WO2020190104A1 - 뇌신경계 질환의 예방 또는 치료용 조성물 - Google Patents
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Definitions
- the present invention relates to a composition for preventing or treating diseases of the cranial nerve system.
- degenerative neurological diseases such as stroke, dementia, and Alzheimer's disease
- decreases in memory, attention, cognitive ability, and emotional control are observed, which are the result of neuronal death and atrophy of nerve branches.
- the elongation of the nerve branch of the nerve cell plays an important role in the memory and learning functions of the neural circuit by increasing the neuroplasticity. Accordingly, it is predicted that the active ingredient that promotes nerve branch elongation and nerve regeneration of nerve cells may be developed as a new therapeutic agent for degenerative neurological diseases.
- a binding molecule that specifically binds to Lrig-1 (leucine-rich and immunoglobulin-like domains 1) protein present in regulatory T cells (Treg cells) is used as an active ingredient. It relates to a composition for preventing, improving, or treating diseases of the cranial nerve system, including.
- the "binding molecule" used in the present invention is an intact immunoglobulin including a monoclonal antibody such as a chimeric, humanized or human monoclonal antibody, or an immunoglomline that binds to an antigen, for example It refers to a variable domain comprising an immunoglobulin fragment that competes with an intact immunoglobulin for binding to the monomeric HA or trimeric HA of the influenza A virus. Regardless of structure, the antigen-binding fragment binds the same antigen recognized by the intact immunoglobulin.
- Antigen-binding fragments include two or more consecutive groups of the amino acid sequence of the binding molecule, 20 or more consecutive amino acid residues, 25 or more consecutive amino acid residues, 30 or more consecutive amino acid residues, 35 or more consecutive amino acid residues, 40 or more consecutive amino acid residues.
- amino acid residues 50 or more consecutive amino acid residues, 60 or more consecutive amino acid residues, 70 or more consecutive amino acid residues, 80 or more consecutive amino acid residues, 90 or more consecutive amino acid residues, 100 or more consecutive amino acid residues, 125 or more consecutive amino acid residues, Peptides or polypeptides comprising an amino acid sequence of 150 or more contiguous amino acid residues, 175 or more contiguous amino acid residues, 200 or more contiguous amino acid residues, or 250 or more contiguous amino acid residues.
- Antigen-binding fragment is in particular Fab, F(ab'), F(ab')2, Fv, dAb, Fd, complementarity determining region (CDR) fragment, single-chain antibody (scFv), bivalent Single-chain antibodies, single-chain phage antibodies, diabodies, triabodies, tetrabodies, polypeptides containing one or more fragments of an immunoglobulin sufficient to bind a specific antigen to the polypeptide, and the like.
- the fragments can be produced synthetically or by enzymatic or chemical degradation of complete immunoglobulins, or can be produced genetically by recombinant DNA technology. Methods of production are well known in the art.
- the "Lrig-1 (leucine-rich and immunoglobulin-like domains 1) protein” is a transmembrane protein consisting of 1091 amino acids present on the surface of regulatory T cells, and a leucine repeat sequence on the extracellular or lumen side (leucine-rich repeat (LRR)), three immunoglobulin-like domains, a transmembrane sequence, and a cytoplasmic tail.
- the LRIG gene family includes LRIG1, LRIG2 and LRIG3, and amino acids between them are very conservatively composed.
- 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 polypeptide represented by SEQ ID NO: 1 derived from human or a polypeptide represented by SEQ ID NO: 3 derived from a mouse, but is not limited thereto.
- the Lrig-1 protein represented by SEQ ID NO: 1 may be encoded by a polynucleotide represented by SEQ ID NO: 2, but is not limited thereto.
- the Lrig-1 protein represented by SEQ ID NO: 3 may be encoded by a polynucleotide represented by SEQ ID NO: 4, but is not limited thereto.
- the binding molecule In the present invention, the binding molecule,
- Heavy chain CDR1 consisting of the amino acid sequence represented by SEQ ID NO: 5 or 13
- Heavy chain CDR2 consisting of the amino acid sequence represented by SEQ ID NO: 6 or 14
- a heavy chain variable region comprising; a heavy chain CDR3 consisting of an amino acid sequence represented by SEQ ID NO: 7 or 15;
- Light chain CDR1 represented by the amino acid sequence represented by SEQ ID NO: 8 or 16
- Light chain CDR2 represented by the amino acid sequence represented by SEQ ID NO: 9 or 17
- It may be a binding molecule comprising a light chain variable region including; light chain CDR3 represented by the amino acid sequence represented by SEQ ID NO: 10 or 18.
- the binding molecule In the present invention, the binding molecule,
- a heavy chain variable region comprising a heavy chain CDR1 represented by SEQ ID NO: 13, a heavy chain CDR2 represented by SEQ ID NO: 14, and a heavy chain CDR3 represented by SEQ ID NO: 15; a heavy chain variable region selected from the group consisting of;
- a light chain variable region comprising a light chain CDR1 represented by SEQ ID NO: 16, a light chain CDR2 represented by SEQ ID NO: 17, and a light chain CDR3 represented by SEQ ID NO: 18; a light chain variable region selected from the group consisting of; It may be a binding molecule.
- the binding molecule In the present invention, the binding molecule,
- a heavy chain variable region comprising a heavy chain CDR1 represented by SEQ ID NO: 5, a heavy chain CDR2 represented by SEQ ID NO: 6, and a heavy chain CDR3 represented by SEQ ID NO: 7; And a light chain variable region comprising a light chain CDR1 represented by SEQ ID NO: 8, a light chain CDR2 represented by SEQ ID NO: 9, and a light chain CDR3 represented by SEQ ID NO: 10; And
- a heavy chain variable region comprising a heavy chain CDR1 represented by SEQ ID NO: 13, a heavy chain CDR2 represented by SEQ ID NO: 14, and a heavy chain CDR3 represented by SEQ ID NO: 15;
- a light chain CDR1 represented by SEQ ID NO: 16 a light chain CDR2 represented by SEQ ID NO: 17, and a light chain variable region comprising a light chain CDR3 represented by SEQ ID NO: 18; may be a binding molecule selected from the group consisting of: have.
- the binding molecule In the present invention, the binding molecule,
- a heavy chain variable region consisting of an amino acid sequence represented by SEQ ID NO: 11 or 19;
- It may be a binding molecule including a light chain variable region consisting of the amino acid sequence represented by SEQ ID NO: 12 or 20.
- the binding molecule In the present invention, the binding molecule,
- a binding molecule comprising a heavy chain variable region represented by SEQ ID NO: 11 and a light chain variable region represented by SEQ ID NO: 12;
- It may be a binding molecule selected from the group consisting of; a binding molecule including a heavy chain variable region represented by SEQ ID NO: 19 and a light chain variable region represented by SEQ ID NO: 20.
- the binding molecule may further include an Fc region (fragment crystallization region) or a constant region (constant region).
- the Fc region may be an Fc region of an IgA, IgD, IgE, IgM, IgG1, IgG2, IgG3 or IgG4 antibody, may be derived therefrom, or may be a hybrid Fc region.
- the Fc region may be a mammalian-derived IgA, IgD, IgE, IgM, IgG1, IgG2, IgG3 or IgG4 antibody Fc region, preferably human-derived IgA, IgD, IgE, IgM, IgG1, IgG2, It may be the Fc region of an IgG3 or IgG4 antibody, but is not limited thereto.
- the constant region may be a mouse-derived IgG2a constant region represented by SEQ ID NO: 21, but is not limited thereto.
- the constant region may be a mouse-derived immunoglobulin kappa constant region represented by SEQ ID NO: 22, but is not limited thereto.
