Anti-CD300c antibody or an antigen-binding fragment thereof and its use for preventing or treating neurodegenerative diseases

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating degenerative brain diseases, comprising at least one of an anti-CD300c antibody and an antigen-binding fragment thereof, a method for preventing or treating degenerative brain diseases using the same, a feed composition, a food composition for preventing or improving degenerative brain diseases, comprising at least one of the anti-CD300c antibody and an antigen-binding fragment thereof, and use of the anti-CD300c antibody and an antigen-binding fragment thereof for preventing or treating degenerative brain diseases.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition for preventing or treating a degenerative brain disease, a method for preventing or treating a degenerative brain disease using the same, a feed composition or a food composition for preventing or improving a degenerative brain disease, each containing at least one of an anti-CD300c antibody and an antigen-binding fragment thereof, and use of the anti-CD300c antibody and / or its antigen-binding fragment for preventing or treating a degenerative brain disease.

Background Art

[0002] Alzheimer's disease (AD) is a typical example of a degenerative brain disease characterized by progressive loss of cognitive and memory functions and neurodegeneration in the central nervous system, accounting for about 50% of the onset forms of dementia. AD is characterized by the presence of amyloid plaques, neurofibrillary tangles, synaptic loss, selective neuronal death, etc. Amyloid plaques are induced by abnormal levels of extracellular amyloid-β peptide, while neurofibrillary tangles are associated with the presence of hyperphosphorylated tau protein intracellularly. The symptoms are characterized by amnesia, along with dysphasia, dyspraxia, and agnosia (the ability to recognize objects, people, sounds, forms, or scents), which contribute to the relevance with the cortical association area. AD has an increasing incidence particularly after the age of 65 and is rapidly increasing worldwide as the population ages.

[0003] Commercially available AD therapeutic agents mainly include AChE inhibitors and NMDA receptor antagonists that support cognitive function improvement and aim for temporary symptom relief. "Aducanumab", a monoclonal antibody drug targeting amyloid-β, was approved by the FDA in 2021. Different from conventional symptom-improving agents, it is a treatment method targeting the fundamental pathophysiology, but there are still ongoing controversies regarding its efficacy and side effects. In addition, research on treating Alzheimer's disease by targeting the PD-1 / PD-L1 signaling process has been reported (Non-Patent Document 1). This research presented the possibility of an immunological method that increases monocyte-derived macrophages in the brain parenchyma by blocking PD-1 / PD-L1 signaling, resulting in a reduction in plaques and brain lesions. The development of AD therapeutic agents is highly difficult and the success rate is extremely low. However, as the aging society accelerates, the number of AD patients increases, and the socio-economic cost burden due to AD gradually increases, there is a demand for a multi-faceted development of fundamental therapeutic drugs rather than symptomatic relief drugs.

[0004] On the other hand, CD300c (CD300 antigen-like family member C) protein is a protein encoded by the CD300c gene in humans. It exists on the surface of various tumor cells and monocytes. It has been disclosed that inhibiting the activity or expression of CD300c protein can reduce the proliferation of cancer cells through the resulting improvement of immune function (for example, T cell activation) (Patent Document 1).

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

Non-Patent Documents

[0006]

Non-Patent Document 1

[0007] The problems to be solved by the present invention are to provide a pharmaceutical composition for preventing or treating a degenerative brain disease, which contains at least one of an anti-CD300c antibody and its antigen-binding fragment, a method for preventing or treating a degenerative brain disease using the same, a feed composition or a food composition for preventing or improving a degenerative brain disease, which contains at least one of an anti-CD300c antibody and its antigen-binding fragment, and the use of the anti-CD300c antibody and / or its antigen-binding fragment for preventing or treating a degenerative brain disease. [Means for Solving the Problems]

[0008] The present invention aims to solve all of the above problems.

[0009] In addition, the present invention aims to provide an antibody pharmaceutical for the prevention or treatment of degenerative brain diseases.

[0010] Furthermore, the present invention aims to provide a composition for the prevention or treatment of degenerative brain diseases.

[0011] Furthermore, the present invention aims to provide a method for preventing or treating degenerative brain diseases.

[0012] Furthermore, the present invention aims to provide the use of the anti-CD300c antibody and its antigen-binding fragment for the prevention or treatment of degenerative brain diseases.

Effects of the Invention

[0013] According to the present invention, an antibody that specifically binds to CD300c and its antigen-binding fragment can be effectively used as a preventive or therapeutic agent for degenerative brain diseases.

[0014] Using a Y-maze test and a Morris water maze test with 5xFAD mice mutated to express genes related to degenerative brain diseases, it was confirmed that the anti-CD300c antibody or its antigen-binding fragment significantly restored the cognitive ability and memory of degenerative brain disease mouse models. Therefore, the anti-CD300c antibody or its antigen-binding fragment has a drug effect effective for the prevention or treatment of degenerative brain diseases.

Brief Description of the Drawings

[0015]

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Embodiments for Carrying out the Invention

[0016] Hereinafter, these will be specifically described. Note that each description and embodiment disclosed in the present invention is also applicable to other descriptions and embodiments. That is, any combination of various elements disclosed in the present invention is included in the present invention. Further, the present invention is not limited to the following specific description. Furthermore, many papers and patent documents are referred to throughout this specification, and their citations are indicated. The entire disclosure contents of the cited papers and patent documents are incorporated herein by reference, whereby the level of the technical field to which the present invention belongs and the content of the present invention are more clearly explained.

[0017] One aspect of the present invention provides a pharmaceutical composition for the prevention or treatment of degenerative brain diseases, comprising at least one of an anti-CD300c antibody and an antigen-binding fragment thereof as an active ingredient.

[0018] As an example, the antibody of the present invention has the ability to promote the differentiation of monocytes into MDM (Monocyte-derived macrophage) or M1 macrophages, and the promotion ability is improved compared with general degenerative brain disease therapeutic agents and immunotherapeutic agents, but is not limited thereto. In the present invention, the MDM may be M1-MDM.

[0019] The anti-CD300c antibody and its antigen-binding fragment in the present invention mean an antigen-binding molecule that specifically binds to the CD300c protein and inhibits the reaction of CD300c, but are not limited thereto.

[0020] "CD300c" in the present invention is used interchangeably with "CD300c protein" or "CD300c antigen", and is a type of CD300 family which is a cell surface cell involved in immune regulation, and is expressed in antigen presenting cells, cancer cells or immune cells, but is not limited thereto.

[0021] The "antibody" in the present invention means an immunoglobulin or a part thereof having reactivity with a specific antigen immunologically, and a proteinaceous molecule that specifically recognizes an antigenic site. The antibodies of the present invention include all polyclonal antibodies, monoclonal antibodies, whole antibodies and antibody fragments. Also, the antibodies of the present invention may be of any origin, such as mouse, human, rabbit, rat antibodies. The antibodies of the present invention include animal antibodies, chimeric antibodies (e.g., humanized mouse antibodies), humanized antibodies, multispecific antibodies, bivalent or bispecific molecules (e.g., bispecific antibodies), diabodies, triabodies, tetra-bodies, minibodies and antibody fusions (e.g., fusions of antibodies with (poly)peptides, or fusions of antibodies with compounds). The antibodies of the present invention further include single-chain antibodies having a binding function to FcRn (neonatal Fc receptor), scabs, derivatives of antibody constant regions, and artificial antibodies based on protein scaffolds. A whole antibody has a structure having two full-length light chains (LC) and two full-length heavy chains (HC), and each light chain is linked to the heavy chain by a disulfide bond. The whole antibody includes any antibody such as IgA, IgD, IgE, IgM, IgG, and IgG includes subtypes IgG1, IgG2, IgG3 and IgG4. Such antibodies can be prepared from the obtained protein by cloning each gene into an expression vector by a conventional method to obtain the protein encoded by the marker gene, but are not limited thereto.

[0022] As used herein, the prefix "anti-" means, with respect to an antigen, that the antibody is reactive with the antigen. Antibodies reactive with a particular antigen can be generated by synthetic and / or recombinant methods such as selection from a recombinant antibody library in a phage or similar vector, or by immunization of an animal with the antigen or antigen-encoding nucleic acid, but are not limited thereto.

[0023] As one example, the anti-CD300c antibody in the present invention means an antibody reactive with CD300c.

[0024] As used herein, "fragment" or "antibody fragment" means any part of an antibody, and scFv, dsFv, Fab, Fab’, F(ab’)2, Fc, Fd, sdAb, nanobody, etc., and combinations thereof are antibody fragments, and the antibody fragments include, but are not limited to, those containing an antigen recognition site.

[0025] As used herein, "antigen-binding fragment" means a fragment having an antigen-binding function. In the present invention, the antigen-binding fragment may be a fragment containing a site that recognizes an antigenic site.

[0026] In the present invention, Fd means the heavy chain portion contained in the Fab fragment. In the present invention, Fab has a structure having a variable region of a light chain and a heavy chain, a constant region of the light chain, and a first constant region (CH1 domain) of the heavy chain, and has one antigen-binding site. Fab’ is different from Fab in that it has a hinge region containing at least one cysteine residue at the C-terminus of the heavy chain CH1 domain. The F(ab’)2 antibody is produced by the disulfide bonding of the cysteine residues in the hinge region of Fab’. Fv (variable fragment) means the smallest antibody fragment having only the heavy chain variable region and the light chain variable region. In disulfide-stabilized Fv (dsFv), the heavy chain variable region and the light chain variable region are linked by a disulfide bond, and in single-chain Fv (single chain variable fragment; scFv), the heavy chain variable region and the light chain variable region are generally covalently linked via a peptide linker. Disulfide-stabilized single-chain Fv is a single-chain Fv in which the heavy chain variable region and the light chain variable region are further linked by a disulfide bond. The sdAb and nanobody are single variable domain antibody fragments, for example, among heavy chain antibodies containing a naturally occurring single variable domain (VH) and two constant domains (CH2 and CH3), antibody fragments prepared by proteolysis or gene recombination techniques in the variable domain thereof, and single domain antibody fragments prepared by artificially modifying the antibody light chain or heavy chain variable domain, but are not limited thereto. Such antibody fragments can be obtained by using proteases (for example, when whole antibody is digested with papain, Fab is obtained, and when digested with pepsin, F(ab’)2 fragment is obtained), and can be prepared by gene recombination techniques, but are not limited thereto.

[0027] As an example, the anti-CD300c antibody of the present invention may be a monoclonal antibody.

[0028] As used herein, the term "monoclonal antibody" refers to an antibody molecule of a single molecular composition obtained from a substantially identical antibody population, and this monoclonal antibody exhibits single binding specificity and affinity for a specific epitope.

[0029] Generally, an antibody has a heavy chain and a light chain, and each heavy chain and light chain includes a constant region and a variable region. The variable regions of the light chain and the heavy chain include three highly variable regions called complementarity-determining regions (CDRs) and four framework regions (FRs).

[0030] The 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 in order from the N-terminus, and are also identified by the chain on which a specific CDR is located. The complementarity-determining regions are arranged between regions called relatively conserved constant regions (FRs). Each VH (heavy chain variable region) and VL (light chain variable region) consists of three CDRs and four FRs, and are arranged in the order of FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4 from the N-terminus to the C-terminus. The variable regions of the heavy chain and the light chain contain a binding domain that interacts with the antigen. The CDRs of the heavy chain variable region are called HCDR1, HCDR2, and HCDR3, the CDRs of the light chain variable region are called LCDR1, LCDR2, and LCDR3, the FRs of the heavy chain variable region are called HFR1, HFR2, HFR3, and HFR4, and the FRs of the light chain variable region are called LFR1, LFR2, LFR3, and LFR4.

