Anti-human NR1 antibody derivatives

Abstract

The present invention relates to anti-human NR1 antibody derivatives. Specifically, the present invention provides a single-arm anti-human NR1 antibody, a polynucleotide encoding the antibody, an expression vector containing the polynucleotide, a host cell transformed from the expression vector, a method for producing the antibody, a pharmaceutical composition containing the antibody, and use of the antibody in manufacturing the pharmaceutical composition, and methods of treating anti-NMDAR encephalitis using the antibodies.

Description

[0001] This application is a divisional application of the Chinese patent application with an application date of May 26, 2021, application number 202180058596.9, and invention name “Anti-human NR1 antibody derivatives” (the corresponding PCT application with an application date of May 26, 2021 and application number PCT / JP2021 / 019929). Technical Field

[0002] The present invention relates to anti-human NR1 antibody derivatives for use as active ingredients in pharmaceutical compositions. Background Art

[0003] The relationship between the autoantibodies for nerve cells and diseases has recently become clear. The autoantibodies for nerve cells are called anti-neuronal antibodies, and they are considered to be the cause of disease of nervous system diseases (such as autoimmune encephalitis). In recent years, novel anti-neuronal antibodies for cell surface and synaptic antigens have been identified in succession. Many of them are antibodies (Journal of Clinical and Experimental Medicine (IGAKU NO AYUMI), 2015, volume 25, phase 5, pages 497-503 / Neuro-oncol.2014., volume 16, pages 771-778) for receptors expressed on nerve cells or their associated molecules.

[0004] In 2007, Dalmau et al. found that in encephalitis with a unique clinical course complicated by ovarian teratoma, the autoantibodies against cell surface antigens present in the patient's blood and cerebrospinal fluid were antibodies against the NR1 (also known as GluN1) subunit of the NMDA (N-methyl-D-aspartate) receptor (hereinafter referred to as "NMDAR"), and named this encephalitis "anti-NMDAR encephalitis". Among autoimmune encephalitis, anti-NMDAR encephalitis is one of the most common autoimmune encephalitis, and its clinical manifestations are well defined. In patients with anti-NMDAR encephalitis, psychiatric symptoms usually appear first, followed by various neurological symptoms, including memory impairment, speech disorders, disorientation, seizures, autonomic symptoms, central hypoventilation, and involuntary movements. The pathogenesis of anti-NMDAR encephalitis progresses rapidly, and in some cases, the course of the disease is severe, requiring intensive treatment within weeks of the initial symptoms, with treatment lasting for several months to more than a year. The anti-NR1 antibody titer in the patient's cerebrospinal fluid reflects the course of the disease. Anti-NMDAR encephalitis rarely occurs in children, the elderly, and men, but is more common in young women. It has been reported that many women with the disease also have ovarian teratomas (Lancet Neurol., 2013, Vol. 12, pp. 157-165).

[0005] In pathology, it is reported that IgG deposition and NMDAR expression are observed to reduce (Acta Neuropathol., 2009, volume 118, 737-743 pages, non-patent literature 1) in the patient's brain suffering from anti-NMDAR encephalitis. On the other hand, owing to not observing the deposition of cytotoxic T cells or complement in the patient's brain (Acta Neuropathol., 2009, volume 118, 737-743 pages), it is assumed that NR1 antibody affects pathological formation separately. In vitro experiments have reported that the NR1 antibody of patient origin is cross-linked with NMDAR and internalizes NMDAR to reduce the NMDAR (non-patent literature 1) in postsynaptic membrane. In addition, due to the symptoms of anti-NMDAR encephalitis and the symptoms observed when NMDAR antagonists (ketamine and phencyclidine) are applied to healthy subjects, it is believed that the reduction of NMDAR clusters in the internalization of NMDAR and the subsequent postsynaptic membrane in the patient's body causes the function of NMDAR to decline, thereby causing anti-NMDAR encephalitis symptoms.

[0006] In tumor-related cases of anti-NMDAR encephalitis, early tumor resection and immunotherapy are recommended. As immunotherapy, steroid pulse therapy, plasma exchange and immunoglobulin therapy are used. In refractory cases, cyclophosphamide pulse therapy or rituximab (which is an anti-CD20 antibody) is administered. However, due to the severity of the disease and the extension of the course of the disease, not all patients have a good prognosis. It is reported that complete or near complete recovery accounts for only 75%, while 25% are still severely disabled or die (Lancet Neurol., 2008, Vol. 7, pp. 1091-1098).

[0007] Current treatments for anti-NMDAR encephalitis do not specifically control or eliminate the autoantibodies that cause the pathological state.

[0008] NMDAR is a glutamate receptor that is primarily expressed in the central nervous system and is involved in memory and learning. NMDAR is an ion channel-coupled receptor that allows the permeation of cations (such as sodium, potassium, and calcium ions) by binding to glutamate as a ligand. NMDAR has four subunits, consisting of two groups of heterodimers, NR1 and NR2. There are four types of NR2: NR2A, NR2B, NR2C, and NR2D. The NR2 subunit has a binding site for glutamate.

[0009] As anti-NR1 monoclonal antibody, M68 (non-patent literature 2), MAB363 (non-patent literature 3), R1JHL (non-patent literature 4) and D65B8 (non-patent literature 5) have been reported. In addition, it has been reported that the N-terminal site with people NR1 is combined and suppresses the monoclonal antibody (patent literature 1) interacting with t-PA. In addition, several anti-NR1 monoclonal antibodies (non-patent literature 6, patent literature 2) derived from anti-NMDAR encephalitis patients have been identified. The anti-NR1 antibody in a kind of anti-NMDAR encephalitis patient source of separation has reduced NMDAR aggregation in vitro and suppressed the NMDAR function (non-patent literature 6) in the primary neuron derived from mouse hippocampus.

[0010] On the other hand, there are no reports that anti-human NR1 antibodies or derivatives thereof show therapeutic effects in patients with anti-NMDAR encephalitis.

[0011] Prior art literature

[0012] [Patent Document]

[0013] Patent Document 1: WO2014 / 187879

[0014] Patent Document 2: WO2017 / 029299

[0015] [Non-patent literature]

[0016] Non-patent literature 1: [Journal of Neuroscience, (J. Neurosci.)], (USA), 2010; 30(17): 5866-5875

[0017] Non-patent document 2: [Science (Science)], (USA), 2016; 352(6288): 982-986 Non-patent document 3: [Journal of neurodegenerative diseases (J. Neurodegener. Dis.)], (UK), 2014; Article ID: 938530

[0018] Non-patent literature 4: [JCI Insight (JCI Insight)], (USA), 2019; 4(15): e127736 Non-patent literature 5: [Experimental Neurology (Exp. Neurol.)], (USA), 2017; 289: 31-45

[0019] Non-patent literature 6: [Brain (Brain)], (UK), 2016; 139(10): 2641-2652 Summary of the Invention

[0020] Problems to be solved by the present invention

[0021] The present invention addresses the problem of providing novel therapeutic agents for treating patients suffering from anti-NMDAR encephalitis.

[0022] Means used to solve problems

[0023] The present inventor has carried out a large amount of research in terms of the novel therapeutic agent for treating the patient suffering from anti-NMDAR encephalitis in production.First, the present inventor has produced one-armed anti-human NR1 antibodies from the sequence information of the anti-human NR1 antibody clones with high binding activity to NMDAR derived from anti-NMDAR encephalitis patients, and found that when combined with human NMDAR in vitro, the one-armed anti-human NR1 antibodies have restored the cell surface expression level and function (embodiment 1-4) of the people NMDAR caused by the pathogenic NR1 antibodies of patient origin. In addition, based on these findings, the present inventor has also produced multiple one-armed anti-human NR1 antibodies, which show a binding affinity higher than pathogenic NR1 antibodies, which significantly restores the cell surface expression level and function (embodiment 5-10) of the NMDAR caused by pathogenic anti-human NR1 antibodies. In addition, the present inventor has found that, compared with control antibodies, the newly obtained one-armed anti-human NR1 antibodies have significantly improved the symptom (embodiment 12) of anti-NMDAR encephalitis animal model. Therefore, the present inventor has completed the present invention.