- the constant region may be a human-derived IgG1 constant region represented by SEQ ID NO: 23 or 24, but is not limited thereto.
- the constant region may be a human-derived immunoglobulin kappa constant region represented by SEQ ID NO: 25, but is not limited thereto.
- the constant region may be a human-derived IgG2 constant region represented by SEQ ID NO: 26, but is not limited thereto.
- the constant region may be a human-derived IgG3 constant region represented by SEQ ID NO: 27, but is not limited thereto.
- the constant region may be a human-derived IgG4 constant region represented by SEQ ID NO: 28, but is not limited thereto.
- the Fc region may be a human-derived immunoglobulin lambda constant region, but is not limited thereto.
- the "hybrid Fc" may be derived from a combination of human IgG subclass or a combination of human IgD and IgG.
- the hybrid Fc binds to a biologically active molecule, a polypeptide, etc., not only increases the serum half-life of the biologically active molecule, but also increases the expression level of the polypeptide when the nucleotide encoding the Fc-polypeptide fusion protein is expressed.
- the hybrid Fc region may be a hybrid Fc represented by SEQ ID NO: 29, but is not limited thereto.
- the Fc or constant region may be linked to the variable region by a linker.
- a linker is connected to the C-terminus of the Fc or constant region, and the N-terminus of the binding molecule of the present invention may be connected to the linker, but is not limited thereto.
- the "linker” may include a sequence that can be cleaved by an enzyme overexpressed in a tissue or cell of a target disease. When it can be cleaved by the enzyme overexpressed as described above, it is possible to effectively prevent the activity of the polypeptide from being lowered due to the Fc or the constant region.
- a peptide linker consisting of 33 amino acids located at the 282 th to 314 th part of human albumin most frequently present in the blood, more preferably 13 amino acids located at the 292 th to 304 th part It may be a peptide linker, and this portion is a portion that is mostly exposed to the outside due to a three-dimensional structure, and the possibility of inducing an immune response in the body is minimized. However, it is not limited thereto.
- the binding molecule of the present invention may further include a heavy chain constant region consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 21, 23, 24, 26, 27, 28 and 29.
- the binding molecule of the present invention may further include a light chain constant region consisting of an amino acid sequence represented by SEQ ID NO: 22 or 25.
- binding molecule of the present invention is a binding molecule of the present invention.
- a heavy chain constant region consisting of the amino acid sequence represented by SEQ ID NO: 21;
- It may further include a light chain constant region consisting of the amino acid sequence represented by SEQ ID NO: 22.
- binding molecule of the present invention is a binding molecule of the present invention.
- a heavy chain constant region consisting of an amino acid sequence represented by SEQ ID NO: 23, 24, 26, 27 or 28;
- It may further include a light chain constant region consisting of the amino acid sequence represented by SEQ ID NO: 25.
- binding molecule of the present invention is a binding molecule of the present invention.
- It may further include a heavy chain constant region consisting of the amino acid sequence represented by SEQ ID NO: 29.
- binding molecule of the present invention is a binding molecule of the present invention.
- a binding molecule comprising a heavy chain represented by SEQ ID NO: 30 and a light chain represented by SEQ ID NO: 31;
- a binding molecule comprising a heavy chain represented by SEQ ID NO: 32 and a light chain represented by SEQ ID NO: 33;
- It may be a binding molecule selected from the group consisting of; a binding molecule including a heavy chain represented by SEQ ID NO: 34 and a light chain represented by SEQ ID NO: 35.
- the binding molecule of the present invention is characterized in that it is an antibody, but is not limited thereto.
- the antibody has the ability to bind to the Lrig-1 protein as a monoclonal antibody, a full-length antibody, or a part of the antibody, and binds to the Lrig-1 antigen determining site competitively with the binding molecule of the present invention. Includes all possible antibody fragments.
- 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 a 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 "monoclonal antibody” refers to an antibody molecule of a single molecular composition obtained from substantially the same antibody population, and indicates a single binding specificity and affinity for a specific epitope.
- 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 "antibody fragment” refers to a fragment having an antigen-binding function, and includes Fab, Fab', F(ab') 2 and Fv.
- the Fab has a structure having a variable region of a light and heavy chain, a constant region of a light chain, and a first constant region of a heavy chain (CH1 domain), and has one antigen-binding site.
- Fab' differs from Fab in that it has a hinge region including at least one cysteine residue at the C-terminus of the heavy chain CH1 domain.
- F(ab') 2 antibodies are produced by disulfide bonds between cysteine residues in the hinge region of Fab'.
- Fv (Variable fragment) refers to the smallest antibody fragment having only a heavy chain variable region and a light chain variable region.
- the double-chain Fv (dsFv) is a disulfide bond to connect the heavy chain variable region and the light chain variable region
- the single-chain Fv (scFv) is generally covalently linked to the heavy chain variable region and the light chain variable region through a peptide linker.
- the antibody fragment can obtain a Fab or F(ab') 2 fragment, and can be produced through gene recombination technology.
- the antibody is a chimeric antibody, humanized antibody, bivalent, bispecific molecule, minibody, domain antibody, bispecific antibody, antibody mimic, uni It may be a unibody diabody, a triabody, a tetrabody, or a fragment thereof, but is not limited thereto.
- 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 preferred human antibody constant region to produce a humanized antibody.
- the binding molecule may bind to Lrig-1 protein, and may also be provided as a bispecific antibody or bispecific antigen-binding fragment capable of binding to other proteins.
- the bispecific antibody and bispecific antigen-binding fragment may include the binding molecule according to the present invention.
- the bispecific antibody and the bispecific antigen-binding fragment include an antigen-binding domain capable of binding to Lrig-1 protein, wherein the antigen-binding domain capable of binding to Lrig-1 protein is It may comprise or consist of a binding molecule according to the invention.
- the bispecific antibody and bispecific antigen-binding fragment provided by the present invention comprises an antigen-binding domain, which is a binding molecule capable of binding to the Lrig-1 protein according to the present invention, and an antigen-binding domain capable of binding to other target proteins.
- the antigen-binding domain capable of binding to another target protein is a protein other than the Lrig-1 protein, but is not limited thereto, for example, PD-1 or an antigen-binding domain capable of binding to a cell surface receptor. However, it is not limited thereto.
- bispecific antibodies and bispecific antigen binding fragments according to the invention can be in any suitable format, e.g., Kontermann MAbs 2012, 4(2): 182-197, incorporated herein by reference in its entirety. It can be provided in the format described in.
- a bispecific antibody or bispecific antigen binding fragment may be a bispecific antibody conjugate (e.g., IgG2, F(ab')2 or CovX-body), a bispecific IgG or IgG-type molecule (e.g.
- Db diabody
- dsDb dsDb
- DART scDb
- tandAbs tandem scFv
- tandem dAb/VHH triple body
- Fab-scFv Fab-scFv
- F(ab')2-scFv2 bispecific Fc and CH3 fusion proteins
- taFv-Fc di-diabody, scDb-CH3, scFv-Fc-scFv, HCAb-VHH, scFv-kih-Fc, or scFv-kih-CH3), or a bispecific fusion protein (e.g., scFv2-albumin , scDb-albumin, taFv-toxin, DNL-Fab3, DNL-Fab4-IgG, DNL-Fab4-IgG-cytokine2).
- a bispecific fusion protein e.g., scFv2-albumin , scDb-albumin, taFv-toxin, DNL-Fab3, DNL-Fab4-IgG, DNL-Fab4-IgG-cytokine2.
