있다.
[95]
[96] 한편,상기이소프레노이드트랜스퍼라아제가인식할수있는서열인 C-말단의 CAAX서열 (C는시스테인올 , A는독립적으로지방족아미노산을, X는 모티프가효소의서브스트레이트임을결정하는아미노산)에있어서,상기단계 (b)이후에 -AAX부를잘려나가게하는단계가추가로포함될수있다.
[97]
[98] 또한본발명은 (a)리피바디유도체의 C-말단하나이상에효소가인식할수 있는아미노산모티프가결합된단백질을제조하는단계; (b)효소의기질에하나 이상의약물을결합시켜결합체를제조하는단계; (c)상기 (a)단계에서제조된 단백질과상기 (b)단계에서얻은결합체를반웅시켜리피바디유도체 -약물 복합체를제조하는단계;를포함하는것을특징으로하는단백질 -약물복합체 제조방법에관한것이다.
[99]
[100] 상기제조방법들을통해기질특이성을갖는리피바디유도체 -약물접합체를 균질하게제조할수있다.
[101]
[102] 또한본발명은리피바디유도체 -약물복합체를이용한질병진단,예방및
치료용약학조성물에관한것이다.본발명에서상기질병은제한되지는않으나 통상적으로알려져있는모든질병을포함할수있으며,예를들어소화기질환, 호흡기질환,심장혈관질환,신장질환,내분비질환,면역질환,혈액질환, 유전병,선천성대사장애,성병,암,정신과질환,중독또는외과계질환에 해당하는질병등을포함한다.일례로서보다상세하게는뇌암,백혈병,위암, 대장암,직장암,간암,폐암,식도암,전립선암,유방암,피부암,자궁암등의암을 포함하여,감기,폐렴,결핵,에이즈 (AIDS),흑사병,프리온병등의전염병 , Β형 간염,동맥경화,탈장,천연두,빈혈,소아마비,알레르기,천식,당뇨병,동맥경화, 신장병,중풍,알츠하이머병,비만등의기타질병둥이포함된다.
[103] 본발명에서상기약학조성물의제형 (dosage form)은제한되지는않으나산제, 과립제,정계,캡술제,현탁액,에멀젼,및시럽으로이루어진군으로부터 선택되는경구용제형일수있다.
[104] 본발명에서상기조성물중리피바디유도체 -약물복합체의양은제한되지는
않지만전체조성물중량의 0.01내지 95중량 %로가할수있다.상기조성물은 제한되지는않지만산제,과립제,정제,캡슐제,현탁액,에멀견,시럽,에어로졸 등의경구형제형,외용제,좌제및멸균주사용액의형태로제형화하여사용될 수있다.또한상기조성물은제한되지는않지만담체,부형제및희석제를더 포함할수있으며 ,바람직하게는락토오스 (lactose),덱스트로즈,
수크로스 (sucrose),솔비를,만니롤,자일리틀,에리스리를,말티톨,전분, 아카시아고무,알지네이트,젤라틴,칼슘포스페이트,칼슘실리케이트, 셀를로즈,메틸셀를로즈,미정질셀를로스,폴리비닐피롤리돈,물,
메틸히드록시벤조에이트,프로필히드록시벤조에이트,탈크,마그네슘
스테아레이트및광물유를사용할수있다.
[105] 상기조성물을제제화할경우에는보통사용하는층진제,증량제,결합제, 습윤제,붕해제,계면약물등의회석제또는부형제를사용하여조제된다.
경구투여를위한고형제제에는정제,환 (丸)제,산제,과립제,캡슐제등이포함될 수있으며,이러한고형제제는상기조성물에적어도하나이상의부형제예를 들면,전분,칼슴카보네이트 (calcium carbonate),수크로스또는락토오스,젤라틴 등을섞어조제할수있다.또한단순한부형제이외에마그네슴스테아레이트, 탈크같은윤활제들도사용될수있다.경구를위한액상제제로는현탁제, 내용액제,유제,시럽제등이해당되는데흔히사용되는단순회석제인물, 리퀴드파라핀이외에여러가지부형제,예를들면습윤제,감미제,방향제, 보존제등이포함될수있다.비경구투여를위한제제에는멸균된수용액, 비수성용제,현탁제,유제,동결건조제제,좌제가포함된다.비수성용제, 현탁제로는프로필렌글리콜 (propylene glycol),폴리에틸렌글리콜,올리브 오일과같은식물성기름,에틸을레이트와같은주사가능한에스테르등이 사용될수있다.좌제의기제로는위텝솔 (witepsol),마크로골,트원 (tween) 61, 카카오지,라우린지,글리세로제라틴등이사용될수있다.상기조성물은독성 및부작용은거의없으므로예방또는치료목적으로장기간복용시에도 안심하고사용할수있다.
