WO2022268050A1 - 一种药物组合及其用途 - Google Patents
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- A61K47/68—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 the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
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Definitions
- the invention relates to the technical field of biomedicine, in particular to the use of methyl- ⁇ -cyclodextrin in ADC pharmaceutical preparations.
- ADC Antibody-drug conjugate
- Drug biologically active cytotoxin
- Antibody antibody
- Linker chemical linker
- the antibody-drug conjugate uses the targeting of monoclonal antibodies to specifically recognize and bind to receptors on the surface of cancer cells, and then enters the interior of the cell through endocytosis, using intracellular proteases Release cytotoxins to prevent cancer cells from multiplying and kill cancer cells.
- mammalian cells are generally used to produce and express antibodies, and the highly purified antibodies are coupled with the cytotoxin MMAE through a linker to obtain antibody-drug conjugates.
- Antibody-drug conjugation technology integrates small-molecule toxin drugs and biological proteins, and has the strengths of both, becoming a new generation of therapeutic products, which greatly enhances drug efficacy and reduces side effects.
- ADC has made a breakthrough in the treatment of malignant tumors, making it a new treatment method after surgery, chemotherapy and radiotherapy. But as of June 2021, only 12 ADCs have been approved globally (10 approved by FDA in the US, one approved by PMDA in Japan, and one approved in China).
- Methyl- ⁇ -cyclodextrin (CAS No.: 128446-36-6) is a macrocyclic compound with a molecular formula of C 54 H 94 O 35 and a molecular weight of 1303.3, which can form clathrates with many guest molecules. Compared with the parent ⁇ -cyclodextrin, it has higher solubility in aqueous solution and higher solubilization and complexing ability. At the same time, it can also increase the solubility of non-polar substances, such as fatty acids, lipids, vitamins and cholesterol, and can be used in cell culture.
- non-polar substances such as fatty acids, lipids, vitamins and cholesterol
- the present invention surprisingly finds that by using an effective amount of methyl- ⁇ -cyclodextrin, the dosage of ADC drugs can be reduced, and the safety of ADC drugs can be further ensured while ensuring the therapeutic effect.
- the present invention provides a use of an effective amount of methyl- ⁇ -cyclodextrin in reducing the dosage of antibody-drug conjugate drugs in treatment.
- the use refers to the combined application of an effective amount of methyl- ⁇ -cyclodextrin and antibody drug conjugate preparation, or methyl- ⁇ -cyclodextrin as an auxiliary material component of antibody drug conjugate preparation.
- the molar ratio of the methyl- ⁇ -cyclodextrin to the antibody-drug conjugate in the drug is 100-60000: 0.001-100; or 200-50000: 0.001-50; or 200-40000: 0.01 ⁇ 50; or 200 ⁇ 40000: 0.01 ⁇ 20; or 200 ⁇ 40000: 0.01 ⁇ 10; the preferred molar ratio is 250 ⁇ 39000: 0.01 ⁇ 1; or 200 ⁇ 39000: 0.01 ⁇ 0.5; the more preferred molar ratio is 300 ⁇ 38170: 0.02 ⁇ 0.2.
- the antibody drug conjugate is used for treating tumors, autoimmune diseases or infectious diseases.
- the target of the antibody drug conjugate is selected from BCMA, CD79B, c-Met, GPNMB, IL2RA, LY6E, CD1, CD1a, CD2, CD3, CD4, CD5, CD8, CD11A , CD14, CD15, CD16, CD18, CD19, CD20, CD21, CD22, CD23, CD25, CD29, CD30, CD32b, CD33, CD37, CD38, CD40, CD40L, CD44, CD45, CD46, CD52, CD54, CD55, CD59 , CD64, CD67, CD70, CD74, CD79a, CD79b, CD80, CD83, CD95, CD126, CD133, CD138, CD147, CD154, CD166, CD276, HER1, HER2, HER3, MUC1, PTK7, STEAP1, VTCN1, AXL, BCMA , CA9, CASP, CASP3, CDH3, CDKs, CEACAM5, CLDN18, c-Met, Crip
- the target of the antibody drug conjugate is selected from CD19, EGFR, BCMA, Trop-2, TOP1, NECTIN4, CD79B, CD22, HER2, CD30, CD33, c-Met, Cytokines, Tubulins and combinations.
- the antibody-drug conjugate is selected from the group consisting of Loncastuximab tesirine, Cetuximab sarotalocan, Belantamab mafodotin (mabetuzumab), Sacituzumab govitecan (goxatuzumab), Fam-trastuzumab deruxtecan, Enfortumab vedotin, Polatuzumab vedotin, Inotuzumab Ozogamicin, Ado-trastuzumab emtansine, Brentuximab vedotin, Gemtuzumab ozogamicin, Disitamab Vedotin cetuzumab), Tisotumab vedotin, Depatuxizumab mafodotin, TAA-013, Trastuzumab duocarmazine, KSI-301, BAT-8001, Rovalpituzumab tesi
- the CDRs of the heavy chain variable region of the antibody or antigen-binding portion of the antibody drug conjugate are shown in SEQ ID NO: 1-3 (Kabat numbering), and the light chain variable region CDR is shown in SEQ ID NO: 4-6 (Kabat numbering); Specifically, the amino acid sequence of its heavy chain variable region and light chain variable region is shown in SEQ ID NO: 7-8; More specifically, its The amino acid sequences of the heavy and light chains are shown in SEQ ID NO: 9-10.
- SEQ ID NO: 1 (heavy chain variable region CDR1):
- SEQ ID NO: 2 (heavy chain variable region CDR2):
- SEQ ID NO: 3 (heavy chain variable region CDR3):
- SEQ ID NO: 4 (light chain variable region CDR1):
- SEQ ID NO: 5 (light chain variable region CDR2):
- SEQ ID NO: 6 (light chain variable region CDR3):
- SEQ ID NO: 8 (light chain variable region):
- the antibody drug conjugate has the following structure:
- C-Met represents an antibody targeting C-Met, and in some preferred embodiments, the target The antibody to C-Met is a monoclonal antibody or a functional fragment thereof.
- the C-Met antibody has the CDR sequence of the heavy chain variable region described in SEQ ID NO: 1-3 , and/or have the CDR sequence of the light chain variable region described in SEQ ID NO: 4-6.
- the C-Met antibody has the amino acid sequence of the heavy chain variable region described in SEQ ID NO:7 and/or the amino acid sequence of the light chain variable region described in SEQ ID NO:8 .
- the c-Met antibody has the heavy chain amino acid sequence described in SEQ ID NO:9 and/or the light chain amino acid sequence described in SEQ ID NO:10.
- the antibody drug conjugate has the following structure:
- the heavy chain variable region CDR sequence of the Ab2 is shown in SEQ ID NO: 1-3, and the light chain variable region sequence CDR sequence is shown in SEQ ID NO: 4-6, and the heavy chain variable region sequence is shown in As shown in SEQ ID NO: 7, the light chain variable region sequence is shown in SEQ ID NO: 8, the heavy chain amino acid sequence is shown in SEQ ID NO: 9, and the light chain amino acid sequence is shown in SEQ ID NO: 10; and Its average DAR value is 4.02.
- the CDRs of the heavy chain variable region of the antibody or antigen-binding portion of the antibody drug conjugate are shown in SEQ ID NO: 11-13 (IMGT numbering), and the light chain variable region The CDR is shown in SEQ ID NO: 14-16 (IMGT numbering); specifically, the amino acid sequences of its heavy chain variable region and light chain variable region are shown in SEQ ID NO: 17-18; more specifically, its The amino acid sequences of the heavy and light chains are shown in SEQ ID NO: 19-20.
- SEQ ID NO: 12 (heavy chain variable region CDR2):
- SEQ ID NO: 14 (light chain variable region CDR1):
- SEQ ID NO: 15 (light chain variable region CDR2):
- SEQ ID NO: 16 (light chain variable region CDR3):
- SEQ ID NO: 18 (light chain variable region):
- the antibody drug conjugate has the following structure:
- n represents an integer selected from 1, 2, 3, 4, 5, 6, 7, 8;
- Her2 represents an antibody targeting Her2, and in some preferred embodiments, the antibody targeting Her2 It is a monoclonal antibody or a functional fragment thereof.
- the Her2 antibody has the CDR sequence of the heavy chain variable region described in SEQ ID NO: 11-13, and/or has SEQ ID NO : CDR sequences of the light chain variable region described in 14-16.
- the Her2 antibody has the amino acid sequence of the heavy chain variable region described in SEQ ID NO: 17 and/or the amino acid sequence of the light chain variable region described in SEQ ID NO: 18.
- the Her2 antibody has the heavy chain amino acid sequence described in SEQ ID NO:19 and/or the light chain amino acid sequence described in SEQ ID NO:20.
- the antibody drug conjugate is Vidicumumab (i.e. Disitamab Vedotin)
- the tumor is a solid tumor or a non-solid tumor; preferably, the tumor is selected from hematopoietic tumor, carcinoma, sarcoma, melanoma or glial tumor; more preferably, the tumor is selected from Breast cancer, ovarian cancer, cervical cancer, uterine cancer, prostate cancer, kidney cancer, urethral cancer, bladder cancer, liver cancer, stomach cancer, endometrial cancer, salivary gland cancer, esophageal cancer, lung cancer, colon cancer, rectal cancer, colorectal cancer , bone cancer, skin cancer, thyroid cancer, pancreatic cancer, melanoma, glioma, neuroblastoma, glioma multiforme, sarcoma, lymphoma and leukemia and other solid or hematological tumors;
- the autoimmune disease is non-limitingly selected from immune-mediated thrombocytopenia, dermatomyositis, Sjögren's syndrome, multiple sclerosis, Sidenham's chorea, myasthenia gravis, Systemic lupus erythematosus, lupus nephritis, rheumatic fever, rheumatoid arthritis, polyglandular syndrome, bullous pemphigoid, diabetes mellitus, Henschler's purpura, poststreptococcal nephritis, nodular Erythema, Takayasu arteritis, Addison's disease, sarcoidosis, ulcerative colitis, erythema multiforme, IgA nephropathy, polyarteritis nodosa, ankylosing spondylitis, Goodpasque syndrome, Thromboangiitis obliterans, primary biliary cirrhos
- infectious disease is non-limitingly selected from human immunodeficiency virus (HIV), Mycobacterium tuberculosis, Streptococcus agalactiae, methicillin-resistant Staphylococcus aureus, Legionella pneumophila, Streptococcus pyogenes Cocci, Escherichia coli, Neisseria gonorrhoeae, Neisseria meningitidis, Pneumococcus, Haemophilus influenzae type B, Treponema pallidum, Lyme disease, West Nile virus, Pseudomonas aeruginosa, Mycobacterium leprae, Bacillus abortus, Rabies virus, Influenza virus, Cytomegalovirus, Herpes simplex virus type I, Herpes simplex virus type II, Human serum parvovirus, Respiratory syncytial virus, Varicella zoster virus, Hepatitis B Virus, measles
- the methyl- ⁇ -cyclodextrin is used as one of the auxiliary material components of the antibody-drug conjugate preparation.