[0024] According to the present invention, the following inventions are provided as medically and industrially useful substances or methods, for example: [1]

[0026] A one-armed anti-human NR1 antibody selected from any one of the following (1) to (5):

[0027] (1) A one-armed anti-human NR1 antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 26 to 34 of SEQ ID NO: 2, a CDR2 consisting of an amino acid sequence of amino acids 52 to 58 of SEQ ID NO: 2, and a CDR3 consisting of an amino acid sequence of amino acids 97 to 109 of SEQ ID NO: 2, and the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 26 to 33 of SEQ ID NO: 4, a CDR2 consisting of an amino acid sequence of amino acids 51 to 53 of SEQ ID NO: 4, and a CDR3 consisting of an amino acid sequence of amino acids 92 to 100 of SEQ ID NO: 4;

[0028] (2) a one-armed anti-human NR1 antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 31 to 35 of SEQ ID NO: 6, a CDR2 consisting of an amino acid sequence of amino acids 50 to 66 of SEQ ID NO: 6, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 110 of SEQ ID NO: 6, and the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 8, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 8, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 98 of SEQ ID NO: 8;

[0029] (3) a one-armed anti-human NR1 antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 31 to 35 of SEQ ID NO: 10, a CDR2 consisting of an amino acid sequence of amino acids 50 to 66 of SEQ ID NO: 10, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 111 of SEQ ID NO: 10, and the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 12, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 12, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 97 of SEQ ID NO: 12;

[0030] (4) a one-armed anti-human NR1 antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 31 to 36 of SEQ ID NO: 14, a CDR2 consisting of an amino acid sequence of amino acids 51 to 66 of SEQ ID NO: 14, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 108 of SEQ ID NO: 14, and the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 16, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 16, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 97 of SEQ ID NO: 16;

[0031] (5) A one-armed anti-human NR1 antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acid numbers 31 to 36 of SEQ ID NO: 18, a CDR2 consisting of an amino acid sequence of amino acid numbers 51 to 66 of SEQ ID NO: 18, and a CDR3 consisting of an amino acid sequence of amino acid numbers 99 to 108 of SEQ ID NO: 18, and the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acid numbers 24 to 34 of SEQ ID NO: 20, a CDR2 consisting of an amino acid sequence of amino acid numbers 50 to 56 of SEQ ID NO: 20, and a CDR3 consisting of an amino acid sequence of amino acid numbers 89 to 97 of SEQ ID NO: 20. [2]

[0033] A one-armed anti-human NR1 antibody as described in [1] selected from any one of the following (1) to (5):

[0034] (1) A one-armed anti-human NR1 antibody comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 2, and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 4;

[0035] (2) a one-armed anti-human NR1 antibody comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 6, and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 8;

[0036] (3) a one-armed anti-human NR1 antibody comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 10, and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 12;

[0037] (4) a one-armed anti-human NR1 antibody comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 14, and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 16;

[0038] (5) A one-armed anti-human NR1 antibody comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 18, and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 20. [3]

[0040] A one-armed anti-human NR1 antibody as described in [1] selected from any one of the following (1) to (5):

[0041] (1) A one-armed anti-human NR1 antibody comprising a heavy chain, a light chain, and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region comprising a CDR1 consisting of an amino acid sequence of amino acids 26 to 34 of SEQ ID NO: 2, a CDR2 consisting of an amino acid sequence of amino acids 52 to 58 of SEQ ID NO: 2, and a CDR3 consisting of an amino acid sequence of amino acids 97 to 109 of SEQ ID NO: 2, and the light chain comprises a light chain variable region comprising a CDR1 consisting of an amino acid sequence of amino acids 26 to 33 of SEQ ID NO: 4, a CDR2 consisting of an amino acid sequence of amino acids 51 to 53 of SEQ ID NO: 4, and a CDR3 consisting of an amino acid sequence of amino acids 92 to 100 of SEQ ID NO: 4;

[0042] (2) A one-armed anti-human NR1 antibody comprising a heavy chain, a light chain, and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 31 to 35 of SEQ ID NO: 6, a CDR2 consisting of an amino acid sequence of amino acids 50 to 66 of SEQ ID NO: 6, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 110 of SEQ ID NO: 6, and the light chain comprises a light chain variable region, wherein the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 8, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 8, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 98 of SEQ ID NO: 8;

[0043] (3) a one-armed anti-human NR1 antibody comprising a heavy chain, a light chain, and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 31 to 35 of SEQ ID NO: 10, a CDR2 consisting of an amino acid sequence of amino acids 50 to 66 of SEQ ID NO: 10, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 111 of SEQ ID NO: 10, and the light chain comprises a light chain variable region, wherein the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 12, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 12, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 97 of SEQ ID NO: 12;

[0044] (4) A one-armed anti-human NR1 antibody comprising a heavy chain, a light chain, and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region comprising a CDR1 consisting of an amino acid sequence of amino acids 31 to 36 of SEQ ID NO: 14, a CDR2 consisting of an amino acid sequence of amino acids 51 to 66 of SEQ ID NO: 14, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 108 of SEQ ID NO: 14, and the light chain comprises a light chain variable region comprising a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 16, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 16, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 97 of SEQ ID NO: 16;

[0045] (5) A one-armed anti-human NR1 antibody comprising a heavy chain, a light chain and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 31 to 36 of SEQ ID NO: 18, a CDR2 consisting of an amino acid sequence of amino acids 51 to 66 of SEQ ID NO: 18, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 108 of SEQ ID NO: 18, and the light chain comprises a light chain variable region, wherein the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 20, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 20, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 97 of SEQ ID NO: 20. [4]

[0047] A one-armed anti-human NR1 antibody as described in [3] selected from any one of the following (1) to (5):

[0048] (1) A one-armed anti-human NR1 antibody comprising a heavy chain, a light chain, and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 2, and the light chain comprises a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 4;

[0049] (2) A one-armed anti-human NR1 antibody comprising a heavy chain, a light chain, and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 6, and the light chain comprises a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 8;

[0050] (3) A one-armed anti-human NR1 antibody comprising a heavy chain, a light chain, and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 10, and the light chain comprises a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 12;

[0051] (4) A one-armed anti-human NR1 antibody comprising a heavy chain, a light chain, and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 14, and the light chain comprises a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 16;

[0052] (5) A one-armed anti-human NR1 antibody comprising a heavy chain, a light chain, and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region, and the heavy chain variable region consists of the amino acid sequence shown in SEQ ID NO: 18; and the light chain comprises a light chain variable region, and the light chain variable region consists of the amino acid sequence shown in SEQ ID NO: 20. [5]

[0054] The one-armed anti-human NR1 antibody of any one of [1] to [4], comprising an Fc region comprising LALA mutations (L234A and L235A). [6]

[0056] The one-armed anti-human NR1 antibody according to any one of [1] to [4], comprising an Fc region comprising a knob-to-hole mutation. [7]

[0058] The one-armed anti-human NR1 antibody according to any one of [1] to [4], comprising an Fc region comprising a LALA mutation (L234A and L235A) and a knob-to-hole mutation. [8]

[0060] The one-armed anti-human NR1 antibody as described in [6] or [7], wherein the knob-to-hole mutation is a T366W mutation in one Fc polypeptide forming the Fc region, and T366S, L368A and Y407V mutations in another Fc polypeptide forming the Fc region. [9]

[0062] The one-armed anti-human NR1 antibody according to any one of [1] to [8], wherein the one-armed anti-human NR1 antibody is a human antibody or a humanized antibody.

[10]

[0064] A one-armed anti-human NR1 antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 22, a light chain consisting of the amino acid sequence shown in SEQ ID NO: 24, and an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42.

[11]

[0066] A one-armed anti-human NR1 antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 26, a light chain consisting of the amino acid sequence shown in SEQ ID NO: 28, and an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42.

[12]

[0068] A one-armed anti-human NR1 antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 30, a light chain consisting of the amino acid sequence shown in SEQ ID NO: 32, and an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42.

[13]

[0070] A one-armed anti-human NR1 antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34, a light chain consisting of the amino acid sequence shown in SEQ ID NO: 36, and an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42.