[106] 상기조성물은지시된비율의필수성분으로서상기조성물을함유하는것
외에는다른성분에는제한이없으며여러가지향미제또는천연탄수화물등을 추가성분으로서함유할수있다.상술한천연탄수화물의예는모노사카라이드, 예를들어,포도당,과당등;디사카라이드,예를들어말토스,슈크로스등;및 폴리사카라이드,예를들어덱스트린,시클로텍스트린등과같은통상적인당, 및자일리롤,소르비를,에리트리를등의당알콜이다.상술한것이외의 향미제로서천연향미제 (타우마틴),스테비아추출물 (예를들어레바우디오시드 A,글리시르히진등)및합성향미제 (사카린,아스파르탐둥)를유리하게사용할 수있다.상기천연탄수화물의비율은본발명의리피바디유도체 -약물복합체 100 mg당일반적으로약 1내지 20g,바람직하게는약 5내지 12g이다.상기외에 본발명의조성물은여러가지영양제,비타민,광물 (전해질),합성풍미제및
천연풍미제등의풍미제,착색제및중진제 (치즈,초콜릿둥),펙트산및그의염, 알긴산및그의염,유기산,보호성콜로이드증점제, pH조절제,안정화제, 방부제,글리세린,알콜,탄산음료에사용되는탄산화제등을함유할수있다. 이러한첨가제의비율은제한되지는않지만본발명의조성물 100중량부당 0 내지약 20중량부의범위에서선택되는것이바람직하다.
[107] 본발명에서상기리피바디유도체 -약물복합체를이용한조성물은
제한되지는않으나상기기술한통상적으로알려져있는질병진단의
정보제공방법을제공하기위하여사용될수있다.상기조성물을질병진단의 정보를얻기위한대상에직접적으로투여하거나,질병특이적인표적으로 알려져있는유전자,단백질,세포등을검출하기위하여제작된바이오칩상의 기질에부착시키고상기유전자,단백질또는세포등을동시에검출할수 있도록하는방법을통해높은정확도와신뢰도를갖는질병진단의
정보제공방법을제공하는목적으로활용이가능하다.
[108] 또한본발명은상기리피바디유도체를코딩하는폴리뉴클레오티드에관한 것이다.
[109] 또한본발명은상기폴리뉴클레오티드를포함하는재조합백터에관한
것이다.본발명에서상기백터의종류는통상적으로사용되는범위에서 제한되지않고선택하여사용할수있다.
[1 10] 또한본발명은상기재조합백터로형질전환된미생물에관한것이다.본
발명에서상기형질전환을위한미생물은특별히제한되지는않으나,상기 재조합백터의과발현이가능한미생물을임의선택하여사용할수있으며, 바람직하게는유전자조작이용이하고널리알려진대장균 (E«^en'c/» i coli)올 사용할수있다.
발명의효과
[111] 본발명에따른리피바디유도체 -약물복합체 (RDC)는리피바디가제공하는 높은기질특이성과우수한조직및종양침투능에,생물학적활성을지닌약물이 결합된것으로서,리피바디단독으로사용하는경우에비해월등한효능을 지니고,화합물단독으로사용하는경우에비해표적세포에대한특이적 선택성을지님으로써독성을최소화할수있다는장점올가지고있을뿐만 아니라,종래의항체와는달리,대장균에서수용성형태 (soluble form)로 발현되어저렴한비용으로쉽게대량생산이가능하고,열역학적으로매우 안정하며,조직침투력이매우우수한점등의장점을가지고있으면서,표적 단백질에특이적으로결합함으로써표적세포를사멸시키는기존항체 -약물 복합체의장점은그대로살린새로운형태의약물복합체를제공한다.
도면의간단한설명
[1 12] 도 1은 MCF7 (EGFR저발현유방암세포주), A431 (EGFR과발현표피암
세포주)및 HCC827 (EGFR과발현폐암세포주)를사용하여세포특이적결합
여부를면역형광 (immunofluorescence)법으로확인한결과이다.
[113] 도 2는리피바디유도체 -약물복합체구조의개념도이다
[114] 도 3은리피바디유도체 (A)로부터 Farnesyl analog로활성화된중간단계 (B)를 거처리피바디유도체 -약물복합체 (C)제조단계각각의 HIC-HPLC피크확인 결과이다.
[115] 도 4는항 -EGFR리피바디유도체인 Erep-Vl을이용하여제조한
항 -EGFR-리피바디유도체 -약물복합체 ERDC-V1의 A431, MCF-7에대한! ·η vitro 세포독성을측정한결과이다.
[116] 도 5는항 -EGFR리피바디유도체 Erep-Vl과이를모체로하여 EGFR에대한 결합능을향상시킨리피바디유도체 Erep-V2, Erep-V3를이용하여제조한 리피바디유도체ᅵ약물복합체 ERDC-Vl, ERDC-V2, ERDC-V3각각의 A431에 대한 in vitro세포독성을측정한결과이다.
[117] 도 6은 ERDC-Vl, ERDC-V2, ERDC-V3들의 HCC827에대한 in vitro
세포독성을측정한결과이다.
[118] 도 7은 ERDC-V3의 HCC827에대한 in vivo이종이식마우스효능시험의
종양성장억제능에대한결과로,약물은매일간격으로총 6회투여하였다.