[0031] As an example of an embodiment, at least one of the antibody and its antigen-binding fragment of the present invention comprises (i) a CDR1 consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 7, SEQ ID NO: 19, SEQ ID NO: 31, SEQ ID NO: 43, SEQ ID NO: 55, SEQ ID NO: 67, SEQ ID NO: 79, SEQ ID NO: 91, SEQ ID NO: 103, SEQ ID NO: 115, SEQ ID NO: 127, SEQ ID NO: 139, SEQ ID NO: 151, SEQ ID NO: 163, SEQ ID NO: 175, SEQ ID NO: 187, SEQ ID NO: 199, SEQ ID NO: 211, SEQ ID NO: 223, SEQ ID NO: 235, SEQ ID NO: 247, SEQ ID NO: 259, SEQ ID NO: 271, SEQ ID NO: 283, and SEQ ID NO: 295, a CDR2 consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 8, SEQ ID NO: 20, SEQ ID NO: 32, SEQ ID NO: 44, SEQ ID NO: 56, SEQ ID NO: 68, SEQ ID NO: 80, SEQ ID NO: 92, SEQ ID NO: 104, SEQ ID NO: 116, SEQ ID NO: 128, SEQ ID NO: 140, SEQ ID NO: 152, SEQ ID NO: 164, SEQ ID NO: 176, SEQ ID NO: 188, SEQ ID NO: 200, SEQ ID NO: 212, SEQ ID NO: 224, SEQ ID NO: 236, SEQ ID NO: 248, SEQ ID NO: 260, SEQ ID NO: 272, SEQ ID NO: 284, and SEQ ID NO: 296, and a CDR3 consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 9, SEQ ID NO: 21, SEQ ID NO: 33, SEQ ID NO: 45, SEQ ID NO: 57, SEQ ID NO: 69, SEQ ID NO: 81, SEQ ID NO: 93, SEQ ID NO: 105, SEQ ID NO: 117, SEQ ID NO: 129, SEQ ID NO: 141, SEQ ID NO: 153, SEQ ID NO: 165, SEQ ID NO: 177, SEQ ID NO: 189, SEQ ID NO: 201, SEQ ID NO: 213, SEQ ID NO: 225, SEQ ID NO: 237, SEQ ID NO: 249, SEQ ID NO: 261, SEQ ID NO: 273, SEQ ID NO: 285, and SEQ ID NO: 297, and (ii) a CDR1 consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 10, SEQ ID NO: 22, SEQ ID NO: 34, SEQ ID NO: 46, SEQ ID NO: 58, SEQ ID NO: 70, SEQ ID NO: 82, SEQ ID NO: 94, SEQ ID NO: 106, SEQ ID NO: 118, SEQ ID NO: 130, SEQ ID NO: 142, SEQ ID NO: 154, SEQ ID NO: 166, SEQ ID NO: 178, SEQ ID NO: 190, SEQ ID NO: 202, SEQ ID NO: 214, SEQ ID NO: 226, SEQ ID NO: 238, SEQ ID NO: 250, SEQ ID NO: 262, SEQ ID NO: 274, SEQ ID NO: 286, and SEQ ID NO: 298, a CDR2 consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 11, SEQ ID NO: 23, SEQ ID NO: 35, SEQ ID NO: 47, SEQ ID NO: 59, SEQ ID NO: 71, SEQ ID NO: 83, SEQ ID NO: 95, SEQ ID NO: 107,A light chain variable region may include a CDR2 consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 119, SEQ ID NO: 131, SEQ ID NO: 143, SEQ ID NO: 155, SEQ ID NO: 167, SEQ ID NO: 179, SEQ ID NO: 191, SEQ ID NO: 203, SEQ ID NO: 215, SEQ ID NO: 227, SEQ ID NO: 239, SEQ ID NO: 251, SEQ ID NO: 263, SEQ ID NO: 275, SEQ ID NO: 287, and SEQ ID NO: 299, and a CDR3 consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 12, SEQ ID NO: 24, SEQ ID NO: 36, SEQ ID NO: 48, SEQ ID NO: 60, SEQ ID NO: 72, SEQ ID NO: 84, SEQ ID NO: 96, SEQ ID NO: 108, SEQ ID NO: 120, SEQ ID NO: 132, SEQ ID NO: 144, SEQ ID NO: 156, SEQ ID NO: 168, SEQ ID NO: 180, SEQ ID NO: 192, SEQ ID NO: 204, SEQ ID NO: 216, SEQ ID NO: 228, SEQ ID NO: 240, SEQ ID NO: 252, SEQ ID NO: 264, SEQ ID NO: 276, SEQ ID NO: 288, and SEQ ID NO: 300.,

[0032] As an example, in the anti-CD300c antibody of the present invention or the amino acid sequence from the first amino acid to before CDR1 of the entire amino acid sequence of the heavy chain variable region of its antigen-binding fragment may be FR1 of the heavy chain variable region, the amino acid sequence from after CDR1 to before CDR2 may be FR2 of the heavy chain variable region, the amino acid sequence from after CDR2 to before CDR3 may be FR3 of the heavy chain variable region, and the sequence from after CDR3 to the last amino acid of the entire amino acid sequence of the heavy chain variable region may be FR4 of the heavy chain variable region. In the anti-CD300c antibody of the present invention or the amino acid sequence from the first amino acid to before CDR1 of the entire amino acid sequence of the light chain variable region of its antigen-binding fragment may be FR1 of the light chain variable region, the amino acid sequence from after CDR1 to before CDR2 may be FR2 of the light chain variable region, the amino acid sequence from after CDR2 to before CDR3 may be FR3 of the light chain variable region, and the sequence from after CDR3 to the last amino acid of the entire amino acid sequence of the light chain variable region may be FR4 of the light chain variable region. Further, the polynucleotides of FR1 to FR4 of the heavy chain variable region and FR1 to FR4 of the light chain variable region are also defined in the same manner as the amino acid sequences. Therefore, in the antibody of the present invention, the amino acid sequences of FR1 to FR4 of the heavy chain variable region and FR1 to FR4 of the light chain variable region and the polynucleotide sequences encoding them can be confirmed from SEQ ID NOs: 1 to 400.

[0033] As another example, at least one of the antibody of the present invention and its antigen-binding fragment may include: (i) a heavy-chain variable region including a CDR1 consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 79, SEQ ID NO: 115, and SEQ ID NO: 211, a CDR2 consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 80, SEQ ID NO: 116, and SEQ ID NO: 212, and a CDR3 consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 81, SEQ ID NO: 117, and SEQ ID NO: 213; and (ii) a light-chain variable region including a CDR1 consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 82, SEQ ID NO: 118, and SEQ ID NO: 214, a CDR2 consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 83, SEQ ID NO: 119, and SEQ ID NO: 215, and a CDR3 consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 84, SEQ ID NO: 120, and SEQ ID NO: 216.

[0034] As an example of the above-described embodiments, at least one of the antibody of the present invention and its antigen-binding fragment may be selected from: (i) those including a heavy-chain variable region including a CDR1 consisting of SEQ ID NO: 79, a CDR2 consisting of SEQ ID NO: 80, and a CDR3 consisting of SEQ ID NO: 81, and a light-chain variable region including a CDR1 consisting of SEQ ID NO: 82, a CDR2 consisting of SEQ ID NO: 83, and a CDR3 consisting of SEQ ID NO: 84; (ii) those including a heavy-chain variable region including a CDR1 consisting of SEQ ID NO: 115, a CDR2 consisting of SEQ ID NO: 116, and a CDR3 consisting of SEQ ID NO: 117, and a light-chain variable region including a CDR1 consisting of SEQ ID NO: 118, a CDR2 consisting of SEQ ID NO: 119, and a CDR3 consisting of SEQ ID NO: 120; and (iii) those including a heavy-chain variable region including a CDR1 consisting of SEQ ID NO: 211, a CDR2 consisting of SEQ ID NO: 212, and a CDR3 consisting of SEQ ID NO: 213, and a light-chain variable region including a CDR1 consisting of SEQ ID NO: 214, a CDR2 consisting of SEQ ID NO: 215, and a CDR3 consisting of SEQ ID NO: 216.

[0035] As an example of the foregoing embodiments, at least one of the antibody of the present invention and its antigen-binding fragment may include: (i) a heavy chain variable region comprising a CDR1 consisting of the amino acid sequence represented by SEQ ID NO: 79, a CDR2 consisting of the amino acid sequence represented by SEQ ID NO: 80, and a CDR3 consisting of the amino acid sequence represented by SEQ ID NO: 81; and (ii) a light chain variable region comprising a CDR1 consisting of the amino acid sequence represented by SEQ ID NO: 82, a CDR2 consisting of the amino acid sequence represented by SEQ ID NO: 83, and a CDR3 consisting of the amino acid sequence represented by SEQ ID NO: 84.

[0036] As an example, at least one of the anti-CD300c antibody of the present invention and its antigen-binding fragment includes a heavy chain variable region consisting of any one of SEQ ID NO: 303, SEQ ID NO: 307, SEQ ID NO: 311, SEQ ID NO: 315, SEQ ID NO: 319, SEQ ID NO: 323, SEQ ID NO: 327, SEQ ID NO: 331, SEQ ID NO: 335, SEQ ID NO: 339, SEQ ID NO: 343, SEQ ID NO: 347, SEQ ID NO: 351, SEQ ID NO: 355, SEQ ID NO: 359, SEQ ID NO: 363, SEQ ID NO: 367, SEQ ID NO: 371, SEQ ID NO: 375, SEQ ID NO: 379, SEQ ID NO: 383, SEQ ID NO: 387, SEQ ID NO: 391, SEQ ID NO: 395, and SEQ ID NO: 399, and a light chain variable region consisting of any one of SEQ ID NO: 304, SEQ ID NO: 308, SEQ ID NO: 312, SEQ ID NO: 316, SEQ ID NO: 320, SEQ ID NO: 324, SEQ ID NO: 328, SEQ ID NO: 332, SEQ ID NO: 336, SEQ ID NO: 340, SEQ ID NO: 344, SEQ ID NO: 348, SEQ ID NO: 352, SEQ ID NO: 356, SEQ ID NO: 360, SEQ ID NO: 364, SEQ ID NO: 368, SEQ ID NO: 372, SEQ ID NO: 376, SEQ ID NO: 380, SEQ ID NO: 384, SEQ ID NO: 388, SEQ ID NO: 392, SEQ ID NO: 396, and SEQ ID NO: 400, but is not limited thereto.

[0037] As an example of the foregoing embodiments, at least one of the anti-CD300c antibody and its antigen-binding fragment includes a heavy chain variable region consisting of any one of SEQ ID NO: 327, SEQ ID NO: 339, and SEQ ID NO: 371, and a light chain variable region consisting of any one of SEQ ID NO: 328, SEQ ID NO: 340, and SEQ ID NO: 372, but is not limited thereto.

[0038] As an example of the above-described embodiments, at least one of the anti-CD300c antibody and its antigen-binding fragment includes a heavy-chain variable region consisting of SEQ ID NO: 327 and a light-chain variable region consisting of SEQ ID NO: 328, but is not limited thereto.

[0039] As one embodiment, the heavy-chain variable region of at least one of the anti-CD300c antibody and its antigen-binding fragment of the present invention is encoded by any one of SEQ ID NO: 305, SEQ ID NO: 309, SEQ ID NO: 313, SEQ ID NO: 317, SEQ ID NO: 321, SEQ ID NO: 325, SEQ ID NO: 329, SEQ ID NO: 333, SEQ ID NO: 337, SEQ ID NO: 341, SEQ ID NO: 345, SEQ ID NO: 349, SEQ ID NO: 353, SEQ ID NO: 357, SEQ ID NO: 361, SEQ ID NO: 365, SEQ ID NO: 369, SEQ ID NO: 373, SEQ ID NO: 377, SEQ ID NO: 381, SEQ ID NO: 385, SEQ ID NO: 389, SEQ ID NO: 393, SEQ ID NO: 397, and SEQ ID NO: 341, and the light-chain variable region of at least one of the anti-CD300c antibody and its antigen-binding fragment of the present invention is encoded by any one of SEQ ID NO: 306, SEQ ID NO: 310, SEQ ID NO: 314, SEQ ID NO: 318, SEQ ID NO: 322, SEQ ID NO: 326, SEQ ID NO: 330, SEQ ID NO: 334, SEQ ID NO: 338, SEQ ID NO: 342, SEQ ID NO: 346, SEQ ID NO: 350, SEQ ID NO: 354, SEQ ID NO: 358, SEQ ID NO: 362, SEQ ID NO: 366, SEQ ID NO: 370, SEQ ID NO: 374, SEQ ID NO: 378, SEQ ID NO: 382, SEQ ID NO: 386, SEQ ID NO: 390, SEQ ID NO: 394, SEQ ID NO: 398, and SEQ ID NO: 402, but is not limited thereto.

[0040] As another embodiment, at least one of the antibody and its antigen-binding fragment of the present invention may include a heavy-chain variable region containing CDR1 to CDR3 consisting of the amino acid sequences represented by the following formulas (1) to (3), respectively, and a light-chain variable region containing CDR1 to CDR3 consisting of the amino acid sequences represented by the following formulas (4) to (6), respectively.

[0041]

Chemical formula

[0042] In the above formula, X1 = G or S, X2 = S, R or D, X3 = N or Y, X4 = Y, A, G or H, and X5 = S or H.

[0043]

Chemical formula

[0044] In the above formula, X1 = T or A, X2 = G or S, X3 = T or G, X4 = S or Y, and X5 = D or E.

[0045]

Chemical formula

[0046] In the above formula, X1 = R or S, X2 = G or S, X3 = M, S, Y or I, X4 = W, Q, G or R, X5 = G or L, X6 = M, I or P, X7 = D, F or L, X8 = V or D, and X9 = I or Y, or X9 does not exist.

[0047]

Chemical formula

[0048] In the above formula, X1 = T or S, X2 = G or R, X3 = K, N or S, X4 = H, N or S, X5 = R, I or G, X6 = H, G or I, X7 = T, I or S, X8 = R, A or K, or X8 does not exist, X9 = R, S or G, or X9 does not exist, X10 = N, or X10 does not exist, X11 = Y, or X11 does not exist, and X12 = N, H or Q.

[0049]

Chemical formula

[0050] In the above formula, X1 = L, S, R or E, X2 = D, K or N, X3 = S or N, X4 = E, N, Q or K, and X5 = P or R.

[0051]

Chemical formula

[0052] In the above formula, X1 = Q, A or S, X2 = S or A, X3 = Y or W, X4 = D or A, X5 = S, D or G, X6 = S, N or T, X7 = S, L, N or K, X8 = V, S, N or G, X9 = G, L or V, or X9 does not exist, X10 = P, or X10 does not exist.

[0053] As an example, at least one of the antibody and antigen-binding fragment of the present invention may include one or more of the 25 antibodies of CK1, CK2, CK3, CL4, CL5, CL6, CB201, CL8, CL9, CL10, SK11, SK12, SK13, SK14, SK15, SK16, SK17, SL18, CB301_H3L1_A10, CB301_H3L1_A12, CB301_H3L1_E6, CB301_H3L1_F4, CB301_H3L1_G11, CB301_OPALTL_B5 and CB301_OPALTL_E6 shown in Table 1.

[0054]

Table 1-1

[0055]

Table 1-2

[0056]

Table 1-3

[0057]

Table 1-4

[0058]

Table 1-5

[0059]

Table 1-6

[0060]

Table 1-7

[0061]

Table 1-8

[0062]

Table 1-9

[0063]

Table 1-10

[0064]

Table 1-11

[0065]

Table 1-12

[0066] In the present invention, the CDRs of the variable regions were determined in a conventional manner using the system devised by Kabat et al. (see Non-Patent Document 2). The CDR numbering used in the present invention is the Kabat method, but antibodies containing CDRs determined by other methods such as the IMGT method, the Chothia method, and the AbM method are also included in the present invention.