[14]

[0072] A one-armed anti-human NR1 antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 38, a light chain consisting of the amino acid sequence shown in SEQ ID NO: 40, and an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42.

[15]

[0074] A one-armed anti-human NR1 antibody, wherein the one-armed anti-human NR1 antibody competitively binds to human NR1 with an anti-human NR1 antibody comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 2 and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 4, and inhibits NMDAR cellular internalization caused by pathogenic anti-human NR1 antibodies derived from patients with anti-NMDAR encephalitis.

[16]

[0076] The one-armed anti-human NR1 antibody according to any one of [1] to

[15] , wherein the one-armed anti-human NR1 antibody is post-translationally modified.

[17]

[0078] The one-armed anti-human NR1 antibody as described in

[16] , wherein the post-translational modification is pyroglutamylation of the N-terminal heavy chain variable region and / or deletion of the C-terminal heavy chain lysine.

[18]

[0080] A polynucleotide comprising the nucleotide sequence listed in (a) and / or (b) below:

[0081] (a) a nucleotide sequence encoding the heavy chain variable region of the one-armed anti-human NR1 antibody according to any one of (2) to (5) of [1] and (2) to (5) of [2];

[0082] (b) A nucleotide sequence encoding the light chain variable region of the one-armed anti-human NR1 antibody according to any one of (2) to (5) of [1] and (2) to (5) of [2].

[19]

[0084] A polynucleotide comprising the nucleotide sequence listed in (a) and / or (b) below:

[0085] (a) a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody according to any one of (2) to (5) of [3] and (2) to (5) of [4];

[0086] (b) A nucleotide sequence encoding the light chain of the one-armed anti-human NR1 antibody according to any one of (2) to (5) of [3] and (2) to (5) of [4].

[20]

[0088] A polynucleotide comprising the nucleotide sequence listed in (a) and / or (b) below:

[0089] (a) a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 26;

[0090] (b) A nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 28. [twenty one]

[0092] A polynucleotide comprising the nucleotide sequence listed in (a) and / or (b) below:

[0093] (a) a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 30;

[0094] (b) A nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 32. [twenty two]

[0096] A polynucleotide comprising the nucleotide sequence listed in (a) and / or (b) below:

[0097] (a) a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34;

[0098] (b) A nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 36. [twenty three]

[0100] A polynucleotide comprising the nucleotide sequence listed in (a) and / or (b) below:

[0101] (a) a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 38;

[0102] (b) A nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 40. [twenty four]

[0104] A polynucleotide comprising the nucleotide sequence listed in (a) and / or (b) below:

[0105] (a) a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as described in

[15] ;

[0106] (b) The nucleotide sequence encoding the light chain of the one-armed anti-human NR1 antibody as described in

[15] .

[25]

[0108] An expression vector comprising a polynucleotide comprising the nucleotide sequence listed in (a) and / or (b) below:

[0109] (a) a polynucleotide comprising a nucleotide sequence encoding the heavy chain variable region of a one-armed anti-human NR1 antibody as set forth in any one of (2) to (5) of [1] and (2) to (5) of [2];

[0110] (b) A polynucleotide comprising a nucleotide sequence encoding the light chain variable region of the one-armed anti-human NR1 antibody as set forth in any one of (2) to (5) of [1] and (2) to (5) of [2].

[26]

[0112] An expression vector comprising a polynucleotide comprising the nucleotide sequence listed in (a) and / or (b) below:

[0113] (a) a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as set forth in any one of (2) to (5) of [3] and (2) to (5) of [4];

[0114] (b) A polynucleotide comprising a nucleotide sequence encoding the light chain of the one-armed anti-human NR1 antibody as set forth in any one of (2) to (5) of [3] and (2) to (5) of [4].

[27]

[0116] The expression vector as described in

[25] or

[26] further comprises a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide.

[28]

[0118] An expression vector comprising the polynucleotide listed in (a) and / or (b) below, and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42:

[0119] (a) a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 22;

[0120] (b) A polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 24.

[29]

[0122] An expression vector comprising the polynucleotide listed in (a) and / or (b) below:

[0123] (a) a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 26;

[0124] (b) A polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 28.

[30]

[0126] An expression vector comprising the polynucleotide listed in (a) and / or (b) below:

[0127] (a) a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 30;

[0128] (b) A polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 32.

[31]

[0130] An expression vector comprising the polynucleotide listed in (a) and / or (b) below:

[0131] (a) a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34;

[0132] (b) A polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 36.

[32]

[0134] An expression vector comprising the polynucleotide listed in (a) and / or (b) below:

[0135] (a) a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 38;

[0136] (b) A polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 40.

[33]

[0138] The expression vector as described in any one of

[29] to

[32] , further comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42.

[34]

[0140] An expression vector comprising a polynucleotide comprising a nucleotide sequence listed in (a) to (f) below:

[0141] (a) a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as described in

[15] ;

[0142] (b) a polynucleotide comprising a nucleotide sequence encoding the light chain of the one-armed anti-human NR1 antibody as described in

[15] ;

[0143] (c) a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as described in

[15] , and a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody;

[0144] (d) a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as described in

[15] , and a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody;

[0145] (e) a polynucleotide comprising a nucleotide sequence encoding the light chain of the one-armed anti-human NR1 antibody as described in

[15] , and a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody; (f) a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as described in

[15] , a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody, and a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody.

[35]

[0147] A host cell transformed with one or more expression vectors selected from the following (a) to (d):

[0148] (a) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain variable region of the one-armed anti-human NR1 antibody as set forth in any one of (2) to (5) of [1] and (2) to (5) of [2];

[0149] (b) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain variable region of the one-armed anti-human NR1 antibody as set forth in any one of (2) to (5) of [1] and (2) to (5) of [2];

[0150] (c) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain variable region of the one-armed anti-human NR1 antibody as set forth in any one of (2) to (5) of [1] and (2) to (5) of [2], and a polynucleotide comprising a nucleotide sequence encoding the light chain variable region of the antibody;

[0151] (d) An expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain variable region of the one-armed anti-human NR1 antibody as set forth in any one of (2) to (5) of [1] and (2) to (5) of [2], and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain variable region of the antibody.

[36]

[0153] A host cell transformed with one or more expression vectors selected from the following (a) to (d):

[0154] (a) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as set forth in any one of (2) to (5) of [3] and (2) to (5) of [4];

[0155] (b) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the one-armed anti-human NR1 antibody as set forth in any one of (2) to (5) of [3] and (2) to (5) of [4];

[0156] (c) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as set forth in any one of (2) to (5) of [3] and (2) to (5) of [4], and a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody;

[0157] (d) An expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as set forth in any one of (2) to (5) of [3] and (2) to (5) of [4], and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody.

[37]

[0159] A host cell transformed with one or more expression vectors selected from the following (a) to (i): (a) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as set forth in any one of (1) to (5) of [3] and (1) to (5) of [4], and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide of the antibody;

[0160] (b) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the one-armed anti-human NR1 antibody as set forth in any one of (1) to (5) of [3] and (1) to (5) of [4], and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody;

[0161] (c) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as set forth in any one of (1) to (5) of [3] and (1) to (5) of [4] and a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody;

[0162] (d) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as set forth in any one of (1) to (5) of [3] and (1) to (5) of [4], an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody;

[0163] (e) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as set forth in any one of (1) to (5) of [3] and (1) to (5) of [4] and a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody;

[0164] (f) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the one-armed anti-human NR1 antibody as set forth in any one of (1) to (5) of [3] and (1) to (5) of [4], and a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody;

[0165] (g) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as set forth in any one of (1) to (5) of [3] and (1) to (5) of [4], an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody; (h) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as set forth in any one of (1) to (5) of [3] and (1) to (5) of [4], an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody;

[0166] (i) An expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as set forth in any one of (1) to (5) of [3] and (1) to (5) of [4], a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody, and a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody.