[119] 도 8은도 7의실험에서마우스몸무게를측정한결과이다.
[120] 도 9는 5-포밀살리실산으로부터화합물 F의제조단계에관한것이다.
[121] 도 10은리피바디유도체 -약물복합체 ERDC-Vl, ERDC-V2, ERDC-V3및
ERDC-NV의화학구조이다.
발명의실시를위한최선의형태
[122] 이하본발명을실시예를참조하여상세히설명한다.그러나이들은본발명을 보다상세하게설명하기위한것으로,본발명의권리범위가하기의실시예에 의해한정되는것은아니다.
[123]
[124] [실시예 1] EGFR특이적리피바디의특이적결합능확인
[125] 서열번호 1의폴리펩티드서열을갖는리피바디 (KR2014-0062391,이하
RP-E1V1으로명명한다)는 OrigamiB (DE3) (Novagen,미국)를숙주세포로 0.5 mM IPTG로과발현한후,친화력및젤투과크로마토그래피를통해단백질을 순수하게정제하였다. RP-E1V1가 EGFR을발현하는암세포에특이적으로 결합하는지확인하기위해 MCF7 (EGFR저발현유방암세포주)과 A431 (EGFR 과발현표피암세포주)및 HCC827 (EGFR과발현폐암세포주)를사용하여세포 특이적결합여부를확인하였다.플루오레세인 (fluorescein)을사용하여
RP-E1V1를표지하고,각각의암세포에 1 g/mL의농도로 3시간정도처리한후, 공초점현미경 (confocal microscopy)를이용하여세포에결합된형광물질을 관찰하였다.
[126] 도 1에나타난결과와같이 , MCF7의경우형광이거의관찰되지않는데반해
A431과 HCC827은강한형광신호를확인할수있었다.이러한결과는 EGFR의 세포외도메인에결합하는리피바디 RP-E1V1가해당세포에매우특이적으로 결합할수있음을의미한다.
[127]
[128] [실시예 2]리피바디유도체제조
[129] RP-E1V1의 C-말단에글리신 (glycine) 7개, CAAX모티프로서
시스테인 (cysteine) -발린 (valine) -이소류신 (isoleucine) -메티오닌 (methionine)을 차례로연결시켜서열번호 2의리피바디의유도체 (이하 Erep-Vl으로
명명한다)를제조하였다.
[131 ] <Erep-Vl의구조〉
[132] pET21a (Novagen,미국)발현백터에 Erep-Vl을코딩하는유전자를클로닝하고 대장균 (E. coli) BL21 (DE3) (Novagen,미국)에형질전환하였다. 100 g/mL의 앰피실린 (ampicillin)항생제를투여한 LB (Luria-Bertani)배지 (Duchefa, 네덜란드)에상기대장균의단일콜로니 (colony)를접종하고 37 °C에서 12시간 배양하였다.상기배양액올 1/100의농도로희석하여새롭게준비한
앰피실린 -LB배지에접종하고마찬가지로 37 °C에서배양한후, OD600이 0.5에 도달하면최종농도가 0.5 mM이되도록 IPTG
(isopropyip-D-l-thiogalactopyranoside)를넣어단백질발현을유도하였다.이후 18 °C로온도를낮추어 20시간배양하였다.
[133] 상기와같은방법으로 Erep-Vl을모체로하여 EGFR에대한결합능을
향상시킨리피바디유도체 Erep-V2(서열번호 4)와 Erep-V3(서열번호 6),그리고 EGFR에결합하지않는음성대조물질 Erep-NV (서열번호 8)를제조하였다.
[134]
[137] 목적화합물 A는미국공개특허 US2012-0308584 A1에서기재된방법과
동일한방법으로제조하였다.
[138]
[139] [실시예 4]프레닐화 (prenylation)방법
[140] Faraesyl analog (화합물 A)및 FTase(#344145, Calbiochem, USA)를사용하여 리피바디의프레닐화를수행하였다.프레닐화반응은 5 mM MgCl2,10 M ZnCl2 및 5 mM DTT를함유하는 50 mM트리스 -HC1 (pH 7.4)완충용액을사용하여 30 °C에서 12시간동안수행하였다.반응을완료한후, PD-10탈염컬럼 (desalting column; GE Lifescience)으로탈염하고 Vivaspin 2를이용하여농축한뒤 PBS로 버퍼를교체하였다.이후 Nanodrop과 BCA방법으로단백질정량하였다.
[141]
[142] 1.리피바디유도체의프레닐화 (prenylation)반웅
[143] 리피바디를위에서기재된방법에따라화합물 A와 FTase를사용하여
프레닐화하였다.상기와같이제조된물질을프레닐화리피바디유도체라 명명하였다. Erep-Vl, Erep-V2, Erep-V3,그리고 Erep-NV를화합물 A와프레닐화 하여얻어진프레닐화리피바디유도체는각각 Erep-Vl의경우화합물 B, Erep-V2의경우화합물 C, Erep-V3의경우화합물 D, Erep-NV의경우화합물 E 라고명명하였다.이들화합물의구조는아래와같다.