- Fig. 2 of Kontermann MAbs 2012, 4(2): 182-19 One of skill in the art can design and prepare bispecific antibodies and bispecific antigen binding
- the method for producing the bispecific antibody in the present invention is described in, for example, Segal and Bast, 2001. Production of Bispecific Antibodies. Current Protocols in Immunology. 14:IV: 2.13:2.13.1-2.13.16) and chemical crosslinking of the antibody or antibody fragment with a reducing disulfide or non-reducing thioether linkage.
- a reducing disulfide or non-reducing thioether linkage For example, N-succinimidyl-3-(-2-pyridyldithio)-propionate (SPDP) is a disulfide linked bispecific F(ab)2 heterodimer, for example, It can be used to chemically crosslink Fab fragments through hinge region SH-groups.
- bispecific antibodies in the present invention are described, for example, in DM and Bast, BJ 2001. Production of Bispecific Antibodies. Current Protocols in Immunology. 14:IV:2.13:2.13 .1-2.13.16), comprising fusion of antibody-producing hybridomas, for example with polyethylene glycol, to generate quadroma cells capable of secreting bispecific antibodies.
- Bispecific antibodies and bispecific antigen-binding fragments according to the invention can also be used, for example, in Antibody Engineering: Methods and Protocols, Second Edition (Humana Press, 2012), both of which are incorporated herein by reference in their entirety. ), at Chapter 40: Production of Bispecific Antibodies: Diabodies and Tandem scFv (Hornig and Farber-Schwarz), or French, How to make bispecific antibodies, Methods Mol. Med. 2000; 40:333-339), as described in For example, it can be produced recombinantly by expression from a nucleic acid construct encoding a polypeptide for an antigen binding molecule.
- two antigen binding domains i.e., a light and heavy chain variable domain for an antigen binding domain capable of binding to PD-1, etc., and a light and heavy chain variable domain for an antigen binding domain capable of binding other target proteins.
- a DNA construct comprising a sequence encoding a dimerization domain or a suitable linker between the antigen binding domains
- Recombinant bispecific antibodies can then be produced by expression of the construct (eg, in vitro) in a suitable host cell (eg mammalian host cell), and the expressed recombinant bispecific antibody can then be optionally purified.
- Antibodies can be produced by an affinity maturation process in which a modified antibody with improved affinity of the antibody for an antigen is produced compared to an unmodified parental antibody.
- Affinity matured antibodies are described in the art, for example, Marks et al., Rio/Technology 10:779-783 (1992); Barbas et al. Proc Nat. Acad. Sci. USA 91:3809- 3813 (1994); Schier et al. Gene 169:147-155 (1995); Yelton et al. J. Immunol. 155:1994-2004 (1995); Jackson et al., J. Immunol. 154(7): 3310-159 (1995); and Hawkins et al, J. Mol. Biol. 226:889-896 (1992)).
- the binding molecule provided by the present invention may include a variant of the amino acid sequence as long as it can specifically bind to the Lrig-1 protein.
- changes can be made to the amino acid sequence of an antibody to improve its binding affinity and/or other biological properties. Such modifications include, for example, deletions, insertions and/or substitutions of amino acid sequence residues of the antibody.
- amino acid variations are made based on the relative similarity of amino acid side chain substituents, such as hydrophobicity, hydrophilicity, charge, size, and the like.
- amino acid side chain substituents such as hydrophobicity, hydrophilicity, charge, size, and the like.
- arginine, lysine and histidine are all positively charged residues; Alanine, glycine and serine have similar sizes; It can be seen that phenylalanine, tryptophan and tyrosine have similar shapes.
- arginine, lysine and histidine; Alanine, glycine and serine; And phenylalanine, tryptophan, and tyrosine are biologically functional equivalents.
- the hydropathic index of the amino acid can be considered.
- Each amino acid is assigned a hydrophobicity index according to its hydrophobicity and charge: isoleucine (+4.5); Valine (+4.2); Leucine (+3.8); Phenylalanine (+2.8); Cysteine/cysteine (+2.5); Methionine (+1.9); Alanine (+1.8); Glycine (-0.4); Threonine (-0.7); Serine (-0.8); Tryptophan (-0.9); Tyrosine (-1.3); Proline (-1.6); Histidine (-3.2); Glutamate (-3.5); Glutamine (-3.5); Aspartate (-3.5); Asparagine (-3.5); Lysine (-3.9); And arginine (-4.5).
- the hydrophobic amino acid index is very important in imparting an interactive biological function of a protein. It is a known fact that similar biological activities can be retained only by substitution with amino acids having a similar hydrophobicity index. When introducing a mutation with reference to the hydrophobicity index, substitutions are made between amino acids having a hydrophobicity index difference of preferably within ⁇ 2, more preferably within ⁇ 1, and even more preferably within ⁇ 0.5.
- the binding molecule of the present invention is interpreted to include a sequence exhibiting substantial identity with the sequence listed in the sequence listing.
- the term "substantial identity” means that the sequence of the present invention and any other sequence are parallel to each other as much as possible, and when the parallel sequence is analyzed using an algorithm commonly used in the art, at least 61% It means a sequence showing homology, more preferably 70% homology, even more preferably 80% homology, and most preferably 90% homology. Alignment methods for sequence comparison are known in the art. Various methods and algorithms for alignment are described in Smith and Waterman, Adv. Appl. Math. 2:482 (1981); Needleman and Wunsch, J. Mol. Bio. 48:443 (1970); Pearson and Lipman, Methods in Mol. Biol.
- NBCI National Center for Biological Information
- blastp blasm
- It can be used in conjunction with sequence analysis programs such as blastx, tblastn and tblastx.
- the BLSAT is accessible at http://www.ncbi.nlm.nih.gov/BLAST/.
- sequence homology comparison method using this program can be confirmed online (http://www.ncbi.nlm.nih.gov/BLAST/blast_help.html).
- the binding molecule preferably the antibody
- the binding molecule may be produced by a conventional method for producing an antibody, but may be produced by affinity maturation.
- the affinity maturation refers to a process in which activated B cells produce an antibody with increased affinity for an antigen during an immune response.
- the affinity maturation may be the same as a process occurring in nature, and an antibody or antibody fragment generated by affinity maturation may be generated based on the principle of mutation and selection.
- the binding molecule, preferably the antibody, provided by the present invention can effectively prevent, improve or treat neurodegenerative diseases or neuroinflammatory diseases, particularly as neurological disorders.
- a nucleic acid molecule encoding the binding molecule provided in the present invention;
- a host cell line transfected with the expression vector it provides a composition for preventing, improving or treating cranial nervous system diseases comprising as an active ingredient.
- the nucleic acid molecule of the present invention includes all nucleic acid molecules in which the amino acid sequence of the binding molecule 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
- 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 with bacterial origin of replication).
- vectors eg, non-episomal mammalian vectors
- vectors can be incorporated into the host cell's genome as it enters the host cell, thereby replicating with the host genome.
- some vectors are capable of directing the expression of genes to which they are operative.
- 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 the plasmid is the most commonly used form of 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, 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 depending on 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 an 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 are all available in the present invention.
- 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 because of natural, accidental or deliberate mutations.
- Host cells include cells transfected 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 Escherichia 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 is not limited thereto, and all cells that can be used as host cell lines known to those skilled in the art may be used.
- bacterial cells such as Escherichia coli
- compositions for preventing, improving or treating cranial nervous system diseases comprising an antibody-drug conjugate (ADC) containing the antibody and drug provided in the present invention as an active ingredient
- 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 a cell, which is a concept including DNA, RNA, or peptide.
- the drug may be 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-terminal 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 drug may be included irrespective of its kind as long as it is a drug capable of treating a neurodegenerative disease or a neuroinflammatory disease.
- composition provided by the present invention may be a neurodegenerative disease or a neuro-inflammatory disease for the prevention, improvement or treatment of neurological disorders.