[38]

[0168] A host cell transformed with one or more expression vectors selected from the following (a) to (i): (a) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 22, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0169] (b) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 22 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0170] (c) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 24, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0171] (d) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 24 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0172] (e) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 22 and a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 24, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0173] (f) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 22 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 24;

[0174] (g) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 22, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 24, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0175] (h) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 22, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 24, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0176] (i) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 22, a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 24, and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42.

[39]

[0178] A host cell transformed with one or more expression vectors selected from the following (a) to (m):

[0179] (a) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 26;

[0180] (b) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 28;

[0181] (c) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 26 and a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 28;

[0182] (d) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 26, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 28;

[0183] (e) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 26 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0184] (f) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 28 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0185] (g) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 26, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0186] (h) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 28, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0187] (i) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 26 and a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 28, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0188] (j) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 26 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 28;

[0189] (k) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 26, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 28, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0190] (1) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 26, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 28, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0191] (m) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 26, a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 28, and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42.

[40]

[0193] A host cell transformed with one or more expression vectors selected from the following (a) to (m):

[0194] (a) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 30;

[0195] (b) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 32;

[0196] (c) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 30 and a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 32;

[0197] (d) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 30, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 32;

[0198] (e) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 30 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0199] (f) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 32 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0200] (g) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 30, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0201] (h) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 32, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0202] (i) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 30 and a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 32, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0203] (j) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 30 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 32;

[0204] (k) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 30, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 32, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0205] (1) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 30, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 32, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0206] (m) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 30, a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 32, and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42.

[41]

[0208] A host cell transformed with one or more expression vectors selected from the following (a) to (m):

[0209] (a) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34;

[0210] (b) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 36;

[0211] (c) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34 and a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 36;

[0212] (d) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 36;

[0213] (e) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0214] (f) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 36 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0215] (g) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0216] (h) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 36, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0217] (i) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34 and a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 36, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0218] (j) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34 and a polynucleotide comprising a nucleotide sequence comprising an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 36;

[0219] (k) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 36, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0220] (1) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 36, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0221] (m) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34, a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 36, and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42.

[42]

[0223] A host cell transformed with one or more expression vectors selected from the following (a) to (m):

[0224] (a) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 38;

[0225] (b) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 40;

[0226] (c) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 38 and a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 40;

[0227] (d) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 38, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 40;

[0228] (e) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 38 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0229] (f) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 40 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0230] (g) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 38, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0231] (h) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 40, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0232] (i) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 38 and a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 40, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0233] (j) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 38 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 40;

[0234] (k) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 38, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 40, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0235] (1) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 38, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 40, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0236] (m) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 38, a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 40, and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42.

[43]

[0238] A host cell transformed with one or more expression vectors selected from the following (a) to (m):

[0239] (a) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as described in

[15] ;

[0240] (b) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the one-armed anti-human NR1 antibody as described in

[15] ;

[0241] (c) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as described in

[15] and a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody;

[0242] (d) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as described in

[15] , and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody;

[0243] (e) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as described in

[15] and a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody;

[0244] (f) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the one-armed anti-human NR1 antibody as described in

[15] and a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody;

[0245] (g) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as described in

[15] , and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody;

[0246] (h) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the one-armed anti-human NR1 antibody as described in

[15] , and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody;

[0247] (i) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as described in

[15] and a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody;

[0248] (j) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as described in

[15] and a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody;

[0249] (k) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as described in

[15] , and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody and a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody;

[0250] (1) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as described in

[15] , an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody;

[0251] (m) An expression vector comprising a polynucleotide containing a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as described in

[15] , a polynucleotide containing a nucleotide sequence encoding the light chain of the antibody, and a polynucleotide containing a nucleotide sequence encoding the Fc polypeptide of the antibody.

[44]

[0253] A method for producing a one-armed anti-human NR1 antibody, comprising culturing the host cell described in any one of

[35] to

[43] and expressing a polypeptide constituting the one-armed anti-human NR1 antibody.

[45]

[0255] A pharmaceutical composition comprising the one-armed anti-human NR1 antibody according to any one of [1] to

[17] and a pharmaceutically acceptable excipient.

[46]

[0257] The pharmaceutical composition as described in

[45] , wherein the pharmaceutical composition is used to treat anti-NMDAR encephalitis.

[47]

[0259] A method for treating anti-NMDAR encephalitis, comprising administering a therapeutically effective amount of the one-armed anti-human NR1 antibody described in any one of [1] to

[17] .

[48]

[0261] The one-armed anti-human NR1 antibody according to any one of [1] to

[17] , for use in treating anti-NMDAR encephalitis.

[49]

[0263] Use of the one-armed anti-human NR1 antibody as described in any one of [1] to

[17] in producing a pharmaceutical composition for treating anti-NMDAR encephalitis.

[50]

[0265] A monovalent anti-human NR1 antibody derivative selected from any one of the following (1) to (4):

[0266] (1) A monovalent anti-human NR1 antibody derivative comprising a heavy chain variable region comprising a CDR1 consisting of an amino acid sequence of amino acids 31 to 35 of SEQ ID NO: 6, a CDR2 consisting of an amino acid sequence of amino acids 50 to 66 of SEQ ID NO: 6, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 110 of SEQ ID NO: 6, and a light chain variable region comprising a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 8, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 8, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 98 of SEQ ID NO: 8;

[0267] (2) A monovalent anti-human NR1 antibody derivative comprising a heavy chain variable region comprising a CDR1 consisting of an amino acid sequence of amino acids 31 to 35 of SEQ ID NO: 10, a CDR2 consisting of an amino acid sequence of amino acids 50 to 66 of SEQ ID NO: 10, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 111 of SEQ ID NO: 10, and a light chain variable region comprising a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 12, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 12, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 97 of SEQ ID NO: 12;

[0268] (3) A monovalent anti-human NR1 antibody derivative comprising a heavy chain variable region comprising a CDR1 consisting of an amino acid sequence of amino acids 31 to 36 of SEQ ID NO: 14, a CDR2 consisting of an amino acid sequence of amino acids 51 to 66 of SEQ ID NO: 14, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 108 of SEQ ID NO: 14, and a light chain variable region comprising a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 16, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 16, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 97 of SEQ ID NO: 16;

[0269] (4) A monovalent anti-human NR1 antibody derivative comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acid numbers 31 to 36 of SEQ ID NO: 18, a CDR2 consisting of an amino acid sequence of amino acid numbers 51 to 66 of SEQ ID NO: 18, and a CDR3 consisting of an amino acid sequence of amino acid numbers 99 to 108 of SEQ ID NO: 18, and the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acid numbers 24 to 34 of SEQ ID NO: 20, a CDR2 consisting of an amino acid sequence of amino acid numbers 50 to 56 of SEQ ID NO: 20, and a CDR3 consisting of an amino acid sequence of amino acid numbers 89 to 97 of SEQ ID NO: 20.

[51]

[0271] A monovalent anti-human NR1 antibody derivative selected from any one of the following (1) to (4):

[0272] (1) A monovalent anti-human NR1 antibody derivative comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 6, and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 8;

[0273] (2) a monovalent anti-human NR1 antibody derivative comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 10, and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 12;

[0274] (3) a monovalent anti-human NR1 antibody derivative comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 14, and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 16;

[0275] (4) A monovalent anti-human NR1 antibody derivative comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 18, and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 20.

[52]

[0277] A monovalent anti-human NR1 antibody derivative, wherein the antibody competitively binds to human NR1 with an anti-human NR1 antibody comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 2 and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 4, and inhibits NMDAR cellular internalization caused by pathogenic anti-human NR1 antibodies derived from patients with anti-NMDAR encephalitis.

[53]

[0279] A polypeptide comprising a nucleotide sequence encoding the monovalent anti-human NR1 antibody derivative as described in any one of

[50] to

[52] .

[54]

[0281] An expression vector comprising the polynucleotide described in

[53] .

[55]

[0283] A host cell transformed with the expression vector as described in

[54] .

[56]

[0285] A method for producing a monovalent anti-human NR1 antibody derivative, comprising culturing the host cell as described in

[55] and expressing a polypeptide constituting the monovalent anti-human NR1 antibody derivative.