[147] <화합물 C,화합물 D,그리고화합물 E의구조 >
[148]
[149] [실시예 5] Linker-MMAF화합물 F (LCB14-0645)의제조
1a 1b
1c 1d
1e
[152]
[153] 질소대기하상온에서화합물 13 (10 ^ 59.3 !1^01)를 -다이메틸품아마이드 (90 mL)에용해시킨후소듬아자이드 (5.78g, 88.9mmol)를첨가하고상기 흔합물을 100 °C에서 13시간동안교반하였다.반응을완료한후클로로품 (200 mL)과증류수 (300 mL)를첨가한후추출하여유기층을무수황산나트륨으로 건조시키고감압하에농축시켰다.잔사를컬럼크로마토그래피시켜화합물 lb 를수득하였다 (10.3 g, 99 %).
[154] Ή-NMR (600 MHz, CDC13)6 3.75-3.73 (m, 2H), 3.70-3.68 (m, 6H), 3.63-3.61 (m, 2H), 3.40 (t, 7 = 5.4 Hz, 2H), 2.20 (t, / = 6.0 Hz, 1H)
[155]
[156] 화함물 lc의제조
[157] 질소대기하 0 0C에서테트라브로모메테인 (21.4 g, 64.6 mmol)를
다이클로로메테인 (100 mL)에용해시킨후다이클로로메테인 (100 mL)에용해 시킨트라이페닐포스핀 (16.9 g, 64.6 mmol)과화합물 lb (10.3 g, 58.7 mmol)올 첨가하고상기혼합물을상은에서 13시간동안교반하였다.반웅을완료한후 다이클로로메테인 (300 mL)와증류수 (300 mL)를첨가한후추출하여유기층을 무수황산나트륨으로건조시키고감압하에농축시켰다.잔사를컬럼
크로마토그래피시켜화합물 lc를수득하였다 (12 g, 85 %).
[158] 'H-NMR(400MHz,CDCl3)0 3.83 (t, 7 = 6.4 Hz, 2H), 3.72-3.67 (m, 6H), 3.48 (t, 7 = 6.0 Hz, 2H), 3.40 (t, = 4.8 Hz, 2H)
[159]
[160] 하함몸 Id의제조
[161] 질소대기하상온에서화합물 lc (1.0 g, 4.20 mmol)를아세토나이트릴에용해 시킨후 N-Boc-하이드록실아민 (643 mg, 4.82 mmol)과
1,8-다이아자바이싸이클로 [5,4,0]운데 -7-인 (DBU) (0.659 mL, 4.41 mmol)를 첨가하고상기혼합물을 60 °C에서 13시간동안교반하였다.반웅을완료한후 다이클로로메테인 (300 mL)와증류수 (300 mL)를첨가한후추출하여유기층을 무수황산나트륨으로건조시키고감압하에농축시켰다.잔사를컬럼
크로마토그래피시켜화합물 Id를수득하였다 (748 mg, 70%).
[162] Ή-NMR (400 MHz, CDC13)0 7.55 (s, 1H), 4.05-4.03 (m, 2H), 3.76-3.74 (m, 2H), 3.74-3.69 (m, 6H), 3.42 (t, 7 = 4.8 Hz, 2H), 1.49 (s, 9H). EI-MS m/z: 291 (M+)
[163]
[164] 화합물 le의제조
[165] 화합물 Id (200 mg, 0.688 mmol)을메탄을 (5 mL)에용해시킨후 Pd/C (10 wt. %,
70 mg)를첨가하여수소대기하에 3시간교반하였다.반웅을완료한후상기 흔합물을셀라이트필터하여감압하에농축시켜화합물 le를수득하였다 (180 mg, 98 %).
[166] Ή-NMR (400 MHz, CDC13)6 4.04-4.01 (m, 2H), 3.74-3.62 (m, 7H), 3.55 (t, J = 5.2 Hz, 1H), 2.88 (t, 7 = 5.2 Hz, 1H) 2.81 (t, J = 5.2 Hz, 1H), 1.64 (s, 2H), 1.48 (s, 9H). EI-MS m/z: 265 (M+)
[167]
[168] 화합물 2a의제조
[169] 도 9와같이,질소대기하 0 °C에서 5-포밀살리실산 (2.0 g, 12.04 mmol) N,N -다이메틸폼아마이드에용해시킨후 2- (트리메틸실릴)에탄올 (1.72 mL, 12.04 mmol), 4- (다이메틸아미노)피리딘 (147 mg, 1.20 mmol),그리고
다이싸이클로핵실카보다이이마이드 (2.5 g, 12.04 mmol)를순서대로
첨가하였다.상기흔합물을상온에서 12시간동안교반하였다.반웅을완료한 후,에틸아세테이트 (100 mL)및증류수 (100 mL)를가한후추출하였다.이렇게 수득한유기층올무수황산나트륨으로건조시키고,감압하에농축시켰다. 잔사를컬럼크로마토그래피시켜화합물 2a를수득하였다 (1.6 g, 50 %).