[0067] When the antibody of the present invention contains a constant region, it may be a constant region derived from IgG, IgA, IgD, IgE, or IgM, or a constant region formed by a combination or a hybrid thereof.

[0068] In the present invention, "combination" means that when forming a dimer or multimer, a polypeptide encoding a single-chain immunoglobulin constant region of the same origin binds to a single-chain polypeptide of a different origin. For example, a dimer or multimer can be formed from at least two constant regions selected from the group consisting of the constant regions of IgG, IgA, IgD, IgE, and IgM.

[0069] In the present invention, "hybrid" means that within a single-chain immunoglobulin heavy-chain constant region, there are sequences corresponding to at least two immunoglobulin heavy-chain constant regions of different origins. For example, hybrids of 1 to 4 domains selected from the group consisting of CH1, CH2, CH3, and CH4 of IgG, IgA, IgD, IgE, and IgM are possible.

[0070] Also, in the present invention, the variable region and the constant region of the antibody may be derived from the same source or different sources, and the CDR, the variable region excluding it, and the constant region may be derived from the same source or different sources.

[0071] As an example of the foregoing embodiments, at least one of the anti-CD300c antibody and the antigen-binding fragment may include a sequence having a sequence identity of 80% or more, 85% or more, 90% or more, more preferably 95% or more, and most preferably 98% or more as compared with the CDR sequences or the heavy-chain variable region and light-chain variable region sequences shown in Table 1.

[0072] As one embodiment, amino acid sequence variants of the antibody of the present invention are also included. As long as the anti-CD300c antibody and its antigen-binding fragment of the present invention have the same or corresponding properties as the present invention, variants prepared at a level generally practiced in the art are also included in the present invention in order to maintain or improve the functions of the anti-CD300c antibody and its antigen-binding fragment of the present invention. For example, they may improve the binding affinity of the antibody and / or other biological properties. Amino acid sequence variants of the antibody can be prepared by introducing appropriate modifications into the nucleotide sequence encoding the molecule or by peptide synthesis. The modifications include, for example, deletion of residues from the amino acid sequence of the antibody, insertion of residues into the amino acid sequence, and / or substitution of residues in the amino acid sequence. Any combination of deletions, insertions, and substitutions is made to reach the final product, but the final product must retain the desired properties, such as antigen-binding properties. Sites targeted for the induction of substitution mutations include the heavy-chain variable region (HVR) and the framework region (FR). Preferred substitutions for conservative substitutions are shown in the "Preferred Substitutions" column of Table 2. Further description is given below based on amino acid side-chain classifications (1) to (6). Amino acid substitutions are introduced into products screened for the target molecule and desired activities, such as retained / improved antigen binding, reduced immunogenicity, or improved ADCC or CDC.

[0073]

Table 2

[0074] Amino acids are grouped as follows according to the nature of their normal side chains. (1) Hydrophobic: norleucine, Met, Ala, Val, Leu, Ile (2) Neutral hydrophilic: Cys, Ser, Thr, Asn, Gln (3) Acidic: Asp, Glu (4) Basic: His, Lys, Arg (5) Residues affecting the orientation of the chain: Gly, Pro (6) Aromatic: Trp, Tyr, Phe

[0075] Non-conservative substitutions involve replacing a component of any of these classifications with another classification.

[0076] The "amino acid sequence variant" in the present invention includes substantial variants having amino acid substitutions at at least one hypervariable region residue of a parental antibody binding molecule (e.g., a humanized or human antibody). Generally, variants selected and generated for further study have modified, e.g., improved (e.g., enhanced affinity, reduced immunogenicity), and / or substantially maintained, certain biological properties of the parental antibody binding molecule as compared to the parental antibody binding molecule. Examples of substitution variants include affinity matured antibodies, which can be readily generated, e.g., using phage display-based affinity maturation techniques known in the art. Briefly, at least one HVR (Hyper-variable region) residue is mutated, the variant antigen binding molecule is displayed on a phage, and a specific biological activity (e.g., binding affinity) is screened. In a specific embodiment, substitutions, insertions or deletions may be made in one or more HVRs, provided that such modifications do not substantially reduce the ability of the antigen binding molecule to bind to the antigen. For example, conservative modifications (e.g., conservative substitutions as described herein) that do not substantially reduce the binding affinity may be made in the HVRs. Amino acid sequence insertions include not only insertions of single or multiple amino acid residue sequences, but also N-terminal and / or C-terminal fusions ranging from one residue in length to polypeptides of 100 residues or more. Examples of terminal insertions include antibodies having an N-terminal methionyl residue. Other insertion variants of the molecule include fusions of polypeptides that extend the serum half-life of the antibody to the N-terminus or C-terminus. Also, other insertion variants of the molecule include fusions of polypeptides to the N-terminus or C-terminus to facilitate passage through the blood-brain barrier (BBB).