[57]

[0287] A pharmaceutical composition comprising the monovalent anti-human NR1 antibody derivative described in any one of

[50] to

[52] and a pharmaceutically acceptable excipient.

[58]

[0289] The pharmaceutical composition as described in

[57] , wherein the pharmaceutical composition is used to treat anti-NMDAR encephalitis.

[59]

[0291] A method for treating anti-NMDAR encephalitis, comprising administering a therapeutically effective amount of the monovalent anti-human NR1 antibody derivative described in any one of

[50] to

[52] .

[60]

[0293] The monovalent anti-human NR1 antibody derivative as described in any one of

[50] to

[52] , for use in treating anti-NMDAR encephalitis.

[61]

[0295] Use of a monovalent anti-human NR1 antibody derivative as described in any one of

[50] to

[52] in producing a pharmaceutical composition for treating anti-NMDAR encephalitis.

[0296] Effects of the present invention

[0297] The monovalent human NR1 antibody derivatives of the present invention can be used as therapeutic agents by competitively binding to NMDAR with pathogenic anti-human NR1 antibodies derived from patients with anti-NMDAR encephalitis and inhibiting NMDAR internalization. BRIEF DESCRIPTION OF THE DRAWINGS

[0298] Figure 1The binding activity of pathogenic anti-human NR1 antibody P003-102 and one-armed anti-human NR1 antibody (ABN-5) derived from P003-102 to HEK cells expressing NMDAR is shown. The vertical axis represents binding activity (ΔGeoMFI: the difference between the geometric mean fluorescence intensity when the test antibody is added and the geometric mean fluorescence intensity when no test antibody is added (fluorescently labeled secondary antibody only)), and the horizontal axis represents antibody concentration.

[0299] Figure 2 The figure shows the inhibitory activity of the novel mouse anti-human NR1 antibody isolated in Example 5 against the binding of the pathogenic anti-human NR1 antibody P003-102 to human NR1. The vertical axis represents the inhibitory activity (inhibition rate) of the mouse anti-human NR1 antibody against the binding of biotin-labeled P003-102 to human NR1 protein. The horizontal axis represents the antibody concentration.

[0300] Figure 3 The binding activity of humanized one-armed anti-human NR1 antibody to HEK cells expressing NMDAR is shown. The vertical axis represents the geometric mean fluorescence intensity (GeoMFI), and the horizontal axis represents the antibody concentration.

[0301] Figure 4 The inhibitory activity of ABN-2, ABN-4, and ABN-5 against the pathogenic anti-human NR1 antibody P003-102 is shown. The vertical axis represents the inhibitory activity (inhibition rate) of biotin-labeled P003-102 against binding to human NR1 protein, and the horizontal axis represents the antibody concentration.

[0302] Figure 5 The figure shows the rescue effect of ABN-2 on the expression level of NMDAR on the cell surface caused by the pathogenic anti-human NR1 antibody mixture. The vertical axis represents the NR1 expression rate (%) on the cell surface of HEK cells expressing NMDAR, and the horizontal axis represents the antibody concentration.

[0303] Figure 6 The figure shows the rescue effect of ABN-2 on the decreased NMDAR ion channel function caused by the pathogenic anti-human NR1 antibody P003-102. The vertical axis represents the calcium ion influx caused by NMDAR stimulation, and the horizontal axis represents the antibody concentration.

[0304] Figure 7The therapeutic effect of ABN-2 on common marmosets (hereinafter referred to as "marmosets") in which anti-NMDAR encephalitis-like symptoms were induced by continuous intracerebroventricular administration of the pathogenic anti-human NR1 antibody P003-102. Day 0 was the day when P003-102 was started to be administered to marmosets in the control antibody administration group (P003-102 + control antibody, n = 3) and the ABN-2 administration group (P003-102 + ABN-2, n = 9). From day 14 (day 14) to day 28 (day 28), the control antibody or ABN-2 was administered intracerebroventricularly for 14 consecutive days. Figure 7 The left, middle, and right vertical axes represent the Abnormal Rating Scale (ARS), which is a modification of the Unified Parkinson's Disease Rating Scale (UPDRS, Behav. Brain Res. 2008, Vol. 194, pp. 152-161). Figure 7 The left side shows the ARS of the control antibody administration group and the ABN-2 administration group on day 0, Figure 7 The middle shows the ARS on day 14, and Figure 7 The right side shows the ARS at day 28.

[0305] Figure 8 The therapeutic effect of ABN-2 on common marmosets is shown, in which anti-NMDAR encephalitis-like symptoms were induced by continuous intracerebroventricular administration of pathogenic anti-human NR1 antibody P003-102 for each individual in the ABN-2 administration group (P003-102+ABN-2) as the change of ARS over time.

[0306] Figure 9 A schematic diagram of a one-armed antibody is shown. DETAILED DESCRIPTION

[0307] The following is a detailed description of the present invention.

[0308] Antibody (or immunoglobulin) molecules are glycoproteins composed of multiple units. There are five classes of antibodies: IgG, IgM, IgA, IgD, and IgE. The basic structure of antibody molecules common to all classes is a Y-shaped four-chain structure, which includes two heavy chains with a molecular weight of 50,000 to 70,000 and two light chains with a molecular weight of 20,000 to 30,000. The heavy chain is generally composed of a polypeptide chain containing approximately 440 amino acids and has a characteristic structure depending on the class. They are called Igγ, Igμ, Igα, Igδ, and Igε, corresponding to IgG, IgM, IgA, IgD, and IgE, respectively. In addition, IgG has subclasses of IgG1, IgG2, IgG3, and IgG4, and the corresponding heavy chains are called Igγ1, Igγ2, Igγ3, and Igγ4, respectively. Light chains typically consist of a polypeptide chain containing approximately 220 amino acids, and two types are known: L-type and K-type, referred to as Igλ and Igκ, respectively. These two types of light chains can pair with any type of heavy chain. The peptide component of the basic structure of an antibody molecule consists of two identical heavy chains and two identical light chains, each linked by disulfide bonds and non-covalent bonds, and the molecular weight of the antibody molecule is 150,000 to 190,000.

[0309] Antibody molecules have four intrachain disulfide bonds in the heavy chain (five in Igμ and Igε) and two in the light chain, with each 100 to 110 amino acid residues forming a loop. Their conformations between the loops are similar and are referred to as structural units or domains. The domains located at the N-terminus of both the heavy and light chains have different amino acid sequences and are referred to as variable regions, even if the samples are from the same class (subclass) of the same animal species. Each N-terminal domain of the heavy and light chains is referred to as "heavy chain variable region (VH) and light chain variable region (VL)", respectively. The amino acid sequence of the C-terminal domain downstream of the variable region is almost constant for each class or subclass and is referred to as a "constant region". The heavy chain constant region (CH) is further divided into three domains from the N-terminal side: CH1, CH2 and CH3. The light chain constant region is referred to as "CL".

[0310] In the Y-shaped structure of an antibody, the portion corresponding to the vertical line in the lower half of the Y-shape is called the "Fc (fragment, crystallizable) region". The Fc region is composed of two "Fc polypeptides". The Fc polypeptide is composed of the CH2 and CH3 domains of the heavy chain. On the other hand, in the Y-shaped structure of an antibody, in the upper half of the Y-shaped structure, the portion corresponding to the diagonal line that constitutes the V-shaped portion is called the "Fab (fragment, antigen binding) region". The Fab region is composed of the VH and CH1 domains of the heavy chain and light chain (VL and CL). The antibody binds to the antigen at the tip part (antigen binding site) of the V-shape composed of the two Fab regions. The Fab region and the Fc region of the heavy chain are connected by a region called the hinge region. In addition, the two heavy chains of the antibody are connected by disulfide bonds.

[0311] "Antigen binding site " is made up of VH and VL, and the binding specificity to antigen is determined by the amino acid sequence at this site. On the other hand, biological activity (such as binding to complement and various Fc receptor expressing cells) reflects the structural differences of the constant region of each Ig class. The mutability of light chain and heavy chain variable region has been understood to be limited to three small hypervariable regions, which are present in two chains and are referred to as "complementarity determining regions (CDRs)" and have relatively large changes in amino acid sequence. On the other hand, the remainder of the variable region is referred to as framework region (FR), which is composed of FR1 to FR4, and the change of amino acid sequence is relatively small.