[170] Ή-NMR (400 MHz, CDC13) δ 11.38 (s, 1Η), 9.77 (s, 1H), 7.48 (d, / = 8.4 Hz, 1H), 6.61 (dd, J = 8.4, 2.0 Hz, 1H), 6.53 (d, J = 2.0 Hz, 1H), 5.36-5.25 (m, 4H), 4.23 (m, 1H), 3.73 (s, 1H), 2.06 (s, 9H)
[171]
[172] 화합물 2b의제조
[173] 질소대기하상은에서화합물 2a (60 mg, 0.225 mmol)을아세토나이트릴 (2 mL)에용해시킨후화합물 3 (90 mg, 0.225 mmol, US 2012/030858에기재된 내용과유사내지동일한방법으로제조하였다),산화은 (209 mg, 0.900 mmol)및 분자체 (4 A, 90 mg)를첨가시켰다.상기흔합물을상은에서 2시간동안 교반하였다.반웅을완료한후,에틸아세테이트 (50 mL)및증류수 (30 mL)를 가한후추출하였다.이렇게수득한유기층을무수황산나트륨으로건조시키고, 감압하에농축시켰다.잔사를:컬럼크로마토그래피시켜화합물 2b를
수득하였다 (103 mg, 79 %).
[174] Ή-NMR (400 MHz, CDC13) δ 9.93 (s, 1Η), 8.22 (d, J = 2.0 Hz, 1H), 7.97 (dd, J = 6.4, 2.0 Hz, 1H), 7.26 (d, J = 9.2 Hz, 1H), 5.42-5.27 (m, 4H), 4.42-4.30 (m, 2H), 4.24 (d, 7 = 9.2 Hz, 1H), 3.70 (s, 3H), 2.06-2.04 (m, 9H), 1.14-1.08 (m, 2H), 0.07 (s, 9H)
[175]
[176] 화함묽 2c의제조
[177] 질소대기하 0 0C에서화합물 2b (lOOmg, O. nimmol)을 2-프로판올 (0.3 mL)및 클로로폼 (1.5 mL)에용해시킨후실리카겔 (720 mg)및소듐보로하이드라이드 (16 mg, 0.427 mmol)를첨가시켰다.상기흔합물을 3시간동안교반하였다. 반웅을완료한후,에틸아세테이트 (50 mL)및증류수 (20 mL)를가한후 추출하였다.이렇게수득한유기층을무수황산나트륨으로건조시키고, 감압하에농축시켰다.잔사를컬럼크로마토그래피시켜화합물 2c를수득하였다 (94 mg, 94 %).
[178] Ή-NMR (400 MHz, CDC13) δ 7.71 (d, J = 2.0 Hz, 1H), 7.45 (dd, J = 6.4, 2.0 Hz, 1H), 7.17 (d, 7 = 8.4 Hz, 1H), 5.40-5.30 (m, 3H), 5.16-5.14 (m, 1H), 4.67 (s, 2H), 4.40-4.29 (m, 2H), 4.18 (d, 7 = 8.8 Hz, 1H), 3.74 (s, 3H), 2.08-2.04 (m, 9H), 1.14-1.09 (m, 2H), 0.08 (s, 9H)
[179]
[180] 화함물 2d의제조
[181] 질소대기하 0 °C에서화합물 2c (90 mg, 0.154 mmol)을 Ν,Ν
-다이메틸품아마이드 (1.0 mL)에용해시킨후비스 (4-나이트로페닐)카보네이트 (94 mg, 0.308 mmol)및 N,N-다이아이소프로필에틸아민 (40 vL, 0.231 mmol)를 첨가시켰다.상기흔합물을상온에서 3시간동안교반하였다.반응올완료한후, 에틸아세테이트 (50 mL)및증류수 (20 mL)를가한후추출하였다.이렇게 수득한유기층을무수황산나트륨으로건조시키고,감압하에농축시켰다.
잔사를컬럼크로마토그래피시켜화합물 2d를수득하였다 (104 mg, 90 %).
[182] Ή-NMR (400 MHz, CDC13) δ 8.28 (m, 2Η), 7.80 (d, J = 2.4 Hz, 1H), 7.53 (dd, J = 6.4, 2.0 Hz, 1H), 7.37 (m, 2H), 7.20 (d, 7 = 8.8 Hz, 1H), 5.41-5.33 (m, 3H), 5.25 (s, 2H), 5.20-5.18(m, 1H), 4.41-4.30 (m, 2H), 4.20 (d, 7 = 8.8 Hz, 1H), 3.74 (s, 3H), 2.08-2.05 (m, 9H), 1.18-1.06 (m, 2H), 0.08 (s, 9H)
[183]
[184] 화함물 2e의제조
[185] 질소대기하상온에서화합물 2d (1.5 g, 2.00 mmol)을 N,N-다이메틸폼아마이드 (8 mL)에용해시킨후 MMAF-OMe (1.34 g, 1.80 mmol)을첨가한다음,이어서 무수 1-하이드록시벤조트리아졸 (54 mg, 0.4 mmol),피리딘 (5.4 mL)및 Ν,Ν -다이아이소프로필에틸아민 (0.38 mL, 2.2 mmol)으로처리하였다.상기 혼합물을상온에서 12시간동안교반하였다.반응을완료한후,에틸
아세테이트 (200 mL)및증류수 (300 mL)를가한후추출하였다.이렇게수득한 유기층을무수황산나트륨으로건조시키고,감압하에농축시켰다.잔사를컬럼 크로마토그래피시켜화합물 2e를수득하였다 (1.7 g, 70 %).