[0077] In the present invention, the polynucleotide sequences encoding the heavy-chain variable region CDR1 to CDR3 of antibody CK1 are shown as SEQ ID NO: 1 to SEQ ID NO: 3 respectively, the polynucleotide sequences encoding the light-chain variable region CDR1 to CDR3 of antibody CK1 are shown as SEQ ID NO: 4 to SEQ ID NO: 6 respectively, the amino acid sequences of the heavy-chain variable region CDR1 to CDR3 of antibody CK1 are shown as SEQ ID NO: 7 to SEQ ID NO: 9 respectively, the amino acid sequences of the light-chain variable region CDR1 to CDR3 of antibody CK1 are shown as SEQ ID NO: 10 to SEQ ID NO: 12 respectively, the polynucleotide sequences encoding the heavy-chain variable region CDR1 to CDR3 of antibody CK2 are shown as SEQ ID NO: 13 to SEQ ID NO: 15 respectively, the polynucleotide sequences encoding the light-chain variable region CDR1 to CDR3 of antibody CK2 are shown as SEQ ID NO: 16 to SEQ ID NO: 18 respectively, the amino acid sequences of the heavy-chain variable region CDR1 to CDR3 of antibody CK2 are shown as SEQ ID NO: 19 to SEQ ID NO: 21 respectively, the amino acid sequences of the light-chain variable region CDR1 to CDR3 of antibody CK2 are shown as SEQ ID NO: 22 to SEQ ID NO: 24 respectively, the polynucleotide sequences encoding the heavy-chain variable region CDR1 to CDR3 of antibody CK3 are shown as SEQ ID NO: 25 to SEQ ID NO: 27 respectively, the polynucleotide sequences encoding the light-chain variable region CDR1 to CDR3 of antibody CK3 are shown as SEQ ID NO: 28 to SEQ ID NO: 30 respectively, the amino acid sequences of the heavy-chain variable region CDR1 to CDR3 of antibody CK3 are shown as SEQ ID NO: 31 to SEQ ID NO: 33 respectively, the amino acid sequences of the light-chain variable region CDR1 to CDR3 of antibody CK3 are shown as SEQ ID NO: 34 to SEQ ID NO: 36 respectively, the polynucleotide sequences encoding the heavy-chain variable region CDR1 to CDR3 of antibody CL4 are shown as SEQ ID NO: 37 to SEQ ID NO: 39 respectively, the polynucleotide sequences encoding the light-chain variable region CDR1 to CDR3 of antibody CL4 are shown as SEQ ID NO: 40 to SEQ ID NO: 42 respectively, the amino acid sequences of the heavy-chain variable region CDR1 to CDR3 of antibody CL4 are shown as SEQ ID NO: 43 to SEQ ID NO: 45 respectively, the amino acid sequences of the light-chain variable region CDR1 to CDR3 of antibody CL4 are shown as SEQ ID NO: 46 to SEQ ID NO: 48 respectively, the polynucleotide sequences encoding the heavy-chain variable region CDR1 to CDR3 of antibody CL5 are shown as SEQ ID NO: 49 to SEQ ID NO: 51 respectively, the polynucleotide sequences encoding the light-chain variable region CDR1 to CDR3 of antibody CL5 are shown as SEQ ID NO: 52 to SEQ ID NO: 54 respectively,The amino acid sequences of CDR1 to CDR3 of the heavy chain variable region of antibody CL5 are shown in SEQ ID NO: 55 to SEQ ID NO: 57 respectively, the amino acid sequences of CDR1 to CDR3 of the light chain variable region of antibody CL5 are shown in SEQ ID NO: 58 to SEQ ID NO: 60 respectively, the polynucleotide sequences encoding CDR1 to CDR3 of the heavy chain variable region of antibody CL6 are shown in SEQ ID NO: 61 to SEQ ID NO: 63 respectively, the polynucleotide sequences encoding CDR1 to CDR3 of the light chain variable region of antibody CL6 are shown in SEQ ID NO: 64 to SEQ ID NO: 66 respectively, the amino acid sequences of CDR1 to CDR3 of the heavy chain variable region of antibody CL6 are shown in SEQ ID NO: 67 to SEQ ID NO: 69 respectively, the amino acid sequences of CDR1 to CDR3 of the light chain variable region of antibody CL6 are shown in SEQ ID NO: 70 to SEQ ID NO: 72 respectively, the polynucleotide sequences encoding CDR1 to CDR3 of the heavy chain variable region of antibody CL6 are shown in SEQ ID NO: 61 to SEQ ID NO: 63 respectively, the polynucleotide sequences encoding CDR1 to CDR3 of the light chain variable region of antibody CL6 are shown in SEQ ID NO: 64 to SEQ ID NO: 66 respectively, the amino acid sequences of CDR1 to CDR3 of the heavy chain variable region of antibody CL6 are shown in SEQ ID NO: 67 to SEQ ID NO: 69 respectively, the amino acid sequences of CDR1 to CDR3 of the light chain variable region of antibody CL6 are shown in SEQ ID NO: 70 to SEQ ID NO: 72 respectively, the polynucleotide sequences encoding CDR1 to CDR3 of the heavy chain variable region of antibody CB201 are shown in SEQ ID NO: 73 to SEQ ID NO: 75 respectively, the polynucleotide sequences encoding CDR1 to CDR3 of the light chain variable region of antibody CB201 are shown in SEQ ID NO: 76 to SEQ ID NO: 78 respectively, the amino acid sequences of CDR1 to CDR3 of the heavy chain variable region of antibody CB201 are shown in SEQ ID NO: 79 to SEQ ID NO: 81 respectively, the amino acid sequences of CDR1 to CDR3 of the light chain variable region of antibody CB201 are shown in SEQ ID NO: 82 to SEQ ID NO: 84 respectively, the polynucleotide sequences encoding CDR1 to CDR3 of the heavy chain variable region of antibody CL8 are shown in SEQ ID NO: 85 to SEQ ID NO: 87 respectively, the polynucleotide sequences encoding CDR1 to CDR3 of the light chain variable region of antibody CL8 are shown in SEQ ID NO: 88 to SEQ ID NO: 90 respectively, the amino acid sequences of CDR1 to CDR3 of the heavy chain variable region of antibody CL8 are shown in SEQ ID NO: 91 to SEQ ID NO: 93 respectively, the amino acid sequences of CDR1 to CDR3 of the light chain variable region of antibody CL8 are shown in SEQ ID NO: 94 to SEQ ID NO: 96 respectively,The polynucleotide sequences encoding CDR1 to CDR3 of the heavy chain variable region of antibody CL9 are shown in SEQ ID NO: 97 to SEQ ID NO: 99 respectively, the polynucleotide sequences encoding CDR1 to CDR3 of the light chain variable region of antibody CL9 are shown in SEQ ID NO: 100 to SEQ ID NO: 102 respectively, the amino acid sequences of CDR1 to CDR3 of the heavy chain variable region of antibody CL9 are shown in SEQ ID NO: 103 to SEQ ID NO: 105 respectively, the amino acid sequences of CDR1 to CDR3 of the light chain variable region of antibody CL9 are shown in SEQ ID NO: 106 to SEQ ID NO: 108 respectively, the polynucleotide sequences encoding CDR1 to CDR3 of the heavy chain variable region of antibody CL10 are shown in SEQ ID NO: 109 to SEQ ID NO: 111 respectively, the polynucleotide sequences encoding CDR1 to CDR3 of the light chain variable region of antibody CL10 are shown in SEQ ID NO: 112 to SEQ ID NO: 114 respectively, the amino acid sequences of CDR1 to CDR3 of the heavy chain variable region of antibody CL10 are shown in SEQ ID NO: 115 to SEQ ID NO: 117 respectively, the amino acid sequences of CDR1 to CDR3 of the light chain variable region of antibody CL10 are shown in SEQ ID NO: 118 to SEQ ID NO: 120 respectively, the polynucleotide sequences encoding CDR1 to CDR3 of the heavy chain variable region of antibody SK11 are shown in SEQ ID NO: 121 to SEQ ID NO: 123 respectively, the polynucleotide sequences encoding CDR1 to CDR3 of the light chain variable region of antibody SK11 are shown in SEQ ID NO: 124 to SEQ ID NO: 126 respectively, the amino acid sequences of CDR1 to CDR3 of the heavy chain variable region of antibody SK11 are shown in SEQ ID NO: 127 to SEQ ID NO: 129 respectively, the amino acid sequences of CDR1 to CDR3 of the light chain variable region of antibody SK11 are shown in SEQ ID NO: 130 to SEQ ID NO: 132 respectively, the polynucleotide sequences encoding CDR1 to CDR3 of the heavy chain variable region of antibody SK12 are shown in SEQ ID NO: 133 to SEQ ID NO: 135 respectively, the polynucleotide sequences encoding CDR1 to CDR3 of the light chain variable region of antibody SK12 are shown in SEQ ID NO: 136 to SEQ ID NO: 138 respectively, the amino acid sequences of CDR1 to CDR3 of the heavy chain variable region of antibody SK12 are shown in SEQ ID NO: 139 to SEQ ID NO: 141 respectively, the amino acid sequences of CDR1 to CDR3 of the light chain variable region of antibody SK12 are shown in SEQ ID NO: 142 to SEQ ID NO: 144 respectively, the polynucleotide sequences encoding CDR1 to CDR3 of the heavy chain variable region of antibody SK13 are shown in SEQ ID NO: 145 to SEQ ID NO: 147 respectively,The polynucleotide sequences encoding CDR1 to CDR3 of the light chain variable region of antibody SK13 are shown in SEQ ID NO: 148 to SEQ ID NO: 150 respectively, the amino acid sequences of CDR1 to CDR3 of the heavy chain variable region of antibody SK13 are shown in SEQ ID NO: 151 to SEQ ID NO: 153 respectively, the amino acid sequences of CDR1 to CDR3 of the light chain variable region of antibody SK13 are shown in SEQ ID NO: 154 to SEQ ID NO: 156 respectively, the polynucleotide sequences encoding CDR1 to CDR3 of the heavy chain variable region of antibody SK14 are shown in SEQ ID NO: 157 to SEQ ID NO: 159 respectively, the polynucleotide sequences encoding CDR1 to CDR3 of the light chain variable region of antibody SK14 are shown in SEQ ID NO: 160 to SEQ ID NO: 162 respectively, the amino acid sequences of CDR1 to CDR3 of the heavy chain variable region of antibody SK14 are shown in SEQ ID NO: 163 to SEQ ID NO: 165 respectively, the amino acid sequences of CDR1 to CDR3 of the light chain variable region of antibody SK14 are shown in SEQ ID NO: 166 to SEQ ID NO: 168 respectively, the polynucleotide sequences encoding CDR1 to CDR3 of the heavy chain variable region of antibody SK15 are shown in SEQ ID NO: 169 to SEQ ID NO: 171 respectively, the polynucleotide sequences encoding CDR1 to CDR3 of the light chain variable region of antibody SK15 are shown in SEQ ID NO: 172 to SEQ ID NO: 174 respectively, the amino acid sequences of CDR1 to CDR3 of the heavy chain variable region of antibody SK15 are shown in SEQ ID NO: 175 to SEQ ID NO: 177 respectively, the amino acid sequences of CDR1 to CDR3 of the light chain variable region of antibody SK15 are shown in SEQ ID NO: 178 to SEQ ID NO: 180 respectively, the polynucleotide sequences encoding CDR1 to CDR3 of the heavy chain variable region of antibody SK16 are shown in SEQ ID NO: 181 to SEQ ID NO: 183 respectively, the polynucleotide sequences encoding CDR1 to CDR3 of the light chain variable region of antibody SK16 are shown in SEQ ID NO: 184 to SEQ ID NO: 186 respectively, the amino acid sequences of CDR1 to CDR3 of the heavy chain variable region of antibody SK16 are shown in SEQ ID NO: 187 to SEQ ID NO: 189 respectively, the amino acid sequences of CDR1 to CDR3 of the light chain variable region of antibody SK16 are shown in SEQ ID NO: 190 to SEQ ID NO: 192 respectively, the polynucleotide sequences encoding CDR1 to CDR3 of the heavy chain variable region of antibody SK17 are shown in SEQ ID NO: 193 to SEQ ID NO: 195 respectively, the polynucleotide sequences encoding CDR1 to CDR3 of the light chain variable region of antibody SK17 are shown in SEQ ID NO: 196 to SEQ ID NO: 198 respectively,The amino acid sequences of CDR1 to CDR3 of the heavy chain variable region of antibody SK17 are shown in SEQ ID NO: 199 to SEQ ID NO: 201 respectively, the amino acid sequences of CDR1 to CDR3 of the light chain variable region of antibody SK17 are shown in SEQ ID NO: 202 to SEQ ID NO: 204 respectively, the polynucleotide sequences encoding CDR1 to CDR3 of the heavy chain variable region of antibody SL18 are shown in SEQ ID NO: 205 to SEQ ID NO: 207 respectively, the polynucleotide sequences encoding CDR1 to CDR3 of the light chain variable region of antibody SL18 are shown in SEQ ID NO: 208 to SEQ ID NO: 210 respectively, the amino acid sequences of CDR1 to CDR3 of the heavy chain variable region of antibody SL18 are shown in SEQ ID NO: 211 to SEQ ID NO: 213 respectively, the amino acid sequences of CDR1 to CDR3 of the light chain variable region of antibody SL18 are shown in SEQ ID NO: 214 to SEQ ID NO: 216 respectively, the polynucleotide sequences encoding CDR1 to CDR3 of the heavy chain variable region of antibody CB301_H3L1_A10 are shown in SEQ ID NO: 217 to SEQ ID NO: 219 respectively, the polynucleotide sequences encoding CDR1 to CDR3 of the light chain variable region of antibody CB301_H3L1_A10 are shown in SEQ ID NO: 220 to SEQ ID NO: 222 respectively, the amino acid sequences of CDR1 to CDR3 of the heavy chain variable region of antibody CB301_H3L1_A10 are shown in SEQ ID NO: 223 to SEQ ID NO: 225 respectively, the amino acid sequences of CDR1 to CDR3 of the light chain variable region of antibody CB301_H3L1_A10 are shown in SEQ ID NO: 226 to SEQ ID NO: 228 respectively, the polynucleotide sequences encoding CDR1 to CDR3 of the heavy chain variable region of antibody CB301_H3L1_A12 are shown in SEQ ID NO: 229 to SEQ ID NO: 231 respectively, the polynucleotide sequences encoding CDR1 to CDR3 of the light chain variable region of antibody CB301_H3L1_A12 are shown in SEQ ID NO: 232 to SEQ ID NO: 234 respectively, the amino acid sequences of CDR1 to CDR3 of the heavy chain variable region of antibody CB301_H3L1_A12 are shown in SEQ ID NO: 235 to SEQ ID NO: 237 respectively, the amino acid sequences of CDR1 to CDR3 of the light chain variable region of antibody CB301_H3L1_A12 are shown in SEQ ID NO: 238 to SEQ ID NO: 240 respectively, the polynucleotide sequences encoding CDR1 to CDR3 of the heavy chain variable region of antibody CB301_H3L1_E6 are shown in SEQ ID NO: 241 to SEQ ID NO: 243 respectively,The polynucleotide sequences encoding CDR1 to CDR3 of the light chain variable region of antibody CB301_H3L1_E6 are shown in SEQ ID NOs: 244 to 246, respectively, and the amino acid sequences of CDR1 to CDR3 of the heavy chain variable region of antibody CB301_H3L1_E6 are shown in SEQ ID NOs: 247 to, Shown in Sequence No. 249, the amino acid sequences of CDR1 to CDR3 of the light chain variable region of antibody CB301_H3L1_E6 are shown in Sequence Nos. 250 to 252 respectively, the polynucleotide sequences encoding CDR1 to CDR3 of the heavy chain variable region of antibody CCB301_H3L1_F4 are shown in Sequence Nos. 253 to 255 respectively, the polynucleotide sequences encoding CDR1 to CDR3 of the light chain variable region of antibody CB301_H3L1_F4 are shown in Sequence Nos. 256 to 258 respectively, the amino acid sequences of CDR1 to CDR3 of the heavy chain variable region of antibody CB301_H3L1_F4 are shown in Sequence Nos. 259 to 261 respectively, the amino acid sequences of CDR1 to CDR3 of the light chain variable region of antibody CB301_H3L1_F4 are shown in Sequence Nos. 262 to 264 respectively, the polynucleotide sequences encoding CDR1 to CDR3 of the heavy chain variable region of antibody CB301_H3L1_G11 are shown in Sequence Nos. 265 to 267 respectively, the polynucleotide sequences encoding CDR1 to CDR3 of the light chain variable region of antibody CB301_H3L1_G11 are shown in Sequence Nos. 268 to 270 respectively, the amino acid sequences of CDR1 to CDR3 of the heavy chain variable region of antibody CB301_H3L1_G11 are shown in Sequence Nos. 271 to 273 respectively, the amino acid sequences of CDR1 to CDR3 of the light chain variable region of antibody CB301_H3L1_G11 are shown in Sequence Nos. 274 to 276 respectively, the polynucleotide sequences encoding CDR1 to CDR3 of the heavy chain variable region of antibody CB301_OPALTL_B5 are shown in Sequence Nos. 277 to 279 respectively, the polynucleotide sequences encoding CDR1 to CDR3 of the light chain variable region of antibody CB301_OPALTL_B5 are shown in Sequence Nos. 280 to 282 respectively, the amino acid sequences of CDR1 to CDR3 of the heavy chain variable region of antibody CB301_OPALTL_B5 are shown in Sequence Nos. 283 to 285 respectively, the amino acid sequences of CDR1 to CDR3 of the light chain variable region of antibody CB301_OPALTL_B5 are shown in Sequence Nos. 286 to 288 respectively, the polynucleotide sequences encoding CDR1 to CDR3 of the heavy chain variable region of antibody CB301_OPALTL_E6 are shown in Sequence Nos. 289 to 291 respectively,The polynucleotide sequences encoding CDR1 to CDR3 of the light chain variable region of antibody CB301_OPALTL_E6 are shown in SEQ ID NO: 292 to SEQ ID NO: 294, respectively. The amino acid sequences of CDR1 to CDR3 of the heavy chain variable region of antibody CB301_OPALTL_E6 are shown in SEQ ID NO: 295 to SEQ ID NO: 297, respectively. The amino acid sequences of CDR1 to CDR3 of the light chain variable region of antibody CB301_OPALTL_E6 are shown in SEQ ID NO: 298 to SEQ ID NO: 300, respectively.