- the methyl- ⁇ -cyclodextrin is developed into a methyl- ⁇ -cyclodextrin preparation and used in combination with an antibody-drug conjugate drug.
- the present invention also provides the use of methyl- ⁇ -cyclodextrin in the preparation of medicines for reducing the therapeutic dosage of antibody-drug conjugates.
- the present invention also provides an antibody-drug conjugate preparation, which contains an effective amount of methyl- ⁇ -cyclodextrin auxiliary material.
- the molar ratio of the methyl- ⁇ -cyclodextrin to the antibody-drug conjugate is 100-60000: 0.001-100; or 200-50000: 0.001-50; or 200-40000: 0.01-50 ; or 200-40000: 0.01-20; or 200-40000: 0.01-10; the preferred molar ratio is 250-39000: 0.01-1; or 200-39000: 0.01-0.5; the more preferred molar ratio is 290-38360 : 0.02 to 0.15. .
- the present invention also provides a method for treating diseases with combination drugs, characterized in that the drug combination comprises: an effective dose of methyl- ⁇ -cyclodextrin or its pharmaceutically acceptable adjuvant, and Antibody drug conjugate or its pharmaceutically acceptable adjuvant; wherein, the disease is selected from tumor, autoimmune disease or infectious disease.
- the molar ratio of the methyl- ⁇ -cyclodextrin to the antibody drug conjugate is 200-40000:0.001-100; the preferred molar ratio is 250-39000:0.01-10 ; The more preferred molar ratio is 290-38360:0.02-0.15. .
- the methyl- ⁇ -cyclodextrin and antibody drug conjugate used in the present invention can be a liquid preparation or a freeze-dried preparation. In the case of combined drug administration, simultaneous or sequential administration can be used.
- the present invention also provides preparations formed of methyl- ⁇ -cyclodextrin or its pharmaceutically acceptable adjuvants, and antibody-drug conjugates or preparations formed of pharmaceutically acceptable adjuvants in the preparation of treatment of cancer, self Use in immune diseases and infectious diseases.
- the methyl- ⁇ -cyclodextrin discovered in the present invention can significantly improve the efficacy of ADCs, making it possible for some ADC drugs that have safety problems due to excessive dosage to continue to be developed. It can reduce the dosage of ADC drugs, thereby ensuring safety while ensuring effectiveness, and significantly improving the possibility of successful development of ADC drugs. And due to the reduction of the dosage of ADC drugs, the production cost is also greatly reduced, and the economic burden on patients is significantly reduced.
- Fig. 3 The effect of Vedicumumab and methyl- ⁇ -cyclodextrin used alone on tumor cell proliferation;
- antibody drug conjugate used in the present invention refers to a compound in which an antibody or antigen-binding fragment, a linking unit, and an active drug unit are linked together through a chemical reaction, and its structure usually consists of three parts : an antibody or antibody-like ligand, a drug part (ie, an active drug unit), and a linker that couples the antibody or antibody-like ligand and the drug part.
- antibody used in the present invention refers to a macromolecular compound that can recognize and bind to an antigen or receptor associated with a target cell.
- the function of the antibody is to present the drug to the target cell population bound to the antibody.
- These antibodies include but are not limited Protein hormones, lectins, growth factors, antibodies, or other molecules that bind to cells.
- antibodies include murine antibodies, chimeric antibodies, primatized antibodies, humanized antibodies (i.e. humanized) and fully human antibodies (i.e. human), preferably humanized antibodies and fully humanized antibodies Human antibodies.
- murine antibody in this disclosure refers to an antibody prepared using a mouse according to the knowledge and skill in the art. hybridization in which test subjects are injected with a specific antigen and then isolated expressing antibodies with desired sequence or functional properties
- chimeric antibody is an antibody formed by fusing the variable region of a murine antibody with the constant region of a human antibody, which can reduce the immune response induced by the murine antibody.
- To establish a chimeric antibody it is necessary to first establish a hybridoma that secretes a mouse-derived specific monoclonal antibody, then clone the variable region gene from the mouse hybridoma cell, and then clone the constant region gene of the human antibody as required, and then clone the mouse variable region gene It is connected with the human constant region gene to form a chimeric gene and inserted into an expression vector, and finally expresses the chimeric antibody molecule in a eukaryotic system or a prokaryotic system.
- humanized antibody is also called CDR-grafted antibody (CDR-grafted antibody), which refers to the antibody variable region framework grafted with the mouse CDR sequence, that is, a different type of human germline antibody framework Antibodies generated in the sequence. It can overcome the heterologous reaction induced by chimeric antibodies due to carrying a large number of murine protein components.
- CDR-grafted antibody CDR-grafted antibody
- Such framework sequences can be obtained from public DNA databases or published references that include germline antibody gene sequences.
- the germline DNA sequences of the human heavy and light chain variable region genes can be found in the "VBase" human germline sequence database (available on the Internet at www.mrccpe.com/ac.uk/vbase), as well as in Kabat, E.A. et al.
- the humanized antibody of the present invention also includes the humanized antibody after affinity maturation of CDR by phage display. Further descriptions of methods involving the use of mouse antibodies in humanization include, for example, the methods of Queen et al., Proc., Natl. Acad. Sci.
- the development of monoclonal antibodies has gone through four stages, namely: murine monoclonal antibodies, chimeric monoclonal antibodies, humanized monoclonal antibodies and fully human monoclonal antibodies.
- the invention is a fully human monoclonal antibody.
- the relevant technologies for the preparation of fully human antibodies mainly include: human hybridoma technology, EBV transformed B lymphocyte technology, phage display technology (phage display), transgenic mouse antibody preparation technology (transgenic mouse) and single B cell antibody preparation technology, etc.
- the term "antigen-binding fragment” refers to one or more fragments of an antibody that retain the ability to specifically bind an antigen.
- binding fragments included in “antigen-binding fragments” include (i) Fab fragments, monovalent fragments consisting of VL, VH, CL and CH1 domains; (ii) F(ab') 2 fragments, comprising (iii) Fd fragment consisting of VH and CH1 domains; (iv) Fv fragment consisting of VH and VL domains of a single arm of an antibody; (v ) a single domain or dAb fragment (Ward et al., (1989) Nature 341:544-546) consisting of a VH domain; and (vi) isolated complementarity determining regions (CDRs) or (vii) optionally via A combination of two or more isolated CDRs joined by a synthetic linker.
- CDRs complementarity determining regions
- the two domains VL and VH of the Fv fragment are encoded by separate genes, they can be linked by a synthetic linker using recombinant methods, thus making it possible to produce a single protein in which the VL and VH regions pair to form a monovalent molecule. chain (referred to as single-chain Fv (scFv); see, eg, Bird et al. (1988) Science 242:423-426 and Huston et al. (1988) Proc. Nat L. Acad. Sci. USA 85:5879-5883).
- single chain antibodies are also intended to be encompassed within the term "antigen-binding fragment" of an antibody.
- Antigen-binding portions can be produced by recombinant DNA techniques or by enzymatic or chemical cleavage of intact immunoglobulins.
- Antibodies can be of different isotypes, eg, IgG (eg, IgG1, IgG2, IgG3 or IgG4 subtype), IgAl, IgA2, IgD, IgE or IgM antibodies.
- Fab is an antibody fragment having a molecular weight of about 50,000 and having antigen-binding activity among fragments obtained by treating an IgG antibody molecule with the protease papain (cleaving the amino acid residue at position 224 of the H chain), wherein the H chain N About half of the end sides and the entire L chain are held together by disulfide bonds.
- F(ab') 2 is obtained by digesting the lower part of the two disulfide bonds in the IgG hinge region with the enzyme pepsin, having a molecular weight of about 100,000 and having antigen-binding activity and comprising two Fab regions connected at the hinge position Antibody fragments.
- Fab' is an antibody fragment having a molecular weight of about 50,000 and having antigen-binding activity obtained by cleaving the disulfide bond of the hinge region of the above-mentioned F(ab')2.
- the Fab' fragment can be produced by inserting DNA encoding a Fab' fragment of an antibody into a prokaryote expression vector or a eukaryote expression vector and introducing the vector into a prokaryote or eukaryote to express the Fab'.
- single-chain construct includes, but is not limited to, "single-chain antibody”, “single-chain Fv” or “scFv”, and is meant to comprise an antibody heavy chain variable domain or region (i.e., VH) and an antibody light chain connected by a linker.
- Such scFv molecules may have the general structure: NH2-VL-linker-VH-COOH or NH2-VH-linker-VL-COOH.
- Suitable prior art linkers consist of the repeated GGGGS amino acid sequence or variants thereof, for example using 1-4 repeat variants (Holliger et al. (1993), proc. Natl. Acad. Sci.
- monoclonal antibodies can be obtained by injecting a mouse with a composition comprising an antigen, removing the spleen to obtain B lymphocytes, fusing the B lymphocytes with myeloma cells to generate hybridomas, cloning the hybrid tumors, positive clones producing antibodies against the antigen are selected, the clones producing antibodies against the antigen are cultured, and the antibodies are isolated from the hybridoma culture.
- Isolation and purification from hybridoma cultures can be accomplished by a number of well-established techniques. Such separation techniques include protein A or protein G sepharose affinity chromatography, size exclusion chromatography, and ion exchange chromatography.
- linking unit refers to a chemical structural fragment or bond that is connected to the antibody/antigen-binding fragment at one end and the drug at the other end, thus serving as a "bridge” between the antibody/antigen-binding fragment and the drug molecule connect them. It may include linkers, spacers and amino acid units, and may be synthesized by methods known in the art, such as described in US2005-0238649A1. As used herein, “linker units” can be divided into two categories: non-cleavable linkers and cleavable linkers.
- Non-cleavable linkers are relatively stable linkers whose structure is difficult to degrade and break in vivo.
