WO2021091359A1 - 조절 t 세포 표면 항원의 에피토프 및 이에 특이적으로 결합하는 항체 - Google Patents
조절 t 세포 표면 항원의 에피토프 및 이에 특이적으로 결합하는 항체 Download PDFInfo
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- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
Definitions
- the present invention relates to an epitope of Lrig-1 (leucine-rich and immunoglobulin-like domains 1) protein, which is an antigen present on the surface of regulatory T cells, and an antibody or antigen-binding fragment specifically binding thereto.
- Lrig-1 leucine-rich and immunoglobulin-like domains 1
- the most important trait in all normal individuals is that they do not react detrimentally to the antigenic substances that make up their own, while the ability to recognize and eliminate non-self antigens. .
- the non-response of a living body to its own antigen is called immunologic unresponsiveness or tolerance.
- Self-tolerance occurs by removing lymphocytes that may have specific receptors for self-antigens, or by inactivating their ability to respond after contact with self-antigens.
- an immune response to the self-antigen occurs, and a disease resulting from this is called an autoimmune disease.
- the regulatory T cells play an important role in naturally preventing the occurrence of excessive inflammation and immune responses, but when autoimmune diseases and chronic inflammatory diseases occur, the function and number of regulatory T cells are significantly reduced. Reported. Therefore, in the case of patients with immune diseases and inflammatory diseases, it is important that regulatory T cells are produced at a normal level, which can be one of the treatments for these diseases.
- CDR complementarity determining regions
- An object of the present invention is to provide an epitope of Lrig-1 (leucine-rich and immunoglobulin-like domains 1) protein present on the surface of regulatory T cells (Treg cells).
- Another object of the present invention is to provide an antibody or antigen-binding fragment capable of specifically binding to the epitope.
- Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer comprising an antibody or antigen-binding fragment capable of specifically binding to the epitope as an active ingredient.
- Another object of the present invention is to provide an antibody-drug conjugate (ADC) in which, for example, an anticancer agent is combined with the antibody and a drug.
- ADC antibody-drug conjugate
- Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer comprising an antibody-drug conjugate as an active ingredient.
- Another object of the present invention is an antibody or antigen-binding fragment capable of specifically binding to the epitope; And it is to provide a method of preventing or treating cancer using an antibody-drug conjugate.
- the present invention relates to an epitope of Lrig-1 (leucine-rich and immunoglobulin-like domains 1) protein or an antibody or antigen-binding fragment that specifically binds to the epitope.
- Lrig-1 leucine-rich and immunoglobulin-like domains 1
- the "Lrig-1 protein” is a transmembrane protein present on the surface of a regulatory T cell, and the extracellular or lumen side leucine-rich repeat (LRR) and three immune body-like domains (immunoglobulin-like domains), transmembrane sequence and cytoplasmic tail.
- the LRIG gene family includes LRIG1, LRIG2 and LRIG3, and the amino acids constituting each family are highly conservative.
- the LRIG1 gene is highly expressed in normal skin and can be expressed in basal and hair follicle cells to regulate the proliferation of epithelial stem cells.
- the Lrig-1 protein may be a protein present in humans or mice, but is not limited thereto.
- the Lrig-1 protein may be a Lrig-1 protein derived from mammals, including primates such as humans and monkeys, rodents such as mice and rats, and the like.
- the Lrig-1 protein may be a human-derived Lrig-1 protein represented by SEQ ID NO: 1, which may be encoded by a nucleic acid sequence represented by SEQ ID NO: 2, but is not limited thereto.
- the Lrig-1 protein may be a mouse-derived Lrig-1 protein represented by SEQ ID NO: 3, which may be encoded by a nucleic acid sequence represented by SEQ ID NO: 4, but is not limited thereto.
- the Lrig-1 protein may be an extracellular domain of the Lrig-1 protein, but is not limited thereto.
- the Lrig-1 extracellular domain of the present invention may be an extracellular domain of Lrig-1 protein derived from mammals, including primates such as humans and monkeys, rodents such as mice and rats, and the like.
- the extracellular protein of the Lrig-1 protein may be an extracellular domain of the Lrig-1 protein derived from human or mouse, but is not limited thereto.
- the extracellular domain of the Lrig-1 protein may be represented by SEQ ID NO: 5 corresponding to the 35th to 794th amino acid sequence of the human-derived Lrig-1 protein, but is not limited thereto.
- the extracellular domain of the Lrig-1 protein may be represented by SEQ ID NO: 6 corresponding to the 35th to 794th amino acid sequence of the mouse-derived Lrig-1 protein, but is not limited thereto.
- an epitope of the Lrig-1 protein some amino acids of the Lrig-1 protein represented by SEQ ID NOs: 1, 3, 5, and 5, for example, 2 to 50; 6 to 45; Or 10 to 44 amino acids, but is not limited thereto.
- an amino acid sequence represented by SEQ ID NOs: 7 to 70 it provides an epitope comprising at least one polypeptide selected from the group consisting of polypeptides consisting of.
- the epitope of the Lirg-1 protein may be an epitope including a polypeptide consisting of an amino acid sequence represented by SEQ ID NO: 71 or SEQ ID NO: 72, but is not limited thereto.
- the epitope of the present invention may be a conformational epitope.
- the "stereoscopic epitope" of the present invention is composed of a discontinuous amino acid sequence, unlike a one-dimensional linear epitope composed of a continuous sequence. These conformational epitopes react with the three-dimensional structure of the antibody antigen-binding site.
- nucleic acid molecule encoding the epitope provided by the present invention is provided.
- the nucleic acid molecule of the present invention includes all nucleic acid molecules in which the amino acid sequence of the polypeptide provided by the present invention is translated into a polynucleotide sequence as known to those skilled in the art. Therefore, various polynucleotide sequences can be prepared by ORF (open reading frame), all of which are also included in the nucleic acid molecule of the present invention.
- ORF open reading frame
- an expression vector into which the isolated nucleic acid molecule provided in the present invention is inserted is provided.
- the "vector” is a nucleic acid molecule capable of transporting another nucleic acid to which a nucleic acid molecule is linked.
- a vector which refers to circular double-stranded DNA to which additional DNA segments can be ligated.
- a phage vector Another type of vector is a viral vector, in which additional DNA segments can be ligated to the viral genome.
- Certain vectors are capable of autonomous replication in the host cell into which they have been introduced (eg, bacterial vectors are episomal mammalian vectors that have a bacterial origin of replication).
- vectors e.g., non-episomal mammalian vectors
- vectors can be incorporated into the host cell's genome as it enters the host cell, through which it replicates with the host genome.
- some vectors are capable of directing the expression of genes to which they are linked in the operating dimension.
- Such vectors are referred to herein as “recombinant expression vectors” or simply “expression vectors”.
- expression vectors useful in recombinant DNA techniques often exist in the form of plasmids.
- plasmid and vector may be used interchangeably because plasmid is the most commonly used form among vectors.
- the expression vector in the present invention include commercially widely used pCDNA vector, F, R1, RP1, Col, pBR322, ToL, Ti vector; Cosmid; Phages such as lambda, lambdoid, M13, Mu, p1 P22, Q ⁇ , T-even, T2, T3, and T7; It may be selected from the group consisting of plant viruses, but is not limited thereto, and all expression vectors known as expression vectors to those skilled in the art can be used in the present invention, and when selecting an expression vector, it depends on the properties of the target host cell.
- the vector When the vector is introduced into the host cell, it may be performed by calcium phosphate transfection, viral infection, DEAE-dextran control transfection, lipofectamine transfection, or electroporation, but is not limited thereto, and those skilled in the art use.
- An introduction method suitable for an expression vector and a host cell can be selected and used.
- the vector contains one or more selection markers, but is not limited thereto, and may be selected according to whether or not the product is produced using a vector that does not contain a selection marker.
- the selection of the selection marker is selected by the host cell of interest, and the present invention is not limited thereto because it uses a method already known to those skilled in the art.
- a tag sequence may be inserted and fused onto the expression vector.
- the tags include, but are not limited to, a hexa-histidine tag, a hemagglutinin tag, a myc tag, or a flag tag, and tags that facilitate purification known to those skilled in the art can all be used in the present invention.
- a host cell line transformed with the expression vector provided by the present invention is provided.
- the "host cell” includes individual cells or cell cultures that may be recipients of the vector(s) for incorporation of the polypeptide insert or were recipients.
- a host cell includes the progeny of a single host cell, which progeny may not necessarily be completely identical (morphologically or in genomic DNA complement) to the original parental cell due to natural, accidental or deliberate mutations.
- Host cells include cells transformed in vivo with the polypeptide(s) herein.
- the host cells may include cells of mammalian, plant, insect, fungal or cellular origin, and include bacterial cells such as E. coli, Streptomyces, and Salmonella typhimurium; Fungal cells such as yeast cells and Pichia pastoris; Insect cells such as Drozophila and Spodoptera Sf9 cells; CHO (Chinese hamster ovary cells), SP2/0 (mouse myeloma), human lymphoblastoid, COS, NSO (mouse myeloma), 293T, Bow melanoma cells, HT-1080, BHK (Baby Hamster Kidney cells), HEK (Human Embryonic Kidney cells) or PERC.6 (Human Retinal Cells) animal cells; Alternatively, it may be a plant cell, but the present invention is not limited thereto, and any cell that can be used as a host cell line known to those skilled in the art may be used.
- bacterial cells such as E. coli,
- the transformation method of the present invention is an arbitrary method of injecting a vector of interest into the host cell, and any known method capable of injecting the vector into the host cell may be included.
- a method using CaCl 2 Electroporation method, microinjection method, calcium phosphate precipitation method, electroporation method, liposome-mediated transfection method, DEAE-dextran treatment method, transformation method using gene bombadment and virus, etc., but are limited thereto. It is not.
- an antibody or antigen-binding fragment that specifically binds to the epitope of the present invention.
- the "antibody” refers to a protein molecule that acts as a receptor for specifically recognizing an antigen, including immunoglobulin molecules that are immunologically reactive with a specific antigen.