[0078] In addition, the polynucleotide sequence encoding the heavy chain variable region of antibody CK1, the polynucleotide sequence encoding the light chain variable region of antibody CK1, the amino acid sequence of the heavy chain variable region of antibody CK1, and the amino acid sequence of the light chain variable region of antibody CK1 are shown in SEQ ID NOs: 301 to 304 respectively. The polynucleotide sequence encoding the heavy chain variable region of antibody CK2, the polynucleotide sequence encoding the light chain variable region of antibody CK2, the amino acid sequence of the heavy chain variable region of antibody CK2, and the amino acid sequence of the light chain variable region of antibody CK2 are shown in SEQ ID NOs: 305 to 308 respectively. The polynucleotide sequence encoding the heavy chain variable region of antibody CK3, the polynucleotide sequence encoding the light chain variable region of antibody CK3, the amino acid sequence of the heavy chain variable region of antibody CK3, and the amino acid sequence of the light chain variable region of antibody CK3 are shown in SEQ ID NOs: 309 to 312 respectively. The polynucleotide sequence encoding the heavy chain variable region of antibody CL4, the polynucleotide sequence encoding the light chain variable region of antibody CL4, the amino acid sequence of the heavy chain variable region of antibody CL4, and the amino acid sequence of the light chain variable region of antibody CL4 are shown in SEQ ID NOs: 313 to 316 respectively. The polynucleotide sequence encoding the heavy chain variable region of antibody CL5, the polynucleotide sequence encoding the light chain variable region of antibody CL5, the amino acid sequence of the heavy chain variable region of antibody CL5, and the amino acid sequence of the light chain variable region of antibody CL5 are shown in SEQ ID NOs: 317 to 320 respectively. The polynucleotide sequence encoding the heavy chain variable region of antibody CL6, the polynucleotide sequence encoding the light chain variable region of antibody CL6, the amino acid sequence of the heavy chain variable region of antibody CL6, and the amino acid sequence of the light chain variable region of antibody CL6 are shown in SEQ ID NOs: 321 to 324 respectively. The polynucleotide sequence encoding the heavy chain variable region of antibody CB201, the polynucleotide sequence encoding the light chain variable region of antibody CB201, the amino acid sequence of the heavy chain variable region of antibody CB201, and the amino acid sequence of the light chain variable region of antibody CB201 are shown in SEQ ID NOs: 325 to 328 respectively. The polynucleotide sequence encoding the heavy chain variable region of antibody CL8, the polynucleotide sequence encoding the light chain variable region of antibody CL8, the amino acid sequence of the heavy chain variable region of antibody CL8, and the amino acid sequence of the light chain variable region of antibody CL8 are shown in SEQ ID NOs: 329 to 332 respectively. The polynucleotide sequence encoding the heavy chain variable region of antibody CL9,The polynucleotide sequences encoding the light chain variable regions of antibody CL9, the amino acid sequences of the heavy chain variable regions of antibody CL9, and the amino acid sequences of the light chain variable regions of antibody CL9 are shown in SEQ ID NOs: 333 to 336 respectively. The polynucleotide sequences encoding the heavy chain variable regions of antibody CL10, the polynucleotide sequences encoding the light chain variable regions of antibody CL10, the amino acid sequences of the heavy chain variable regions of antibody CL10, and the amino acid sequences of the light chain variable regions of antibody CL10 are shown in SEQ ID NOs: 337 to 340 respectively. The polynucleotide sequences encoding the heavy chain variable regions of antibody SK11, the polynucleotide sequences encoding the light chain variable regions of antibody SK11, the amino acid sequences of the heavy chain variable regions of antibody SK11, and the amino acid sequences of the light chain variable regions of antibody SK11 are shown in SEQ ID NOs: 341 to 344 respectively. The polynucleotide sequences encoding the heavy chain variable regions of antibody SK12, the polynucleotide sequences encoding the light chain variable regions of antibody SK12, the amino acid sequences of the heavy chain variable regions of antibody SK12, and the amino acid sequences of the light chain variable regions of antibody SK12 are shown in SEQ ID NOs: 345 to 348 respectively. The polynucleotide sequences encoding the heavy chain variable regions of antibody SK13, the polynucleotide sequences encoding the light chain variable regions of antibody SK13, the amino acid sequences of the heavy chain variable regions of antibody SK13, and the amino acid sequences of the light chain variable regions of antibody SK13 are shown in SEQ ID NOs: 349 to 352 respectively. The polynucleotide sequences encoding the heavy chain variable regions of antibody SK14, the polynucleotide sequences encoding the light chain variable regions of antibody SK14, the amino acid sequences of the heavy chain variable regions of antibody SK14, and the amino acid sequences of the light chain variable regions of antibody SK14 are shown in SEQ ID NOs: 353 to 356 respectively. The polynucleotide sequences encoding the heavy chain variable regions of antibody SK15, the polynucleotide sequences encoding the light chain variable regions of antibody SK15, the amino acid sequences of the heavy chain variable regions of antibody SK15, and the amino acid sequences of the light chain variable regions of antibody SK15 are shown in SEQ ID NOs: 357 to 360 respectively. The polynucleotide sequences encoding the heavy chain variable regions of antibody SK16, the polynucleotide sequences encoding the light chain variable regions of antibody SK16, the amino acid sequences of the heavy chain variable regions of antibody SK16, and the amino acid sequences of the light chain variable regions of antibody SK16 are shown in SEQ ID NOs: 361 to 364 respectively. The polynucleotide sequences encoding the heavy chain variable regions of antibody SK17, the polynucleotide sequences encoding the light chain variable regions of antibody SK17,The amino acid sequences of the heavy chain variable region of antibody SK17 and the light chain variable region of antibody SK17 are shown in SEQ ID NOs: 365 to 368 respectively. The polynucleotide sequences encoding the heavy chain variable region of antibody SL18, the polynucleotide sequences encoding the light chain variable region of antibody SL18, the amino acid sequences of the heavy chain variable region of antibody SL18, and the amino acid sequences of the light chain variable region of antibody SL18 are shown in SEQ ID NOs: 369 to 372 respectively. The polynucleotide sequences encoding the heavy chain variable region of antibody CB301_H3L1_A10, the polynucleotide sequences encoding the light chain variable region of antibody CB301_H3L1_A10, the amino acid sequences of the heavy chain variable region of antibody CB301_H3L1_A10, and the amino acid sequences of the light chain variable region of antibody CB301_H3L1_A10 are shown in SEQ ID NOs: 373 to 376 respectively. The polynucleotide sequences encoding the heavy chain variable region of antibody CB301_H3L1_A12, the polynucleotide sequences encoding the light chain variable region of antibody CB301_H3L1_A12, the amino acid sequences of the heavy chain variable region of antibody CB301_H3L1_A12, and the amino acid sequences of the light chain variable region of antibody CB301_H3L1_A12 are shown in SEQ ID NOs: 377 to 380 respectively. The polynucleotide sequences encoding the heavy chain variable region of antibody CB301_H3L1_E6, the polynucleotide sequences encoding the light chain variable region of antibody CB301_H3L1_E6, the amino acid sequences of the heavy chain variable region of antibody CB301_H3L1_E6, and the amino acid sequences of the light chain variable region of antibody CB301_H3L1_E6 are shown in SEQ ID NOs: 381 to 384 respectively. The polynucleotide sequences encoding the heavy chain variable region of antibody CB301_H3L1_F4, the polynucleotide sequences encoding the light chain variable region of antibody CB301_H3L1_F4, the amino acid sequences of the heavy chain variable region of antibody CB301_H3L1_F4, and the amino acid sequences of the light chain variable region of antibody CB301_H3L1_F4 are shown in SEQ ID NOs: 385 to 388 respectively. The polynucleotide sequences encoding the heavy chain variable region of antibody CB301_H3L1_G11, the polynucleotide sequences encoding the light chain variable region of antibody CB301_H3L1_G11, the amino acid sequences of the heavy chain variable region of antibody CB301_H3L1_G11, and the amino acid sequences of the light chain variable region of antibody CB301_H3L1_G11 are shown in SEQ ID NOs: 389 to 392 respectively.The polynucleotide sequences encoding the heavy chain variable region of antibody CB301_OPALTL_B5, the polynucleotide sequences encoding the light chain variable region of antibody CB301_OPALTL_B5, the amino acid sequences of the heavy chain variable region of antibody CB301_OPALTL_B5, and the amino acid sequences of the light chain variable region of antibody CB301_OPALTL_B5 are shown in SEQ ID NOs: 393 to 396 respectively. The polynucleotide sequences encoding the heavy chain variable region of antibody CB301_OPALTL_E6, the polynucleotide sequences encoding the light chain variable region of antibody CB301_OPALTL_E6, the amino acid sequences of the heavy chain variable region of antibody CB301_OPALTL_E6, and the amino acid sequences of the light chain variable region of antibody CB301_OPALTL_E6 are shown in SEQ ID NOs: 397 to 400 respectively. The amino acid sequence of CD300C ECD and the polynucleotide sequence encoding the same are shown in SEQ ID NOs: 401 and 402 respectively.,

[0079] At least one of the antibodies and antigen-binding fragments thereof of the present invention can induce promotion of differentiation into MDM (Monocyte-derived macrophage) or M1 macrophages by engagement with CD300c, but is not limited thereto.

[0080] As an example of the above-described embodiments, the anti-CD00c antibody and antigen-binding fragment thereof may specifically bind to the extracellular domain of the CD300c protein. The extracellular domain of CD300c may be the extracellular domain of the human CD300c protein, or may include the amino acid sequence represented by SEQ ID NO: 402.

[0081] As an example, the antibody and / or antigen-binding fragment thereof of the present invention has the ability to restore or improve the cognitive function of a subject having or at risk of having a degenerative brain disease, and the cognitive function includes cognitive ability, memory, language ability, spatio-temporal ability, orientation ability, executive ability, or a combination thereof.

[0082] As an example, the antibody of the present invention may have the ability to promote the differentiation of monocytes into MDM (Monocyte-derived macrophage) or M1 macrophages, and may have improved promotion ability compared to general therapeutic agents for degenerative brain diseases and immunotherapeutic agents. Thereby, it is expected to exhibit a significant preventive or therapeutic effect on degenerative brain diseases even in patients with degenerative brain diseases that cannot be treated with general therapeutic agents for degenerative brain diseases and immunotherapeutic agents.

[0083] The "degenerative brain disease" in the present invention means a brain disease caused by damage to nerve cells, which may be accompanied by cognitive impairment. The cognitive impairment includes a decrease in cognitive ability, memory impairment, language impairment, decrease in spatio-temporal ability, disorientation, impairment of executive ability, or a combination thereof.

[0084] As an example, the degenerative brain disease includes, but is not limited to, at least one selected from the group consisting of dementia, Alzheimer's disease, Huntington's disease, Parkinson's disease, cerebral amyloid angiopathy, amyloid stroke, Dutch type amyloidosis, tauopathy, mild cognitive impairment, corticobasal degeneration, posterior cortical atrophy, primary progressive aphasia, progressive supranuclear palsy, corticobasal deteneration (CBD), amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, amnesia, learning disorder, and memory disorder.

[0085] The dementia refers to a decline or progressive decline in cognitive function caused by brain damage or disease, and generally includes loss of sense of direction, impairment of memory, judgment, and intelligence, unstable emotions, or a combination thereof. The dementia includes, but is not limited to, at least one selected from the group consisting of Alzheimer's disease-type dementia, Huntington's disease-type dementia, Parkinson's disease-type dementia, cerebrovascular dementia, neuroinflammatory dementia, cerebral infarction dementia, senile dementia, Lewy body dementia (Dimentia with Lewy bodies, DLB), multi-infarct dementia (Multi-Infarct Dementia, MID), frontotemporal lobar degeneration (Frontotemporal lobar degeneration, FTLD), Creutzfeldt-Jakob disease-type dementia, Pick's disease-type dementia, dementia caused by corticobasal degeneration, dementia caused by normal pressure hydrocephalus, and dementia caused by head trauma.

[0086] As an example, the degenerative brain disease may be Alzheimer's disease.

[0087] In one embodiment of the present invention, when a Y-maze test was performed using a degenerative brain disease-induced 5xFAD mouse, it was confirmed that the spontaneous alternation behavior decreased by the induction of degenerative brain disease was statistically significantly restored by the administration of an anti-CD300c antibody.

[0088] In another embodiment of the present invention, when a Morris water maze test was performed using a degenerative brain disease-induced 5xFAD mouse, it was confirmed that the cognitive ability and memory of the mouse decreased by the induction of degenerative brain disease were statistically significantly restored by the administration of an anti-CD300c antibody.

[0089] Furthermore, in yet another embodiment of the present invention, it was confirmed that the anti-CD300c antibody of the present invention has the ability to promote the differentiation of monocytes into MDM (Monocyte-derived macrophage) or M1 macrophages. The degenerative brain disease of the present invention may be one that prevents or treats by promoting the differentiation of monocytes into MDM or M1 macrophages. These results suggest that the anti-CD300c antibody and / or its antigen-binding fragment of the present invention can also treat various degenerative brain diseases (such as Huntington's disease and Parkinson's disease) that can be treated by promoting the differentiation into MDM (Monocyte-derived macrophage) or M1 macrophages.

[0090] The composition of the present invention prevents or treats degenerative brain diseases, and at least one of the antibody and its antigen-binding fragment contained therein may restore or improve the cognitive function of a subject having or at risk of having a degenerative brain disease.

[0091] "Treatment" in the present invention generally means obtaining the intended pharmacological and / or physiological effects, and includes any act of improving, delaying, or favorably changing the symptoms of a degenerative brain disease by administering the composition of the present invention. Also, due to the nature of brain diseases, an act of maintaining the current state without the symptoms worsening is also included in the above treatment. These effects have a therapeutic effect from the perspective of partially or completely treating the disease and / or its side effects caused by the disease. Preferred therapeutic effects include, but are not limited to, preventing the occurrence or recurrence of the disease, improving symptoms, reducing any direct or indirect pathological consequences of the disease, decreasing the disease progression rate, improving or alleviating the disease state, and improving the prognosis.

[0092] "Prevention" in the present invention means preventive treatment, that is, not treating the disease but obtaining an effect for prevention. The above prevention means obtaining the intended preventive pharmacological and / or physiological effects from the perspective of partially or completely preventing the disease or its symptoms.

[0093] The pharmaceutical composition may further contain a pharmaceutically acceptable carrier.

[0094] The "pharmaceutically acceptable carrier" in the present invention means a carrier or diluent that does not stimulate the organism and does not impair the biological activity and properties of the administered compound. Pharmaceutically acceptable carriers that are acceptable in compositions formulated as liquid solutions are those that are sterile and biocompatible, and include saline, sterile water, Ringer's solution, buffered saline, albumin injection solution, glucose solution, maltodextrin solution, glycerin, ethanol, and at least one of their components can be mixed and used, and other conventional additives such as antioxidants, buffers, bacteriostatic agents, etc. can be added as necessary. Further, a diluent, dispersant, surfactant, binder, and lubricant can be added to formulate into injection dosage forms such as aqueous solutions, suspensions, emulsions, pills, capsules, granules, or tablets.

[0095] The pharmaceutical composition may be in various oral or parenteral dosage forms. When formulating, it is usually prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, etc. Examples of oral solid preparations include tablets, pills, powders, granules, capsules, etc. These solid preparations are prepared by mixing at least one compound with at least one excipient, such as starch, calcium carbonate, sucrose or lactose, gelatin, etc. In addition to ordinary excipients, lubricants such as magnesium stearate and talc are also used. Examples of oral liquid preparations include suspensions, oral solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used ordinary diluents, various excipients such as wetting agents, sweeteners, fragrances, preservatives, etc. are used. Examples of parenteral preparations include, for example, sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories. As non-aqueous solvents and suspensions, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, etc. are used. As the base of suppositories, witepsol, macrogol, tween 61, cocoa butter, laurin fat, glycerogelatin, etc. are used.

[0096] The pharmaceutical composition may have any dosage form selected from the group consisting of tablets, pills, powders, granules, capsules, suspensions, oral solutions, emulsions, syrups, sterile aqueous solution preparations, non-aqueous solvents, lyophilized preparations and suppositories.

[0097] The pharmaceutical composition of the present invention is administered to a subject in a pharmaceutically effective amount.

[0098] The "pharmaceutically effective amount" in the present invention means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment. The effective dosage level is determined by factors including the type and severity of the individual, age, gender, type of brain disease, activity of the drug, sensitivity to the drug, administration time, administration route and excretion rate, treatment period, factors including drugs used simultaneously, and other factors known in the medical field. The compositions of the present invention may be administered alone or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents. Also, single or multiple administrations may be performed. It is important to administer an amount that can obtain the maximum effect with the minimum amount without side effects considering all the above factors, and this can be easily determined by those skilled in the art.

[0099] The "subject" in the present invention is used interchangeably with "patient" and "individual", and is a mammal in need of prevention or treatment of a degenerative brain disease, such as a primate (e.g., human), pet (e.g., dog, cat, etc.), livestock animal (e.g., cow, pig, horse, sheep, goat, etc.) and experimental animal (e.g., rat, mouse, guinea pig, etc.). As an example of an embodiment of the present invention, the subject may be other than human or may be human.

[0100] Another aspect of the present invention provides a method for preventing or treating a degenerative brain disease, comprising the step of administering at least one of an anti-CD300c antibody and an antigen-binding fragment thereof to a subject having or at risk of having a degenerative brain disease.

[0101] The anti-CD300c antibody, its antigen-binding fragment, degenerative brain disease, subject, prevention, treatment, etc. are as described above.

[0102] "Administration" in the present invention means a method of providing a substance (e.g., at least one of an anti-CD300c antibody and an antigen-binding fragment thereof) to a subject to achieve a prophylactic or therapeutic purpose (e.g., prevention or treatment of a degenerative brain disease).