- the drug release mechanism is as follows: after the conjugates bind to the antigen and are endocytosed by cells, the antibody is enzymatically hydrolyzed in lysosomes, releasing the drug, linker, An active molecule composed of antibody amino acid residues. The resulting change in the molecular structure of the drug does not reduce its cytotoxicity, but since the active molecule is charged (amino acid residues), it cannot penetrate neighboring cells.
- a cleavable linker can break within the target cell and release the active drug (the small molecule drug itself).
- Cleavable linkers can be divided into two main categories: chemically labile linkers and enzymatically labile linkers.
- Chemically unstable linkers can be selectively cleaved due to differences in plasma and cytoplasmic properties. Such properties include pH, glutathione concentration, etc.
- Linkers that are sensitive to pH are also commonly referred to as acid-cleavable linkers. Such linkers are relatively stable in the neutral environment of blood (pH 7.3-7.5), but will be hydrolyzed in the weakly acidic endosomes (pH 5.0-6.5) and lysosomes (pH 4.5-5.0). Most of the first-generation antibody-drug conjugates use such linkers, such as hydrazones, carbonates, acetals, and ketals. Due to the limited plasma stability of acid-cleavable linkers, antibody drug conjugates based on such linkers usually have a short half-life (2-3 days). This short half-life limits the application of pH-sensitive linkers in the new generation of antibody-drug conjugates to some extent.
- Glutathione-sensitive linkers also known as disulfide linkers. Drug release is based on the difference between the high concentration of intracellular glutathione (millimolar range) and the relatively low concentration of glutathione in the blood (micromolar range). This is especially true for tumor cells, where low oxygen levels lead to increased reductase activity and thus higher glutathione concentrations. Disulfide bonds are thermodynamically stable, so they have good stability in plasma.
- Enzyme-labile linkers such as peptide linkers, allow better control of drug release.
- Peptide linkers can be efficiently cleaved by endolysosomal proteases such as cathepsin B or plasmin (these enzymes are increased in some tumor tissues). This peptide linkage is thought to be very stable in the plasma circulation because proteases are generally inactive outside the cell due to unfavorable extracellular pH and serum protease inhibitors.
- Enzyme-labile linkers are widely used as cleavable linkers for antibody-drug conjugates due to their high plasma stability and good intracellular cleavage selectivity and efficiency.
- the suicide linker is generally embedded between the cleavable linker and the active drug, or is itself a part of the cleavable linker.
- the mechanism of action of the suicide linker is: when the cleavable linker is broken under suitable conditions, the suicide linker can spontaneously undergo structural rearrangement, and then release the active drug linked to it.
- Common suicide linkers such as p-aminobenzyl alcohol (PAB) and so on.
- the "linkage unit” or “linker” can be selected from the following without limitation, wherein the wavy line represents the covalent connection site with the antibody (antibody) and toxin (drug):
- toxin drug
- drug moiety drug unit
- drug unit used in the present invention generally refer to the same structure, and can be used with any name in the present invention. They generally refer to any compound with desired biological activity and reactive functional groups for the preparation of the conjugates of the present invention. Desired biological activities include diagnosing, curing, mitigating, treating, preventing disease in humans or other animals. As new drugs are continuously discovered and developed, these new drugs should also be included in the drugs described in the present invention.
- Any substance that can have harmful effects on the growth or proliferation of cells can be small molecule toxins and their derivatives from bacteria, fungi, plants or animals, it can include but not limited to cytotoxic drugs, cell differentiation factors, stem cell nutrition Factors, steroid drugs, drugs for the treatment of autoimmune diseases, anti-inflammatory drugs or drugs for the treatment of infectious diseases; or further tubulin inhibitors or DNA damage agents; or further dolastatins (dolastatin), Auristatins, maytansines; calicheamicins, duocarmycins, antramycin derivatives PBD, camptothecin derivatives SN -38; amanitins, anthracyclines, baccatins, camptothecins, cemadotins, colchicines, colchicum Colcimids, combretastatins, cryptophycins, discodermolides, docetaxel, doxorubicin, echinomycins, eleutherobins, e
- toxin can be camptothecin derivatives such as isatecan, maytansinoids and their derivatives (CN101573384 ) such as DM1, DM3, DM4, auristatin F (AF) and its derivatives, such as MMAF, MMAE, 3024 (WO 2016/127790A1), diphtheria toxin, exotoxin, ricin (ricin) A chain, acacia toxin Protein (abrin) chain A, modeccin, ⁇ -sarcin, tung oil (Aleutites fordii) toxin, carnation (dianthin) toxin, pokeweed (Phytolaca americana) toxin (PAPI, PAPII and PAP-S), Momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, serlinin (mitogellin) restrictocin
- camptothecin derivatives such as isatecan
- Antibody-drug conjugates were prepared using a general preparation method:
- HIC-HPLC hydrophobic chromatography
- HIC-HPLC hydrophobic chromatography
- the following two antibody-drug conjugates were prepared by any of the above methods: Vidicumumab (Disitamab Vedotin) and AAJ8D6-ADC (C-Met-Mc-Val-Cit-MMAE, a C-Met-Mc-Val-Cit-MMAE targeting C -Met target antibody drug conjugate).
- Vidicumumab (Disitamab Vedotin) (average DAR value 4.01):
- n represents an integer selected from 1, 2, 3, 4, 5, 6, 7, 8;
- Ab1 represents a Her2 antibody, and its heavy chain and light chain amino acid sequences are respectively as SEQ ID NO: 19 and SEQ ID NO: 20 Shown:
- AAJ8D6-ADC (average DAR value 4.02):
- m represents an integer selected from 1, 2, 3, 4, 5, 6, 7, 8;
- Ab2 represents targeting C-Met monoclonal antibody, and its heavy chain and light chain amino acid sequences are respectively as SEQ ID NO: 9 and Shown in SEQ ID NO:10:
- Example 2 Combination of Disitamab Vedotin and Methyl- ⁇ -cyclodextrin In Vitro Anticancer Activity of Drug Combinations on SK-BR-3 Cells
- SK-BR-3 cells were inoculated into a 96-well plate at a concentration of 5 ⁇ 10 4 /mL, 100 ⁇ L/well, administered according to the concentration ratio of the combined drugs in Table 2, and the cell viability was detected by CCK8 method after 72 hours.
- the drug concentration refers to the final concentration of the drug.
- Chou-Talalay method (combination index, abbreviated as CI) was used to evaluate the inhibitory effect of vedicumumab and methyl- ⁇ -cyclodextrin in different ratios on the proliferation of SK-BR-3 cells for 72 hours
- CI combination index
- Example 3 Combination of Disitamab Vedotin and Methyl- ⁇ -cyclodextrin In Vitro Anticancer Activity of Drug Combinations on NCI-N87 Cells
- NCI-N87 cells were inoculated into a 96-well plate at a concentration of 5 ⁇ 10 4 /mL, 100 ⁇ L/well, administered according to the concentration ratio of the combined drugs in Table 4, and the cell viability was detected by the CCK8 method after 72 hours.
- Combined Drug Combinations 2-4 14.0ng/mL 6250ng/mL Combination drug combination 2-5 14.0ng/mL 3125ng/mL Combined Drug Combinations 2-6 14.0ng/mL 1562.5ng/mL Combined Drug Combinations 2-7 14.0ng/mL 781.25ng/mL Combined Drug Combinations 2-8 14.0ng/mL 390.625ng/mL Control group 2-1 14.0ng/mL 0
- Example 4 AAJ8D6-ADC and methyl- ⁇ -cyclodextrin combined drug combination on MKN-45 In vitro anticancer activity of cells
- MKN-45 cells were inoculated into a 96-well plate at a concentration of 5 ⁇ 10 4 /mL, 100 ⁇ L/well, administered according to the concentration ratio of the combined drugs in Table 6, and the cell viability was detected by the CCK8 method 72 hours later.