- the “nerve degenerative disease” may mean a disease caused by a decrease or loss of the function of nerve cells
- the “nerve inflammatory disease” may mean a disease caused by an excessive inflammatory reaction of the nervous system.
- Specific examples of the neurodegenerative disease or neuroinflammatory disease in the present invention include stroke, dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, and Niemann-Pick disease.
- composition provided by the present invention may be used as a pharmaceutical composition or a food composition, but is not limited thereto.
- the “prevention” of the present invention may be included without limitation, as long as it blocks symptoms caused by neurodegenerative diseases or neuroinflammatory diseases by using the composition of the present invention, or suppresses or delays the symptoms.
- treatment and “improvement” of the present invention include, without limitation, any action that enables or benefits symptoms caused by neurodegenerative diseases or neuroinflammatory diseases using the composition of the present invention. I can.
- 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 for humans.
- the pharmaceutical composition of the present invention is not limited thereto, but can be formulated and used in the form of oral dosage forms such as powders, granules, capsules, tablets, aqueous suspensions, etc., external preparations, suppositories, and sterile injectable solutions according to a conventional method. have.
- 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, painlessness, etc. for injections.
- Agents, solubilizers, isotonic agents, stabilizers, and the like can be mixed and used, and in the case of topical administration, a base agent, excipient, lubricant, preservative, etc. can be used.
- the formulation of the pharmaceutical composition of the present invention can be variously prepared by mixing with a pharmaceutically acceptable carrier as described above.
- a pharmaceutically acceptable carrier for example, for oral administration, 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.
- Others, solutions, suspensions, tablets, capsules can be formulated as sustained-release preparations.
- suitable carriers, excipients and diluents for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil may be used.
- fillers, anti-aggregating agents, lubricants, wetting agents, flavoring agents, emulsifying agents, preservatives, and the like may additionally be included.
- the route of administration of the pharmaceutical composition according to the present invention 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.
- parenteral includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
- the pharmaceutical composition of the present invention can also be administered in the form of suppositories for rectal administration.
- the pharmaceutical composition of the present invention varies depending on a number of 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.
- the dosage of the pharmaceutical composition may vary 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 or It can be administered at 0.001 to 50 mg/kg.
- the administration may be administered once or several times a day. The above dosage does not in any way limit the scope of the present invention.
- the pharmaceutical composition according to the present invention may be formulated as a pill, dragee, capsule, liquid, gel, syrup, slurry, or suspension.
- the food composition comprising the composition of the present invention as an active ingredient can be prepared in the form of various foods, for example, beverages, gum, tea, vitamin complexes, powders, granules, tablets, capsules, confectionery, rice cakes, and bread. . Since the food composition of the present invention is composed of plant extracts with little toxicity and side effects, it can be safely used even when taken for a long time for prophylactic purposes.
- the amount may be added in a proportion of 0.1 to 50% of the total weight.
- the food composition is prepared in the form of a beverage
- various flavoring agents or natural carbohydrates, etc. may be included as in a conventional beverage. That is, as natural carbohydrates, monosaccharides such as glucose, disaccharides such as fructose, and common sugars such as sucrose and polysaccharides, dextrins and cyclodextrins, and sugar alcohols such as xylitol, sorbitol, and erythritol are included. can do.
- flavoring agent examples include natural flavoring agents (taumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.).
- the food composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavors and natural flavoring agents, coloring agents, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners. , pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonates used in carbonated beverages, and the like.
- These components may be used independently or in combination.
- the proportion of these additives is not so important, but is generally selected in the range of 0.1 to about 50 parts by weight per 100 parts by weight of the composition of the present invention.
- the binding molecule provided by the present invention; A nucleic acid molecule encoding the binding molecule; An expression vector into which the nucleic acid molecule is inserted; A host cell line transfected with the expression vector; Or it provides a method for preventing, improving, or treating cranial nervous system diseases comprising administering an antibody-drug conjugate (ADC) provided by the present invention.
- ADC antibody-drug conjugate
- the "individual” is an individual suspected of developing a cranial nervous system disease
- the suspicious individual of the disease refers to a mammal including mice, livestock, etc., including humans who have or may develop the disease.
- Subjects that can be treated with the effective substance provided by the present invention are included without limitation.
- the cranial nervous system disease treated by the method of the present invention may be a neurodegenerative disease or a neuroinflammatory disease, and specific examples thereof include stroke, dementia, Alzheimer's disease, Parkinson's disease, and Huntington's disease. ), Niemann-Pick disease, multiple sclerosis, prion disease, Creutzfeldt-Jakob disease, frontotemporal dementia, Lewis dementia, AlzAmyotrophic lateral sclerosis , Paraneoplastic syndrome, basal cortical degeneration, multiple system atrophy, progressive nuclear paralysis, autoimmune disease of the nervous system, spinocerebellar ataxia, inflammatory and neuropathic pain, cerebrovascular disease, spinal cord injury spinal cord injury) and tauopathy may be selected from the group consisting of, but is not limited thereto.
- the method of the present invention comprises a binding molecule provided by the present invention; A nucleic acid molecule encoding the binding molecule; An expression vector into which the nucleic acid molecule is inserted; A host cell line transfected with the expression vector; Or it may include administering the antibody-drug conjugate (ADC) provided by the present invention in a pharmaceutically effective amount.
- ADC antibody-drug conjugate
- a specific therapeutically effective amount for a specific patient is a composition containing the active ingredient, the age of the patient, including the type and degree of the reaction to be achieved, whether other agents are used in some cases, Body weight, general health status, sex and diet, administration time, administration route, and secretion rate of a composition containing the active ingredient, treatment period, various factors including drugs used or concurrently used with a specific composition and well known in the field of medicine It is desirable to apply differently depending on the similarity factor.
- the method of preventing or treating a cranial nervous system disease may be a combination therapy further comprising administering a compound or substance having therapeutic activity against one or more diseases.
- the "combination" should be understood to represent simultaneous, individual or sequential administration.
- the interval between administrations of the second component should be such that the beneficial effects of the combination are not lost.
- the dosage of the 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.
- composition for diagnosis of neurological disorders including the binding molecule provided by the present invention.
- the "diagnosis” means to confirm the presence or characteristics of a pathological condition, and for the purposes of the present invention, the diagnosis is to confirm the presence or absence of a cranial nervous system disease, particularly a neurodegenerative disease or a neuroinflammatory disease.
- the present invention by measuring the expression level of the Lrig-1 protein using the binding molecule, it is possible to diagnose neurological disorders.
- a diagnostic kit for cranial nervous system diseases comprising the diagnostic composition of the present invention.
- the kit refers to a set of compositions and accessories necessary for a specific purpose.
- the kit of the present invention can diagnose the disease by checking the expression level of the Lrig-1 protein.
- the kit of the present invention includes a primer for measuring the expression level of a diagnostic marker of an immune-related disease, a probe, or an antibody that selectively recognizes the marker, as well as one or more other component compositions, solutions, or devices suitable for the assay method. I can.
- the kit may be an RT-PCR kit, a DNA chip kit, an ELISA kit, a protein chip kit, a rapid kit, or a multiple reaction monitoring (MRM) kit, but is not limited thereto.
- MRM multiple reaction monitoring
- the diagnostic kit of the present invention may further include one kind or more other component compositions, solutions, or devices suitable for the analysis method.
- the diagnostic kit of the present invention may further include essential elements necessary to perform a reverse transcription polymerase reaction.
- the reverse transcription polymerase reaction kit contains a pair of primers specific for the gene encoding the marker protein.
- the primer is a nucleotide having a sequence specific to the nucleic acid sequence of the gene, and may have a length of about 7 bp to 50 bp, more preferably about 10 bp to 30 bp.