- the antigen may be Lrig-1 protein present on the surface of regulatory T cells. Preferably, it may specifically recognize the leucine rich region or immunoglobulin-like domain of the Lrig-1 protein, but is not limited thereto.
- the "immunoglobulin” has a heavy chain and a light chain, and each of the heavy and light chains includes a constant region and a variable region.
- the variable regions of the light and heavy chains include three multivariable regions and four framework regions, referred to as complementarity determining regions (hereinafter referred to as "CDR").
- CDRs mainly play a role in binding to the epitope of the antigen.
- the CDRs of each chain are typically referred to as CDR1, CDR2 and CDR3 sequentially starting from the N-terminus, and are also identified by the chain in which the particular CDR is located.
- the "full-length antibody” is a structure having two full-length light chains and two full-length heavy chains, each light chain is connected by a heavy chain and a disulfide bond, IgA, IgD, IgE, IgM, and IgG.
- the IgG is a subtype, and includes IgG1, IgG2, IgG3 and IgG4.
- the "antigen-binding fragment” refers to a fragment having an antigen-binding function
- examples of the antigen-binding fragment include (1) the variable region of the light chain (VL) and the variable region of the heavy chain (VH) and the light chain.
- a proteolytic enzyme such as papain or pepsin
- the antibody is a monoclonal antibody, a polyclonal antibody, a chimeric antibody, a humanized antibody, a human antibody, a bivalent, Bispecific molecule, minibody, domain antibody, bispecific antibody, antibody mimic, unibody, diabody, triabody, tetrabody, or It may be a fragment thereof, but is not limited thereto.
- the "monoclonal antibody” refers to an antibody molecule having a single molecular composition obtained from substantially the same antibody population, and exhibits a single binding specificity and affinity for a specific epitope.
- the "chimeric antibody” is an antibody obtained by recombining the variable region of a mouse antibody and the constant region of a human antibody, and has an improved immune response compared to a mouse antibody.
- the "humanized antibody” refers to an antibody in which the protein sequence of an antibody derived from a non-human species is modified to resemble an antibody variant naturally produced in humans.
- the humanized antibody can be prepared by recombining a mouse-derived CDR with a human antibody-derived FR to produce a humanized variable region, and then recombining it with a desired human antibody constant region to prepare a humanized antibody.
- the "binding" or “specific binding” refers to the affinity of the antibody or antibody composition of the present application for an antigen.
- “Specific binding” in antigenic antibody binding can be distinguished from non-specific background binding, typically when the dissociation constant (Kd) is less than 1x10 -5 M or less than 1x10 -6 M or less than 1x10 -7 M.
- Specific binding can be detected by methods known in the art, such as ELISA, surface plasmon resonance (SPR), immunoprecipitation, coprecipitation, etc., and non-specific binding and specific binding Include appropriate controls that can be distinguished.
- the antibody or antigen-binding fragment of the present invention may exist as a multimer, such as a dimer, a trimer, a tetramer, or a pentamer including at least a part of the antigen-binding ability of the monomer.
- Such multimers also include homomultimers, or heteromultimers. Since the antibody multimer contains a large number of antigen-binding sites, it has excellent antigen-binding ability compared to monomers.
- Antibody multimers are also easy to produce bifunctional, trifunctional, and tetrafunctional antibodies.
- multifunctional refers to an antibody or antigen-binding fragment having two or more activities or functions (eg, antigen-binding ability, enzyme activity, ligand or receptor-binding ability).
- the antibody of the present invention is Polypeptides having enzymatic activity such as luciferase, acetyltransferase, galactosidase, and the like can be combined.
- Multifunctional antibodies also include antibodies in multivalent or bispecific, trispecific, etc. forms.
- composition comprising an antibody or antigen-binding fragment as an active ingredient
- the antibody according to the present invention specifically binds to an epitope containing a polypeptide represented by any one of SEQ ID NOs: 7 to 72 present on regulatory T cells to activate or maintain the function of the regulatory T cells. Let it be; Or by inhibiting, it is possible to prevent or treat cancer by regulating the activity of effector T cells.
- the “cancer” of the present invention represents or refers to a physiological condition characterized by unregulated cell growth, typically in mammals.
- the cancer to be prevented, improved or treated may be a solid tumor composed of a mass generated by abnormal cell growth in a solid organ, and gastric cancer, liver cancer, or Gliocytoma, ovarian cancer, colon cancer, head and neck cancer, bladder cancer, kidney cell cancer, breast cancer, metastatic cancer, prostate cancer, pancreatic cancer, melanoma, or lung cancer, but are not limited thereto.
- the antibody or antigen-binding fragment provided by the present invention provides an antibody-drug conjugate (Antibody-Drug Conjugate, ADC) comprising a drug.
- ADC Antibody-Drug Conjugate
- the "antibody-drug conjugate (ADC)" refers to a form in which a drug and an antibody are chemically linked without reducing the biological activity of the antibody and the drug.
- the antibody-drug conjugate is a form in which a drug is bound to an amino acid residue at the N-terminus of the heavy and/or light chain of an antibody, specifically, a drug at the N-terminus, an ⁇ -amine group of the heavy and/or light chain of the antibody It refers to this combined form.
- the "drug” may mean any substance having a specific biological activity in cells, which is a concept including DNA, RNA, or peptide.
- the drug may be in a form including a reactive group capable of crosslinking by reacting with an ⁇ -amine group, and also includes a form in which a linker including a reactive group capable of crosslinking by reacting with an ⁇ -amine group is connected.
- an example of a reactive group capable of crosslinking by reacting with the ⁇ -amine group is not particularly limited as long as it can be crosslinked by reacting with an ⁇ -amine group at the N-terminus of the heavy or light chain of an antibody. All types that react with known amine groups are included. Examples include Isothiocyanate, Isocyanates, Acyl azide, NHS ester, Sulfonyl chloride, Aldehyde, Glyoxal, Epoxide, Oxirane, Carbonate, Aryl halide, Imidoester, Carbodiimide, Anhydride and Fluorophenyl ester), but is not limited thereto.
- the antibody-drug conjugate is an epitope of the present invention, that is, Lrig-1 protein; Or an epitope comprising a polypeptide consisting of a partial amino acid sequence of the extracellular domain of the Lrig-1 protein; An epitope comprising a polypeptide consisting of an amino acid sequence represented by Formula 1 above; Or an antibody or antigen-binding fragment that specifically binds to an epitope comprising a polypeptide represented by the amino acid sequence of any one of SEQ ID NOs: 48 to 113, wherein the drug is used to treat diseases targeted by the Lrig-1 antibody.
- Any drug that can be included may be included, and for example, it may be a drug capable of treating an anticancer agent capable of treating cancer, but is not limited thereto.
- the anticancer agent may be included without limitation as long as it is a drug used for the prevention, improvement or treatment of cancer, for example, nitrogen mustard, imatinib, oxaliplatin, rituximab, erlotinib, nerati Nip, Lapatinib, Gefitinib, Vandetanib, Nirotinib, Semasanib, Bosutinib, Akcitinib, Cediranib, Restaurtinib, Trastuzumab, Gefitinib, Bortezomib, Sunitinib, Carbople Latin, sorafenib, bevacizumab, cisplatin, cetuximab, viscum album, asparaginase, tretinoin, hydroxycarbamide, dasatinib, estramustine, gemtuzumab ozogamycin, ibritumomab tusetan
- composition comprising an antibody-drug conjugate (ADC) as an active ingredient
- the antibody or antigen-binding fragment provided by the present invention provides a pharmaceutical composition for the prevention or treatment of cancer comprising an antibody-drug conjugate (Antibody-Drug Conjugate, ADC) as an active ingredient.
- an antibody-drug conjugate Antibody-Drug Conjugate, ADC
- the antibody or antigen-binding fragment contained as an active ingredient in the pharmaceutical composition;
- the antibody-drug conjugate to which the drug is bound specifically binds to an epitope comprising a polypeptide represented by any one of SEQ ID NOs: 7 to 72, thereby inhibiting the function of the regulatory T cells, and inhibiting the function of the effector T cells.
- cancer By maintaining or increasing activity, cancer can be treated very effectively.
- the cancer may be a solid tumor consisting of a mass caused by abnormal cell growth in a solid organ, and as a specific example, gastric cancer, liver cancer, gliocytoma, ovarian cancer, depending on the site of the solid organ.
- gastric cancer gastric cancer
- liver cancer gliocytoma
- ovarian cancer depending on the site of the solid organ.
- Colon cancer, head and neck cancer, bladder cancer, kidney cell cancer, breast cancer, metastatic cancer, prostate cancer, pancreatic cancer, melanoma, or lung cancer but are not limited thereto.
- prevention may include, without limitation, any action of blocking, suppressing or delaying the symptoms of a disease using the pharmaceutical composition of the present invention.
- treatment may include, without limitation, any action that improves or benefits the symptoms of a disease by using the pharmaceutical composition of the present invention.
- the pharmaceutical composition may be in the form of capsules, tablets, granules, injections, ointments, powders, or beverages, and the pharmaceutical composition may be characterized in that it is intended for humans.
- the pharmaceutical composition is not limited thereto, but each is formulated in the form of oral dosage forms such as powders, granules, capsules, tablets, aqueous suspensions, external preparations, suppositories, and sterile injection solutions according to conventional methods.
- the pharmaceutical composition of the present invention may contain a pharmaceutically acceptable carrier.
- Pharmaceutically acceptable carriers can be used as binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, coloring agents, flavoring agents, etc. for oral administration, and buffers, preservatives, and painlessness in the case of injections. Agents, solubilizers, isotonic agents, stabilizers, etc.
- the formulation of the pharmaceutical composition of the present invention can be prepared in various ways by mixing with a pharmaceutically acceptable carrier as described above.
- a pharmaceutically acceptable carrier as described above.
- it when administered orally, it can be prepared in the form of tablets, troches, capsules, elixir, suspension, syrup, wafers, etc., and in the case of injections, it can be prepared in unit dosage ampoules or multiple dosage forms. have.