[0312] There are three CDRs at each N-terminus of the heavy and light chains, in the order "CDR1," "CDR2," and "CDR3," consisting of approximately 5 to 10 amino acid residues. The heavy chain CDRs are particularly known to contribute to antigen binding. Furthermore, of CDR1 to CDR3, CDR3 is known to contribute the most.

[0313] As used herein, the numbering of amino acid residues of antibodies may be defined according to their numbering systems by designating Kabat numbering or the EU index (Kabat, Sequences of Proteins of Immunological Interest, 5th Edition, 1991, NIH Publication No. 91-3242).

[0314] "Antibody derivatives" herein are molecules comprising at least one polypeptide chain derived from a full-length immunoglobulin molecule, which have antigen binding activity. Representative antibody derivatives include single-chain variable region fragments (scFv), Fab fragments, Fab' fragments and F(ab')2 fragments. "scFv" is a monovalent antibody derivative consisting of VH and VL connected by a linker. "Fab fragment" is a monovalent antibody derivative consisting of a light chain and heavy chain fragment comprising a portion of VH, CH1 domain and hinge region. "F(ab')2Fab' fragment" is a monovalent antibody derivative consisting of a light chain and heavy chain fragment comprising a portion of VH, CH1 domain and hinge region, and this portion of the hinge region comprises a cysteine ​​residue that constitutes SS binding between heavy chains. The term "monovalent" means that it contains one antigen binding site.

[0315] "One-armed antibody" is also a type of antibody derivative. In this article, "one-armed antibody" is a monovalent antibody derivative comprising a Fab region and an Fc region, wherein the Fab region is connected to one of the two Fc polypeptides in the Fc region. The Fab region and an Fc polypeptide can be connected via a hinge region or a peptide linker. In one embodiment, the one-armed antibody comprises a heavy chain (VH, CH1 domain, hinge region, Fc polypeptide (CH2 domain and CH3 domain)), a light chain (VL and CL) and an Fc polypeptide ( Figure 9 In one embodiment, the one-armed antibody is a one-armed antibody comprising one heavy chain, one light chain and an Fc polypeptide, wherein a hinge region is added to the Fc polypeptide ( Figure 9 - left). In one embodiment, the one-armed antibody is a one-armed antibody consisting of one heavy chain, one light chain and an Fc polypeptide, wherein the CH1 domain is connected to the Fc polypeptide via a hinge region ( Figure 9 - middle). In one embodiment, the one-armed antibody is a one-armed antibody consisting of a heavy chain, a light chain and an Fc polypeptide ( Figure 9 – right). In one embodiment, a one-armed antibody may have two Fc polypeptides bound by an SS bond between the heavy chains in the hinge region ( Figure 9 - left and center), or the two Fc polypeptides may contain modified residues or added cysteine ​​residues in one or both Fc polypeptides to allow them to bind to each other ( Figure 9 -right).

[0316] "Anti-human NR1 antibody" herein means an antibody that binds to human NR1. Whether it binds to human NR1 can be determined using a well-known method for measuring binding activity. The method for measuring binding activity includes, for example, enzyme-linked immunosorbent assay (ELISA). If ELISA is used, for example, the full-length or partial polypeptide of the human NR1 protein that can be produced by reference to the amino acid sequence shown in GenBank accession number NP_015566.1 is immobilized on an ELISA plate, and after reacting by adding the test antibody, it is reacted with a second antibody (such as an anti-IgG antibody labeled with an enzyme such as horseradish peroxidase (HRP)). After the reaction, the binding of the second antibody is identified by performing a washing operation and activity measurement using a reagent that detects its activity, and it can be confirmed whether the test antibody binds to human NR1. As a specific evaluation method, for example, the method described in Example 5 below can be used.

[0317] In addition to anti-human NR1, the anti-human NR1 antibody of the present invention also includes an antibody that binds to NR1 derived from another animal (eg, anti-monkey NR1), as long as the antibody binds to human NR1.

[0318] <One-armed anti-human NR1 antibody of the present invention>

[0319] Herein, a "one-armed anti-human NR1 antibody" is a one-armed antibody that binds to human NR1.

[0320] The one-armed anti-human NR1 antibody of the present invention comprises a one-armed anti-human NR1 antibody selected from any one of the following (1) to (5):

[0321] (1) A one-armed anti-human NR1 antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 26 to 34 of SEQ ID NO: 2, a CDR2 consisting of an amino acid sequence of amino acids 52 to 58 of SEQ ID NO: 2, and a CDR3 consisting of an amino acid sequence of amino acids 97 to 109 of SEQ ID NO: 2, and the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 26 to 33 of SEQ ID NO: 4, a CDR2 consisting of an amino acid sequence of amino acids 51 to 53 of SEQ ID NO: 4, and a CDR3 consisting of an amino acid sequence of amino acids 92 to 100 of SEQ ID NO: 4;

[0322] (2) a one-armed anti-human NR1 antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 31 to 35 of SEQ ID NO: 6, a CDR2 consisting of an amino acid sequence of amino acids 50 to 60 of SEQ ID NO: 6, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 110 of SEQ ID NO: 6, and the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 8, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 8, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 98 of SEQ ID NO: 8;

[0323] (3) a one-armed anti-human NR1 antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 31 to 35 of SEQ ID NO: 10, a CDR2 consisting of an amino acid sequence of amino acids 50 to 66 of SEQ ID NO: 10, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 111 of SEQ ID NO: 10, and the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 12, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 12, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 97 of SEQ ID NO: 12;

[0324] (4) a one-armed anti-human NR1 antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 31 to 36 of SEQ ID NO: 14, a CDR2 consisting of an amino acid sequence of amino acids 51 to 66 of SEQ ID NO: 14, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 108 of SEQ ID NO: 14, and the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 16, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 16, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 97 of SEQ ID NO: 16;

[0325] (5) A one-armed anti-human NR1 antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acid numbers 31 to 36 of SEQ ID NO: 18, a CDR2 consisting of an amino acid sequence of amino acid numbers 51 to 66 of SEQ ID NO: 18, and a CDR3 consisting of an amino acid sequence of amino acid numbers 99 to 108 of SEQ ID NO: 18, and the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acid numbers 24 to 34 of SEQ ID NO: 20, a CDR2 consisting of an amino acid sequence of amino acid numbers 50 to 56 of SEQ ID NO: 20, and a CDR3 consisting of an amino acid sequence of amino acid numbers 89 to 97 of SEQ ID NO: 20.

[0326] In one embodiment, the one-armed anti-human NR1 antibody of the present invention is a one-armed anti-human NR1 antibody selected from any one of the following (6) to (10):

[0327] (6) a one-armed anti-human NR1 antibody comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 2, and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 4;

[0328] (7) a one-armed anti-human NR1 antibody comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 6, and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 8;

[0329] (8) A one-armed anti-human NR1 antibody comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 10, and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 12;

[0330] (9) A one-armed anti-human NR1 antibody comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 14, and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 16;

[0331] (10) A one-armed anti-human NR1 antibody comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 18, and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 20.