- a primer specific to the nucleic acid sequence of the control gene may be included.
- reverse transcription polymerase reaction kits include test tubes or other suitable containers, reaction buffers (various pH and magnesium concentrations), deoxynucleotides (dNTPs), enzymes such as Taq-polymerase and reverse transcriptase, DNase, RNase inhibitor DEPC. - May include DEPC-water, sterilized water, etc.
- the diagnostic kit of the present invention may include essential elements necessary to perform a DNA chip.
- the DNA chip kit may include a substrate to which cDNA or oligonucleotide corresponding to a gene or fragment thereof is attached, and reagents, agents, enzymes, etc. for preparing a fluorescently labeled probe.
- the substrate may include a cDNA or oligonucleotide corresponding to a control gene or a fragment thereof.
- the diagnostic kit of the present invention may contain essential elements necessary for performing ELISA.
- ELISA kits contain antibodies specific for the protein. Antibodies are antibodies that have high specificity and affinity for a marker protein and have little cross-reactivity with other proteins, and are monoclonal, polyclonal, or recombinant antibodies.
- the ELISA kit may contain an antibody specific for a control protein.
- Other ELISA kits include reagents capable of detecting bound antibodies, such as labeled secondary antibodies, chromophores, enzymes (e.g., conjugated with antibodies) and their substrates or antibodies capable of binding. Other materials may be included.
- the "object of interest” refers to a cranial nervous system disease, in particular, an individual whose onset of a neurodegenerative disease or a neuroinflammatory disease is uncertain, and refers to an individual with a high probability of onset.
- the "biological sample” is any material, tissue, cell, whole blood, serum, plasma, tissue autopsy sample (brain, skin, lymph node, spinal cord, etc.) obtained from or derived from an individual, cell culture supernatant, rupture Eukaryotic cells and bacterial expression systems are mentioned, but they may be preferably regulatory T cells.
- the present invention as a method for measuring or comparing the expression level of the Lrig-1 protein, protein chip analysis, immunoassay, ligand binding assay, MALDI-TOF (Matrix Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry) analysis, SELDI -TOF (Sulface Enhanced Laser Desorption/Ionization Time of Flight Mass Spectrometry) analysis, radiation immunity analysis, radiation immunity diffusion method, octeroni immunity diffusion method, rocket immunoelectrophoresis, tissue immunostaining, complement fixation analysis, two-dimensional electrophoresis analysis , Liquid chromatography-Mass Spectrometry (LC-MS), LC-MS/MS (liquid chromatography-Mass Spectrometry/ Mass Spectrometry), Western blotting or ELISA (enzyme linked immunosorbentassay), etc. It is not limited.
- MALDI-TOF Microx Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry
- the expression level of the Lrig-1 protein measured for the biological sample of the object of the present invention is increased or decreased compared to the normal control, predicting that the possibility of developing neurodegenerative diseases or neuroinflammatory diseases is high. can do.
- the cranial nervous system disease which is a disease to be diagnosed through the diagnostic composition, the diagnostic kit, or the information providing method, may be a neurodegenerative disease or a neuroinflammatory disease.
- Alzheimer's disease Parkinson's disease, Huntington's disease, Niemann-Pick disease, multiple sclerosis, prion disease, Creutzfeldt-Jakob disease, frontal head Temporal dementia, Louis dementia, AlzAmyotrophic lateral sclerosis, paraneoplastic syndrome, cortical basal degeneration, multiple system atrophy, progressive nuclear paralysis, autoimmune neurological disorder, spinocerebellar ataxia , Inflammatory and neuropathic pain, cerebrovascular disease, spinal cord injury, and tauopathy may be selected from the group consisting of, but is not limited thereto.
- the binding molecules provided by the present invention can specifically prevent, improve, or treat various neurodegenerative or neuroinflammatory diseases, as well as provide a method for diagnosing them.
- 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 results of predicting the epitope of the Lrig-1 protein according to an embodiment of the present invention.
- Figure 4 shows the results of predicting the antigenic determinant (epitope) of the Lrig-1 protein 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 mRNA according to an embodiment of the present invention.
- FIG. 7 shows the expression level of Lrig-1 mRNA according to an embodiment of the present invention.
- FIG. 8 shows the expression levels of Lrig-1, Lrig-2, and Lrig-3 mRNA according to an embodiment of the present invention.
- FIG 10 shows the expression of Lrig-1 protein on the surface of regulatory T cells according to an embodiment of the present invention.
- FIG. 11 shows the results of analyzing the binding ability of the Lrig-1 protein-specific monoclonal antibody to the Lrig-1 protein according to an embodiment of the present invention.
- FIG. 12 is a diagram showing an experimental design for confirming the effect of treating multiple sclerosis of the Lrig-1 protein-specific monoclonal antibody according to an embodiment of the present invention.
- FIG. 13 shows the results of analyzing the therapeutic effect of multiple sclerosis after administration of the Lrig-1 protein-specific monoclonal antibody according to an embodiment of the present invention.
- FIG 16 shows the results of analyzing the therapeutic effect of Alzheimer's after administration of the Lrig-1 protein-specific monoclonal antibody according to an embodiment of the present invention.
- FIG 17 shows the results of analyzing the therapeutic effect of Alzheimer's after administration of the Lrig-1 protein-specific monoclonal antibody according to an embodiment of the present invention.
- the present invention comprises as an active ingredient a binding molecule that specifically binds to Lrig-1 (leucine-rich and immunoglobulin-like domains 1) protein present in regulatory T cells (Treg cells) It relates to a composition for preventing, improving or treating diseases.
- Lrig-1 leucine-rich and immunoglobulin-like domains 1
- the binding molecule is,
- Heavy chain CDR1 consisting of the amino acid sequence represented by SEQ ID NO: 5 or 13
- Heavy chain CDR2 consisting of the amino acid sequence represented by SEQ ID NO: 6 or 14
- a heavy chain variable region comprising; a heavy chain CDR3 consisting of an amino acid sequence represented by SEQ ID NO: 7 or 15;
- Light chain CDR1 represented by the amino acid sequence represented by SEQ ID NO: 8 or 16
- Light chain CDR2 represented by the amino acid sequence represented by SEQ ID NO: 9 or 17
- It may be a binding molecule comprising a light chain variable region including; light chain CDR3 represented by the amino acid sequence represented by SEQ ID NO: 10 or 18.
- T cell subtypes Th0, Th1, Th2, Th17 and iTreg were prepared.
- the iTreg refers to cells artificially induced differentiation in a medium containing the following composition, unlike naturally isolated nTregs.
- 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 to induce differentiation into each cell through culture for 72 hours in a 37°C, 5% CO 2 incubator.
- 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.
- the nucleotide sequence was predicted using the Ellipro server (http://tools.iedb.org/ellipro/), which is epitope prediction software based on the structure of the Lrig-1 protein.
- the Ellipro search engine corresponds to a search engine known to have the highest reliability among algorithms for predicting existing antigenic determinants and uses it.
- Example 1 After inputting the extracellular domain analyzed in Example 1 into the epitope prediction software, the predicted contiguous or discontinuous amino acid sequences of the predicted epitope are shown in FIGS. 3 and 4.
- 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.
- the antibody 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 to allow the Lrig-1 protein to 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 the mlgG2a Fc region to prepare a monoclonal antibody.
- the sequence of the monoclonal antibody is shown in Table 2 below.
- 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 then, 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 the relative gene expression levels were calculated using the ⁇ CT method, and normalized using HPRT, and the results are shown in FIGS. 5 to 8.