- it can be formulated as a solution, suspension, tablet, capsule, sustained-release preparation, and the like.
- suitable carriers, excipients and diluents for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose , Methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil.
- fillers, anti-coagulants, lubricants, wetting agents, flavoring agents, emulsifiers, preservatives, and the like may additionally be included.
- the route of administration of the pharmaceutical composition is not limited thereto, but oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, Includes sublingual or rectal. Oral or parenteral administration is preferred.
- the "parenteral" includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or injection techniques.
- the pharmaceutical composition of the present invention may also be administered in the form of suppositories for rectal administration.
- the pharmaceutical composition of the present invention depends on several factors, including the activity of the specific compound used, age, weight, general health, sex, formulation, time of administration, route of administration, excretion rate, drug formulation, and the severity of the specific disease to be prevented or treated. It may vary in various ways, and the dosage of the pharmaceutical composition varies depending on the patient's condition, weight, degree of disease, drug form, route and duration of administration, but may be appropriately selected by those skilled in the art, and 0.0001 to 50 mg/kg per day Alternatively, it may be administered at 0.001 to 50 mg/kg. Administration may be administered once a day, or may be divided several times. The above dosage does not limit the scope of the present invention in any way.
- the pharmaceutical composition according to the present invention may be formulated as a pill, dragee, capsule, liquid, gel, syrup, slurry, or suspension.
- the antibody or antigen-binding fragment according to the present invention relates to a method for preventing or treating cancer comprising administering an Antibody-Drug Conjugate (ADC) to an individual.
- ADC Antibody-Drug Conjugate
- the “cancer” of the present invention represents or refers to a physiological condition characterized by unregulated cell growth, typically in mammals.
- the cancer to be prevented, improved or treated may be a solid tumor composed of a mass generated by abnormal cell growth in a solid organ, and gastric cancer, liver cancer, or Gliocytoma, ovarian cancer, colon cancer, head and neck cancer, bladder cancer, kidney cell cancer, breast cancer, metastatic cancer, prostate cancer, pancreatic cancer, melanoma, or lung cancer, but are not limited thereto.
- the antibody or antigen-binding fragment of the present invention specifically binds to an epitope comprising a polypeptide represented by any one of the amino acid sequences of SEQ ID NOs: 7 to 72, thereby inhibiting the function of the regulatory T cells, and maintaining or increasing the activity of the effector T cells. So that cancer can be treated very effectively.
- the "individual” is an individual suspected of developing cancer, and the suspected individual means a mammal, including mice, livestock, etc., including humans who have or may develop the disease.
- Individuals treatable with the antibody or antibody-drug conjugate of the invention are included without limitation.
- the methods of the present invention may comprise administering an antibody or antibody-drug conjugate in a pharmaceutically effective amount.
- the appropriate total daily use amount may be determined by the treating physician within the range of correct medical judgment, and may be administered once or in several divided doses.
- a specific therapeutically effective amount for a specific patient is a specific composition, including the type and degree of reaction to be achieved, whether other agents are used in some cases, the patient's age, weight, general health condition, It is preferable to apply differently according to various factors including sex and diet, administration time, administration route and secretion rate of the composition, treatment period, drugs used with or concurrently with the specific composition, and similar factors well known in the medical field.
- the method of preventing or treating cancer may be a combination therapy further comprising administering a compound or substance having therapeutic activity against one or more cancer diseases.
- the "combination" should be understood to represent simultaneous, individual or sequential administration.
- the interval between administration of the second component should be such that the beneficial effect of the combination is not lost.
- the dosage of the antibody or antibody-drug conjugate may be about 0.0001 ⁇ g to 500 mg per 1 kg of the patient's body weight, but is not limited thereto.
- the antibody or antigen-binding fragment that specifically binds to the epitope of the Lrig-1 protein according to the present invention specifically binds to the epitope of the present invention present on the regulatory T cell to inhibit the function of the regulatory T cell, and an effector By maintaining or increasing the activity of T cells, it can be used very efficiently in the prevention, improvement or treatment of cancer.
- FIG 1 shows the structure of the Lrig-1 protein according to an embodiment of the present invention.
- FIG. 2 shows the structure of the Lrig-1 protein according to an embodiment of the present invention.
- FIG. 3 shows the level of expression of Lrig-1 mRNA according to an embodiment of the present invention.
- Figure 4 shows the level of expression of Lrig-1 mRNA according to an embodiment of the present invention.
- FIG. 5 shows the level of expression of Lrig-1 mRNA according to an embodiment of the present invention.
- FIG. 6 shows the level of expression of Lrig-1, Lrig-2, and Lrig-3 mRNA according to an embodiment of the present invention.
- FIG. 7 shows a result of comparing the expression levels of Lrig-1 protein in regulatory T cells and non-regulated T cells according to an embodiment of the present invention.
- FIG 8 shows the expression of Lrig-1 protein on the surface of regulatory T cells according to an embodiment of the present invention.
- Lrig-1 protein GTC210-01, GTC210-02, GTC210-03, GTC210-04, GTC110-01, GTC110-02, GTC110-03 and GTC110
- -04 regulatory mechanisms of Lrig-1 protein-induced Stat3 phosphorylation in T cells were analyzed.
- FIG. 11 shows a design diagram of a cancer treatment experiment using a monoclonal antibody specific for Lrig-1 protein in an embodiment of the present invention.
- FIG. 12 shows the effect of cancer treatment using monoclonal antibodies (GTC110-01, GTC110-02, GTC110-03 and GTC110-04) specific to Lrig-1 protein in an embodiment of the present invention.
- 16 and 17 show the results of covalent labeling MS using chymotrypsin in the extracellular domain of the Lirg-1 protein according to an embodiment of the present invention.
- FIG. 22 shows the results of cross-linked MS using chymotrypsin in the extracellular domain of the Lirg-1 protein according to an embodiment of the present invention.
- 25 shows an epitope site to which the GTC110-04 antibody specifically binds in the extracellular domain of the Lrig-1 protein according to an embodiment of the present invention.
- the present invention relates to an epitope of Lrig-1 (leucine-rich and immunoglobulin-like domains 1) protein or an antibody or antigen-binding fragment that specifically binds to the epitope.
- Lrig-1 leucine-rich and immunoglobulin-like domains 1
- the extracellular domain of the Lrig-1 protein may be represented by SEQ ID NO: 5 corresponding to the 35th to 794th amino acid sequence of the human-derived Lrig-1 protein, but is not limited thereto.
- the extracellular domain of the Lrig-1 protein may be represented by SEQ ID NO: 6 corresponding to the 35th to 794th amino acid sequence of the mouse-derived Lrig-1 protein, but is not limited thereto.
- T cell subtypes Th0, Th1, Th2, Th17 and iTreg were prepared. Unlike the naturally isolated nTreg, iTreg refers to cells artificially inducing differentiation in a medium containing the following composition.
- T cells The subtype of T cells is RPMI1640 (Invitrogen Gibco, Grand Island, NY) containing 10% fetal bovine serum (FBS; hyclone, logan, UT) after separating naive T cells obtained from the spleen of mice.
- FBS fetal bovine serum
- Table 1 Each of the components of Table 1 below was further included in the nutrient medium, and differentiation was induced into each cell through culture for 72 hours in an incubator at 37°C and 5% CO 2.
- the three-dimensional structure of the extracellular domain of the Lrig-1 protein was predicted.
- LRR1 to LRR15 were present in the Lrig-LRR domain (amino acid sequence 41 to 494) of the extracellular domain of the Lrig-1 protein.
- LRR domains consisted of 23 to 27 amino acids, and 3 to 5 leucines were present.
- three immunoglobulin-like domains were present in amino acid sequences 494 to 781 of the Lrig-1 protein among the extracellular domains of the Lrig-1 protein.
- Lrig-1 protein can act as a specific biomarker for regulatory T cells.
- CD4 + T cells were isolated from the spleen of mice using a magnet-activated cell sorting (MACS) through CD4 beads. Thereafter, control T (CD4 + CD25 + T) cells and non-regulated T (CD4 + CD25 - T) cells were isolated using a fluorescent active cell sorter (FACS) using a CD25 antibody.
- FACS fluorescent active cell sorter
- mRNA was extracted using Trizol, and for genomic RNA, gDNA was removed by a protocol provided by the manufacturer using a gDNA extraction kit (Qiagen). . The mRNA from which gDNA was removed was synthesized as cDNA through the BDsprint cDNA synthesis kit (Clonetech).
- the real-time polymerase chain reaction was performed under the conditions of 40 cycles at 95°C for 3 minutes, 61°C for 15 seconds, and 72°C for 30 seconds according to the protocol provided by the manufacturer using SYBR Green (Molecular Probes). Primers were used, and relative gene expression levels were calculated using the ⁇ CT method, and normalized using HPRT, and the results are shown in FIGS. 3 to 6.
- Lrig-1 is 18.1 times higher in regulatory T (CD4 + CD25 + T) cells than in non-regulated T (CD4 + CD25 -T) cells. This was about a 10-fold higher level of expression compared to Lag3 and Ikzf4, which are known regulatory T cell markers.
- Lrig-1 was the highest among Lrig-1, Lrig-2, and Lrig-3 corresponding to the Lrig family.
- the Lrig-1 protein according to the present invention is specifically expressed in regulatory T cells, particularly naturally occurring regulatory T cells.
- Lrig-1 protein expressed from Lrig-1 mRNA was specifically expressed only in regulatory T cells.
- a FOXP3-RFP-injected (Knock-in) mouse with RFP (Red fluorescence protein) bound to the FOXP3 promoter, which is a regulatory T cell-specific transcription factor a magnet-activated cell sorter (magnet-activated) from the spleen of the mouse to CD4 beads.