[0332] In one embodiment, the one-armed anti-human NR1 antibody of the present invention is a one-armed anti-human NR1 antibody selected from any one of the following (1) to (5):

[0333] (1) A one-armed anti-human NR1 antibody comprising a heavy chain, a light chain, and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region comprising a CDR1 consisting of an amino acid sequence of amino acids 26 to 34 of SEQ ID NO: 2, a CDR2 consisting of an amino acid sequence of amino acids 52 to 58 of SEQ ID NO: 2, and a CDR3 consisting of an amino acid sequence of amino acids 97 to 109 of SEQ ID NO: 2, and the light chain comprises a light chain variable region comprising a CDR1 consisting of an amino acid sequence of amino acids 26 to 33 of SEQ ID NO: 4, a CDR2 consisting of an amino acid sequence of amino acids 51 to 53 of SEQ ID NO: 4, and a CDR3 consisting of an amino acid sequence of amino acids 92 to 100 of SEQ ID NO: 4;

[0334] (2) A one-armed anti-human NR1 antibody comprising a heavy chain, a light chain, and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 31 to 35 of SEQ ID NO: 6, a CDR2 consisting of an amino acid sequence of amino acids 50 to 66 of SEQ ID NO: 6, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 110 of SEQ ID NO: 6, and the light chain comprises a light chain variable region, wherein the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 8, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 8, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 98 of SEQ ID NO: 8;

[0335] (3) a one-armed anti-human NR1 antibody comprising a heavy chain, a light chain, and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 31 to 35 of SEQ ID NO: 10, a CDR2 consisting of an amino acid sequence of amino acids 50 to 66 of SEQ ID NO: 10, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 111 of SEQ ID NO: 10, and the light chain comprises a light chain variable region, wherein the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 12, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 12, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 97 of SEQ ID NO: 12;

[0336] (4) A one-armed anti-human NR1 antibody comprising a heavy chain, a light chain, and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region comprising a CDR1 consisting of an amino acid sequence of amino acids 31 to 36 of SEQ ID NO: 14, a CDR2 consisting of an amino acid sequence of amino acids 51 to 66 of SEQ ID NO: 14, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 108 of SEQ ID NO: 14, and the light chain comprises a light chain variable region comprising a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 16, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 16, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 97 of SEQ ID NO: 16;

[0337] (5) A one-armed anti-human NR1 antibody comprising a heavy chain, a light chain and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 31 to 36 of SEQ ID NO: 18, a CDR2 consisting of an amino acid sequence of amino acids 51 to 66 of SEQ ID NO: 18, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 108 of SEQ ID NO: 18, and the light chain comprises a light chain variable region, wherein the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 20, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 20, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 97 of SEQ ID NO: 20.

[0338] In one embodiment, the one-armed anti-human NR1 antibody of the present invention is a one-armed anti-human NR1 antibody selected from any one of the following (6) to (10):

[0339] (6) A one-armed anti-human NR1 antibody comprising a heavy chain, a light chain, and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 2, and the light chain comprises a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 4;

[0340] (7) A one-armed anti-human NR1 antibody comprising a heavy chain, a light chain, and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 6, and the light chain comprises a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 8;

[0341] (8) A one-armed anti-human NR1 antibody comprising a heavy chain, a light chain, and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 10, and the light chain comprises a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 12;

[0342] (9) A one-armed anti-human NR1 antibody comprising a heavy chain, a light chain, and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 14, and the light chain comprises a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 16;

[0343] (10) A single-armed anti-human NR1 antibody comprising a heavy chain, a light chain, and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region, and the heavy chain variable region consists of the amino acid sequence shown in SEQ ID NO: 18; and the light chain comprises a light chain variable region, and the light chain variable region consists of the amino acid sequence shown in SEQ ID NO: 20.

[0344] As the heavy chain constant region from which the CH1 domain and Fc polypeptide of the one-armed anti-human NR1 antibody of the present invention are derived, any one of the Igγ, Igμ, Igα, Igδ, or Igε constant regions can be selected. For example, Igγ can be selected from Igγ1, Igγ2, Igγ3, or Igγ4. In one embodiment, the one-armed anti-human NR1 antibody of the present invention comprises a CH1 domain and an Fc polypeptide derived from an Igγ1 constant region. In one embodiment, the one-armed anti-human NR1 antibody of the present invention comprises a CH1 domain and an Fc polypeptide derived from a human Igγ1 constant region.

[0345] As the CL of the one-armed anti-human NR1 antibody of the present invention, either Igλ or Igκ constant region can be selected. In one embodiment, the one-armed anti-human NR1 antibody of the present invention comprises a CL as an Igκ constant region. In one embodiment, the one-armed anti-human NR1 antibody of the present invention comprises a CL as a human Igκ constant region.

[0346] The heavy chain constant region of the one-armed anti-human NR1 antibody of the present invention may have a mutation that reduces antibody-dependent cellular cytotoxicity activity or complement-dependent cytotoxicity activity. L234A represents a substitution of leucine with alanine at amino acid position 234 according to the EU index in the human Igγ1 constant region. L235A represents a substitution of leucine with alanine at amino acid position 235 according to the EU index in the human Igγ1 constant region. Human Igγ1 constant regions having L234A and L235A amino acid mutations (hereinafter referred to as "LALA mutations") include, for example, human Igγ1 constant regions consisting of an amino acid sequence of amino acid numbers 121 to 450 in SEQ ID NO: 22. It is known that the mutation reduces the antibody-dependent cellular cytotoxicity activity and complement-dependent cytotoxicity activity of the antibody (Mol. Immunol., 1992, Vol. 29, pp. 633-639 / J. Immunol., 2000, Vol. 164, pp. 4178-4184). In addition, in mouse antibodies, the D265A amino acid mutation in IgG1 is known to reduce the antibody-dependent cellular cytotoxicity activity and complement-dependent cytotoxicity activity of the antibody (J. Immunol., 2008, Vol. 181, pp. 6664-6669 / Nat. Med., 2000, Vol. 6, pp. 443-446). If the effect of an antibody with reduced antibody-dependent cellular cytotoxicity activity or complement-dependent cytotoxicity activity is to be observed in a mouse model, a mouse antibody with the D265A amino acid mutation can be used instead of a human antibody with the LALA mutation.

[0347] Other mutations based on known techniques can also be introduced into the heavy chain constant region of the one-armed anti-human NR1 antibody of the present invention. For example, the one-armed anti-human NR1 antibody of the present invention can have a mutation based on the knob-in-hole technique (hereinafter referred to as "knob-in-hole mutation"). The knob-in-hole technique is a technique for efficiently obtaining the desired heterodimeric antibody molecule by replacing the amino acid side chains present in the CH3 region of one heavy chain with a larger side chain (knob) and replacing the amino acid side chains present in the CH3 region of the other heavy chain with a smaller side chain (hole) so that the knob is located within the hole (Nature, 1994, Vol. 372, pp. 379-383 / Nature Biotech., 1998, Vol. 16, pp. 677-681 / J. Mol. Biol., 1997, Vol. 270, pp. 26-35 / Proc. Natl. Acad. Sci. USA, 2013, Vol. 110, pp. E2987-E2996).

[0348] In one embodiment, the one-armed anti-human NR1 antibody of the invention comprises an Fc region having L234A and L235A amino acid mutations (LALA mutation).

[0349] In one embodiment, a one-armed anti-human NR1 antibody of the invention comprises an Fc region with a knob-to-hole mutation.

[0350] In one embodiment, the one-armed anti-human NR1 antibody of the invention comprises an Fc region having L234A and L235A amino acid mutations (LALA mutations) and a knob-to-hole mutation.

[0351] In one embodiment, the knob-to-hole mutation of the one-armed anti-human NR1 antibody of the present invention is a T366W mutation in one Fc polypeptide forming its Fc region and T366S, L368A, and Y407V mutations in another Fc polypeptide forming its Fc region (see WO1998 / 050431).

[0352] "Human antibody" herein refers to an antibody having the amino acid sequence of a human immunoglobulin. "Humanized antibody" herein refers to an antibody in which some, most or all of the amino acid residues other than the CDRs are substituted with amino acid residues derived from human immunoglobulin molecules. Humanized antibodies can be produced by reference to, for example, U.S. Patent No. 5,225,539 and U.S. Patent No. 6,180,370.

[0353] In one embodiment, the one-armed anti-human NR1 antibody of the invention is a human antibody or a humanized antibody.

[0354] In one embodiment, the one-armed anti-human NR1 antibody of the present invention is a one-armed anti-human NR1 antibody comprising the following: a heavy chain consisting of the amino acid sequence shown in SEQ ID NO:22, a light chain consisting of the amino acid sequence shown in SEQ ID NO:24, and an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO:42.

[0355] The heavy chain comprising the amino acid sequence shown in SEQ ID NO:22 has a LALA mutation, and the mutation is located in the alanine residues at amino acid numbers 237 and 238 in SEQ ID NO:22.