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Abstract
提供了一种药物组合及其用途,通过使用有效量的甲基-β-环糊精作为制剂成分或联合辅助用药能够显著提升ADC药效上的效果,使得部分因用量过高而产生安全性问题的ADC药物得以开发,并且由于ADC药物剂量的降低,也使得生产成本及患者的治疗成本大幅降低,从而获益。
Description
本发明涉及生物医药技术领域,尤其涉及甲基-β-环糊精在ADC药物制剂中的用途。
近年来,全球恶性肿瘤的总体发病率呈现持续升高的趋势,严重威胁着人类的健康和生存。目前临床上治疗恶性肿瘤主要以手术、化疗和放疗为主,但是都很难达到满意的疗效。抗体药物偶联物(antibody-drug conjugate,ADC)是一种通过化学连接子(Linker)将具有生物活性的细胞毒素(Drug)和抗体(Antibody)连接起来的一类生物药,当抗体与细胞毒素偶联后,抗体药物偶联物利用单克隆抗体的靶向性,特异性地识别癌细胞表面的受体,并与之结合,然后经内吞作用进入到细胞内部,利用细胞内的蛋白酶释放细胞毒素阻止癌细胞繁殖与杀灭癌细胞。现有技术一般采用哺乳动物细胞培养生产表达抗体,经过高度纯化后的抗体与细胞毒素MMAE通过连接子偶联,获得抗体药物偶联物。抗体药物偶联技术使小分子毒素药物与生物蛋白融为一体,兼具二者之长,成为新一代治疗产品,在极大增强药效的同时减少毒副作用。
目前,ADC在治疗恶性肿瘤方面取得了突破性的进展,使其成为了继手术、化疗、放疗后的一大新兴治疗方法。但截止到2021年6月,全球仅批准了12种ADC(美国FDA批准了10种,日本PMDA批准了一种,中国批准了一种)。
表1 已上市抗体药物偶联物
注:Mylotarg于2000年获批上市后在2010年撤市,后于2017年重新获批上市。
之所以ADC批准这么少的原因,主要受限于ADC药物制剂的偶联技术、靶向性、有效性、安全性等问题的困扰,在所有的失败案例中,药效和安全性是最主要的原因,比例高达52%及24%。通过制剂成分或联合辅助用药来提高ADC药物的效果是目前的一个探索途径。
甲基-β-环糊精(CAS号:128446-36-6)是分子式为C
54H
94O
35,分子量为1303.3的一种大环化合物,可以与许多客体分子形成包合物。它与母体β-环糊精相比,在水溶液中的溶解度更高,增溶和络合能力更高。同时它还可增加非极性物质的溶解性,如脂肪酸、脂类、维生素和胆固醇,可用于细胞培养中。
发明内容
本发明惊奇的发现,通过使用有效量的甲基-β-环糊精,可以降低ADC药物的用量,在保障治疗效果的同时又进一步保障了ADC药物的安全性。
具体的,本发明提供了一种有效量的甲基-β-环糊精在降低抗体药物偶联物药物在治疗中用量的用途。其中,所述的用途是指有效量的甲基-β-环糊精和抗体药物偶联物制剂联合应用,或者甲基-β-环糊精作为抗体药物偶联物药物制剂的辅料成分。
进一步的,所述甲基-β-环糊精与所述药物中抗体药物偶联物的摩尔比为100~60000:0.001~100;或200~50000:0.001~50;或200~40000:0.01~50;或200~40000:0.01~20;或200~40000:0.01~10;优选的摩尔比为250~39000:0.01~1;或200~39000:0.01~0.5;更优选的摩尔比为300~38170:0.02~0.2。
进一步的,所述抗体药物偶联物用于治疗肿瘤、自身免疫疾病或感染性疾病。
在一些具体的实施例中,所述的抗体药物偶联物的靶点选自BCMA、CD79B、c-Met、GPNMB、IL2RA、LY6E、CD1、CD1a、CD2、CD3、CD4、CD5、CD8、CD11A、CD14、CD15、CD16、CD18、CD19、CD20、CD21、CD22、CD23、CD25、CD29、CD30、CD32b、CD33、CD37、CD38、CD40、CD40L、CD44、CD45、CD46、CD52、CD54、CD55、CD59、CD64、CD67、CD70、CD74、CD79a、CD79b、CD80、CD83、CD95、CD126、CD133、CD138、CD147、CD154、CD166、CD276、HER1、HER2、HER3、MUC1、PTK7、STEAP1、VTCN1、AXL、BCMA、CA9、CASP、CASP3、CDH3、CDKs、CEACAM5、CLDN18、c-Met、Cripto-1、CTL4、DLL3、EF2、EFNA4、EGFR、ENPP3、EphA2、ETBR、FGFR2、FGFR3、FOLR1、FOLR1、Ganglioside、GCPII、HER2、HER3、HGFR、HLA-DR、IGF1R、IL3RA、ITGAV、ITGB3、KIT、LAMP1、Lewis-Y、LRRC15、LY75、LYPD3、MCP、MELTF、MSLN、MUC1、MUC16、NaPi-2b、NCAM1、NECTIN4、NOTCH3、Prolactin receptor、RNA polymerase II、ROR1、SDC1、SGLT2、SLAMF6、SLAMF7、SLITRK6、STAR、STING、TfR、TIM1、TLR8、TNF、TOP1、TPBG、Trop-2、VEGF、ZIP6、细胞因子、微管蛋白及组合;
在一些更具体的实施例中,所述的抗体药物偶联物的靶点选自CD19、EGFR、BCMA、Trop-2、TOP1、NECTIN4、CD79B、CD22、HER2、CD30、CD33、c-Met、细胞因子、微管蛋白及组合。
在一些特定的实施例中,所述的抗体药物偶联物选自Loncastuximab tesirine、Cetuximab sarotalocan、Belantamab mafodotin(玛贝妥单抗)、 Sacituzumab govitecan(戈沙妥组单抗)、Fam-trastuzumab deruxtecan、Enfortumab vedotin、Polatuzumab vedotin、Inotuzumab Ozogamicin(奥英妥珠单抗)、Ado-trastuzumab emtansine(恩美曲妥珠单抗)、Brentuximab vedotin(维布妥昔单抗)、Gemtuzumab ozogamicin、Disitamab Vedotin(维迪西妥单抗)、Tisotumab vedotin、Depatuxizumab mafodotin、TAA-013、Trastuzumab duocarmazine、KSI-301、BAT-8001、Rovalpituzumab tesirine、SAR-408701、datopotamab、Mirvetuximab soravtansine、ARX-788、Trastuzumab emtansine、Telisotuzumab vedotin、SHR-A1403。其中:
在另一些特定的实施例中,所述的抗体药物偶联物的抗体或抗原结合部分的重链可变区CDR如SEQ ID NO:1-3所示(Kabat编号),轻链可变区CDR如SEQ ID NO:4-6所示(Kabat编号);具体的,其重链可变区和轻链可变区的氨基酸序列如SEQ ID NO:7-8所示;更具体的,其重链和轻链的氨基酸序列如SEQ ID NO:9-10所示。
SEQ ID NO:1(重链可变区CDR1):
SEQ ID NO:2(重链可变区CDR2):
SEQ ID NO:3(重链可变区CDR3):
SEQ ID NO:4(轻链可变区CDR1):
SEQ ID NO:5(轻链可变区CDR2):
SEQ ID NO:6(轻链可变区CDR3):
SEQ ID NO:7(重链可变区):
SEQ ID NO:8(轻链可变区):
SEQ ID NO:9(重链):
SEQ ID NO:10(轻链):
在另一些具体的实施例中,所述的抗体药物偶联物具有以下结构:
其中:m代表选自1、2、3、4、5、6、7、8的整数;“C-Met”代表靶向C-Met的抗体,在一些优选的实施例中,所述的靶向C-Met的抗体为单克隆抗体或其功能性片段,在一些具体的实施例中,所述的C-Met 抗体具有SEQ ID NO:1-3所述的重链可变区的CDR序列,和/或具有SEQ ID NO:4-6所述的轻链可变区的CDR序列。在一些更具体的实施例中,所述的C-Met抗体具有SEQ ID NO:7所述的重链可变区氨基酸序列和/或SEQ ID NO:8所述的轻链可变区氨基酸序列。在另一些更更具体的实施例中,所述的C-Met抗体具有SEQ ID NO:9所述的重链氨基酸序列和/或SEQ ID NO:10所述的轻链氨基酸序列。
在一些具体的实施例中,所述的抗体药物偶联物具有以下结构:
所述的Ab2的重链可变区CDR序列如SEQ ID NO:1-3所示,和轻链可变区序列CDR序列如SEQ ID NO:4-6所示,重链可变区序列如SEQ ID NO:7所示,轻链可变区序列如SEQ ID NO:8所示,重链氨基酸序列如SEQ ID NO:9所示,轻链氨基酸序列如SEQ ID NO:10所示;且其平均DAR值为4.02。
在另一些特定的实施例中,所述的抗体药物偶联物的抗体或抗原结合部分的重链可变区CDR如SEQ ID NO:11-13所示(IMGT编号),轻链可变区CDR如SEQ ID NO:14-16所示(IMGT编号);具体的,其重链可变区和轻链可变区的氨基酸序列如SEQ ID NO:17-18所示;更具体的,其重链和轻链的氨基酸序列如SEQ ID NO:19-20所示。
SEQ ID NO:11(重链可变区CDR1):
SEQ ID NO:12(重链可变区CDR2):
SEQ ID NO:13(重链可变区CDR3):
SEQ ID NO:14(轻链可变区CDR1):
SEQ ID NO:15(轻链可变区CDR2):
SEQ ID NO:16(轻链可变区CDR3):
SEQ ID NO:17(重链可变区):
SEQ ID NO:18(轻链可变区):
SEQ ID NO:19(重链):
SEQ ID NO:20(轻链):
在一些具体的实施例中,所述的抗体药物偶联物具有以下结构:
其中:n代表选自1、2、3、4、5、6、7、8的整数;“Her2”代表靶向Her2的抗体,在一些优选的实施例中,所述的靶向Her2的抗体为单克隆抗体或其功能性片段,在一些具体的实施例中,所述的Her2抗体具有SEQ ID NO:11-13所述的重链可变区的CDR序列,和/或具有SEQ ID NO:14-16所述的轻链可变区的CDR序列。在一些更具体的实施例中,所述的Her2抗体具有SEQ ID NO:17所述的重链可变区氨基酸序列和/或SEQ ID NO:18所述的轻链可变区氨基酸序列。在另一些更更具体的实施例中,所述的Her2抗体具有SEQ ID NO:19所述的重链氨基酸序列和/或SEQ ID NO:20所述的轻链氨基酸序列。