- CD4 + T cells were isolated using cell sorting; MACS). Thereafter, using the RFP protein, regulated T (CD4 + RFP + T) cells and non-regulated T (CD4 + RFP - T) cells were isolated and obtained through a fluorescent active cell sorter (FACS). Each of the cells was stained with the purchased Lrig-1 antibody and the negative control isotype, and the expression level of Lrig-1 was measured with a fluorescently active cell sorter, and the results are shown in FIG. 7.
- the Lrig-1 protein according to the present invention is specifically expressed in regulatory T cells.
- the Lrig-1 protein In order for the Lrig-1 protein to be a target for cell therapy, it must be expressed on the surface of regulatory T cells for more effective target treatment, so it was confirmed whether the Lrig-1 protein was expressed on the surface.
- Each of the differentiated T cell subtypes of Preparation Example 1 was stained with anti-CD4-APC and anti-Lrig-1-PE antibodies, and the surface of each cell using a fluorescence-activated cell sorter (FACS).
- FACS fluorescence-activated cell sorter
- the Lrig-1 protein according to the present invention is not only specifically expressed in regulatory T cell (Treg) cells, but is particularly highly expressed on the surface of regulatory T cells.
- An antibody specific for the Lrig-1 protein according to the present invention was prepared. This antibody was not produced by specifying a specific antigenic determinant, and an antibody capable of binding to the Lrig-1 protein at any site was produced.
- cells expressing the Lrig-1 protein were prepared. More specifically, after cutting the DNA fragment and pcDNA (hygro) corresponding to SEQ ID NO: 2 with a cleavage enzyme, incubating at 37°C for ligation, and inserting the DNA sequence of the Lrig-1 protein. The prepared pcDNA was produced. The prepared pcDNA into which SEQ ID NO: 2 was inserted was introduced into L cells through transfection, so that the Lrig-1 protein could be expressed on the surface of the L cells.
- pcDNA hygro
- a total of eight heavy chains and light chains were selected by selecting the sequence of the light chain and heavy chain amino acids capable of binding to Lrig-1 expressed on the cell surface in the Human scFv library.
- the selected heavy and light chain amino acid sequences were fused with mlgG2a Fc region or human IgG1 Fc region to prepare a monoclonal antibody.
- the sequence of the monoclonal antibody is shown in Table 3 below.
- each of the antibodies of Preparation Examples 1 to 8 was added to L cells stably expressing Lrig-1. After binding, a secondary antibody conjugated with eFlour 670 while being able to recognize a mouse antibody was added, and the binding force of the monoclonal antibody to the Lrig-1 protein was analyzed using FACS. Is shown in FIG. 9.
- Lrig-1 protein-specific monoclonal antibodies (GTC210-01, GTC210-02, GTC210-03 and GTC210-04) according to the present invention have the same level of phosphorylation of Stat3 as Th17 cells. It could be confirmed that the increase was made. On the other hand, Lrig-1 protein-specific monoclonal antibodies (GTC110-01, GTC110-02, GTC110-03 and GTC110-04) according to the present invention continue to maintain the phosphorylation of Stat3 at the same level as iTreg cells, and It was confirmed to reduce.
- the Lrig-1 protein-specific monoclonal antibody according to the present invention inhibits the growth of various solid cancer cells and can effectively prevent, improve, or treat them.
- Each of the extracellular domains (antigens) of the Lrig-1 protein was prepared.
- DEPC Diethyl pyrocarbonate
- Methanol was added to each of the samples after the reaction was terminated, and the supernatant was removed by centrifugation. Thereafter, a solution containing 8 M of urea and 0.1 M of NaCl was added, resuspended, and then chymotrypsin was added to allow the peptide bond to be broken.
- mass spectrometry Q Exactive TM Plus Mass Spectrometer (Thermo SCIENTIFIC) was performed according to the conditions described in FIGS. 13 to 15, and mass spectrometry values of the measured antigen-antibody conjugate and the antigen were compared, and the results are shown in FIG. 16 Wow, it is shown in Table 5. Further, the measured mass spectrometric value was calculated as an antigen-antibody conjugate/antigen and shown in FIG. 17.
- the polypeptides listed in the above results have the potential of an epitope, and in particular, SEQ ID NO: It can be seen that the polypeptide consisting of the amino acid sequence represented by 29 to 32 is more likely to be an epitope of the Lrig-1 protein against the GTC110-04 antibody.
- the polypeptides listed in the above results have the potential of an epitope, and in particular, SEQ ID NO: 32 It can be seen that a polypeptide consisting of an amino acid sequence represented by any one of SEQ ID NOs: 40 to 42, 64, and 68 is more likely to be an epitope of the Lrig-1 protein against the GTC110-04 antibody.
- the GTC110-04 antibody is the 46-87th in the extracellular domain of the Lrig-1 protein; Alternatively, it can be seen that it can specifically bind to a polypeptide consisting of amino acids 46-64 (circled portions in Fig. 25).
- the antibody or antigen-binding fragment that specifically binds to the epitope of the Lrig-1 protein according to the present invention specifically binds to the epitope of the present invention present on the regulatory T cell to inhibit the function of the regulatory T cell, and an effector By maintaining or increasing the activity of T cells, it can be used very efficiently in the prevention, improvement or treatment of cancer.
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Abstract
Description
분화 세포 | 조성 |
Th0 | anti-CD3, anti-CD28 |
Th1 | IL-12, anti-IL-4 항체 |