- Lrig-1 As shown in Fig. 5, it can be seen that the expression of Lrig-1 is 18.1 times higher in regulatory T ((CD4 + CD25 + T) cells than in non-regulated T (CD4 + CD25 - T) cells. Compared to the known regulatory T cell markers Lag3 and Ikzf4, the expression level was about 10 times higher. In addition, as shown in Figs. 6 and 7, compared to other types of immune cells, regulatory T cells, especially induction, were induced. The expression of Lrig-1 mRNA was remarkably higher in the naturally isolated regulatory T cells (nTreg) compared to the controlled T cells (iTreg).
- Lrig-1 was 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 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, controlled T (CD4 + RFP + T) cells and non-regulated T (CD4 + RFP - T) cells were separated 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. 9.
- RFP red fluorescence protein
- the non-regulatory T cells indicated by the dotted line showed almost the same expression level of Lrig-1 as the negative control, but in the case of the regulatory T cells, there were a number of cells with high Lrig-1 expression levels. .
- 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 become 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). The expression level of Lrig-1 was measured, and the results are shown in FIG. 10.
- the Lrig-1 protein according to the present invention is not only specifically expressed in regulatory T cell (Treg) cells, but also more highly expressed on the surface of Treg cells.
- 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. 11.
- mice is immobile, but one forelimb is responsive to stimulation
- a group was designed as shown in Table 4 below. Specifically, 7-month-old Alzheimer-induced 5xFAD mice were injected intravenously with GTC110-04 antibody and GTC210-01 antibody in an amount of 10 mpk, respectively, for 1 month. 8-month-old Alzheimer's mice were injected subcutaneously for 3 weeks with glatiramer acetate (GA, Copaxone®) as a positive control in an amount of 100 ug.
- GTC110-04 antibody and GTC210-01 antibody 8-month-old Alzheimer's mice were injected subcutaneously for 3 weeks with glatiramer acetate (GA, Copaxone®) as a positive control in an amount of 100 ug.
- the normal control group (G1) was measured as 0.51 ⁇ 0.06
- the G2 group (vehicle) was measured as 0.42 ⁇ 0.04
- the Alzheimer-inducing group (G2) was measured as the normal control group (G1).
- the preference value was observed to be lower than that.
- the antibodies according to the present invention GTC210-01 and GTC110-04 antibodies
- the underwater maze test was conducted based on a method devised by Morris. Water (22 ⁇ 1 °C) was filled in a stainless steel pool (diameter 90 cm, height 50 cm) so that the water level was 30 cm. The hidden platform (diameter 5 cm) was positioned 1 cm below the water surface. On the first day of evaluation, three to four training sessions were conducted. The total swimming time per individual was set to 60 seconds, and individuals who found the platform within 60 seconds were allowed to stay on the platform for 10 seconds to induce memory. Objects that cannot find the platform even after 60 seconds are artificially guided to the platform to stay on the platform for 10 seconds, and the escape time at this time is set to 60 seconds.
- a probe test was conducted on the 6th day after swimming practice, and the amount of time spent in the quadrant with the platform was calculated as a percentage of the total swimming time (Percentage of time in SW area, %) , The time taken to reach the location where the platform was (Latency to target, sec) was measured, and the results are shown in FIGS. 16 and 17.
- the analysis was performed using SMART VIDEO TRACKING Software (Panlab, USA). The criteria to be excluded from the interpretation of the results were set as individuals who turn only a specific area without searching through swimming.
- the time spent in the quadrant with the platform was calculated as a percentage of the total swimming time (Percentage of time in SW area, %) was significantly increased, and the time taken to reach the location where the platform was (Latency to target, sec) was significantly reduced to a level similar to that of the normal control group.
- the antibody according to the present invention has an effect of preventing, improving or treating cranial and nervous system diseases.
- the present invention relates to a composition for preventing or treating diseases of the cranial nerve system.
- LDLNRNRIRL IEGLTFQGLN
- SLEVLKLQRN NISKLTDGAF WGLSKMHVLH LEYNSLVEVN 240
- RVVSVLTVLH QDWLNGKEYK CKVSNKGLPS SIEKTISKAK GQPREPQVYT LPPSQEEMTK 240
- VVDVSQEDPE VQFNWYVDGV EVHNAKTKPR EEQFNSTYRV VSVLTVLHQD WLNGKEYKCK 120
- TLVTVSSAST TAPSVYPLAP VCGDTTGSSV TLGCLVKGYF PEPVTLTWNS GSLSSGVHTF 180
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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 |
구분 | 클론 | 위치 | 아미노산 서열 | 서열정보 |
제조예 1 | GTC210-01clone | 중쇄 | EVQLLESGGGLVQPGGSLRLSCAASGFTFSGYDMSWVRQAPGKGLEWVSLIYPDSGNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDAGLSWAGAFDYWGQGTLVTVSSASTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK- | 서열번호 30 |
경쇄 | QSVLTQPPSASGTPGQRVTISCSGSSSNIGSNYVTWYQQLPGTAPKLLIYSDSHRPSGVPDRFSGSKSGTSASLAISGLQSEDEADYYCGSWDYSLSAYVFGGGTKLTVLRTVAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC- | 서열번호 31 | ||
제조예 2 | GTC210-02clone | 중쇄 | EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYYMSWVRQAPGKGLEWVSGISPGDSSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKGLYSNPNEPFDYWGQGTLVTVSSASTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK- | - |
경쇄 | QSVLTQPPSASGTPGQRVTISCTGSSSNIGSNYVSWYQQLPGTAPKLLIYDDSQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCGTWDYSLNGYVFGGGTKLTVLRTVAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC- | - | ||
제조예 3 | GTC210-03clone | 중쇄 | EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQAPGKGLEWVSGISPDGSNIYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKVGLRCRYEACSYAYGMDVWGQGTLVTVSSASTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK- | - |
경쇄 | QSVLTQPPSASGTPGQRVTISCSGSSSNIGSNYVSWYQQLPGTAPKLLIYSDSHRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCATWDSSLNGYVFGGGTKLTVLRTVAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC- | - | ||
제조예 4 | GTC210-04clone | 중쇄 | EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYDMSWVRQAPGKGLEWVSSISPSSGSIYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDLDAFWRPSFDYWGQGTLVTVSSASTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK- | - |
경쇄 | QSVLTQPPSASGTPGQRVTISCTGSSSNIGNNNVNWYQQLPGTAPKLLIYSDSHRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCGSWDDSLSAYVFGGGTKLTVLRTVAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC- | - | ||
제조예 5 | GTC110-01clone | 중쇄 | EVQLLESGGGLVQPGGSLRLSCAASGFTFSDYDMSWVRQVPGKGLEWVSWISHGGGSIYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGLGLCKTGLCYYYDAMDVWGQGTLVTVSSASTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK- | - |
경쇄 | QSVLTQPPSASGTPGQRVTISCTGSSSNIGNNSVTWYQQLPGTAPKLLIYADNNRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDSSLSAYVFGGGTKLTVLRTVAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC- | - | ||
제조예 6 | GTC110-02clone | 중쇄 | EVQLLESGGGLVQPGGSLRLSCAASGFTFSDYYMSWVRQAPGKGLEWVSGISHDSGSKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARHWTTFDYWGQGTLVTVSSASTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK- | - |
경쇄 | QSVLTQPPSASGTPGQRVTISCSGSSSNIGSNNVTWYQQLPGTAPKLLIYANSNRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCGAWDYSLSAYVFGGGTKLTVLRTVAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC- | - | ||
제조예 7 | GTC110-03clone | 중쇄 | EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYAMSWVRQAPGKGLEWVSAIYPGGGSIYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDILPCPWGRCYYDYAMDVWGQGTLVTVSSASTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK- | - |
경쇄 | QSVLTQPPSASGTPGQRVTISCSDSSSNIGSNTVSWYQQLPGTAPKLLIYADNNRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCGTWDYSLSGYVFGGGTKLTVLRTVAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC- | - | ||
제조예 8 | GTC110-04clone | 중쇄 | EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYAMSWVRQAPGKGLEWVSVISHGGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARVISNCHLGVCYYSNGMDVWGQGTLVTVSSASTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK- | 서열번호 32 |
경쇄 | QSVLTQPPSASGTPGQRVTISCSGSSSNIGNNDVYWYQQLPGTAPKLLIYSDSQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCGTWDYSLSGYVFGGGTKLTVLRTVAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC- | 서열번호 33 | ||
제조예 9 | GTC110-04인간화 항체 | 중쇄 | EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYAMSWVRQAPGKGLEWVSVISHGGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARVISNCHLGVCYYSNGMDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKY | 서열번호 34 |
경쇄 | QSVLTQPPSASGTPGQRVTISCSGSSSNIGNNDVYWYQQLPGTAPKLLIYSDSQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCGTWDYSLSGYVFGGGTKLTVLRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC | 서열번호 35 |
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' |
그룹 | n/그룹 | 투여 경로 | 용량 | ||
G1 | WT | 대조군 | 14 | - | - |
G2 | 5xFAD | 대조군 | 13 | - | - |
G3 | GTC110-04 항체 | 11 | IV | 10mpk | |
G4 | GTC210-01 항체 | 11 | IV | 10mpk | |
G5 | GA(양성 대조군) | 11 | SC | 100ug |
Claims (26)
- 조절 T 세포(regulatory T cells, Treg cells)에 존재하는 Lrig-1(leucine-rich and immunoglobulin-like domains 1) 단백질에 특이적으로 결합하는 결합 분자를 유효 성분으로 포함하는, 뇌신경계 질환의 예방 또는 치료용 약학 조성물.