[0103] The antibodies and / or antigen-binding fragments of the present invention are administered in various ways depending on whether local or systemic treatment is required and the area to be treated. The method of administering the antibodies and / or antigen-binding fragments of the present invention can be easily determined by those skilled in the art. The route of administration may be oral, parenteral, inhalation or topical. For example, parenteral administration includes, but is not limited to, intravenous administration, subcutaneous administration, intraperitoneal administration, intramuscular administration, rectal administration, vaginal administration, intrathecal administration, intracardiac administration, intracerebroventricular administration, etc. As one example, the antibodies and / or antigen-binding fragments of the present invention may be delivered through the Blood Brain Barrier (BBB) by various suitable compositions and methods described herein or known in the art.

[0104] The effective amount or effective non-toxic amount of the antibodies and / or antigen-binding fragments of the present invention is determined by routine experimentation. For example, the therapeutically active amount of the antibodies and / or antigen-binding fragments of the present invention varies depending on factors such as the stage of the disease, the severity of the disease, the age, sex, medical complications and weight of the subject, and the ability of the antibody to elicit the desired response in the subject. The dosage and dosing regimen of the antibodies and / or antigen-binding fragments of the present invention may be adjusted to provide an optimal therapeutic response. For example, a predetermined divided dose may be administered at intervals such as daily, weekly, every two weeks, every three weeks, every four weeks, etc., and the dose may also be decreased or increased proportionally to the degree of urgency of the treatment situation.

[0105] The antibody and / or antigen-binding fragment of the present invention may be administered in combination with at least one other formulation effective for the prevention or treatment of degenerative brain diseases. The other formulations include, but are not limited to, any formulation that improves or ameliorates degenerative brain diseases, such as compounds, gene therapy agents, proteins (including antibodies). When the antibody and / or antigen-binding fragment of the present invention is administered together with other formulations, they may be formulated as a single composition for co-delivery, or may be formulated separately into at least two compositions (e.g., kits). Each component may be administered to the subject at a time different from the time of administering the other components. As a specific example, each administration is performed at various intervals over a predetermined period of time non-simultaneously (e.g., individually or sequentially). Also, the individual components are administered to the subject by the same or different routes. The pharmaceutical composition of the present invention may be administered in combination with one or more well-known therapeutic agents for degenerative brain diseases.

[0106] Still another aspect of the present invention provides a food composition for preventing or ameliorating degenerative brain diseases, comprising at least one of an anti-CD300c antibody and an antigen-binding fragment thereof.

[0107] The anti-CD300c antibody, its antigen-binding fragment, degenerative brain diseases, prevention, etc. are as described above.

[0108] The food composition may be a functional food.

[0109] "Amelioration" in the present invention means any action of using at least one of the anti-CD300c antibody and its antigen-binding fragment to survive individuals with or suspected of having degenerative brain diseases, reduce recurrence and / or drug resistance, improve symptoms, or cause favorable changes.

[0110] The "food" in the present invention may be any food in the ordinary sense, such as meats, sausages, bread, chocolate, candies, snacks, confectioneries, pizza, ramen, other noodles, gums, dairy products including ice creams, various soups, soft drinks, tea, drink agents, alcoholic beverages, vitamin complexes, functional foods, etc. Any product containing at least one of the anti-CD300c antibody and its antigen-binding fragment of the present invention is acceptable, but not limited thereto. When manufacturing the food composition, raw materials and components that are usually added in the art can be added for manufacturing, and the types thereof are not particularly limited. For example, various herbal extracts, food scientifically acceptable food additives, natural carbohydrates, etc. may be included as additional components in the same manner as ordinary foods, but not limited thereto. The mixing amount of the active ingredient is appropriately determined according to the purpose of use.

[0111] The "functional food" in the present invention is synonymous with "food for special health use (FoSHU)". It is a food manufactured or processed by methods such as extraction, concentration, purification, and mixing of specific ingredients used as raw materials for the purpose of health assistance or specific ingredients contained in food raw materials, and is designed and processed so that biological regulatory functions such as biological defense, regulation of biological rhythms, prevention and recovery of diseases are fully exerted in the living body. The functional food composition has functions related to disease prevention, disease recovery, etc. The functional food of the present invention is used interchangeably with terms known in the art such as health functional foods.

[0112] Still another aspect of the present invention provides a feed composition for preventing or improving degenerative brain diseases, which contains at least one of the anti-CD300c antibody and its antigen-binding fragment.

[0113] The anti-CD300c antibody, its antigen-binding fragment, degenerative brain diseases, prevention, improvement, etc. are as described above.

[0114] The feed composition is for animals other than humans, and includes those for mammals including the individual, such as cows, pigs, sheep, chickens, dogs, humans, etc., and those for birds, but is not limited thereto.

[0115] In addition to the anti-CD300c antibody and its antigen-binding fragment of the present invention, the feed composition may also contain known carriers, stabilizers or additives acceptable for pharmaceutical, food or feed use. For example, binders, emulsifiers, preservatives, etc. added to prevent quality deterioration can be mentioned, and amino acid agents, vitamin agents, enzyme agents, flavoring agents, non-protein nitrogen compounds, silicate agents, buffers, extractants, oligosaccharides, etc. added to the feed to improve efficacy can be mentioned. In addition, it may further contain a feed mixer, etc., but is not limited thereto. The feed composition may contain various nutrients such as vitamins, amino acids, minerals, antioxidants, and other additives as necessary, and its form is in an appropriate state such as powder, granule, pellet, suspension, etc. The feed composition of the present invention may be supplied alone to a single animal or may be supplied by mixing it with the feed. The feed of the present invention is not particularly limited, and can be any feed such as powder feed, solid feed, dry feed, wet feed, moist pellet feed, dry pellet feed, EP (Extruder Pellet) feed, raw feed, etc.

[0116] Yet another aspect of the present invention provides the use of an anti-CD300c antibody and / or its antigen-binding fragment for the prevention or treatment of degenerative brain diseases.

[0117] As an example, the degenerative brain disease may be one that is prevented or treated by promoting the differentiation of monocytes into MDM or M1 macrophages.

[0118] Yet another aspect of the present invention provides the use of an anti-CD300c antibody and / or its antigen-binding fragment for the manufacture of a composition (such as a pharmaceutical) for the prevention or treatment of degenerative brain diseases.

[0119] As described above, the anti-CD300c antibody, its antigen-binding fragment, degenerative brain diseases, prevention, treatment, etc. are as described above.

[0120] Still another aspect of the present invention provides a method for promoting the differentiation of monocytes into MDM or M1 macrophages, including the step of administering at least one of an anti-CD300c antibody and its antigen-binding fragment to a subject, or the step of treating isolated cells with at least one of an anti-CD300c antibody and its antigen-binding fragment.

[0121] The subject is a subject having or at risk of having a degenerative brain disease, but is not limited thereto.

[0122] Still another aspect of the present invention provides the use of an anti-CD300c antibody and / or its antigen-binding fragment for promoting the differentiation into MDM or M1 macrophages.

[0123] The method for promoting the differentiation into MDM or M1 macrophages and / or the use for promoting the differentiation may be in vitro or in vivo.

[0124] The anti-CD300c antibody, its antigen-binding fragment, the subject, etc. are as described above.

Examples

[0125] Hereinafter, the present invention will be described in more detail with reference to examples. However, these examples are only preferred embodiments for exemplifying the present invention, and the present invention is not limited thereto. Technical matters not described in this specification can be fully understood and easily implemented by those skilled in the art in the technical field of the present invention or similar technical fields.

Examples

[0126] Preparation of anti-CD300c antibodies (CB201, CL10 and SL18) Using the nucleotide sequence encoding a monoclonal antibody against CD300c antigen that has a high binding affinity and specifically binds thereto, an antibody expression vector with separated heavy and light chains was prepared.

[0127] For this purpose, using the CB201 CDR sequences shown in Table 3, Table 4, and the sequence listing (the amino acid sequence of CB201 and the polynucleotide sequence encoding the same), genes were inserted into the pCIW3.3 vector to express the heavy and light chains respectively. Known methods were used for the preparation of the vectors. The prepared CB201 heavy and light chain expression vectors were mixed with PEI (polyethylenimine) at a mass ratio of 1:1, transfected into 293T (human colorectal cancer cell line) cells to induce antibody expression. After 8 days, the culture solution was centrifuged to remove cells and the culture solution was obtained. The obtained culture solution was resuspended using a mixed solution of 0.1M NaH 2 PO 4 and 0.1M Na 2 HPO 4 (pH 7.0). The resuspended solution was purified by affinity chromatography using Protein A beads (GE healthcare) and finally eluted using a lysis buffer (Thermofisher).

[0128]

Table 3

[0129]

Table 4

[0130] The anti - CD300c monoclonal antibodies CL10 and SL18 were also prepared in the same manner as CB201 using Tables 5 - 8.

[0131]

Table 5

[0132]

Table 6

[0133]

Table 7

[0134]

Table 8

Examples

[0135] Confirmation of the binding ability of anti-CD300c monoclonal antibody to CD300c antigen (I): Binding ELISA The CD300c antigen (250 μg / mL) was diluted to a concentration of 800 ng / mL in coating buffer (0.1 M sodium carbonate, pH 9.0), and 100 μL of it was added to each well of a 96-well microplate and incubated overnight at 4°C. The next day, the microplate was washed 3 times with 200 μL of PBST. Then, 200 μL of blocking buffer (5% skim milk) was added to each well and blocked at room temperature for 1 hour.

[0136] The anti-CD300c monoclonal antibody CB201 was diluted in PBS at a concentration of 200 μg / mL, and its concentration was confirmed using a Nanodrop (product name: NanoDrop One / Onec). Subsequently, CB201 was serially diluted four-fold from 10 μg / mL with PBS and 100 μL of each dilution was added to each well. Then, it was reacted at room temperature for 1 hour and washed three times with 200 μL of PBST. The secondary antibody (conjugated anti-Fc IgG) was diluted in the blocking buffer at a concentration of 1:10,000, and 100 μL of this dilution was added to each well and reacted at room temperature for 1 hour. Subsequently, 200 μL of PBST was added and it was washed three times. Next, TMB and hydrogen peroxide were mixed at a ratio of 1:1 and 100 μL of the mixture was added to each well, and then it was reacted at room temperature for 7 to 9 minutes. Subsequently, 50 μL of 1N sulfuric acid was added to stop the color development, and then the numerical value at 450 nm was measured using a microplate reader (product name: Varioskan LUX) to obtain the results of the binding affinity.

[0137] Also, the anti-CD300c monoclonal antibodies CL10 and SL18 were also used to obtain the results of the binding affinity in the same manner as CB201.

[0138] As a result, as shown in Figure 1, it was confirmed that all of the anti-CD300c monoclonal antibodies CB201, CL10, and SL18 bind to CD300c in a concentration-dependent manner. This indicates that all of the anti-CD300c monoclonal antibodies CB201, CL10, and SL18 have excellent binding ability and specificity to the antigen CD300c.

[0139] From these results, it was confirmed that not only do the anti-CD300c monoclonal antibodies have excellent binding ability and specificity to CD300c, but also that all of the antibodies CB201, CL10, and SL18 are anti-CD300c monoclonal antibodies with similar properties. This is due to the similarity of the variable region sequences of the three antibodies, as shown in Figure 2.

Example

[0140] Confirmation of the binding ability of anti-CD300c monoclonal antibody to CD300c antigen (II): Surface Plasmon Resonance (SPR) To further confirm the binding affinity between CD300c antigen and anti-CD300c monoclonal antibody CB201, a surface plasmon resonance experiment was conducted.

[0141] To immobilize CD300c on the CM5 chip, 5 μg / ml of CD300c was diluted in 10 mM acetate buffer (pH 5.5). Then, with all flow rates the same at 10 ml / min, the target RU (Resonance Units) was set to 300 RU for each. The CM5 chip was activated with a mixture of 0.2 M EDC and 0.05 M NHS, blocked with 1 M ethanolamine, and the CM5 chip was immobilized so that the final RU of CD300c was 399.2 RU. Then, CB201 was diluted in PBST at concentrations of 0, 0.195, 0.39, 0.78, 1.56, 3.125, and 6.25 μg / ml respectively, and a kinetics / affinity test was conducted with a binding time of 240 seconds, a dissociation time of 900 seconds, and a flow rate of 30 μl / min. Then, 50 mM NaOH was flowed through the CM5 chip immobilized with CD300c at a rate of 30 μl / min for 30 seconds to regenerate the surface.

[0142] As a result, as shown in Figure 3, the analyzed KD value was 5.199E-10 M, and it was confirmed that the binding affinity of the anti-CD300c monoclonal antibody was 0.52 nM at a subnanomol level. This means that the binding ability of the anti-CD300c monoclonal antibody to the antigen is high.

Example

[0143] Confirmation of cell antigen recognition by anti-CD300c monoclonal antibody To confirm that the anti-CD300c monoclonal antibody CB201 recognizes cell antigens, FACS binding was performed.

[0144] Therefore, CD300c was overexpressed in 293T cells (ATCC), and then the cells were dispensed at 2×10 5 cells per microcentrifuge tube. Then, anti-CD300c monoclonal antibodies serially diluted three-fold from 10 μg / ml were reacted with the cells in a CO 2 incubator for 30 minutes, and the tubes were washed twice with FACS buffer. Then, FITC-conjugated anti-human IgG (H+L) diluted in FACS buffer at a ratio of 1:100 was reacted with the anti-CD300c monoclonal antibody bound to the cells in a CO 2 incubator for 30 minutes, and the tubes were washed twice with FACS buffer. Next, the FITC signal was measured using a CytoFLEX instrument from Beckman coulter, and then the MFI value was determined using the CytExpert program. Using the MFI values thus obtained, a sigmoidal curve was drawn using the sigmaplot program, and the EC50 (The effective concentration of drug that causes 50% of the maximum response) was calculated. As a result, an EC50 of 2.7 nM was obtained in 293T cells.

[0145] As shown in Figure 4, in the sigmoidal curve based on the FACS binding results, the anti-CD300c monoclonal antibody bound to CD300c overexpressed on the surface of 293T cells with strong binding affinity. Therefore, it was confirmed that the anti-CD300c monoclonal antibody binds antigen-specifically to CD300c also at the cell level.