Th2 | IL-4, anti-IFNβ |
Th17 | IL-6, TGFβ, anti-IFNβ, anti-IL-4 |
iTreg | IL-2, TGFβ |
프라이머 | 서열 |
쥐 Lrig-1 | Forward 5' - GAC GGA ATT CAG TGA GGA GAA CCT - 3' |
Reverse 5' - CAA CTG GTA GTG GCA GCT TGT AGG - 3' | |
쥐 Lrig-2 | forward 5' - TCA CAA GGA ACA TTG TCT GAA CCA- 3' |
reverse 5' - GCC TGA TCT AAC ACA TCC TCC TCA- 3' | |
쥐 Lrig-3 | forward 5' - CAG CAC CTT GAG CTG AAC AGA AAC - 3' |
reverse 5' - CCA GCC TTT GGT AAT CTC GGT TAG - 3' | |
쥐 FOXP3 | forward 5' - CTT TCA CCT ATC CCA CCC TTA TCC - 3' |
reverse 5' - ATT CAT CTA CGG TCC ACA CTG CTC - 3' | |
ACTG1 | forward 5' - GGC GTC ATG GTG GGC ATG GG - 3' |
reverse 5' - ATG GCG TGG GGA AGG GCG TA - 3' |
구분 | 클론 | 위치 | 아미노산 서열 | 서열정보 |
제조예 1 | GTC210-01 clone | 중쇄 | EVQLLESGGG LVQPGGSLRL SCAASGFTFS GYDMSWVRQA PGKGLEWVSL IYPDSGNKYY 60 ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCARDA GLSWAGAFDY WGQGTLVTVS 120 SASTTAPSVY PLAPVCGDTT GSSVTLGCLV KGYFPEPVTL TWNSGSLSSG VHTFPAVLQS 180 DLYTLSSSVT VTSSTWPSQS ITCNVAHPAS STKVDKKIEP RGPTIKPCPP CKCPAPNLLG 240 GPSVFIFPPK IKDVLMISLS PIVTCVVVDV SEDDPDVQIS WFVNNVEVHT AQTQTHREDY 300 NSTLRVVSAL PIQHQDWMSG KEFKCKVNNK DLPAPIERTI SKPKGSVRAP QVYVLPPPEE 360 EMTKKQVTLT CMVTDFMPED IYVEWTNNGK TELNYKNTEP VLDSDGSYFM YSKLRVEKKN 420 WVERNSYSCS VVHEGLHNHH TTKSFSRTPG K |
서열번호 147 |
경쇄 | QSVLTQPPSA SGTPGQRVTI SCSGSSSNIG SNYVTWYQQL PGTAPKLLIY SDSHRPSGVP 60 DRFSGSKSGT SASLAISGLQ SEDEADYYCG SWDYSLSAYV FGGGTKLTVL RTVAAPTVSI 120 FPPSSEQLTS GGASVVCFLN NFYPKDINVK WKIDGSERQN GVLNSWTDQD SKDSTYSMSS 180 TLTLTKDEYE RHNSYTCEAT HKTSTSPIVK SFNRNEC |
서열번호 148 | ||
제조예 2 | GTC210-02 clone | 중쇄 | EVQLLESGGG LVQPGGSLRL SCAASGFTFS NYYMSWVRQA PGKGLEWVSG ISPGDSSTYY 60 ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCAKGL YSNPNEPFDY WGQGTLVTVS 120 SASTTAPSVY PLAPVCGDTT GSSVTLGCLV KGYFPEPVTL TWNSGSLSSG VHTFPAVLQS 180 DLYTLSSSVT VTSSTWPSQS ITCNVAHPAS STKVDKKIEP RGPTIKPCPP CKCPAPNLLG 240 GPSVFIFPPK IKDVLMISLS PIVTCVVVDV SEDDPDVQIS WFVNNVEVHT AQTQTHREDY 300 NSTLRVVSAL PIQHQDWMSG KEFKCKVNNK DLPAPIERTI SKPKGSVRAP QVYVLPPPEE 360 EMTKKQVTLT CMVTDFMPED IYVEWTNNGK TELNYKNTEP VLDSDGSYFM YSKLRVEKKN 420 WVERNSYSCS VVHEGLHNHH TTKSFSRTPG K |
서열번호 149 |
경쇄 | QSVLTQPPSA SGTPGQRVTI SCTGSSSNIG SNYVSWYQQL PGTAPKLLIY DDSQRPSGVP 60 DRFSGSKSGT SASLAISGLR SEDEADYYCG TWDYSLNGYV FGGGTKLTVL RTVAAPTVSI 120 FPPSSEQLTS GGASVVCFLN NFYPKDINVK WKIDGSERQN GVLNSWTDQD SKDSTYSMSS 180 TLTLTKDEYE RHNSYTCEAT HKTSTSPIVK SFNRNEC |
서열번호 150 | ||
제조예 3 | GTC210-03 clone | 중쇄 | EVQLLESGGG LVQPGGSLRL SCAASGFTFS SYDMSWVRQA PGKGLEWVSG ISPDGSNIYY 60 ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCAKVG LRCRYEACSY AYGMDVWGQG 120 TLVTVSSAST TAPSVYPLAP VCGDTTGSSV TLGCLVKGYF PEPVTLTWNS GSLSSGVHTF 180 PAVLQSDLYT LSSSVTVTSS TWPSQSITCN VAHPASSTKV DKKIEPRGPT IKPCPPCKCP 240 APNLLGGPSV FIFPPKIKDV LMISLSPIVT CVVVDVSEDD PDVQISWFVN NVEVHTAQTQ 300 THREDYNSTL RVVSALPIQH QDWMSGKEFK CKVNNKDLPA PIERTISKPK GSVRAPQVYV 360 LPPPEEEMTK KQVTLTCMVT DFMPEDIYVE WTNNGKTELN YKNTEPVLDS DGSYFMYSKL 420 RVEKKNWVER NSYSCSVVHE GLHNHHTTKS FSRTPGK |
서열번호 151 |
경쇄 | QSVLTQPPSA SGTPGQRVTI SCSGSSSNIG SNYVSWYQQL PGTAPKLLIY SDSHRPSGVP 60 DRFSGSKSGT SASLAISGLR SEDEADYYCA TWDSSLNGYV FGGGTKLTVL RTVAAPTVSI 120 FPPSSEQLTS GGASVVCFLN NFYPKDINVK WKIDGSERQN GVLNSWTDQD SKDSTYSMSS 180 TLTLTKDEYE RHNSYTCEAT HKTSTSPIVK SFNRNEC |
서열번호 152 | ||
제조예 4 | GTC 210-04 clone | 중쇄 | EVQLLESGGG LVQPGGSLRL SCAASGFTFS NYDMSWVRQA PGKGLEWVSS ISPSSGSIYY 60 ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCAKDL DAFWRPSFDY WGQGTLVTVS 120 STTAPSVYPL APVCGDTTGS SVTLGCLVKG YFPEPVTLTW NSGSLSSGVH TFPAVLQSDL 180 YTLSSSVTVT SSTWPSQSIT CNVAHPASST KVDKKIEPRG PTIKPCPPCK CPAPNLLGGP 240 SVFIFPPKIK DVLMISLSPI VTCVVVDVSE DDPDVQISWF VNNVEVHTAQ TQTHREDYNS 300 TLRVVSALPI QHQDWMSGKE FKCKVNNKDL PAPIERTISK PKGSVRAPQV YVLPPPEEEM 360 TKKQVTLTCM VTDFMPEDIY VEWTNNGKTE LNYKNTEPVL DSDGSYFMYS KLRVEKKNWV 420 ERNSYSCSVV HEGLHNHHTT KSFSRTPGK |
서열번호 153 |
경쇄 | QSVLTQPPSA SGTPGQRVTI SCTGSSSNIG NNNVNWYQQL PGTAPKLLIY SDSHRPSGVP 60 DRFSGSKSGT SASLAISGLR SEDEADYYCG SWDDSLSAYV FGGGTKLTVL RTVAAPTVSI 120 FPPSSEQLTS GGASVVCFLN NFYPKDINVK WKIDGSERQN GVLNSWTDQD SKDSTYSMSS 180 TLTLTKDEYE RHNSYTCEAT HKTSTSPIVK SFNRNEC |
서열번호 154 | ||
제조예 5 | GTC110-01 clone | 중쇄 | EVQLLESGGG LVQPGGSLRL SCAASGFTFS NYDMSWVRQA PGKGLEWVSS ISPSSGSIYY 60 ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCAKDL DAFWRPSFDY WGQGTLVTVS 120 SASTTAPSVY PLAPVCGDTT GSSVTLGCLV KGYFPEPVTL TWNSGSLSSG VHTFPAVLQS 180 DLYTLSSSVT VTSSTWPSQS ITCNVAHPAS STKVDKKIEP RGPTIKPCPP CKCPAPNLLG 240 GPSVFIFPPK IKDVLMISLS PIVTCVVVDV SEDDPDVQIS WFVNNVEVHT AQTQTHREDY 300 NSTLRVVSAL PIQHQDWMSG KEFKCKVNNK DLPAPIERTI SKPKGSVRAP QVYVLPPPEE 360 EMTKKQVTLT CMVTDFMPED IYVEWTNNGK TELNYKNTEP VLDSDGSYFM YSKLRVEKKN 420 WVERNSYSCS VVHEGLHNHH TTKSFSRTPG K |
서열번호 155 |
경쇄 | QSVLTQPPSA SGTPGQRVTI SCTGSSSNIG NNSVTWYQQL PGTAPKLLIY ADNNRPSGVP 60 DRFSGSKSGT SASLAISGLR SEDEADYYCA AWDSSLSAYV FGGGTKLTVL RTVAAPTVSI 120 FPPSSEQLTS GGASVVCFLN NFYPKDINVK WKIDGSERQN GVLNSWTDQD SKDSTYSMSS 180 TLTLTKDEYE RHNSYTCEAT HKTSTSPIVK SFNRNEC |
서열번호 156 | ||
제조예 6 | GTC110-02 clone | 중쇄 | EVQLLESGGG LVQPGGSLRL SCAASGFTFS DYYMSWVRQA PGKGLEWVSG ISHDSGSKYY 60 ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCARHW TTFDYWGQGT LVTVSSASTT 120 APSVYPLAPV CGDTTGSSVT LGCLVKGYFP EPVTLTWNSG SLSSGVHTFP AVLQSDLYTL 180 SSSVTVTSST WPSQSITCNV AHPASSTKVD KKIEPRGPTI KPCPPCKCPA PNLLGGPSVF 240 IFPPKIKDVL MISLSPIVTC VVVDVSEDDP DVQISWFVNN VEVHTAQTQT HREDYNSTLR 300 VVSALPIQHQ DWMSGKEFKC KVNNKDLPAP IERTISKPKG SVRAPQVYVL PPPEEEMTKK 360 QVTLTCMVTD FMPEDIYVEW TNNGKTELNY KNTEPVLDSD GSYFMYSKLR VEKKNWVERN 420 SYSCSVVHEG LHNHHTTKSF SRTPGK |
서열번호 157 |
경쇄 | QSVLTQPPSA SGTPGQRVTI SCSGSSSNIG SNNVTWYQQL PGTAPKLLIY ANSNRPSGVP 60 DRFSGSKSGT SASLAISGLR SEDEADYYCG AWDYSLSAYV FGGGTKLTVL RTVAAPTVSI 120 FPPSSEQLTS GGASVVCFLN NFYPKDINVK WKIDGSERQN GVLNSWTDQD SKDSTYSMSS 180 TLTLTKDEYE RHNSYTCEAT HKTSTSPIVK SFNRNEC |