在一些特定的实施例中,所述的抗体药物偶联物为维迪西妥单抗(即Disitamab Vedotin)
进一步的,所述的肿瘤为实体瘤或者非实体瘤;优选的,所述的肿瘤选自造血肿瘤、癌、肉瘤、黑素瘤或神经胶质肿瘤;更优选的,所述的肿瘤选自乳腺癌、卵巢癌、宫颈癌、子宫癌、前列腺癌、肾癌、尿道癌、膀胱癌、肝癌、胃癌、子宫内膜癌、唾液腺癌、食道癌、肺癌、结肠癌、直肠癌、结直肠癌、骨癌、皮肤癌、甲状腺癌、胰腺癌、黑色素瘤、神经胶质瘤、神经母细胞瘤、多形性胶质细胞瘤、肉瘤、淋巴瘤和白血病等实体瘤或血液肿瘤;
进一步的,所述的自身免疫疾病非限制性地选自免疫介导的血小板减少症、皮肌炎、舍格伦氏综合症、多发性硬化、西登哈姆氏舞蹈病、重症肌无力、系统性红斑狼疮、狼疮性肾炎、风湿热、类风湿性关节炎、多腺体综合征、大疱性类天疱疮、糖尿病、亨-舍二氏紫癜、链球菌感染后肾炎、结节性红斑、高安氏动脉炎、阿狄森氏病、结节病、溃疡性结肠炎、多形性红斑、IgA肾病、结节性多动脉炎、强直性脊柱炎、古德帕斯丘综合征、闭塞性血栓性脉管炎、原发性胆汁性肝硬变、桥本甲状腺炎、甲状腺毒症、硬皮病、慢性活动性肝炎、多肌炎/皮肌炎、多软骨炎、寻常天 疱疮、韦格纳氏肉芽肿病、膜性肾病、肌萎缩侧索硬化、脊髓痨、巨细胞动脉炎/多肌痛、恶性贫血、急进性肾小球肾炎、纤维化肺泡炎和青少年糖尿病及新发生的疾病;
进一步的,所述的感染性疾病非限制性地选自人免疫缺陷病毒(HIV)、结核分支杆菌、无乳链球菌、耐甲氧西林金黄色葡萄球菌、嗜肺性军团病菌、酿脓链球菌、大肠杆菌、淋病奈瑟氏菌、脑膜炎奈瑟氏菌、肺炎球菌属、B型流感嗜血杆菌、苍白密螺旋体、莱姆病螺旋体、西尼罗病毒、绿脓假单胞菌、麻风分枝杆菌、流产杆菌、狂犬病病毒、流感病毒、巨细胞病毒、I型单纯疱疹病毒、II型单纯疱疹病毒、人血清细小样病毒、呼吸道合胞病毒、水痘带状疱疹病毒、乙型肝炎病毒、麻疹病毒、腺病毒、人T细胞白血病病毒、埃巴二氏病毒、鼠白血病病毒、腮腺炎病毒、水泡性口膜炎病毒、辛德比斯病毒、淋巴细胞性脉络丛脑膜炎病毒、疣病毒、蓝舌病病毒、仙台病毒、猫白血病病毒、呼肠孤病毒、脊髓灰质炎病毒、猿猴病毒40、鼠乳房肿瘤病毒、登革热病毒、风疹病毒、恶性疟原虫、间日疟原虫、鼠弓形体、让氏锥虫、克氏锥虫、罗德西亚锥虫、布氏锥虫、曼森血吸虫、日本血吸虫、牛巴贝虫、柔嫩艾美球虫、盘尾丝虫、热带利什曼原虫、旋毛线虫、小泰累尔梨浆虫、水泡绦虫、羊绦虫、牛肉绦虫、细粒棘球绦虫、科特氏中殖孔绦虫、关节炎支原体、猪鼻支原体、口腔支原体、精氨酸支原体、莱氏无胆甾原体、唾液支原体和肺炎支原体及新发生的疾病;
在本发明提供的技术方案中,所述甲基-β-环糊精作为抗体药物偶联物制剂的辅料成分之一。
在本发明提供的技术方案中,所述甲基-β-环糊精通过开发为甲基-β-环糊精制剂与抗体药物偶联物药物联合使用。
本发明还提供了甲基-β-环糊精在制备用于降低抗体药物偶联物治疗用量的药物中的用途。
本发明还提供了一种抗体药物偶联物制剂,其包含有效量的甲基-β-环糊精辅料。
进一步的,所述甲基-β-环糊精与所述抗体药物偶联物的摩尔比为 100~60000:0.001~100;或200~50000:0.001~50;或200~40000:0.01~50;或200~40000:0.01~20;或200~40000:0.01~10;优选的摩尔比为250~39000:0.01~1;或200~39000:0.01~0.5;更优选的摩尔比为290~38360:0.02~0.15。。
本发明还提供了一种用联合用药物组合治疗疾病的方法,其特征在于,所述的药物组合包含:有效剂量的甲基-β-环糊精或者其药学上可接受的辅剂,及抗体药物偶联物或者其药学上可接受的辅剂;其中,所述的疾病选自肿瘤、自身免疫疾病或感染性疾病。
在一些优选的实施例中,所述甲基-β-环糊精与所述抗体药物偶联物的摩尔比为200~40000:0.001~100;优选的摩尔比为250~39000:0.01~10;更优选的摩尔比为290~38360:0.02~0.15。。
本发明所采用的甲基-β-环糊精和抗体药物偶联物可以是液体制剂或者是冻干制剂。在联合用药时,可以同步或者顺序给药。
本发明还提供了甲基-β-环糊精或其药学上可接受的辅剂形成的制剂,及抗体药物偶联物或其药学上可接受的辅剂形成的制剂在制备治疗癌症、自身免疫疾病、感染性疾病中的用途。
本发明发现的甲基-β-环糊精可以显著提升ADC药效上的效果,使得部分因用量过高而产生安全性问题的ADC药物存在继续开发的可能。其可以降低ADC药物的用量,从而在保障有效性的同时确保安全性,显著的提升了ADC药物开发成功的可能性。并且由于ADC药物剂量的降低,也使得生产成本大幅降低,并进而显著减轻患者的经济负担。
图1 HIC-HPLC检测维迪西妥单抗DAR值分布;
图2 HIC-HPLC检测AAJ8D6-ADC DAR值分布;
图3维迪西妥单抗和甲基-β-环糊精单独使用对肿瘤细胞增殖的影响;
图4 AAJ8D6-ADC和甲基-β-环糊精单独使用对肿瘤细胞增殖的影响。
【定义】
除非另有限定,本文所用的所有技术和科学术语均与本发明所属领域普通技术人员的通常理解一致。虽然也可采用与本文所述相似或等同的任何方法和材料实施或测试本发明,但本文描述了优选的方法和材料。描述和要求保护本发明时,依据以下定义使用下列术语。
当本发明中使用商品名时,申请人旨在包括该商品名产品的制剂、该商品名产品的非专利药和活性药物部分。
除非有相反陈述,在说明书和权利要求书中使用的术语具有相同的下述含义。
本发明所使用的术语“抗体药物偶联物”(即Antibody drug conjugate,ADC)表示抗体或抗原结合片段、连接单元、活性药物单元经过化学反应连接在一起的化合物,其结构通常由三部分组成:抗体或抗体类配体、药物部分(即活性药物单元)、以及将抗体或抗体类配体及药物部分偶联起来的连接单元(linker)。
本发明所使用的术语“抗体”是指能识别和结合目标细胞相关的抗原或受体的大分子化合物,抗体的作用是将药物呈递给与抗体结合的目标细胞群,这些抗体包括但不限于蛋白类激素、凝集素、生长因子、抗体或其他能与细胞结合的分子。在一些特定的实施例中,抗体包括鼠源抗体、嵌合抗体、灵长类动物化、人源化抗体(即人化)和全人源抗体(即人),优选人源化抗体和全人源抗体。
术语“鼠源抗体”在本公开中为根据本领域知识和技能用鼠制备抗体。制备时用特定抗原注射试验对象,然后分离表达具有所需序列或功能特性的抗体的杂交
术语“嵌合抗体(chimeric antibody)”,是将鼠源性抗体的可变区与人抗体的恒定区融合而成的抗体,可以减轻鼠源性抗体诱发的免疫应答反应。建立嵌合抗体,要先建立分泌鼠源性特异性单抗的杂交瘤,然后从鼠杂交瘤细胞中克隆可变区基因,再根据需要克隆人抗体的恒定区基因,将鼠可变区基因与人恒定区基因连接成嵌合基因后插入表达载体中,最后在真核系统或原核系统中表达嵌合抗体分子。
术语“人源化抗体(humanized antibody)”也称为CDR移植抗体(CDR-grafted antibody),是指将鼠的CDR序列移植到人的抗体可变区框架,即不同类型的人种系抗体框架序列中产生的抗体。可以克服嵌合抗体 由于携带大量鼠蛋白成分,从而诱导的异源性反应。此类构架序列可以从包括种系抗体基因序列的公共DNA数据库或公开的参考文献获得。如人重链和轻链可变区基因的种系DNA序列可以在“VBase”人种系序列数据库(在因特网www.mrccpe.com/ac.uk/vbase可获得),以及在Kabat,E.A.等人,1991Sequences of Proteins of Immunological Interest,第5版中找到。为避免免疫原性下降的同时,引起的活性下降,可对所述的人抗体可变区框架序列进行最少反向突变或回复突变,以保持活性。本发明的人源化抗体也包括进一步由噬菌体展示对CDR进行亲和力成熟后的人源化抗体。进一步描述参与人源化可使用小鼠抗体的方法的文献包括,例如Queen等,Proc.,Natl.Acad.Sci.USA,88,2869,1991和Winter及其同事的方法[Jones.,Nature,321,522,(1986)],Riechmann,等[Nature,332,323-327,1988),Verhoeyen,等,Science,239,1534(1988)]。
术语“全人源抗体”、“全人抗体”或“完全人源抗体”、“人抗体”,也称“全人源单克隆抗体”、,其抗体的可变区和恒定区都是人源的,去除免疫原性和毒副作用。单克隆抗体的发展经历了四个阶段,分别为:鼠源性单克隆抗体、嵌合性单克隆抗体、人源化单克隆抗体和全人源单克隆抗体。本发明为全人源单克隆抗体。全人抗体制备的相关技术主要有:人杂交瘤技术、EBV转化B淋巴细胞技术、噬菌体显示技术(phage display)、转基因小鼠抗体制备技术(transgenic mouse)和单个B细胞抗体制备技术等。
本发明所使用的术语“抗原结合片段”是指抗体的保持特异性结合抗原的能力的一个或多个片段。“抗原结合片段”中包含的结合片段的实例包括(i)Fab片段,由VL、VH、CL和CH1结构域组成的单价片段;(ii)F(ab')
2片段,包含通过铰链区上的二硫桥连接的两个Fab片段的二价片段,(iii)由VH和CH1结构域组成的Fd片段;(iv)由抗体的单臂的VH和VL结构域组成的Fv片段;(v)单结构域或dAb片段(Ward等人,(1989)Nature341:544-546),其由VH结构域组成;和(vi)分离的互补决定区(CDR)或(vii)可任选地通过合成的接头连接的两个或更多个分离的CDR的组合。此外,虽然Fv片段的两个结构域VL和VH由分开的基因编码,但可使用重组方法,通过合成的接头连接它们,从而使得其能够产生为其中VL和VH区配对形成单价分子的单个蛋白质链(称为单链Fv(scFv);参见,例如,Bird等人(1988)Science242:423-426和Huston等人(1988)Proc.NatL.Acad.Sci.USA85:5879-5883)。此类单链抗体也意欲包括在术语抗体的“抗原结合片段"中。使用本领域技术人员己知的常规技 术获得此类抗体片段,并且以与对于完整抗体的方式相同的方式就功用性筛选片段。可通过重组DNA技术或通过酶促或化学断裂完整免疫球蛋白来产生抗原结合部分。抗体可以是不同同种型的抗体,例如,IgG(例如,IgG1,IgG2,IgG3或IgG4亚型),IgA1,IgA2,IgD,IgE或lgM抗体。