Example

[0146] Confirmation of promotion of differentiation ability into MDM (Monocyte-derived macrophage) (I): Observation of cell morphology To confirm the differentiation of monocytes into MDM (monocyte-derived macrophages) in terms of cell morphology when monocytes were treated with an anti-CD300c monoclonal antibody, THP-1 cells (human monocyte cell line) treated with 10 μg / ml of the anti-CD300c monoclonal antibody CB201 were cultured for 48 hours, and then the cell morphology was observed under a microscope.

[0147] As a result, as shown in Figure 5, in the experimental group (CB201) treated with the anti-CD300c monoclonal antibody, it was confirmed that the morphology of THP-1 cells changed from suspension cells to round adherent cells in the form of MDM.

[0148] From these results, it was confirmed that the treatment with the anti-CD300c monoclonal antibody promoted the differentiation of monocyte cells into MDM.

Example

[0149] Confirmation of promotion of differentiation ability into MDM (II): Cell signal transduction To further confirm the improvement of the differentiation ability of monocytes into MDM when THP-1 cells were treated with CB201, an anti-CD300c monoclonal antibody, the signal transduction of MAPK (mitogen-activated protein kinase) and NF-κB, which are typical signals of MDM differentiation, was confirmed.

[0150] For this purpose, THP-1 was dispensed into a 6-well plate at 8.8×10 5 cells / well and treated with 10 μg / mL of the anti-CD300c monoclonal antibody. As a control group, the same amount of phosphate buffer solution (PBS) was injected. These were cultured for 48 hours, and then in the MAPK signal, phosphorylated SAPK / JNK, phosphorylated ERK (p44 / 42), and phosphorylated p38 were confirmed by Western blotting, and in the NF-κB signal, phosphorylated NF-κB was confirmed by Western blotting.

[0151] In addition, the results of confirming the signal transduction of MAPK and NF-Kb are shown in FIG. 6. Compared with the control group, it was confirmed that the amount of phosphorylated MAPK and NF-kB increased when treated with anti-CD300c.

[0152] From these results, it was confirmed that when treated with the anti-CD300c monoclonal antibody, the cell signal transduction leading to differentiation into MDM increased.

Example

[0153] Comparison of the differentiation ability of anti-CD300c monoclonal antibody into MDM: Measurement of the production amounts of three differentiation markers (TNF-α, IL-1β, and IL-8) To confirm the MDM differentiation ability of the anti-CD300c monoclonal antibody and other antibodies, THP-1 was dispensed into a 6-well plate at 8.8×10 5 cells / well and treated with 10 μg / mL of the anti-CD300c monoclonal antibody CB201. The production amounts of the MDM differentiation markers TNF-α, IL-1β, and IL-8 were confirmed using an ELISA kit. As other antibodies, treatment was performed with a human IgG Isotype control at a concentration of 10 μg / mL, and the production amounts of TNF-α, IL-1β, and IL-8 were confirmed using an ELISA kit.

[0154] Also, THP-1 cells were treated with the anti-CD300c monoclonal antibodies CL10 and SL18 in the same manner as CB201, and the production amount of TNF-α was confirmed using an ELISA kit. The results are shown in FIG. 7 (CB201) and FIG. 8 (CL10 and SL18).

[0155] As shown in Fig. 7, it was confirmed that compared with the control group treated with the Isotype control alone, the anti-CD300c monoclonal antibody CB201 significantly increased the production levels of TNF-α, IL-1β, and IL-8. Similarly, as shown in Fig. 8, it was confirmed that compared with the control group treated with the Isotype control alone, the anti-CD300c monoclonal antibodies CL10 and SL18 significantly increased the production level of TNF-α. This suggests that the anti-CD300c monoclonal antibodies CL10 and SL18 have characteristics similar to those of CB201.

[0156] From these results, it was confirmed that the anti-CD300c monoclonal antibody significantly improved the differentiation ability to differentiate monocytes into MDM.

Example

[0157] Confirmation of the promotion of the differentiation ability of anti-CD300c monoclonal antibody into MDM (III): Confirmation of extracellular protein expression markers To confirm the effect of differentiating monocytes into MDM when monocytes were treated with the anti-CD300c monoclonal antibody CB201, similar to Example 6, the expression changes of proteins, which are MDM differentiation markers, were confirmed by FACS in THP-1 cells treated with CB201. The expression changes were confirmed using antibodies that recognize CD11b, a monocyte marker, CD80, an MDM marker, and CD206, an M2 macrophage marker, respectively. As a result, as shown in Fig. 9, it was confirmed that CB80, an MDM marker, increased in the cells treated with CB201.

[0158] From these results, it was confirmed that when monocytes were treated with the anti-CD300c monoclonal antibody CB201, the expression of the MDM marker increased among extracellular proteins. Therefore, it was confirmed that CB201 differentiates monocytes into MDM.

Example

[0159] Preparation of a degenerative brain disease model mouse Eight male and eight female 4- to 8-week-old 5xFAD mice (source: Jackson lab) and three male and three female 6-week-old B6SJLF1 / J (source: Jackson lab) mice were purchased. After a domestication period of about 4 to 5 months, the general condition was observed to confirm the health status, and healthy animals were used in the experiment. 5xFAD mice are mice mutated to express the genes of human APP (Amyloid Precursor Protein) and PSEN1, which cause a total of five AD-related mutations (Swedish (K670N / M671L), Florida (I716V), London (V717I) mutation of APP, and M146L and L286V mutations of PSEN1). Therefore, they were selected as an appropriate model for pathological research related to neurodegenerative diseases including Alzheimer's symptoms and dementia (Non-Patent Document 3). The environmental conditions were set at a temperature of 23 ± 3°C, a relative humidity of 55 ± 15%, a ventilation rate of 10 to 20 times / hr, a lighting time of 12 hours (lighting from 8 am to 8 pm), and an illuminance of 150 to 300 Lux in the third animal breeding area of Knotts Co., Ltd. The experimental animals were classified into three groups: a normal mouse group (G1), a degenerative brain disease mouse group (hereinafter, 5xFAD control group; G2), and a CB201-administered degenerative brain disease mouse group (hereinafter, CB201-administered group; G3). The CB201-administered group was administered CB201 at a dose of 40 mg / kg, and the control groups (normal mouse group and 5xFAD control group) were each administered PBS in the same volume of the administration solution. The administration was performed by intraperitoneal injection twice, on the test substance administration start day (Day 0) and on the 25th day after the start of test substance administration (Day 25). The mouse groups used in the experiment are shown in Table 9 below.

[0160]

Table 9

Example

[0161] Confirmation of the effect of increasing MDM by anti-CD300c monoclonal antibody in vivo To confirm whether the anti-CD300c monoclonal antibody increases MDM in a mouse model, the brain tissues of mice administered with CB201 (CB201-administered group; G3) by the method of Example 9 were excised, and the ratio of MDM in the brain tissues was confirmed using an antibody against iNOS, which is an MDM marker, and an antibody against CD206, which is an M2 macrophage marker.

[0162] In addition, in the preparation of the CB201-administered group in Example 9, 40 mg / kg of a PD-1 antibody was administered to 5xFAD mice instead of 40 mg / kg of CB201, and experimental group mice administered with the anti-PD-1 antibody were also prepared.

[0163] As a result, as shown in Fig. 10, in the brain tissues of the experimental group administered with the anti-PD-1 antibody, which is known to have an effect of improving the symptoms of degenerative brain diseases as an immunotherapeutic agent, MDM increased partially (iNOS increased partially) compared with the control group (degenerative brain disease mice in Table 9; G2). However, in the brain tissues of the experimental group administered with the anti-CD300c monoclonal antibody CB201 (CB201-administered group in Table 9; G3), it was confirmed that MDM increased significantly (iNOS increased significantly) compared with the control group, and almost no M2 macrophages were observed.

[0164] From these results, it was confirmed that the anti-CD300c monoclonal antibody CB201 has a remarkable effect of differentiating monocytes into MDM compared with other immunotherapeutic agents.

Example

[0165] Confirmation of increased expression of MDM differentiation genes of anti-CD300c monoclonal antibody To confirm the effect of CB201, an anti-CD300c monoclonal antibody, on brain MDM under in vivo conditions, the brain tissues of the mice in the CB201 administration group (G3 in Table 9) prepared in Example 9 were excised, and the cells were stained with a staining solution for confirming cell viability (DAPI), an antibody against F4 / 80, which is a macrophage marker, and an antibody against CD11b, which is an MDM marker (obtained from Invitrogen). Then, the data were read out using a CytoFLEX flow cytometer, and the obtained data were analyzed using FlowJo software.

[0166] As a result of quantifying each marker for the surviving cells, as shown in FIG. 11, in the mouse brain tissues treated with the anti-CD300c monoclonal antibody alone compared with the control group, the expression level of F4 / 80, which is a macrophage marker, was comparable, whereas the expression level of the MDM differentiation marker CD11b increased (corresponding to M1 MDM in CD11b+ in FIG. 11).

[0167] As described below, it was confirmed that the anti-CD300c monoclonal antibody has a therapeutic effect on degenerative brain diseases. These results suggest that the administration of the anti-CD300c monoclonal antibody increases the differentiation of MDM in brain tissues and thus provides a therapeutic effect on degenerative brain diseases.

Example

[0168] Nanostring Immune Profiling To confirm the changes in immune cells and the brain tissue environment in a mouse model when an anti-CD300c monoclonal antibody (CB201) was administered to a mouse model of degenerative brain diseases, the brain tissues were excised from the mice in the CB201 administration group (G3 in Table 9) prepared in Example 9. RNA was extracted and purified therefrom, and then the changes in macrophage markers were confirmed by nanostring immune profiling, which is a known method. FIG. 12 shows the results of observing this in comparison with the control group.

[0169] As shown in Fig. 12, it was confirmed that administration of the anti-CD300c monoclonal antibody increased the expression of CD163, Siglec1, Lyve1, and C4b, which are MDM differentiation markers, and decreased the expression of IL-10, which exacerbates the progression of degenerative brain diseases in the brain. Therefore, it was confirmed that MDM in brain tissue differentiates and the immune system of the brain changes in a direction that treats degenerative brain diseases.

Example

[0170] Y-maze test Six-week-old 5xFAD mice were purchased and, after an acclimation period of about 5 months, a degenerative brain disease model showing symptoms related to a neurodegenerative disease including degenerative brain disease symptoms was created.

[0171] Thereafter, 40 mpk of the anti-CD300c monoclonal antibody (CB201) was administered intraperitoneally (I.P.) to the degenerative brain disease model, then administered again on the 28th day, and the Y-maze test was performed on the 31st day. The same amount of PBS was injected into the control group. This experimental period is shown in Fig. 13.

[0172] The experimental apparatus for the Y-maze test consisted of a Y-shaped maze made of a black acrylic plate (10 cm × 41 cm × 25 cm). Each maze was divided into regions A, B, and C, and the experimental animals were placed in an arbitrary region and allowed to move freely for 7 minutes. The number of times and the order in which each experimental animal entered each maze were measured, and spontaneous alternation behavior (spontaneous alteration, %) was evaluated. When the experimental animal entered three different regions sequentially, it was counted as 1 point (alteration, in the order of ABC, BCA, CAB, etc.), and no points were given if it did not enter sequentially. Spontaneous alternation behavior (% spontaneous alteration) was calculated by the following formula.

[0173]

Equation

[0174] As a result, as shown in Fig. 15, when the experiment was conducted, in the degenerative brain disease mouse model, spontaneous alternation behavior decreased compared to normal mice (G1; wild type). In contrast (G2; 5XFAD+Mock), when CB201 was administered to the degenerative brain disease mouse model (G3; 5XFAD+CB201), it was confirmed that the spontaneous alternation behavior recovered to 87% of the level of normal mice (G1; wild type). These results suggest that the anti-CD300c monoclonal antibody can be a drug that alleviates symptoms such as cognitive decline and decreased spontaneous alternation behavior caused by degenerative brain diseases.

Example

[0175] Morris water maze test Similar to Example 13, CB201 was administered to degenerative brain disease model mice, and then the Morris water maze test was conducted on days 35 to 40. The experimental apparatus consisted of a circular water tank (stainless steel, diameter 150 cm, height 45 cm), a escape platform (diameter 10 cm, height 30 cm), and four markers attached to the wall surface that could memorize the position of the escape platform. The water tank was filled with water at a temperature of about 22±2°C, and the escape platform was installed so as to be located 1 cm above the water surface or 0.5 to 1.5 cm below the water surface according to the experimental purpose. When installed below the water surface, the water was made opaque with white watercolor paint so that the escape platform could not be seen with the naked eye. The water maze was divided into quadrants of northeast (NE), northwest (NW), southeast (SE), and southwest (SW). The escape platform was placed at the center of the northeast quadrant, and the remaining one was used as the starting position. The experiment was conducted for a total of 6 days. The starting quadrant of the animal and the position setting of the escape platform are shown in Table 10 below.

[0176]

Table 10

[0177] On the first day, cued learning was conducted to give a clue so that the escape platform could be seen. Five attempts were made at 15-second intervals per individual. 60 seconds was set as the time limit. If the animal found the escape platform within 60 seconds, the animal was made to stay on the escape platform for 5 seconds and then immediately moved back to the breeding cage. If the escape platform could not be found within 60 seconds, the animal was placed on the escape platform for 20 seconds and then immediately moved back to the breeding cage.

[0178] From the second day to the fifth day, a hidden platform was carried out with the escape platform placed underwater and hidden for memory. Five attempts were made at 15-second intervals per individual. 60 seconds was set as the time limit. If the escape platform was found within 60 seconds, the animal was made to stay on the escape platform for 5 seconds and then immediately moved back to the breeding cage. If the escape platform could not be found within 60 seconds, the animal was placed on the escape platform for 20 seconds and then immediately moved back to the breeding cage.