[186] EI-MS m/z: 1357 (M+)
[187]
[188] 화합물 2f의제조
[189] 질소대기하 0 °C에서화합물 2e (1.7 g, 1.25 mmol)을테트라하이드로퓨란 (15 mL)에용해시킨후테트라부틸암모늄플루오라이드 (1 M테트라하이드로퓨란 용액, 2.5 mL, 2.50 mmol)를첨가하고,상온에서 4시간동안교반하였다.반웅을 완료한후,에틸아세테이트 (200 mL)및증류수 (300 mL)를가한후추출하였다. 이렇게수득한유기층을무수황산나트륨으로건조시키고,감압하에 농축시켰다.잔사를컬럼크로마토그래피시켜화합물 2f를수득하였다 (1.34 g, 85 %).
[190] EI-MS m/z: 1257 (M+)
[191]
[192] 화함물 2g의제조
[193] 질소대기하 0 °C에서화합물 2f (1.34 g, 1.07 mmol)및화합물 le (384 mg, 1.28 mmol)을 N,N-다이메틸폼아마이드 (10 mL)에용해시킨후 N,N
-다이아이소프로필에틸아민 (0.46 mL , 2.67 mmol)및
(벤조트리아졸 -1-일옥시)트라이피롤리디노포스포늄핵사플루오로포스페이트 (PyBOP) (832 mg, 1.60 mmol)을첨가한다음,상온에서 4시간동안교반하였다. 반웅을완료한후,에틸아세테이트 (200 mL)및증류수 (300 mL)를가한후 추출하였다.이렇게수득한유기층을무수황산나트륨으로건조시키고, 감압하에농축시켰다.잔사를컬럼크로마토그래피시켜화합물 를
수득하였다 (1.2 g, 75 %).
[194] EI-MS m/z: 1503 (M+)
[195]
[196] 화합물 2h의제조
[197] 질소대기하 -10 °C에서화합물 2g (530 mg, 0.352 mmol)을메탄올 (10 mL)에 용해시킨후물 (8 mL)에용해된리튬하이드록사이드모노하이드레이트 (147 mg, 3.50 mmol)를서서히첨가하고, 1시간동안교반하였다ᅳ반응을완료한후, 클로로폼 (200 mL)및 2 Ν염산수용액 (30 mL, pH 2)를가한후추출하였다. 이렇게수득한유기층을무수황산나트륨으로건조시키고,감압하에 농축시켰다.잔사를고성능액체크로마토그래피 (용리액:
아세토나이트릴 /증류수,각각 0.1 %트라이플루오로아세트산포함)시켜화합물 2h를수득하였다 (260 mg, 45 %).
[198] EI-MS m/z: 1349 (M+)
[199]
[200] 화합물 F의제조
[201] 질소대기하 0 0C에서화합물 2h (260 mg, 0.192 mmol)을다이클로로메테인 (4 mL)및물 (2 mL)에용해시킨후 4 M염산 1,4-다이옥세인용액 (4 mL)올 첨가하고, 0 °C에서 1시간동안교반하였다.반웅올완료한후,
고성능액체크로마토그래피 (용리액:아세토나이트릴 /증류수,각각 0.1 %
트라이폴루오로아세트산포함)시켜화합물 2i를수득하였다 (210 mg, 85 ).
[202] EI-MS m/z: 1249 (M+)
[203]
[204] [실시예 6]화합물 F를이용한약물접합
[205] 1.프레닐화리피바디유도체의약물접합
[206] 화합물 B를 DMSO에녹여 10 mM용액을제조하고프레닐화된리피바디 유도체와독소 (toxin)의옥심 (oxime)결합을위해 1:15의비율로흔합하고 30 °C 배양기에서 24시간반웅시켰다.반웅종료후에 PD-10컬럼으로탈염하고, Vivaspin 2로농축하여 Nanodrop과 BCA방법으로단백질정량하였다.