서열번호 158 | ||
제조예 7 | GTC110-03 clone | 중쇄 | EVQLLESGGG LVQPGGSLRL SCAASGFTFS NYAMSWVRQA PGKGLEWVSA IYPGGGSIYY 60 ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCARDI LPCPWGRCYY DYAMDVWGQG 120 TLVTVSSAST TAPSVYPLAP VCGDTTGSSV TLGCLVKGYF PEPVTLTWNS GSLSSGVHTF 180 PAVLQSDLYT LSSSVTVTSS TWPSQSITCN VAHPASSTKV DKKIEPRGPT IKPCPPCKCP 240 APNLLGGPSV FIFPPKIKDV LMISLSPIVT CVVVDVSEDD PDVQISWFVN NVEVHTAQTQ 300 THREDYNSTL RVVSALPIQH QDWMSGKEFK CKVNNKDLPA PIERTISKPK GSVRAPQVYV 360 LPPPEEEMTK KQVTLTCMVT DFMPEDIYVE WTNNGKTELN YKNTEPVLDS DGSYFMYSKL 420 RVEKKNWVER NSYSCSVVHE GLHNHHTTKS FSRTPGK |
서열번호 159 |
경쇄 | QSVLTQPPSA SGTPGQRVTI SCSDSSSNIG SNTVSWYQQL PGTAPKLLIY ADNNRPSGVP 60 DRFSGSKSGT SASLAISGLR SEDEADYYCG TWDYSLSGYV FGGGTKLTVL RTVAAPTVSI 120 FPPSSEQLTS GGASVVCFLN NFYPKDINVK WKIDGSERQN GVLNSWTDQD SKDSTYSMSS 180 TLTLTKDEYE RHNSYTCEAT HKTSTSPIVK SFNRNEC |
서열번호 160 | ||
제조예 8 | GTC110-04 clone | 중쇄 | EVQLLESGGG LVQPGGSLRL SCAASGFTFS NYAMSWVRQA PGKGLEWVSV ISHGGGSTYY 60 ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCARVI SNCHLGVCYY SNGMDVWGQG 120 TLVTVSSAST TAPSVYPLAP VCGDTTGSSV TLGCLVKGYF PEPVTLTWNS GSLSSGVHTF 180 PAVLQSDLYT LSSSVTVTSS TWPSQSITCN VAHPASSTKV DKKIEPRGPT IKPCPPCKCP 240 APNLLGGPSV FIFPPKIKDV LMISLSPIVT CVVVDVSEDD PDVQISWFVN NVEVHTAQTQ 300 THREDYNSTL RVVSALPIQH QDWMSGKEFK CKVNNKDLPA PIERTISKPK GSVRAPQVYV 360 LPPPEEEMTK KQVTLTCMVT DFMPEDIYVE WTNNGKTELN YKNTEPVLDS DGSYFMYSKL 420 RVEKKNWVER NSYSCSVVHE GLHNHHTTKS FSRTPGK |
서열번호 161 |
경쇄 | QSVLTQPPSA SGTPGQRVTI SCSGSSSNIG NNDVYWYQQL PGTAPKLLIY SDSQRPSGVP 60 DRFSGSKSGT SASLAISGLR SEDEADYYCG TWDYSLSGYV FGGGTKLTVL RTVAAPTVSI 120 FPPSSEQLTS GGASVVCFLN NFYPKDINVK WKIDGSERQN GVLNSWTDQD SKDSTYSMSS 180 TLTLTKDEYE RHNSYTCEAT HKTSTSPIVK SFNRNEC |
서열번호 162 | ||
제조예 9 | GTC110-04 인간화 항체 |
중쇄 | EVQLLESGGG LVQPGGSLRL SCAASGFTFS NYAMSWVRQA PGKGLEWVSV ISHGGGSTYY 60 ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCARVI SNCHLGVCYY SNGMDVWGQG 120 TLVTVSSAST KGPSVFPLAP SSKSTSGGTA ALGCLVKDYF PEPVTVSWNS GALTSGVHTF 180 PAVLQSSGLY SLSSVVTVPS SSLGTQTYIC NVNHKPSNTK VDKKVEPKSC DKTHTCPPCP 240 APELLGGPSV FLFPPKPKDT LMISRTPEVT CVVVDVSHED PEVKFNWYVD GVEVHNAKTK 300 PREEQYNSTY RVVSVLTVLH QDWLNGKEYK CKVSNKALPA PIEKTISKAK GQPREPQVYT 360 LPPSREEMTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS DGSFFLYSKL 420 TVDKSRWQQG NVFSCSVMHE ALHNHYTQKS LSLSPGKY |
서열번호 163 |
경쇄 | QSVLTQPPSA SGTPGQRVTI SCSGSSSNIG NNDVYWYQQL PGTAPKLLIY SDSQRPSGVP 60 DRFSGSKSGT SASLAISGLR SEDEADYYCG TWDYSLSGYV FGGGTKLTVL RTVAAPSVFI 120 FPPSDEQLKS GTASVVCLLN NFYPREAKVQ WKVDNALQSG NSQESVTEQD SKDSTYSLSS 180 TLTLSKADYE KHKVYACEVT HQGLSSPVTK SFNRGEC |
서열번호 164 |
단계 | 전체 시간(min) | 유속 (㎕/min) | 이동상 A* (%) | 이동상 B** (%) |
0 | 0.00 | 100.00 | 95.0 | 5.0 |
1 | 5.00 | 100.00 | 95.0 | 5.0 |
2 | 7.00 | 100.00 | 90.0 | 10.0 |
3 | 48.00 | 100.00 | 70.0 | 30.0 |
4 | 55.00 | 100.00 | 5.0 | 95.0 |
5 | 65.00 | 100.00 | 5.0 | 95.0 |
6 | 66.00 | 100.00 | 95.00 | 5.0 |
7 | 71.00 | 100.00 | 95.00 | 5.0 |
*이동상 A(증류수/0.2% 포름산) ** 이동상 B(아세토니트릴/0.2% 포름산) |
아미노산 번호 | 항원 | 항원-항체 결합체 | 차이 | 비율 | p value | ||
mean | S.D | mean | S.D | ||||
26-64 | 59.56 | 4.11 | 51.51 | 5.56 | 8.05 | 1.16 | ** |
36-64 | 51.37 | 7.00 | 40.77 | 4.25 | 10.60 | 1.26 | ** |
44-64 | 30.46 | 1.29 | 31.87 | 0.66 | -1.41 | 0.96 | * |
65-87 | 47.90 | 0.74 | 43.09 | 4.36 | 4.81 | 1.11 | * |
105-134 | 48.26 | 2.60 | 35.54 | 8.20 | 12.72 | 1.36 | ** |
207-216 | 77.52 | 1.61 | 75.76 | 0.72 | 1.77 | 1.02 | * |
209-216 | 73.44 | 1.19 | 69.09 | 0.63 | 4.34 | 1.06 | *** |
252-254 | 53.84 | 5.08 | 43.75 | 5.22 | 10.09 | 1.23 | ** |
303-317 | 64.17 | 1.22 | 59.52 | 4.26 | 4.65 | 1.08 | * |
303-320 | 53.78 | 0.94 | 48.69 | 0.82 | 5.10 | 1.10 | *** |
308-317 | 44.52 | 2.44 | 38.84 | 1.67 | 5.68 | 1.15 | *** |
321-344 | 62.11 | 4.53 | 81.23 | 1.84 | -19.12 | 0.76 | *** |
324-344 | 35.87 | 2.41 | 32.23 | 4.19 | 3.64 | 1.11 | * |
329-347 | 40.96 | 2.95 | 24.52 | 10.14 | 16.44 | 1.67 | ** |
354-368 | 94.66 | 0.98 | 92.95 | 1.02 | 1.71 | 1.02 | ** |
357-368 | 87.35 | 0.80 | 86.48 | 0.59 | 0.88 | 1.01 | * |
390-395 | 51.34 | 2.27 | 46.62 | 1.05 | 4.72 | 1.10 | *** |
396-401 | 76.00 | 1.59 | 73.84 | 0.93 | 2.15 | 1.03 | ** |
427-440 | 69.31 | 4.49 | 61.15 | 4.78 | 8.16 | 1.13 | ** |
430-446 | 58.32 | 1.57 | 53.15 | 4.67 | 5.17 | 1.10 | * |
447-471 | 27.21 | 1.42 | 28.88 | 1.33 | -1.67 | 0.94 | * |
472-480 | 42.21 | 2.48 | 47.49 | 0.82 | -5.28 | 0.89 | *** |
474-480 | 42.02 | 3.00 | 45.34 | 0.87 | -3.32 | 0.93 | * |
529-535 | 22.96 | 2.26 | 7.52 | 2.03 | 15.44 | 3.05 | *** |
568-579 | 51.68 | 2.04 | 46.19 | 4.75 | 5.49 | 1.12 | ** |
585-598 | 44.89 | 4.28 | 38.20 | 7.01 | 6.69 | 1.18 | * |
599-624 | 22.09 | 2.48 | 16.84 | 4.15 | 5.25 | 1.31 | ** |
599-615 | 12.33 | 1.08 | 9.13 | 1.40 | 3.20 | 1.35 | *** |
599-614 | 13.25 | 1.26 | 10.06 | 2.00 | 3.19 | 1.32 | ** |
599-610 | 8.54 | 1.11 | 7.16 | 0.49 | 1.38 | 1.19 | ** |
599-612 | 12.89 | 0.77 | 9.49 | 1.18 | 3.39 | 1.36 | *** |
599-613 | 11.49 | 1.32 | 9.85 | 0.94 | 1.65 | 1.17 | ** |
624-636 | 3.40 | 0.20 | 2.58 | 0.21 | 0.82 | 1.32 | *** |
637-692 | 53.44 | 2.57 | 49.35 | 2.29 | 4.09 | 1.08 | ** |
679-692 | 15.77 | 0.70 | 13.62 | 0.74 | 2.15 | 1.16 | *** |
694-699 | 59.44 | 1.75 | 56.79 | 2.66 | 2.65 | 1.05 | * |
700-705 | 67.98 | 5.79 | 60.47 | 5.42 | 7.51 | 1.12 | * |
700-713 | 21.98 | 1.53 | 18.80 | 2.73 | 3.18 | 1.17 | * |
700-735 | 9.04 | 1.23 | 5.87 | 1.02 | 3.17 | 1.54 | *** |
702-714 | 24.37 | 2.05 | 20.49 | 3.86 | 3.88 | 1.19 | * |
705-714 | 28.28 | 1.17 | 25.69 | 2.46 | 2.59 | 1.10 | * |
715-727 | 0.66 | 0.26 | 0.35 | 0.11 | 0.31 | 1.88 | ** |
728-735 | 10.05 | 1.56 | 5.58 | 0.81 | 4.47 | 1.80 | *** |
아미노산 번호 | 항원 | 항원-항체 결합체 | 차이 | 비율 | p value | ||
mean | S.D | mean | S.D | ||||
24-37 | 1.67 | 0.34 | 1.11 | 0.19 | 0.56 | 1.51 | ** |