- 제1항에 있어서,상기 Lrig-1 단백질은 서열번호 1 또는 3으로 표시되는 아미노산 서열로 이루어지는 것인, 약학 조성물.
- 제1항에 있어서,상기 Lrig-1 단백질은 서열번호 2 또는 4로 표시되는 폴리뉴클레오티드에 의해 코딩되는 것인, 약학 조성물.
- 제1항에 있어서,상기 결합 분자는,서열번호 5 또는 13으로 표시되는 아미노산 서열로 이루어지는 중쇄 CDR1; 서열번호 6 또는 14로 표시되는 아미노산 서열로 이루어지는 중쇄 CDR2; 서열번호 7 또는 15로 표시되는 아미노산 서열로 이루어지는 중쇄 CDR3;을 포함하는 중쇄 가변 영역; 및서열번호 8 또는 16으로 표시되는 아미노산 서열로 표시되는 경쇄 CDR1; 서열번호 9 또는 17로 표시되는 아미노산 서열로 표시되는 경쇄 CDR2; 서열번호 10 또는 18로 표시되는 아미노산 서열로 표시되는 경쇄 CDR3;를 포함하는 경쇄 가변 영역을 포함하는 것인, 약학 조성물.
- 제1항에 있어서,상기 결합 분자는,(a) 서열번호 5로 표시되는 중쇄 CDR1, 서열번호 6으로 표시되는 중쇄 CDR2, 및 서열번호 7로 표시되는 중쇄 CDR3를 포함하는 중쇄 가변 영역; 및(b) 서열번호 13으로 표시되는 중쇄 CDR1, 서열번호 14로 표시되는 중쇄 CDR2, 및 서열번호 15로 표시되는 중쇄 CDR3를 포함하는 중쇄 가변 영역;으로 이루어진 군에서 선택되는 중쇄 가변 영역; 및(c) 서열번호 8로 표시되는 경쇄 CDR1, 서열번호 9로 표시되는 경쇄 CDR2, 및 서열번호 10으로 표시되는 경쇄 CDR3를 포함하는 경쇄 가변 영역; 및(d) 서열번호 16으로 표시되는 경쇄 CDR1, 서열번호 17로 표시되는 경쇄 CDR2, 및 서열번호 18로 표시되는 경쇄 CDR3를 포함하는 경쇄 가변 영역;으로 이루어진 군에서 선택되는 경쇄 가변 영역;을 포함하는 것인, 약학 조성물.
- 제1항에 있어서,상기 결합 분자는,(1) 서열번호 5로 표시되는 중쇄 CDR1, 서열번호 6으로 표시되는 중쇄 CDR2, 및 서열번호 7로 표시되는 중쇄 CDR3를 포함하는 중쇄 가변 영역; 및 서열번호 8로 표시되는 경쇄 CDR1, 서열번호 9로 표시되는 경쇄 CDR2, 및 서열번호 10으로 표시되는 경쇄 CDR3를 포함하는 경쇄 가변 영역을 포함하는 결합 분자; 및(2) 서열번호 13으로 표시되는 중쇄 CDR1, 서열번호 14로 표시되는 중쇄 CDR2, 및 서열번호 15로 표시되는 중쇄 CDR3를 포함하는 중쇄 가변 영역; 및 서열번호 16으로 표시되는 경쇄 CDR1, 서열번호 17로 표시되는 경쇄 CDR2, 및 서열번호 18로 표시되는 경쇄 CDR3를 포함하는 경쇄 가변 영역을 포함하는 결합 분자;로 이루어진 군에서 선택되는, 약학 조성물.
- 제1항에 있어서,상기 결합 분자는,서열번호 11 또는 19로 표시되는 아미노산 서열로 이루어지는 중쇄 가변 영역; 및서열번호 12 또는 20으로 표시되는 아미노산 서열로 이루어지는 경쇄 가변 영역;을 포함하는 약학 조성물.
- 제1항에 있어서,상기 결합 분자는,서열번호 11로 표시되는 중쇄 가변 영역, 및 서열번호 12로 표시되는 경쇄 가변 영역을 포함하는 결합 분자; 및서열번호 19로 표시되는 중쇄 가변 영역, 및 서열번호 20으로 표시되는 경쇄 가변 영역을 포함하는 결합 분자;로 이루어진 군에서 선택되는, 약학 조성물.
- 제1항에 있어서,상기 결합 분자는 Fc 영역 또는 불변 영역(constant region)을 더 포함하는, 약학 조성물.
- 제9항에 있어서,상기 Fc 영역은 IgA, IgD, IgE, IgM, IgG1, IgG2, IgG3 또는 IgG4 항체의 Fc 영역, 또는 하이브리드 Fc(hybrid Fc) 영역인, 약학 조성물.
- 제1항에 있어서,상기 결합 분자는, 서열번호 21, 23, 24, 26, 27, 28 및 29로 이루어진 군에서 선택되는 아미노산 서열로 이루어지는 중쇄 불변 영역을 더 포함하는, 약학 조성물.
- 제1항에 있어서,상기 결합 분자는, 서열번호 22 또는 25로 표시되는 아미노산 서열로 이루어지는 경쇄 불변 영역을 더 포함하는, 약학 조성물.
- 제1항에 있어서,상기 결합 분자는,서열번호 21로 표시되는 아미노산 서열로 이루어지는 중쇄 불변 영역; 및서열번호 22로 표시되는 아미노산 서열로 이루어지는 경쇄 불변 영역을 더 포함하는, 약학 조성물.
- 제1항에 있어서,상기 결합 분자는,서열번호 23, 24, 26, 27 또는 28로 표시되는 아미노산 서열로 이루어지는 중쇄 불변 영역; 및서열번호 25로 표시되는 아미노산 서열로 이루어지는 경쇄 불변 영역을 더 포함하는, 약학 조성물.