[207]
[208] 상기와같이제조된물질을 ERDC라고명명하며그중대표적인화합물 B와
[210] <ERDC-V1의구조 >
[211]
[212] ERDC- VI제조와유사한방법으로하기구조의 ERDC-V2, ERDC-V3,그리고
[218] <ERDC-NV의구조 >
[219]
[220] [시험예 1] ERDC (anti-EGFR RDC)의 in vitro세포독성분석
[221] 1.세포주
[222] 시판증인 A431세포 (EGFR과발현편평상피암세포주), MCF-7세포 (EGFR 저발현유방암세포주), HCC-827세포 (EGFR과발현비소세포폐암세포주)올 사용하였다.세포주를시판증인세포주와함께제공된권장된명세서에따라 배양하였다.
[223]
[224] 2.시험샘플
[225] 항 -EGFR리피바디유도체 -약물접합체 (ERDC),항 -EGFR리피바디 , ERDC 제조에쓰인 MMAF를사용하였다.
[226]
[227] 3.시험방법
[228] 상술한세포주를이용하여 ERDC의 in vitro활성올측정하였다 (대조물질로 항 -EGFR리피바디와 ERDC제조시사용된록신인 MMAF를이용하였다). A431과 MCF7세포는 well당 lxlO4개, HCC827세포는 5xl03개로 96-well배양 플레이트에플레이팅하였다. 24시간배양후,리피바디와약물및접합체를 다양한농도로첨가하였다. 72시간후살아있는세포의수를 SRB염료를 사용하여계수하였다.흡광도를스펙트라맥스 (SpectraMax) 190(Molecular Devices, USA)를사용하여 540nm에서측정하였다.
[229]
[230] 4.시험결과
[231] 상기실시예를통해,본원발명으로제조한항 -EGFR리피바디유도체 -약물 복합체 (도 2)인 ERDC-V1의경우,제조의검증을위해 HIC-HPLC로분석하여 확인하였으며 (도 3), EGFR을과발현하는 A431편평상피암세포주에대하여는 대조군인항 -EGFR리피바디 Erep-Vl에비해월등하게우수한세포독성을 나타내는한편, EGFR이저발현되는 MCF-7유방암세포주에서는세포독성을 나타내지않는것을확인하였다 (도 4).이어 Erep-Vl을모체로 EGFR에대한 결합능을항상시킨 Erep-V2, Erep-V3리피바디유도체를제조한후,이들을 이용하여항 -EGFR리피바디유도체 -약물복합체 ERDC-V1 , ERDC-V2, ERDC-V3를만들고이들의효능을 in vitro세포독성실험을통해비교한바,
ERDC-V3가 A431세포에서가장우수한세포사멸효과를보임을확인하였다 (도 5).
[232] ERDC-V3의우수한세포독성은 EGFR을과발현하는또다른세포주인
HCC827 (비소세포폐암세포주)을대상으로한실험에서도검증되었다 (도 6).
[233]
[234] [시험예 2] ERDC-V3의 in vivo종양억제능시험
[235]
[236] 1.시험샘플
[237] PBS버퍼, Cetuximab (항 -EGFR항체), Erep-V3 (항 -EGFR리피바디유도체 , 버전 3), ERDC-V3 (항 -EGFR리피바디유도체 -약물복합체)를 in vivo이종이식 마우스효능시험에사용하였다.
[238]
[239] 2.시험방법
[240] Balb/C누드마우스한마리당 HCC-827세포주 5 x 106/200 fiL을투여하고 종양크기가 130 mm3가되는마우스를 6마리씩그룹올나누었다.각그룹에 PBS, Cetuximab (10 mg/kg), Erep-V3 (10 mg/kg), ERDC-V3 (1 mg/kg), ERDC-V3 (10 mg kg)를하루에한번씩 6일동안투여하고 3일에한번씩 20일동안종양의 크기 ((길이 X너비) 2/ 2)와개체군의몸무게를관찰하였다.
[241]
[242] 3.시험결과
[243] 상기실시예를통해,본원발명의방법으로제조한리피바디유도체 -약물
복합체인 ERDC-V3의경우종래의리피바디인 Erep-V3또는항체대조군에비해 종양의생장을가장강력히저해하는것을확인하였으며 (도 7),항체대조군과 리피바디는동일한용량으로투여시종양의생장에있어서동등한효과를 보이고있다. ERDC-V3를 10 mg/kg으로투여한경우에는 14일차까지마우스의 몸무게가약간감소되는양상을보이나,그이후에회복되었다 (도 8).
[244]
[245] 이로부터리피바디유도체 -약물복합체인 ERDC-V3 (항 -EGFR Repebody Drug Conjugate-V3)가 in vitro세포독성및 ίη vivo암세포성장억제에있어리피바디 자체에비해월등히우수한효능을보임을확인함으로본발명을완성하였다. 서열목록 Free Text
[246] 서열목록은별도로작성하여첨부하였다.
Claims
청구범위
[청구항 1] 리피바디유도체 -약물복합체 (Repebody Derivative-Drug Conjugates). [청구항 2] 제 1항에있어서,
리피바디유도체는리피바디단량체,리피바디다량체,또는이들각각에 Fc단백질및 /또는폴리에틸렌글리콜 (PEG)이도입된형태인것을 특징으로하는리피바디 -약물복합체.