38-45 | 5.70 | 0.33 | 4.15 | 0.15 | 1.55 | 1.37 | *** |
46-92 | 76.64 | 1.30 | 73.22 | 3.67 | 3.42 | 1.05 | * |
46-94 | 91.22 | 3.99 | 74.75 | 2.92 | 16.47 | 1.22 | *** |
103-132 | 40.74 | 1.01 | 34.52 | 2.64 | 6.23 | 1.18 | *** |
122-132 | 39.75 | 0.85 | 35.32 | 2.70 | 4.43 | 1.13 | ** |
141-154 | 1.99 | 0.42 | 1.38 | 0.35 | 0.61 | 1.44 | ** |
161-178 | 48.76 | 0.58 | 48.00 | 0.75 | 0.75 | 1.02 | * |
173-178 | 68.68 | 0.96 | 69.78 | 0.72 | -1.10 | 0.98 | * |
179-186 | 0.45 | 0.09 | 0.31 | 0.08 | 0.14 | 1.46 | ** |
179-188 | 3.91 | 0.71 | 4.87 | 0.97 | -0.96 | 0.80 | * |
216-226 | 8.82 | 1.60 | 6.80 | 0.93 | 2.03 | 1.30 | ** |
264-266 | 75.97 | 3.22 | 71.79 | 3.45 | 4.18 | 1.06 | * |
268-274 | 36.31 | 0.82 | 34.17 | 1.44 | 2.14 | 1.06 | ** |
304-318 | 76.26 | 2.16 | 71.49 | 4.45 | 4.77 | 1.07 | * |
304-321 | 94.20 | 0.90 | 91.94 | 1.35 | 2.26 | 1.02 | ** |
367-385 | 37.10 | 0.76 | 34.89 | 2.04 | 2.22 | 1.06 | * |
499-531 | 72.06 | 5.48 | 76.85 | 2.75 | -4.79 | 0.94 | * |
532-540 | 7.00 | 0.24 | 4.85 | 0.56 | 2.16 | 1.44 | *** |
559-569 | 5.17 | 1.00 | 3.93 | 0.77 | 1.24 | 1.31 | * |
570-577 | 28.67 | 0.69 | 26.69 | 2.20 | 1.98 | 1.07 | * |
578-600 | 20.13 | 0.54 | 17.24 | 2.84 | 2.89 | 1.17 | * |
584-600 | 51.23 | 0.73 | 46.30 | 3.49 | 4.93 | 1.11 | ** |
584-610 | 87.90 | 2.41 | 83.13 | 4.53 | 4.77 | 1.06 | * |
614-629 | 16.83 | 0.83 | 13.41 | 1.55 | 3.42 | 1.25 | *** |
669-689 | 99.84 | 0.01 | 99.88 | 0.01 | -0.03 | 1.00 | *** |
682-704 | 18.83 | 1.57 | 16.22 | 0.47 | 2.61 | 1.16 | ** |
690-694 | 0.47 | 0.11 | 0.37 | 0.09 | 0.11 | 1.29 | * |
694-704 | 59.11 | 2.39 | 63.48 | 1.79 | -4.37 | 0.93 | ** |
705-726 | 26.02 | 1.55 | 23.05 | 2.64 | 2.97 | 1.13 | * |
705-739 | 35.21 | 1.46 | 31.44 | 3.05 | 3.77 | 1.12 | ** |
727-739 | 12.04 | 1.75 | 9.20 | 1.58 | 2.85 | 1.31 | ** |
740-754 | 16.35 | 0.37 | 12.98 | 2.51 | 3.37 | 1.26 | ** |
740-753 | 44.06 | 1.69 | 38.00 | 3.84 | 6.07 | 1.16 | ** |
755-769 | 97.94 | 0.77 | 97.13 | 0.58 | 0.81 | 1.01 | * |
아미노산 번호 | 항원 | 항원-항체 결합체 | 차이 | 비율 | p value | ||
mean | S.D | mean | S.D | ||||
1-15 | 14.43 | 2.40 | 10.99 | 3.78 | 3.44 | 1.31 | * |
16-18 | 0.84 | 0.11 | 0.46 | 0.05 | 0.37 | 1.81 | ** |
31-45 | 5.01 | 0.20 | 3.83 | 0.08 | 1.18 | 1.31 | *** |
31-49 | 99.66 | 0.12 | 95.79 | 1.18 | 3.87 | 1.04 | *** |
31-55 | 98.23 | 0.17 | 74.26 | 5.16 | 23.98 | 1.32 | *** |
46-49 | 0.45 | 0.03 | 0.41 | 0.01 | 0.04 | 1.10 | ** |
93-102 | 5.74 | 0.41 | 5.35 | 0.12 | 0.38 | 1.07 | * |
111-132 | 33.35 | 0.92 | 28.93 | 0.61 | 4.42 | 1.15 | *** |
164-182 | 55.69 | 2.33 | 62.83 | 2.27 | -7.14 | 0.89 | *** |
289-318 | 81.31 | 3.28 | 40.46 | 2.89 | 40.86 | 2.01 | *** |
319-326 | 1.66 | 0.08 | 1.86 | 0.03 | -0.20 | 0.89 | *** |
327-338 | 57.92 | 2.43 | 65.19 | 1.55 | -7.27 | 0.89 | *** |
329-338 | 25.18 | 1.80 | 22.95 | 1.06 | 2.22 | 1.10 | ** |
348-352 | 22.88 | 2.16 | 26.19 | 1.63 | -3.32 | 0.87 | ** |
353-361 | 25.13 | 1.63 | 33.14 | 1.62 | -8.00 | 0.76 | *** |
360-361 | 82.60 | 2.14 | 66.35 | 6.14 | 16.24 | 1.24 | *** |
366-389 | 27.95 | 1.36 | 24.58 | 0.83 | 3.36 | 1.14 | *** |
395-396 | 61.42 | 4.84 | 55.89 | 4.32 | 5.52 | 1.10 | * |
397-399 | 76.77 | 0.99 | 73.96 | 0.83 | 2.82 | 1.04 | *** |
397-405 | 77.87 | 1.09 | 81.73 | 2.21 | -3.87 | 0.95 | ** |
400-405 | 22.98 | 1.52 | 20.48 | 0.55 | 2.50 | 1.12 | ** |
456-476 | 23.65 | 0.77 | 30.16 | 0.50 | -6.51 | 0.78 | *** |
477-498 | 100.00 | 0.00 | 98.88 | 0.04 | 1.12 | 1.01 | *** |
498-506 | 11.99 | 0.91 | 7.16 | 0.46 | 4.82 | 1.67 | *** |
507-517 | 48.71 | 2.15 | 37.83 | 1.31 | 10.87 | 1.29 | *** |
557-572 | 63.44 | 0.59 | 66.15 | 0.74 | -2.71 | 0.96 | *** |
573-600 | 15.68 | 0.87 | 11.78 | 0.98 | 3.90 | 1.33 | *** |
585-600 | 44.58 | 0.66 | 33.48 | 0.52 | 11.10 | 1.33 | *** |
601-620 | 10.27 | 2.06 | 6.88 | 0.83 | 3.39 | 1.49 | ** |
601-626 | 7.82 | 0.71 | 5.97 | 0.52 | 1.85 | 1.31 | *** |
605-620 | 12.99 | 2.31 | 8.95 | 0.88 | 4.03 | 1.45 | ** |
611-620 | 19.72 | 2.71 | 14.61 | 1.30 | 5.11 | 1.35 | *** |
611-618 | 19.38 | 2.98 | 15.17 | 1.53 | 4.22 | 1.28 | ** |
627-631 | 91.56 | 5.88 | 80.51 | 6.05 | 11.05 | 1.14 | ** |
627-630 | 7.59 | 0.53 | 6.42 | 0.20 | 1.17 | 1.18 | *** |
632-666 | 0.34 | 0.15 | 1.88 | 0.32 | -1.54 | 0.18 | *** |
667-681 | 4.25 | 0.29 | 3.04 | 0.11 | 1.21 | 1.40 | *** |
682-695 | 8.62 | 0.34 | 8.28 | 0.15 | 0.34 | 1.04 | * |
682-694 | 0.01 | 0.01 | 1.52 | 0.33 | -1.51 | 0.01 | *** |
695-722 | 7.06 | 1.46 | 4.61 | 0.28 | 2.45 | 1.53 | ** |
696-722 | 24.25 | 1.22 | 19.92 | 0.59 | 4.33 | 1.22 | *** |
696-709 | 28.84 | 2.10 | 23.96 | 0.97 | 4.88 | 1.20 | *** |
723-754 | 56.36 | 0.47 | 50.13 | 0.43 | 6.23 | 1.12 | *** |
755-769 | 61.79 | 1.18 | 54.57 | 1.37 | 7.22 | 1.13 | *** |
아미노산 번호 | C % | T % | 링커 사이트 | C % | T % + M/L |
26-46 | 88.9 | 11.1 | T36 | 50.8 | 49.2 |
66-86 | 79.6 | 20.4 | |||
89-110 | 92.0 | 8.0 | K102 | 69.2 | 30.8 |
126-136 | 90.1 | 9.9 | |||
137-144 | 70.5 | 29.5 | |||
158-174 | 96.8 | 3.2 | K163 | 65.1 | 34.9 |
175-179 | 97.1 | 2.9 | K175 | 52.5 | 47.5 |
198-208 | 40.2 | 59.8 | |||
207-224 | 96.4 | 3.6 | K207 | 82.3 | 17.7 |
222-237 | 72.2 | 27.8 | |||
238-246 | 62.0 | 38.0 | |||
252-269 | 65.4 | 34.6 | K267 | 47.2 | 52.8 |
270-280 | 92.2 | 7.8 | K274 | 87.3 | 12.7 |
279-282 | 83.6 | 16.4 | |||
283-293 | 94.0 | 6.0 | T286 | 50.2 | 49.8 |
305-344 | 98.0 | 2.0 | K318 | 55.2 | 44.8 |
348-356 | 94.7 | 5.3 | K352 | 64.5 | 35.5 |
357-368 | 96.7 | 3.3 | K359, 365 | 88.7 | 11.3 |
390-401 | 94.7 | 5.3 | K394 | 85.7 | 14.3 |
417-420 | 80.3 | 19.7 | |||
422-429 | 81.7 | 18.3 | |||
441-453 | 86.7 | 13.3 | K441 | 74.7 | 25.3 |
472-494 | 99.1 | 0.9 | K476 | 97.1 | 2.9 |
495-511 | 98.5 | 1.5 | K497 | 98.2 | 1.8 |
525-530 | 92.9 | 7.1 | T525 | 92.7 | 7.3 |
531-541 | 91.7 | 8.3 | Y541 | 78.9 | 21.1 |
554-559 | 97.7 | 2.3 | K556 | 83.1 | 16.9 |
560-567 | 94.7 | 5.3 | T560 | 92.7 | 7.3 |