- 제1항에 있어서,상기 결합 분자는, 서열번호 29로 표시되는 아미노산 서열로 이루어지는 중쇄 불변 영역을 더 포함하는, 약학 조성물.
- 제1항에 있어서,상기 결합 분자는,서열번호 30으로 표시되는 중쇄, 및 서열번호 31로 표시되는 경쇄를 포함하는 결합 분자;서열번호 32로 표시되는 중쇄, 및 서열번호 33으로 표시되는 경쇄를 포함하는 결합 분자; 및서열번호 34로 표시되는 중쇄, 및 서열번호 35로 표시되는 경쇄를 포함하는 결합 분자;로 이루어진 군에서 선택되는 것인, 약학 조성물.
- 제1항에 있어서,상기 결합 분자는 항체 또는 그 단편인, 약학 조성물.
- 제17항에 있어서,상기 항체는 키메라 항체, 인간화 항체(humanized antibody), 이가(bivalent), 양특이성 분자, 미니바디(minibody), 도메인 항체, 이중특이적 항체(bispecific antibody), 항체 모방체, 유니바디(unibody), 디아바디(diabody), 트리아바디(triabody), 테트라바디(tetrabody) 또는 이의 단편인, 약학 조성물.
- 제18항에 있어서,상기 뇌신경계 질환은 신경 퇴행성 질환 또는 신경 염증성 질환인, 약학 조성물.
- 제19항에 있어서,상기 신경 퇴행성 질환 또는 신경 염증성 질환은 뇌졸중, 치매, 알츠하이머병(Alzheimer's disease), 파킨슨병(Parkinson's disease), 헌팅턴병(Huntington's disease), 니만-피크병(Niemann-Pick disease), 다발성 경화증, 프리온병(prion disease), 크로이펠츠-야콥병(Creutzfeldt-Jakob disease), 전두측두치매, 루이치매, 근위축성 측삭경화증(AlzAmyotrophic lateral sclerosis), 부신생물증후군(Paraneoplastic syndrome), 피질기저퇴행증, 다계통위축병, 진행성핵상마비, 신경계 자가면역질환, 척수 소뇌 실조(spinocerebellar ataxia), 염증성 및 신경병증성 통증, 뇌혈관 질환, 척수 손상(spinal cord injury) 및 타우병증(tauopathy)으로 이루어진 군에서 선택되는, 약학 조성물.
- 서열번호 5 또는 13으로 표시되는 아미노산 서열로 이루어지는 중쇄 CDR1; 서열번호 6 또는 14로 표시되는 아미노산 서열로 이루어지는 중쇄 CDR2; 서열번호 7 또는 15로 표시되는 아미노산 서열로 이루어지는 중쇄 CDR3;을 포함하는 중쇄 가변 영역; 및서열번호 8 또는 16으로 표시되는 아미노산 서열로 표시되는 경쇄 CDR1; 서열번호 9 또는 17로 표시되는 아미노산 서열로 표시되는 경쇄 CDR2; 서열번호 10 또는 18로 표시되는 아미노산 서열로 표시되는 경쇄 CDR3;를 포함하는 경쇄 가변 영역을 포함하는 결합 분자를 코딩하는 핵산 분자; 상기 핵산 분자가 삽입된 발현 벡터; 상기 발현 벡터가 형질 감염된 숙주 세포주를 유효 성분으로 포함하는, 뇌신경계 질환의 예방 또는 치료용 약학 조성물.
- 서열번호 5 또는 13으로 표시되는 아미노산 서열로 이루어지는 중쇄 CDR1; 서열번호 6 또는 14로 표시되는 아미노산 서열로 이루어지는 중쇄 CDR2; 서열번호 7 또는 15로 표시되는 아미노산 서열로 이루어지는 중쇄 CDR3;을 포함하는 중쇄 가변 영역; 및서열번호 8 또는 16으로 표시되는 아미노산 서열로 표시되는 경쇄 CDR1; 서열번호 9 또는 17로 표시되는 아미노산 서열로 표시되는 경쇄 CDR2; 서열번호 10 또는 18로 표시되는 아미노산 서열로 표시되는 경쇄 CDR3;를 포함하는 경쇄 가변 영역을 포함하는 항체-약물 결합체(Antibody-Drug Conjugate, ADC)를 유효 성분으로 포함하는 뇌신경계 질환의 예방 또는 치료용 약학 조성물.
- 서열번호 5 또는 13으로 표시되는 아미노산 서열로 이루어지는 중쇄 CDR1; 서열번호 6 또는 14로 표시되는 아미노산 서열로 이루어지는 중쇄 CDR2; 서열번호 7 또는 15로 표시되는 아미노산 서열로 이루어지는 중쇄 CDR3;을 포함하는 중쇄 가변 영역; 및서열번호 8 또는 16으로 표시되는 아미노산 서열로 표시되는 경쇄 CDR1; 서열번호 9 또는 17로 표시되는 아미노산 서열로 표시되는 경쇄 CDR2; 서열번호 10 또는 18로 표시되는 아미노산 서열로 표시되는 경쇄 CDR3;를 포함하는 경쇄 가변 영역을 포함하는 결합 분자를 포함하는, 뇌신경계 질환의 진단용 조성물.
- 제23항의 진단용 조성물을 포함하는 뇌신경계 질환의 진단 키트.
- 서열번호 5 또는 13으로 표시되는 아미노산 서열로 이루어지는 중쇄 CDR1; 서열번호 6 또는 14로 표시되는 아미노산 서열로 이루어지는 중쇄 CDR2; 서열번호 7 또는 15로 표시되는 아미노산 서열로 이루어지는 중쇄 CDR3;을 포함하는 중쇄 가변 영역; 및서열번호 8 또는 16으로 표시되는 아미노산 서열로 표시되는 경쇄 CDR1; 서열번호 9 또는 17로 표시되는 아미노산 서열로 표시되는 경쇄 CDR2; 서열번호 10 또는 18로 표시되는 아미노산 서열로 표시되는 경쇄 CDR3;를 포함하는 경쇄 가변 영역을 포함하는 결합 분자를 이용하여 목적하는 개체의 생물학적 시료에 존재하는 Lrig-1 단백질 또는 이를 코딩하는 유전자의 발현 수준을 측정하여 뇌신경계 질환의 진단에 관한 정보를 제공하는 방법.
- 투여가 필요한 개체에게,서열번호 5 또는 13으로 표시되는 아미노산 서열로 이루어지는 중쇄 CDR1; 서열번호 6 또는 14로 표시되는 아미노산 서열로 이루어지는 중쇄 CDR2; 서열번호 7 또는 15로 표시되는 아미노산 서열로 이루어지는 중쇄 CDR3;을 포함하는 중쇄 가변 영역; 및서열번호 8 또는 16으로 표시되는 아미노산 서열로 표시되는 경쇄 CDR1; 서열번호 9 또는 17로 표시되는 아미노산 서열로 표시되는 경쇄 CDR2; 서열번호 10 또는 18로 표시되는 아미노산 서열로 표시되는 경쇄 CDR3;를 포함하는 경쇄 가변 영역을 포함하는 결합 분자를 투여하는 단계를 포함하는 뇌신경계 질환의 예방, 개선 또는 치료 방법.
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CN202080022471.6A CN113811330A (zh) | 2019-03-20 | 2020-03-20 | 预防或治疗脑和神经系统疾病的组合物 |
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EP4286412A1 (en) * | 2021-01-27 | 2023-12-06 | Good T Cells, Inc. | Novel binding molecule and use thereof |
EP4375670A1 (en) * | 2021-07-16 | 2024-05-29 | Good T Cells, Inc. | Epitope of regulatory t cell surface antigen, and antibody specifically binding thereto |
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