[청구항 3] 제 2항에있어서,
리피바디유도체는효소가인식할수있는아미노산모티프를 추가적으로갖는형태인것을특징으로하는리피바디 -약물복합체. [청구항 4] 제 3항에있어서,
아미노산모티프는 CAAX, XXCC, XCXC또는 CCXX이고,리피바디 유도체의 C-말단에직접또는스페이서를통하여연결된것으로서,이때, C는시스테인을, A는각각독립적으로지방족아미노산을, X는효소의 기질특이성을결정하는아미노산임을특징으로하는리피바디
유도체-약물복합체.
[청구항 5] 제 1항내지제 4항증어느한항에있어서,
상기리피바디유도체는 1또는 2이상의링커를통하여약물에결합되는 것을특징으로하는리피바디유도체 -약물복합체.
[청구항 6] 제 5항에있어서,
상기링커는,하기 (i)내지 (iv)증적어도하나를만족하는탄소수 1내지 50의알킬렌구조를지님을특징으로하는리피바디유도체 -약물복합체.
(i)상기알킬렌은적어도하나의불포화결합을포함하고,
(ii)상기알킬렌은적어도하나의헤테로아릴렌을포함하고,
(iii)상기알킬렌의탄소원자는질소 (N),산소 (O)및황 (S)으로부터 선택되는하나이상의해테로원자로치환되고,
(iv)상기알킬렌은탄소수 1내지 20의알킬로더치환된다.
[청구항 7] 제 6항에있어서,
상기링커는이소프레노이드트랜스퍼라제에의하여인식될수있는 하기화학식 A의이소프레닐유도체유닛을적어도하나이상포함하는 화합물임을특징으로하는리피바디유도체 -약물복합체.
[화학식 A]
[청구항 8] 제 7항에있어서, (결합유닛은구조식 (또는구조적표현)으로표현불가) 상기링커는 1,3-양극성고리첨가반응 (1,3-dipolar cycloaddition reactions)트리아졸,아이소옥사졸,헤테로-디엘스반웅 (hetero-diels reactions),친핵성치환반웅 (nucloephilic substitution reactions),논 -알돌형 카보닐반웅 (non-aldol type carbonyl reactions),탄소 -탄소다중결합에대한 첨가 (additions to carbon-carbon multiple bonds),산화반응 (oxidation reactions)또는클릭반웅 (click reaction)으로형성된결합유닛 (예, 아세틸렌과아지드와의반응);알데히드또는케톤그룹과하이드라진 또는하이드록실아민과의결합유닛올더포함하는화합물임을특징으로 하는리피바디유도체 -약물복합체.
[청구항 9] 제 8항에있어서,
상기결합유닛은하기화학식 B, C또는 D로표시되는화합물임을 특징으로하는리피바디유도체 -약물복합체.
[화학식 B]
[
상기식증,
1^은단일결합또는탄소수 1내지 30의알킬렌이고;
R„은수소또는탄소수 1내지 10의알킬이고;
L2는탄소수 1내지 30의알킬렌이다.
[청구항 10] 제 7항에있어서,
상기링커는화학식 E또는 F로표시되는연결유닛을더포함하는 화합물임올특징으로하는리피바디유도체 -약물복합체.
[화학식 E]
-(CH2)r(W(CH2)q)p-
[화학식 F]
-(CH2CH2V)X- 상기 W는 -0-, -S-, -NR21 -, -C(0)NR22-,-NR23C(0)-,-NR24S02-또는 S02NR25 -이고;
V는 -0-, d-C8알킬렌또는 -NR21 -이고;
R21내지 R25는각각독립적으로수소, d-C6알킬, d- 알킬 C6-C2。아릴또는 C,- 알킬 C3-C20해테로아릴이고;
r은 1내지 10의정수이고;
q는 0내지 10와정수이고;
p는 1내지 10의정수이고;및
X는 1내지 10의정수이다.
[청구항 U] 제 6항에있어서,
상기링커는 FPP(farnesyl pyrophosphate)의아날로그 (analog)인
FPP-carbonyl analog와결합된것올특징으로하는리피바디유도체 -약물 복합체.
[청구항 12] 제 1항내지제 11항증어느한항에있어서,
상기약물은독소,리간드,검출탐침또는이들의조합인것을특징으로 하는리피바디유도체 -약물복합체.
[청구항 13] 제 3항에있어서,
효소는소르타제 (Sortase), FGE (Formylglycine Generating Enzyme), 트랜스글루타미나제 (Transglutaminase)또는이소프레노이드 트랜스퍼라제 (isoprenoid transferase)인것을특징으로하는리피바디 유도체-약물복합체.
[청구항 I4] 제 13항에있어서,
이소프레노이드트랜스퍼라제는 FTase (Farnesyltransferase)또는 GGTase (Geranylgerany transferase)인것을특징으로하는리피바디유도체 -약물 복합체.
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CN108610415A (zh) * | 2018-05-15 | 2018-10-02 | 大连理工大学 | 一种抗体复合物的制备方法 |
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