[0179] On the sixth day, a Prospective randomized open blinded end-point (probe) Trial was conducted. The escape platform was not placed, and the animal was placed at the farthest point from the quadrant where the escape platform was placed during the experiments on the second to fifth days, and the experiment was conducted only once. 60 seconds was set as the time limit. The escape latency, which is the time required for the experimental animal to find the escape platform during cued learning and hidden platform, and the length of the path until the escape platform was found were measured and recorded. The swimming speed was calculated by dividing the length of the path by the escape latency. During the probe trial on the sixth day, the time the animal stayed in the quadrant where the escape platform had been was recorded.

[0180] The above-described Y-maze test was photographed with a moving image. It is shown in Fig. 14. As shown in Figs. 14 and 15, as a result of the experiment, compared with normal mice (G1; wild type), in the degenerative brain disease mouse model, TSPQ (Time spent in platform quadrants) decreased (G2; 5XFAD+Mock), whereas in the group (G3; 5XFAD+CB201) in which CB201 was administered to the degenerative brain disease animal model, it was confirmed that TSPQ recovered to 107% of that of normal mice (G1; wild type). These results indicate that administration of CB201 to the disease model mice restores the cognitive ability and memory of the degenerative brain disease model mice.

Example

[0181] Statistical analysis Assuming the normality of the data for the test results, it was tested by parametric one-way analysis of variance (One-way ANOVA). If the result was significant, a post hoc test was performed using Dunnett's multiple comparison test to analyze the significant differences from the test groups. The statistical analysis was performed using Prism 7.04 (GraphPad Software Inc., San Diego, CA, USA). If the p-value was less than 0.05, it was determined to be statistically significant.

[0182] From the above description, those skilled in the technical field to which the present invention pertains will understand that the present invention can be implemented in other specific forms without changing its technical idea and essential features. It should be understood that the above examples are merely illustrative and not restrictive. The present invention should be construed as including all modifications or variations derived from the meaning and scope of the claims and their equivalent concepts, rather than the specification.

Claims

1. A pharmaceutical composition for preventing or treating degenerative brain diseases, comprising at least one of an anti-CD300c antibody and an antigen-binding fragment thereof as an active ingredient.

2. The pharmaceutical composition according to claim 1, wherein the degenerative brain disease is a disease accompanied by cognitive impairment.

3. The pharmaceutical composition according to claim 2, wherein the cognitive impairment includes at least one selected from the group consisting of reduced cognitive ability, memory impairment, language impairment, reduced spatio-temporal ability, disorientation, and impaired executive ability.

4. The pharmaceutical composition according to claim 1, wherein the degenerative brain disease includes at least one selected from the group consisting of dementia, Alzheimer's disease, Huntington's disease, Parkinson's disease, cerebral amyloid angiopathy, amyloid stroke, Dutch-type amyloidosis, tauopathy, mild cognitive impairment, corticobasal degeneration, posterior cortical atrophy, primary progressive aphasia, progressive supranuclear palsy, corticobasal degeneration (CBD), amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, amnesia, learning disorder, and memory impairment.

5. The dementia in the pharmaceutical composition according to claim 4 includes at least one selected from the group consisting of Alzheimer's disease type dementia, Huntington's disease type dementia, Parkinson's disease type dementia, cerebrovascular dementia, neuroinflammatory dementia, cerebral infarction dementia, senile dementia, Lewy body dementia (Dimentia with Lewy bodies, DLB), multi-infarct dementia (Multi-Infarct Dementia, MID), frontotemporal lobar degeneration (Frontotemporal lobar degeneration, FTLD), Creutzfeldt-Jakob disease type dementia, Pick's disease type dementia, dementia due to corticobasal degeneration, dementia due to normal pressure hydrocephalus, and dementia due to head trauma.

6. The neurodegenerative disease in the pharmaceutical composition according to claim 1 includes Alzheimer's disease.

7. At least one of the anti-CD300c antibody and its antigen-binding fragment is (i) CDR1 consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 7, SEQ ID NO: 19, SEQ ID NO: 31, SEQ ID NO: 43, SEQ ID NO: 55, SEQ ID NO: 67, SEQ ID NO: 79, SEQ ID NO: 91, SEQ ID NO: 103, SEQ ID NO: 115, SEQ ID NO: 127, SEQ ID NO: 139, SEQ ID NO: 151, SEQ ID NO: 163, SEQ ID NO: 175, SEQ ID NO: 187, SEQ ID NO: 199, SEQ ID NO: 211, SEQ ID NO: 223, SEQ ID NO: 235, SEQ ID NO: 247, SEQ ID NO: 259, SEQ ID NO: 271, SEQ ID NO: 283, and SEQ ID NO: 295, CDR2 consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 8, SEQ ID NO: 20, SEQ ID NO: 32, SEQ ID NO: 44, SEQ ID NO: 56, SEQ ID NO: 68, SEQ ID NO: 80, SEQ ID NO: 92, SEQ ID NO: 104, SEQ ID NO: 116, SEQ ID NO: 128, SEQ ID NO: 140, SEQ ID NO: 152, SEQ ID NO: 164, SEQ ID NO: 176, SEQ ID NO: 188, SEQ ID NO: 200, SEQ ID NO: 212, SEQ ID NO: 224, SEQ ID NO: 236, SEQ ID NO: 248, SEQ ID NO: 260, SEQ ID NO: 272, SEQ ID NO: 284, and SEQ ID NO: 296, A heavy chain variable region comprising a CDR3 consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 9, SEQ ID NO: 21, SEQ ID NO: 33, SEQ ID NO: 45, SEQ ID NO: 57, SEQ ID NO: 69, SEQ ID NO: 81, SEQ ID NO: 93, SEQ ID NO: 105, SEQ ID NO: 117, SEQ ID NO: 129, SEQ ID NO: 141, SEQ ID NO: 153, SEQ ID NO: 165, SEQ ID NO: 177, SEQ ID NO: 189, SEQ ID NO: 201, SEQ ID NO: 213, SEQ ID NO: 225, SEQ ID NO: 237, SEQ ID NO: 249, SEQ ID NO: 261, SEQ ID NO: 273, SEQ ID NO: 285, and SEQ ID NO: 297, and (ii) a CDR1 consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 10, SEQ ID NO: 22, SEQ ID NO: 34, SEQ ID NO: 46, SEQ ID NO: 58, SEQ ID NO: 70, SEQ ID NO: 82, SEQ ID NO: 94, SEQ ID NO: 106, SEQ ID NO: 118, SEQ ID NO: 130, SEQ ID NO: 142, SEQ ID NO: 154, SEQ ID NO: 166, SEQ ID NO: 178, SEQ ID NO: 190, SEQ ID NO: 202, SEQ ID NO: 214, SEQ ID NO: 226, SEQ ID NO: 238, SEQ ID NO: 250, SEQ ID NO: 262, SEQ ID NO: 274, SEQ ID NO: 286, and SEQ ID NO: 298, a CDR2 consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 11, SEQ ID NO: 23, SEQ ID NO: 35, SEQ ID NO: 47, SEQ ID NO: 59, SEQ ID NO: 71, SEQ ID NO: 83, SEQ ID NO: 95, SEQ ID NO: 107, SEQ ID NO: 119, SEQ ID NO: 131, SEQ ID NO: 143, SEQ ID NO: 155, SEQ ID NO: 167, SEQ ID NO: 179, SEQ ID NO: 191, SEQ ID NO: 203, SEQ ID NO: 215, SEQ ID NO: 227, SEQ ID NO: 239, SEQ ID NO: 251, SEQ ID NO: 263, SEQ ID NO: 275, SEQ ID NO: 287, and SEQ ID NO: 299, A pharmaceutical composition according to claim 1, comprising a light chain variable region comprising a CDR3 consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 12, SEQ ID NO: 24, SEQ ID NO: 36, SEQ ID NO: 48, SEQ ID NO: 60, SEQ ID NO: 72, SEQ ID NO: 84, SEQ ID NO: 96, SEQ ID NO: 108, SEQ ID NO: 120, SEQ ID NO: 132, SEQ ID NO: 144, SEQ ID NO: 156, SEQ ID NO: 168, SEQ ID NO: 180, SEQ ID NO: 192, SEQ ID NO: 204, SEQ ID NO: 216, SEQ ID NO: 228, SEQ ID NO: 240, SEQ ID NO: 252, SEQ ID NO: 264, SEQ ID NO: 276, SEQ ID NO: 288, and SEQ ID NO:

300.

8. At least one of the anti-CD300c antibody and its antigen-binding fragment is (i)A CDR1 consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 79, SEQ ID NO: 115, and SEQ ID NO: 211, a CDR2 consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 80, SEQ ID NO: 116, and SEQ ID NO: 212, a CDR3 consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 81, SEQ ID NO: 117, and SEQ ID NO: 213, and a heavy chain variable region, and (ii)A CDR1 consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 82, SEQ ID NO: 118, and SEQ ID NO: 214, a CDR2 consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 83, SEQ ID NO: 119, and SEQ ID NO: 215, a CDR3 consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 84, SEQ ID NO: 120, and SEQ ID NO: 216, and a light chain variable region, the pharmaceutical composition according to claim 1.

9. At least one of the anti-CD300c antibody and its antigen-binding fragment is (i)One comprising a heavy chain variable region containing a CDR1 consisting of SEQ ID NO: 79, a CDR2 consisting of SEQ ID NO: 80, and a CDR3 consisting of SEQ ID NO: 81, and a light chain variable region containing a CDR1 consisting of SEQ ID NO: 82, a CDR2 consisting of SEQ ID NO: 83, and a CDR3 consisting of SEQ ID NO: 84, (ii)One comprising a heavy chain variable region containing a CDR1 consisting of SEQ ID NO: 115, a CDR2 consisting of SEQ ID NO: 116, and a CDR3 consisting of SEQ ID NO: 117, and a light chain variable region containing a CDR1 consisting of SEQ ID NO: 118, a CDR2 consisting of SEQ ID NO: 119, and a CDR3 consisting of SEQ ID NO: 120, and (iii)Selected from those comprising a heavy chain variable region containing a CDR1 consisting of SEQ ID NO: 211, a CDR2 consisting of SEQ ID NO: 212, and a CDR3 consisting of SEQ ID NO: 213, and a light chain variable region containing a CDR1 consisting of SEQ ID NO: 214, a CDR2 consisting of SEQ ID NO: 215, and a CDR3 consisting of SEQ ID NO: 216, the pharmaceutical composition according to claim 1.

10. At least one of the antibody and its antigen-binding fragment is A heavy chain variable region comprising a CDR1 consisting of the amino acid sequence represented by SEQ ID NO: 79, a CDR2 consisting of the amino acid sequence represented by SEQ ID NO: 80, and a CDR3 consisting of the amino acid sequence represented by SEQ ID NO: 81, and a CDR1 consisting of the amino acid sequence represented by SEQ ID NO: 82, a CDR2 consisting of the amino acid sequence represented by SEQ ID NO: 83, and a CDR3 consisting of the amino acid sequence represented by SEQ ID NO: 84, and a light chain variable region comprising the same, the pharmaceutical composition according to claim 1.

11. At least one of the antibody and its antigen-binding fragment is A heavy chain variable region comprising CDR1 to CDR3 each consisting of the amino acid sequence represented by the following formula (1) to (3), A light chain variable region comprising CDR1 to CDR3 each consisting of the amino acid sequence represented by the following formula (4) to (6), and the pharmaceutical composition according to claim 1. 【Chemical 1】 In the above formula, X1 = G or S, X2 = S, R or D, X3 = N or Y, X4 = Y, A, G or H, X5 = S or H. [Chemical 2] In the above formula, X1 = T or A, X2 = G or S, X3 = T or G, X4 = S or Y, X5 = D or E. 【Chemical Formula 3】 In the above formula, X1 = R or S, X2 = G or S, X3 = M, S, Y or I, X4 = W, Q, G or R, X5 = G or L, X6 = M, I or P, X7 = D, F or L, X8 = V or D, X9 = I or Y, or X9 does not exist. 【Chemical Formula 4】 In the above formula, X1 = T or S, X2 = G or R, X3 = K, N or S, X4 = H, N or S, X5 = R, I or G, X6 = H, G or I, X7 = T, I or S, X8 = R, A or K, or X8 does not exist, X9 = R, S or G, or X9 does not exist, X10 = N, or X10 does not exist, X11 = Y, or X11 does not exist, X12 = N, H or Q. 【Chemical Formula 5】 In the above formula, X1 = L, S, R or E, X2 = D, K or N, X3 = S or N, X4 = E, N, Q or K, X5 = P or R. [Chemical Formula 6] In the above formula, X1 = Q, A or S, X2 = S or A, X3 = Y or W, X4 = D or A, X5 = S, D or G, X6 = S, N or T, X7 = S, L, N or K, X8 = V, S, N or G, X9 is G, L, or V, or X9 is absent, X10 is P, or X10 is absent.

12. The pharmaceutical composition according to claim 1, wherein at least one of the antibody and its antigen-binding fragment restores or improves the cognitive function of a subject having or at risk of having a degenerative brain disease.

13. A method for preventing or treating a degenerative brain disease, comprising administering to a subject having or at risk of having a degenerative brain disease at least one of an anti-CD300c antibody and its antigen-binding fragment.

14. A food composition for preventing or improving a degenerative brain disease, comprising at least one of an anti-CD300c antibody and its antigen-binding fragment as an active ingredient.

15. A feed composition for preventing or improving a degenerative brain disease, comprising at least one of an anti-CD300c antibody and its antigen-binding fragment as an active ingredient.

16. Use of an anti-CD300c antibody or its antigen-binding fragment for preventing or treating a degenerative brain disease.

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