术语Fab是通过用蛋白酶木瓜蛋白酶(切割H链的224位的氨基酸残基)处理IgG抗体分子所获得的片段中的具有约50,000的分子量并具有抗原结合活性的抗体片段,其中H链N端侧的约一半和整个L链通过二硫键结合在一起。
术语F(ab')
2是通过用酶胃蛋白酶消化IgG铰链区中两个二硫键的下方部分而获得的分子量为约100,000并具有抗原结合活性并包含在铰链位置相连的两个Fab区的抗体片段。
术语Fab'是通过切割上述F(ab')2的铰链区的二硫键而获得的分子量为约50,000并具有抗原结合活性的抗体片段。此外,可以通过将编码抗体的Fab'片段的DNA插入到原核生物表达载体或真核生物表达载体中并将载体导入到原核生物或真核生物中以表达Fab'来生产所述Fab'。
术语“单链构建体”包括但不限于“单链抗体”、“单链Fv”或“scFv”,意指包含通过接头连接的抗体重链可变结构域或区域(即VH)和抗体轻链可变结构域或区域(即VL)的分子。此类scFv分子可具有一般结构:NH2-VL-接头-VH-COOH或NH2-VH-接头-VL-COOH。合适的现有技术接头由重复的GGGGS氨基酸序列或其变体组成,例如使用1-4个重复的变体(Holliger等人(1993),proc.Natl.Acad.Sci.USA90:6444-6448)。可用于本发明的其他接头由Alfthan等人(1995),Protein Eng.8:725-731,Choi等人(2001),Eur.J.Immuno 1.31:94-106,Hu等人(1996),Cancer Res.56:3055-3061,Kipriyanov等人(1999),J.Mol.Biol.293:41-56和Roovers等人(2001),Cancer Immunol.描述。
用于制备针对实际上任何靶抗原的抗体或其抗原结合片段的技术是本领域公知的。例如,参见Kohler和Milstein,Nature 256:495(1975),以及Coligan等(编),CURRENTPROTOCOLS IN IMMUNOLOGY(免疫学最新实验方案),第1卷,第2.5.1-2.6.7页(John Wiley&Sons,1991)。简言之,单克隆抗体可如下获得:即用包括抗原的组合物注射小鼠,取出脾脏以获得B淋巴细胞,使所述B淋巴细胞与骨髓瘤细胞融合以产生杂交瘤,克隆所述杂交瘤,选择产生针对所述抗原的抗体的阳性克隆,培养产生针对所述抗原的抗体的所述克隆,并从所述杂交瘤培养物中分离所述抗 体。可通过许多充分建立的技术从杂交瘤培养物中分离和纯化。此类分离技术包括蛋白A或蛋白G琼脂糖亲和层析、大小排阻层析以及离子交换层析。例如,参见Coligan第2.7.1-2.7.12页及第2.9.1-2.9.3页。也参见Baines等,“Purification of Immunoglobulin G(IgG)(免疫球蛋白G(IgG)的纯化),”于METHODS IN MOLECULAR BIOLOGY(分子生物学方法),第10卷,第79-104页(The Humana Press,Inc.1992)。在初次引起针对免疫原的抗体后,可对抗体进行测序并随后通过重组技术制备。鼠源抗体和抗体片段的人化和嵌合是本领域技术人员众所周知的。
术语“连接单元”或者“连接子”是指一端与抗体/抗原结合片段连接而另一端与药物相连的化学结构片段或键,因此做为一种“桥梁”将抗体/抗原结合片段与药物分子连接起来。它可以包括连接头、间隔物和氨基酸单元,可以通过本领域己知方法合成,诸如US2005-0238649A1中所记载的。如本文所用,“连接单元”可被分为两类:不可断裂连接子和可断裂连接子。
不可断裂连接子是一种相对比较稳定的连接子,其结构很难在体内环境下降解断裂。对于含有不可断裂连接子的抗体药物偶联物,其药物释放机制为:偶联物与抗原结合并被细胞内吞后,抗体在溶酶体中被酶解,释放出由药物,连接子,和抗体氨基酸残基共同组成的活性分子。由此带来的药物分子结构改变并不减弱其细胞毒性,但由于活性分子是带电荷的(氨基酸残基),从而导致其不能渗入邻近细胞。因此,此类活性药物不能杀死邻近不表达靶向抗原(抗原阴性细胞)的肿瘤细胞(旁观者效应,bystander effect)(Bioconjugate Chem.2010,21,5-13)。常见的连接子例如MC连接子和MCC连接子等,如下结构所示。
可断裂连接子,顾名思义,可以在目标细胞内断裂并释放出活性药物(小分子药物本身)。可断裂连接子可分为两个主要的类别:化学不稳定连接子和酶不稳定连接子。
化学不稳定连接子可以由于血浆和细胞质性质的不同而选择性的断裂。这样的性质包括pH值,谷胱甘肽浓度等。
对pH值敏感的连接子,通常又称为酸断裂连接子。这样的连接子在血液的中性环境下相对稳定(pH 7.3-7.5),但是在弱酸性的内涵体(pH5.0-6.5)和溶酶体(pH 4.5-5.0)内将会被水解。第一代的抗体药物偶联物大多应用这类连接子,例如腙,碳酸酯,缩醛,缩酮类。由于酸断裂连接子有限的血浆稳定性,基于此类连接子的抗体药物偶联物通常具有较短的半衰期(2-3天)。这种较短的半衰期在一定程度上限制了pH敏感连接子在新一代抗体药物偶联物中的应用。
对于谷胱甘肽敏感的连接子,又称二硫键连接子。药物释放是基于细胞内谷胱甘肽的高浓度(毫摩尔范围)与血液中相对较低的谷胱甘肽浓度(微摩尔范围)差异引起的。对于肿瘤细胞而言尤其如此,其低含氧量导致还原酶的活性增强,因而导致更高的谷胱甘肽浓度。二硫键具有热力学稳定性,因此在血浆中具有较好的稳定性。
酶不稳定连接子,如肽连接子,能够更好地控制药物释放。肽连接子能够被溶酶体内蛋白酶,如组织蛋白酶(Cathepsin B)或纤溶酶(在一些肿瘤组织中此类酶含量增加)有效地切断。这种肽连接被认为在血浆循环中非常稳定,这是因为细胞外不合宜的pH值及血清蛋白酶抑制剂导致蛋白酶通常在细胞外不具备活性。鉴于较高的血浆稳定性和良好的细胞内断裂选择性和有效性,酶不稳定连接子被广泛用做抗体药物偶联物的可断裂连接子。
自杀式连接子一般嵌合在可断裂连接子与活性药物之间,或者本身就是可断裂连接子的一部分。自杀式连接子的作用机制是:当可断裂连接子在合宜的条件下断裂后,自杀式连接子能够自发地进行结构重排,进而释放与之连接的活性药物。常见的自杀式连接子如对氨基苄醇类(PAB)等。
在一些特殊的实施例中,所述的“连接单元”或者“连接子”可以非限制性的选自如下,其中波浪线代表与抗体(antibody)和毒素(drug)的共价连接位点:
本发明所使用的术语“毒素”、“药物”以及“药物部分”、“药物单元”泛指同一结构,可以在本发明中以任一名称使用。它们泛指任何具有期望的生物活性,并具有反应性官能团以便制备本发明所述偶联物的化合物。期望的生物活性包括诊断、治愈、缓解、治疗、预防人或其它动物的疾病。随着新型药物不断被发现和发展,这些新药也应纳入本发明所述的药物中。它能够对细胞的生长或增殖产生有害效果的任何物质,可以是来自细菌、真菌、植物或动物的小分子毒素及其衍生物,它可以包括但不限于细胞毒性药物、细胞分化因子、干细胞营养因子、类固醇类药物、治疗自身免疫疾病的药物、抗炎症药物或治疗传染性疾病的药物;或者进一 步为微管蛋白抑制剂或DNA损伤剂;或者更进一步的为海兔毒素(dolastatin)类、奥瑞他汀(auristatin)类、美登素(maytansine)类;卡奇霉素类(calicheamicin)、倍癌霉素(duocarmycin)类、安曲霉素类衍生物PBD、喜树碱类衍生物SN-38;于瓢菌素(amanitins)、蒽环类物(anthracyclines)、浆果赤霉素(baccatins)、喜碱(camptothecins)、西马多丁(cemadotins)、秋水仙碱(colchicines)、秋水树仙胺(colcimids)、考布他汀(combretastatins)、隐菲辛(cryptophycins)、圆皮海绵内酯(discodermolides)、多烯紫杉醇(docetaxel)、阿霉素(doxorubicin)、棘霉素(echinomycins)、艾榴塞洛素(eleutherobins)、埃博霉素(epothilones)、雌莫司汀(estramustines)、偏端霉素(lexitropsins)、美登素(maytansines)、氨甲蝶呤(methotrexate)、纺锤菌素(netropsins)、嘌呤霉素(puromycins)、根瘤菌素(rhizoxins)、紫杉烷(taxanes)、微管蛋白裂解素(tubulysins)、长春花生物碱(vinca alkaloids)、维生素A前体、叶酸。在一些具体的例子中,“毒素”、“药物”以及“药物部分”、“药物单元”可以是喜树碱类衍生物如伊沙替康,美登木素生物碱及其衍生物(CN101573384)如DM1、DM3、DM4,auristatin F(AF)及其衍生物,如MMAF、MMAE、3024(WO 2016/127790A1),白喉毒素、外毒素、蓖麻毒蛋白(ricin)A链、相思豆毒蛋白(abrin)A链、modeccin、α-帚曲霉素(sarcin)、油桐(Aleutites fordii)毒蛋白、香石竹(dianthin)毒蛋白、美洲商陆(Phytolaca americana)毒蛋白(PAPI、PAPII和PAP-S)、苦瓜(Momordica charantia)抑制物、麻疯树毒蛋白(curcin)、巴豆毒蛋白(crotin)、肥皂草(sapaonaria officinalis)抑制物、白树毒蛋白(gelonin)、丝林霉素(mitogellin)局限曲霉素(restrictocin)、酚霉素(phenomycin)、依诺霉素(enomycin)和单端孢菌素(trichothecenes)。在一些更具体的例子中,“毒素”、“药物”以及“药物部分”、“药物单元”可以非限制性的选自如下结构:
【具体实施例】
下面将通过实施例对本发明进行进一步地阐述,需要说明的是,以下实施例是对本发明进行进一步地阐述和解释,而不应被看作是对本发明的限制。
实施例1:抗体药物偶联物的制备
采用通用的制备方法制备抗体药物偶联物:
方法A:用pH=7.4的PBS缓冲液,把抗体配制为10mg/mL的溶液,加入2.4摩尔当量的TCEP,振荡混匀1小时,再加入5.0摩尔当量的连接子-毒素,振荡混匀,反应1h,反应结束后,超滤除去残留的小分子,加载至疏水色谱(HIC-HPLC)进行DAR、药物分布、裸抗比例检测。