568-579 | 97.1 | 2.9 | T568, K569 | 94.9 | 5.1 |
585-598 | 80.2 | 19.8 | |||
624-636 | 80.8 | 19.2 | T626 | 80.7 | 19.3 |
680-693 | 93.3 | 6.7 | 93.3 | 6.7 | |
694-701 | 43.5 | 56.5 | |||
715-727 | 82.6 | 17.4 | |||
736-744 | 75.8 | 24.2 | |||
745-762 | 97.5 | 2.5 | K754 | 91.8 | 8.2 |
아미노산 번호 | C % | T % | 링커 사이트 | C % | T % + M/L |
1-4 | 94.6 | 5.4 | 94.6 | 5.4 | |
46-92 | 91.4 | 8.6 | 91.4 | 8.6 | |
93-102 | 86.8 | 13.2 | |||
164-172 | 98.6 | 1.4 | 98.6 | 1.4 | |
173-178 | 91.9 | 8.1 | K175 | 73.8 | 26.2 |
179-186 | 58.1 | 41.9 | |||
191-207 | 91.0 | 9.0 | K207 | 77.0 | 23.0 |
216-226 | 95.0 | 5.0 | K215 | 88.6 | 11.4 |
264-274 | 94.6 | 5.4 | 94.6 | 5.4 | |
267-274 | 98.7 | 1.3 | K267 | 92.9 | 7.1 |
268-274 | 98.9 | 1.1 | 98.9 | 1.1 | |
275-287 | 94.8 | 5.2 | 94.8 | 5.2 | |
275-303 | 91.6 | 8.4 | 91.6 | 8.4 | |
325-359 | 92.1 | 7.9 | K352 | 89.9 | 10.1 |
360-366 | 96.7 | 3.3 | K361, 365 | 58.0 | 42.0 |
366-385 | 87.8 | 12.2 | |||
386-394 | 91.3 | 8.7 | 91.3 | 8.7 | |
395-424 | 94.2 | 5.8 | K396, 415 | 93.6 | 6.4 |
425-441 | 93.3 | 6.7 | 93.3 | 6.7 | |
442-479 | 99.0 | 1.0 | 99.0 | 1.0 | |
480-498 | 98.4 | 1.6 | 98.4 | 1.6 | |
498-531 | 90.9 | 9.1 | 90.9 | 9.1 | |
532-540 | 91.4 | 8.6 | 91.4 | 8.6 | |
541-556 | 97.5 | 2.5 | K556 | 96.3 | 3.7 |
557-577 | 90.8 | 9.2 | K569 | 87.9 | 12.1 |
615-629 | 95.3 | 4.7 | 95.3 | 4.7 | |
669-681 | 85.8 | 14.2 | |||
754-765 | 93.6 | 6.4 | K754 | 53.0 | 47.0 |
아미노산 번호 | C % | T % | 링커 사이트 | C % | T % + M/L |
46-102 | 93.7 | 6.3 | 93.7 | 6.3 | |
93-102 | 91.6 | 8.4 | 91.6 | 8.4 | |
150-163 | 94.5 | 5.5 | 94.5 | 5.5 | |
164-182 | 98.0 | 2.0 | 98.0 | 2.0 | |
183-207 | 73.7 | 26.3 | |||
208-215 | 94.3 | 5.7 | K215 | 85.1 | 14.9 |
216-226 | 91.4 | 8.6 | 91.4 | 8.6 | |
227-267 | 91.8 | 8.2 | 91.8 | 8.2 | |
268-274 | 97.0 | 3.0 | 97.0 | 3.0 | |
275-318 | 85.6 | 14.4 | |||
319-361 | 96.0 | 4.0 | K352, 361 | 91.6 | 8.4 |
366-399 | 90.1 | 9.9 | K394, 396 | 89.9 | 10.1 |
411-415 | 91.1 | 8.9 | 91.1 | 8.9 | |
442-455 | 72.2 | 27.8 | |||
456-476 | 93.3 | 6.7 | 93.3 | 6.7 | |
477-498 | 93.4 | 6.6 | 93.4 | 6.6 | |
498-506 | 95.5 | 4.5 | 95.5 | 4.5 | |
538-556 | 96.4 | 3.6 | 96.4 | 3.6 | |
557-572 | 99.3 | 0.7 | T560 | 98.5 | 1.5 |
557-600 | 93.6 | 6.4 | 93.6 | 6.4 | |
601-626 | 89.7 | 10.3 | |||
627-630 | 66.0 | 34.0 | K629 | 64.7 | 35.3 |
682-695 | 97.1 | 2.9 | K694 | 79.4 | 20.6 |
723-754 | 91.4 | 8.6 | K754 | 84.1 | 15.9 |
효소 | 아미노산 번호 | 항원 | 항원-항체 결합체 | 차이 | 비율 |
Asp-N Lys-C | 31-45 | 5.01 | 3.83 | 1.18 | 1.31 |
Asp-N Lys-C | 31-55 | 98.23 | 74.26 | 23.98 | 1.32 |
키모트립신 | 36-64 | 51.37 | 40.77 | 10.60 | 1.26 |
트립신 | 38-45 | 5.70 | 4.15 | 1.55 | 1.37 |
트립신 | 46-94 | 91.22 | 74.75 | 16.47 | 1.22 |
효소 | 아미노산 번호 | 항원 | 항원-항체 결합체 | 차이 | 비율 |
트립신 | 24-37 | 1.67 | 1.11 | 0.56 | 1.51 |
키모트립신 | 26-64 | 59.56 | 51.51 | 8.05 | 1.16 |
Asp-N Lys-C | 31-49 | 99.66 | 95.79 | 3.87 | 1.04 |
키모트립신 | 38-64 | 53.47 | 46.30 | 7.16 | 1.15 |
Asp-N Lys-C | 62-92 | 65.30 | 65.51 | -0.22 | 1.00 |
키모트립신 | 65-87 | 47.90 | 43.09 | 4.81 | 1.11 |
키모트립신 | 88-94 | 89.93 | 89.48 | 0.44 | 1.00 |
Claims (12)
- Lrig-1(leucine-rich and immunoglobulin-like domains 1) 단백질의 에피토프로서,서열번호 7 내지 서열번호 70으로 표시되는 아미노산 서열로 이루어진 폴리펩티드로 구성된 군으로부터 선택되는 적어도 어느 하나의 폴리펩티드를 포함하는 에피토프.
- Lrig-1(leucine-rich and immunoglobulin-like domains 1) 단백질의 에피토프로서,서열번호 71 또는 서열번호 72로 표시되는 아미노산 서열로 이루어지는 폴리펩티드를 포함하는 에피토프.
- 서열번호 7 내지 서열번호 70으로 표시되는 아미노산 서열로 이루어진 폴리펩티드로 구성된 군으로부터 선택되는 적어도 어느 하나의 폴리펩티드를 포함하는 에피토프에 특이적으로 결합하는 항체 또는 항원 결합 단편.
- 서열번호 71 또는 서열번호 72로 표시되는 아미노산 서열로 이루어지는 폴리펩티드를 포함하는 에피토프에 특이적으로 결합하는 항체 또는 항원 결합 단편.
- 제1항 또는 제2항의 에피토프를 코딩하는 핵산 분자.
- 제5항의 핵산 분자가 삽입된 발현 벡터.
- 제6항의 발현 벡터가 형질 감염된 숙주 세포주.
- 제3항 또는 제4항의 항체 또는 항원 결합 단편을 유효 성분으로 포함하는 암의 예방 또는 치료용 약학 조성물.
- 제8항에 있어서,상기 암은 위암, 간암, 교세포종, 난소암, 대장암, 두경부암, 방광암, 신장세포암, 유방암, 전이암, 전립선암, 췌장암, 흑색종 또는 폐암인, 약학 조성물.
- 제3항 또는 제4항의 항체 또는 항원 결합 단편; 및 약물을 포함하는 항체-약물 결합체.
- 서열번호 7 내지 서열번호 70으로 표시되는 아미노산 서열로 이루어진 폴리펩티드로 구성된 군으로부터 선택되는 적어도 어느 하나의 폴리펩티드를 포함하는 에피토프에 특이적으로 결합하는 항체 또는 항원 결합 단편을 약학적 유효량으로 개체에 투여하는 단계를 포함하는 암의 예방 또는 치료 방법.
- 서열번호 71 또는 서열번호 72로 표시되는 아미노산 서열로 이루어지는 폴리펩티드를 포함하는 에피토프에 특이적으로 결합하는 항체 또는 항원 결합 단편을 약학적 유효량으로 개체에 투여하는 단계를 포함하는 암의 예방 또는 치료 방법.
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AU2020380072A AU2020380072A1 (en) | 2019-11-08 | 2020-11-09 | Epitope of regulatory T cell surface antigen, and antibody specifically binding thereto |
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KR20230016148A (ko) * | 2021-07-16 | 2023-02-01 | 주식회사 굳티셀 | 조절 t 세포 표면 항원의 에피토프 및 이에 특이적으로 결합하는 항체 |
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KR20180022761A (ko) * | 2018-02-26 | 2018-03-06 | 연세대학교 산학협력단 | 조절자 T 세포에 특이적으로 존재하는 새로운 표면단백질 Lrig-1의 용도 |
KR20180117067A (ko) * | 2017-04-18 | 2018-10-26 | 주식회사 굳티셀 | Lrig-1 단백질에 특이적인 결합 분자 및 이의 용도 |
KR20180116925A (ko) * | 2017-04-18 | 2018-10-26 | 주식회사 굳티셀 | 암 또는 면역 질환의 예방 또는 치료용 약학 조성물 |
KR20180116924A (ko) * | 2017-04-18 | 2018-10-26 | 주식회사 굳티셀 | 면역 세포 표면 단백질의 항원 결정기인 폴리펩티드 |
KR20190124665A (ko) * | 2018-04-26 | 2019-11-05 | 주식회사 굳티셀 | 신규한 융합 단백질 및 이를 포함하는 암의 예방 또는 치료용 약학적 조성물 |
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KR20180116925A (ko) * | 2017-04-18 | 2018-10-26 | 주식회사 굳티셀 | 암 또는 면역 질환의 예방 또는 치료용 약학 조성물 |
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JPWO2023095801A1 (ko) * | 2021-11-24 | 2023-06-01 | ||
WO2023095801A1 (ja) * | 2021-11-24 | 2023-06-01 | レグセル株式会社 | ヒト誘導性制御性t細胞およびその作製方法 |
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KR20210056280A (ko) | 2021-05-18 |
JP2023500248A (ja) | 2023-01-05 |
AU2020380072A1 (en) | 2022-05-19 |
EP4056586A1 (en) | 2022-09-14 |
CN114929733A (zh) | 2022-08-19 |
BR112022008730A2 (pt) | 2022-07-19 |
KR102488967B1 (ko) | 2023-01-16 |
EP4056586A4 (en) | 2024-04-10 |
CA3156600A1 (en) | 2021-05-14 |
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