方法B:用pH=9的硼酸-硼砂缓冲液,把抗体配制为10mg/mL的溶液,加入5.0摩尔当量的TCEP,振荡混匀1小时,再加入6.0摩尔当量的连接子-毒素,振荡混匀,反应3h,反应结束后,超滤除去残留的小分 子,加载至疏水色谱(HIC-HPLC)进行DAR、药物分布、裸抗比例检测。
采用上述任一方法制备了如下两种抗体药物偶联物:维迪西妥单抗(即Disitamab Vedotin)和AAJ8D6-ADC(即C-Met-Mc-Val-Cit-MMAE,一种靶向C-Met靶点的抗体药物偶联物)。
维迪西妥单抗(即Disitamab Vedotin)(平均DAR值为4.01):
其中:n代表选自1、2、3、4、5、6、7、8的整数;Ab1代表Her2抗体,其重链和轻链氨基酸序列分别如SEQ ID NO:19和SEQ ID NO:20所示:
SEQ ID NO:19
SEQ ID NO:20
AAJ8D6-ADC(平均DAR值为4.02):
其中:m代表选自1、2、3、4、5、6、7、8的整数;Ab2代表靶向C-Met单抗,其重链和轻链氨基酸序列分别如SEQ ID NO:9和SEQ ID NO:10所示:
SEQ ID NO:9
SEQ ID NO:10
实施例2:维迪西妥单抗(Disitamab Vedotin)和甲基-β-环糊精联合
用药物组合对SK-BR-3细胞的体外抗癌活性
将SK-BR-3细胞以浓度5×10
4/mL、100μL/孔接种到96孔板中,按照表2的联合用药物使用浓度配比给药,72h后采用CCK8法检测细胞活力。
表2 维迪西妥单抗和甲基-β-环糊精不同配比的联合用药物组合
组别 | 维迪西妥单抗药物使用浓度 | 甲基-β-环糊精药物使用浓度 |
联合用药物组合1-1 | 4.0ng/mL | 50000ng/mL |
联合用药物组合1-2 | 4.0ng/mL | 25000ng/mL |
联合用药物组合1-3 | 4.0ng/mL | 12500ng/mL |
联合用药物组合1-4 | 4.0ng/mL | 6250ng/mL |
联合用药物组合1-5 | 4.0ng/mL | 3125ng/mL |
联合用药物组合1-6 | 4.0ng/mL | 1562.5ng/mL |
联合用药物组合1-7 | 4.0ng/mL | 781.25ng/mL |
联合用药物组合1-8 | 4.0ng/mL | 390.625ng/mL |
对照组1-1 | 4.0ng/mL | 0 |
注:药物使用浓度是指药物的最终浓度。
利用Chou-Talalay法(即联合指数,combination index,简写CI)评价维迪西妥单抗与甲基-β-环糊精在不同配比下联合作用72h对SK-BR-3细胞增殖抑制的协同/拮抗作用,利用CompuSyn软件计算不同配比条件下两种药物联用的CI值,进而评价两种药物的联用效果,评价标准为:
联合指数范围 | 联用效果 |
<0.1 | 极强协同(Very strong synergism) |
0.1-0.3 | 强协同(Strong synergism) |
0.3-0.7 | 协同(Synergism) |
0.7-0.85 | 中度协同(Moderate synergism) |
0.85-0.90 | 轻微协同(Slight synergism) |
0.90-1.10 | 近似相加(Nearly additive) |
1.10-1.20 | 轻微拮抗(Slight antagonism) |
1.20-1.45 | 中度拮抗(Moderate antagonism) |
1.45-3.3 | 拮抗(Antagonism) |
3.3-10 | 强拮抗(Strong antagonism) |
>10 | 极强拮抗(Very strong antagonism) |
结果显示,维迪西妥单抗与甲基-β-环糊精不同配比的联合用药物组合对SK-BR-3细胞的增殖抑制率均高于单药组,尤其是甲基-β-环糊精高剂量联用组(3125~50000ng/mL)(p<0.05),最高可达(70.79±4.02)%,较单药组提高了1.04倍。CI值显示以上联合方案均为协同作用(表3)。
表3 联合用药物组合对SK-BR-3细胞的影响
分组 | 增殖抑制率 | 联合指数(CI) | 联用效果 |
联合用药物组合1-1 | 54.99±1.62** | 0.37 | 协同 |
联合用药物组合1-2 | 68.44±3.54** | 0.28 | 强协同 |
联合用药物组合1-3 | 70.79±4.02** | 0.27 | 强协同 |
联合用药物组合1-4 | 51.34±2.94** | 0.39 | 协同 |
联合用药物组合1-5 | 43.53±1.90* | 0.45 | 协同 |
联合用药物组合1-6 | 40.94±3.71 | 0.48 | 协同 |
联合用药物组合1-7 | 39.43±4.52 | 0.49 | 协同 |
联合用药物组合1-8 | 37.36±1.33 | 0.51 | 协同 |
对照组1-1 | 34.65±0.23 | \ | \ |
注:**:p<0.01;*:p<0.5
实施例3:维迪西妥单抗(Disitamab Vedotin)和甲基-β-环糊精联合
用药物组合对NCI-N87细胞的体外抗癌活性
将NCI-N87细胞以浓度5×10
4/mL、100μL/孔接种到96孔板中,按照表4的联合用药物使用浓度配比给药,72h后采用CCK8法检测细胞活力。
表4 维迪西妥单抗和甲基-β-环糊精不同配比的联合用药物组合
组别 | 维迪西妥单抗药物使用浓度 | 甲基-β-环糊精药物使用浓度 |
联合用药物组合2-1 | 14.0ng/mL | 50000ng/mL |
联合用药物组合2-2 | 14.0ng/mL | 25000ng/mL |
联合用药物组合2-3 | 14.0ng/mL | 12500ng/mL |
联合用药物组合2-4 | 14.0ng/mL | 6250ng/mL |
联合用药物组合2-5 | 14.0ng/mL | 3125ng/mL |
联合用药物组合2-6 | 14.0ng/mL | 1562.5ng/mL |
联合用药物组合2-7 | 14.0ng/mL | 781.25ng/mL |
联合用药物组合2-8 | 14.0ng/mL | 390.625ng/mL |
对照组2-1 | 14.0ng/mL | 0 |
利用Chou-Talalay法(即联合指数,combination index,简写CI)评价维迪西妥单抗与甲基-β-环糊精在不同配比下联合作用72h对NCI-N87细胞增殖抑制的协同/拮抗作用,利用CompuSyn软件计算不同配比条件下两种药物联用的CI值,进而评价两种药物的联用效果,评价标准为:
联合指数范围 | 联用效果 |
<0.1 | 极强协同(Very strong synergism) |
0.1-0.3 | 强协同(Strong synergism) |
0.3-0.7 | 协同(Synergism) |
0.7-0.85 | 中度协同(Moderate synergism) |
0.85-0.90 | 轻微协同(Slight synergism) |
0.90-1.10 | 近似相加(Nearly additive) |
1.10-1.20 | 轻微拮抗(Slight antagonism) |
1.20-1.45 | 中度拮抗(Moderate antagonism) |
1.45-3.3 | 拮抗(Antagonism) |
3.3-10 | 强拮抗(Strong antagonism) |
>10 | 极强拮抗(Very strong antagonism) |
结果显示,维迪西妥单抗与甲基-β-环糊精不同配比的联合用药物组合对NCI-N87细胞的增殖抑制率均高于单药组(除联合用药物组合2-7外),尤其是甲基-β-环糊精高剂量联用组(6250~50000ng/mL)与单药组的差异更显著(p<0.05),最高可达(67.16±9.73)%,较单药组提高了56.81%(表5)。
表5 联合用药物组合对NCI-N87细胞的影响
分组 | 增殖抑制率 | 联合指数(CI) | 联用效果 |
联合用药物组合2-1 | 58.81±2.88* | 0.49 | 协同 |
联合用药物组合2-2 | 67.16±9.73* | 0.35 | 协同 |
联合用药物组合2-3 | 57.10±4.75* | 0.51 | 协同 |
联合用药物组合2-4 | 56.74±1.48* | 0.57 | 协同 |
联合用药物组合2-5 | 45.66±0.76 | 0.72 | 中度协同 |
联合用药物组合2-6 | 44.61±2.35 | 1.06 | 近似相加 |
联合用药物组合2-7 | 40.07±2.74 | 1.18 | 轻微拮抗 |
联合用药物组合2-8 | 47.45±4.49 | 0.70 | 协同 |
对照组2-1 | 42.83±2.21 | \ | \ |
注:**:p<0.01;*:p<0.5
实施例4:AAJ8D6-ADC和甲基-β-环糊精联合用药物组合对MKN-45
细胞的体外抗癌活性
将MKN-45细胞以浓度5×10
4/mL、100μL/孔接种到96孔板中,按照表6的联合用药物使用浓度配比给药,72h后采用CCK8法检测细胞活力。
表6 AAJ8D6-ADC和甲基-β-环糊精不同配比的联合用药物组合
组别 | AAJ8D6-ADC药物使用浓度 | 甲基-β-环糊精药物使用浓度 |
联合用药物组合3-1 | 20.0ng/mL | 50000ng/mL |
联合用药物组合3-2 | 20.0ng/mL | 25000ng/mL |
联合用药物组合3-3 | 20.0ng/mL | 12500ng/mL |
联合用药物组合3-4 | 20.0ng/mL | 6250ng/mL |
联合用药物组合3-5 | 20.0ng/mL | 3125ng/mL |
联合用药物组合3-6 | 20.0ng/mL | 1562.5ng/mL |
联合用药物组合3-7 | 20.0ng/mL | 781.25ng/mL |
联合用药物组合3-8 | 20.0ng/mL | 390.625ng/mL |
对照组3-1 | 20.0ng/mL | 0 |
利用Chou-Talalay法(即联合指数,combination index,简写CI)评价AAJ8D6-ADC与甲基-β-环糊精在不同配比下联合作用72h对MKN-45细胞增殖抑制的协同/拮抗作用,利用CompuSyn软件计算不同配比条件下两种药物联用的CI值,进而评价两种药物的联用效果,评价标准为:
联合指数范围 | 联用效果 |
<0.1 | 极强协同(Very strong synergism) |
0.1-0.3 | 强协同(Strong synergism) |
0.3-0.7 | 协同(Synergism) |
0.7-0.85 | 中度协同(Moderate synergism) |
0.85-0.90 | 轻微协同(Slight synergism) |
0.90-1.10 | 近似相加(Nearly additive) |
1.10-1.20 | 轻微拮抗(Slight antagonism) |
1.20-1.45 | 中度拮抗(Moderate antagonism) |
1.45-3.3 | 拮抗(Antagonism) |
3.3-10 | 强拮抗(Strong antagonism) |
>10 | 极强拮抗(Very strong antagonism) |
结果显示,AAJ8D6-ADC与甲基-β-环糊精不同配比的联合用药物组合对MKN-45细胞的增殖抑制率均高于单药组,尤其是甲基-β-环糊精高剂量联用组(3125~50000ng/mL)(p<0.05),最高可达(80.85±0.63)%,较单药组提高了61.47%。CI值显示以上联合方案均为协同作用(表7)。
表7 联合用药物组合对MKN-45细胞的影响
分组 | 增殖抑制率 | 联合指数(CI) | 联用效果 |
联合用药物组合3-1 | 72.70±2.01** | 0.18 | 强协同 |
联合用药物组合3-2 | 80.85±0.63** | 0.09 | 极强协同 |
联合用药物组合3-3 | 66.90±1.62** | 0.25 | 强协同 |
联合用药物组合3-4 | 67.99±2.09* | 0.24 | 强协同 |
联合用药物组合3-5 | 63.04±2.74** | 0.32 | 协同 |
联合用药物组合3-6 | 63.89±5.71* | 0.30 | 协同 |
联合用药物组合3-7 | 69.76±6.79* | 0.21 | 强协同 |
联合用药物组合3-8 | 64.15±3.15* | 0.30 | 协同 |
对照组3-1 | 50.07±1.68 | \ | \ |
注:**:p<0.01;*:p<0.5
本实施例以不同靶点的两种抗体药物偶联物维迪西妥单抗和AAJ8D6-ADC为例,验证了其与甲基-β-环糊精共同作用能够增强抗体药物偶联物的抗肿瘤药效,降低抗体药物偶联物在治疗中的用量,可以理解的是,本发明仅是以这两种抗体药物偶联物为例进行了技术效果的验证,并应视为对靶点和具体抗体药物偶联物的限定。
本发明已通过各具体实施例作了举例说明。但是,本领域普通技术人员能够理解,本发明并不限于各具体实施方式,普通技术人员在本发明的范文内可以作出各种改动或变型,并且在本说明书中各处提及的各个技术特征可以相互组合,而仍不背离本发明的精神和范围。这样的改动和变型均在本发明的范围之内。
Claims (13)
- 有效量的甲基-β-环糊精在降低抗体药物偶联物在治疗中用量的用途。
- 根据权利要求1所述的用途,其特征在于,所述甲基-β-环糊精与所述的抗体药物偶联物的摩尔比为200~40000:0.001~100;优选的摩尔比为250~39000:0.01~10;更优选的摩尔比为300~38170:0.02~0.2。
- 根据权利要求1所述的用途,所述抗体药物偶联物用于治疗肿瘤、自身免疫疾病或感染性疾病。
- 根据权利要求1所述的用途,其特征在于,所述的抗体药物偶联物的靶点选自BCMA、CD79B、c-Met、GPNMB、IL2RA、LY6E、CD1、CD1a、CD2、CD3、CD4、CD5、CD8、CD11A、CD14、CD15、CD16、CD18、CD19、CD20、CD21、CD22、CD23、CD25、CD29、CD30、CD32b、CD33、CD37、CD38、CD40、CD40L、CD44、CD45、CD46、CD52、CD54、CD55、CD59、CD64、CD67、CD70、CD74、CD79a、CD79b、CD80、CD83、CD95、CD126、CD133、CD138、CD147、CD154、CD166、CD276、HER1、HER2、HER3、MUC1、PTK7、STEAP1、VTCN1、AXL、BCMA、CA9、CASP、CASP3、CDH3、CDKs、CEACAM5、CLDN18、c-Met、Cripto-1、CTL4、DLL3、EF2、EFNA4、EGFR、ENPP3、EphA2、ETBR、FGFR2、FGFR3、FOLR1、FOLR1、Ganglioside、GCPII、HER2、HER3、HGFR、HLA-DR、IGF1R、IL3RA、ITGAV、ITGB3、KIT、LAMP1、Lewis-Y、LRRC15、LY75、LYPD3、MCP、MELTF、MSLN、MUC1、MUC16、NaPi-2b、NCAM1、NECTIN4、NOTCH3、Prolactin receptor、RNA polymerase II、ROR1、SDC1、SGLT2、SLAMF6、SLAMF7、SLITRK6、STAR、STING、TfR、TIM1、TLR8、TNF、TOP1、TPBG、Trop-2、VEGF、ZIP6、细胞因子、微管蛋白及组合;优选的,所述的抗体药物偶联物的靶点选自CD19、EGFR、BCMA、Trop-2、TOP1、NECTIN4、CD79B、CD22、HER2、CD30、CD33、c-Met、细胞因子、微管蛋白及组合。
- 根据权利要求1所述的用途,其特征在于,所述的抗体药物偶联物选自Loncastuximab tesirine、Cetuximab sarotalocan、Belantamab mafodotin(玛贝妥单抗)、Sacituzumab govitecan(戈沙妥组单抗)、Fam-trastuzumab deruxtecan、Enfortumab vedotin、Polatuzumab vedotin、Inotuzumab Ozogamicin(奥英妥珠单抗)、Ado-trastuzumab emtansine(恩美曲妥珠单抗)、Brentuximab vedotin(维布妥昔单抗)、Gemtuzumab ozogamicin、Disitamab Vedotin(维迪西妥单抗)、Tisotumab vedotin、Depatuxizumab mafodotin、TAA-013、Trastuzumab duocarmazine、KSI-301、BAT-8001、Rovalpituzumab tesirine、SAR-408701、datopotamab、Mirvetuximab soravtansine、ARX-788、Trastuzumab emtansine、Telisotuzumab vedotin、SHR-A1403。
- 根据权利要求1所述的用途,其特征在于,所述的肿瘤为实体瘤或者非实体瘤;优选的,所述的肿瘤选自造血肿瘤、癌、肉瘤、黑素瘤或神经胶质肿瘤;更优选的,所述的肿瘤选自乳腺癌、卵巢癌、宫颈癌、子宫癌、前列腺癌、肾癌、尿道癌、膀胱癌、肝癌、胃癌、子宫内膜癌、唾液腺癌、食道癌、肺癌、结肠癌、直肠癌、结直肠癌、骨癌、皮肤癌、甲状腺癌、胰腺癌、黑色素瘤、神经胶质瘤、神经母细胞瘤、多形性胶质细胞瘤、肉瘤、淋巴瘤和白血病等实体瘤或血液肿瘤;所述的自身免疫疾病选自免疫介导的血小板减少症、皮肌炎、舍格伦氏综合症、多发性硬化、西登哈姆氏舞蹈病、重症肌无力、系统性红斑狼疮、狼疮性肾炎、风湿热、类风湿性关节炎、多腺体综合征、大疱性类天疱疮、糖尿病、亨-舍二氏紫癜、链球菌感染后肾炎、结节性红斑、高安氏动脉炎、阿狄森氏病、结节病、溃疡性结肠炎、多形性红斑、IgA肾病、结节性多动脉炎、强直性脊柱炎、古德帕斯丘综合征、闭塞性血栓性脉管炎、原发性胆汁性肝硬变、桥本甲状腺炎、甲状腺毒症、硬皮病、慢性活动性肝炎、多肌炎/皮肌炎、多软骨炎、寻常天疱疮、韦格纳氏肉芽肿病、膜性肾病、肌萎缩侧索硬化、脊髓痨、巨细胞动脉炎/多肌痛、恶性贫血、急进性肾小球肾炎、纤维化肺泡炎和青少年糖尿病及新发生的疾病;所述的感染性疾病为人免疫缺陷病毒(HIV)、结核分支杆菌、无乳链球菌、耐甲氧西林金黄色葡萄球菌、嗜肺性军团病菌、酿脓链球菌、大肠杆菌、淋病奈瑟氏菌、脑膜炎奈瑟氏菌、肺炎球菌属、B型流感嗜血杆菌、苍白密螺旋体、莱姆病螺旋体、西 尼罗病毒、绿脓假单胞菌、麻风分枝杆菌、流产杆菌、狂犬病病毒、流感病毒、巨细胞病毒、I型单纯疱疹病毒、II型单纯疱疹病毒、人血清细小样病毒、呼吸道合胞病毒、水痘-带状疱疹病毒、乙型肝炎病毒、麻疹病毒、腺病毒、人T细胞白血病病毒、埃-巴二氏病毒、鼠白血病病毒、腮腺炎病毒、水泡性口膜炎病毒、辛德比斯病毒、淋巴细胞性脉络丛脑膜炎病毒、疣病毒、蓝舌病病毒、仙台病毒、猫白血病病毒、呼肠孤病毒、脊髓灰质炎病毒、猿猴病毒40、鼠乳房肿瘤病毒、登革热病毒、风疹病毒、恶性疟原虫、间日疟原虫、鼠弓形体、让氏锥虫、克氏锥虫、罗德西亚锥虫、布氏锥虫、曼森血吸虫、日本血吸虫、牛巴贝虫、柔嫩艾美球虫、盘尾丝虫、热带利什曼原虫、旋毛线虫、小泰累尔梨浆虫、水泡绦虫、羊绦虫、牛肉绦虫、细粒棘球绦虫、科特氏中殖孔绦虫、关节炎支原体、猪鼻支原体、口腔支原体、精氨酸支原体、莱氏无胆甾原体、唾液支原体和肺炎支原体及新发生的疾病。
- 根据权利要求1的用途,甲基-β-环糊精作为抗体药物偶联物制剂的辅料成分之一。
- 根据权利要求1的用途,甲基-β-环糊精通过开发为甲基-β-环糊精制剂与抗体药物偶联物联合使用。
- 甲基-β-环糊精在制备用于降低抗体药物偶联物治疗用量的药物中的用途。
- 一种抗体药物偶联物制剂,其包含有效量的甲基-β-环糊精辅料。
- 权利要求10所述的药物组合物,其特征在于,所述甲基-β-环糊精与所述抗体药物偶联物的摩尔比为200~40000:0.001~100;优选的摩尔比为250~39000:0.01~10;更优选的摩尔比为300~38170:0.02~0.2。
- 一种用联合用药物组合治疗疾病的方法,其特征在于,所述的药物组合包含:有效剂量的甲基-β-环糊精或者其药学上可接受的辅剂,及抗体药物偶联物或者其药学上可接受的辅剂。
- 根据权利要求12所述的方法,其特征在于,所述甲基-β-环糊精与所述抗体药物偶联物的摩尔比为200~40000:0.001~100;优选的摩尔 比为250~39000:0.01~10;更优选的摩尔比为300~38170:0.02~0.2。
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