[0356] The heavy chain consisting of the amino acid sequence shown in SEQ ID NO:22 has knob-to-hole mutations (T366S, L368A and Y407V), and the mutations are located in the serine residue at amino acid number 369, the alanine residue at amino acid number 371 and the valine residue at amino acid number 410 in SEQ ID NO:22.

[0357] The Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42 has a LALA mutation, and the mutation is located in the alanine residues at amino acid numbers 9 and 10 in SEQ ID NO: 42. The Fc polypeptide comprising the amino acid sequence shown in SEQ ID NO: 42 also has a knob-to-hole mutation (T366W), and the mutation is located in the tryptophan residue at amino acid number 141.

[0358] In one embodiment, the one-armed anti-human NR1 antibody of the present invention is a one-armed anti-human NR1 antibody comprising the following: a heavy chain consisting of the amino acid sequence shown in SEQ ID NO:26, a light chain consisting of the amino acid sequence shown in SEQ ID NO:28, and an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO:42.

[0359] In one embodiment, the one-armed anti-human NR1 antibody of the present invention is a one-armed anti-human NR1 antibody comprising the following: a heavy chain consisting of the amino acid sequence shown in SEQ ID NO:30, a light chain consisting of the amino acid sequence shown in SEQ ID NO:32, and an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO:42.

[0360] In one embodiment, the one-armed anti-human NR1 antibody of the present invention is a one-armed anti-human NR1 antibody comprising the following: a heavy chain consisting of the amino acid sequence shown in SEQ ID NO:34, a light chain consisting of the amino acid sequence shown in SEQ ID NO:36, and an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO:42.

[0361] In one embodiment, the one-armed anti-human NR1 antibody of the present invention is a one-armed anti-human NR1 antibody comprising the following: a heavy chain consisting of the amino acid sequence shown in SEQ ID NO:38, a light chain consisting of the amino acid sequence shown in SEQ ID NO:40, and an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO:42.

[0362] Like the heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 22, the heavy chains consisting of the amino acid sequences shown in SEQ ID NOs: 26, 30, 34 and 38 also have LALA mutations and knob-to-hole mutations (T366S, L368A and Y407V).

[0363] In one embodiment, the one-armed anti-human NR1 antibody of the present invention competitively binds to human NR1 with an anti-human NR1 antibody comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 2 and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 4, and inhibits NMDAR receptor cellular internalization caused by pathogenic anti-human NR1 antibodies derived from patients with anti-NMDAR encephalitis.

[0364] Herein, two antibodies "competitively" bind to the same antigen protein means that the epitope on the antigen protein to which the two antibodies respectively bind is the same, or a portion of the epitope on the antigen protein to which the two antibodies respectively bind is common, or one of the antibodies binding to the epitope on the antigen protein changes the three-dimensional structure of the antigen protein, which contains the epitope portion on the antigen protein to which the other antibody binds, thereby causing the other antibody to no longer be able to bind to the epitope portion on the antigen protein.

[0365] For example, a person skilled in the art can obtain a plurality of one-armed anti-human NR1 antibodies, which are produced based on antibodies obtained by immunizing mice or rats with human NR1 polypeptides. Then, according to the methods disclosed in Examples 3-5, etc., screening is performed using an anti-human NR1 antibody comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 2 and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 4, and selecting an anti-human NR1 antibody that competitively binds to human NR1 with the anti-human NR1 antibody and inhibits NMDA receptor cellular internalization caused by the pathogenic anti-human NR1 antibody. A one-armed anti-human NR1 antibody can be selected from the plurality of anti-human NR1 antibodies obtained.

[0366] “One-armed anti-human NR1 antibodies that compete for binding to human NR1 with an anti-human NR1 antibody comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 2 and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 4” include, for example, ABN_1-1-175, ABN_1-178.3, ABN_3-385, ABN_3-502 and derivatives thereof, which were identified as a result of the ELISA competition assay described in Example 5 herein.

[0367] “A single-armed anti-human NR1 antibody that competitively binds to human NR1 with an anti-human NR1 antibody comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 2 and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 4 and inhibits NMDAR receptor cellular internalization caused by pathogenic anti-human NR1 antibodies derived from patients with anti-NMDAR encephalitis” includes, for example, ABN_1-175, ABN_1-178, ABN_3-385, ABN_3-502, or a one-armed antibody comprising the antigen binding site of P003-102 described in Example 1, or more specifically, the one-armed anti-human NR1 antibodies ABN-1 to -5 produced in Example 2 or Example 6 herein.

[0368] When antibodies are expressed in cells, they are known to undergo post-translational modifications. Examples of post-translational modifications include cleavage of the heavy chain C-terminal lysine by carboxypeptidases, modification of the heavy and light chain N-terminal glutamine or glutamic acid with pyroglutamic acid by pyroglutamylation, glycosylation, oxidation, deamidation, and glycation. Such post-translational modifications are known to occur in various antibodies (J. Pharm. Sci., 2008, Vol. 97, pp. 2426-2447).

[0369] Examples of the one-armed anti-human NR1 antibodies of the present invention produced by post-translational modification include one-armed anti-human NR1 antibodies that have undergone N-terminal pyroglutamylation of the heavy chain variable region and / or deletion of the heavy chain C-terminal lysine. It is known in the art that such post-translational modifications by N-terminal pyroglutamylation or C-terminal lysine deletion do not affect the activity of the antibody (Anal. Biochem., 2006, Vol. 348, pp. 24-39).

[0370] In one embodiment, the one-armed anti-human NR1 antibody is generated by post-translational modification.

[0371] In one embodiment, the one-armed anti-human NR1 antibody is produced by post-translational modification of the heavy chain variable region by N-terminal pyroglutamylation and / or deletion of the heavy chain C-terminal lysine of the one-armed anti-human NR1 antibody of the invention.

[0372] Based on the VH and VL sequence information of the one-armed anti-human NR1 antibody of the present invention disclosed herein, the one-armed anti-human NR1 antibody of the present invention can be easily produced by those skilled in the art using methods well known in the art. The one-armed anti-human NR1 antibody of the present invention can be produced, for example, by the methods described below in the "Methods for producing the one-armed anti-human NR1 antibody of the present invention, and the one-armed anti-human NR1 antibody produced thereby," but is not limited thereto.

[0373] If necessary, the one-armed anti-human NR1 antibody of the present invention is further purified and formulated by standard methods, and can be used to treat anti-NMDAR encephalitis, etc.

[0374] <Polynucleotide of the present invention>

[0375] The polynucleotides of the present invention include a polynucleotide comprising a nucleotide sequence encoding the heavy chain variable region of the one-armed anti-human NR1 antibody of the present invention and a polynucleotide comprising a nucleotide sequence encoding the light chain variable region of the one-armed anti-human NR1 antibody of the present invention.

[0376] In one embodiment, the polynucleotide of the present invention is a polynucleotide comprising the sequence described in (a) and / or (b) below:

[0377] (a) a nucleotide sequence encoding the heavy chain variable region of a one-armed anti-human NR1 antibody selected from the following (a-1) to (a-4):

[0378] (a-1) a heavy chain variable region comprising a CDR1 consisting of the amino acid sequence of amino acids 31 to 35 of SEQ ID NO: 6, a CDR2 consisting of the amino acid sequence of amino acids 50 to 66 of SEQ ID NO: 6, and a CDR3 consisting of the amino acid sequence of amino acids 99 to 110 of SEQ ID NO: 6;

[0379] (a-2) a heavy chain variable region comprising a CDR1 consisting of the amino acid sequence of amino acids 31 to 35 of SEQ ID NO: 10, a CDR2 consisting of the amino acid sequence of amino acids 50 to 66 of SEQ ID NO: 10, and a CDR3 consisting of the amino acid sequence of amino acids 99 to 111 of SEQ ID NO: 10;

[0380] (a-3) a heavy chain variable region comprising a CDR1 consisting of the amino acid sequence of amino acids 31 to 36 of SEQ ID NO: 14, a CDR2 consisting of the amino acid sequence of amino acids 51 to 66 of SEQ ID NO: 14, and a CDR3 consisting of the amino acid sequence of amino acids 99 to 108 of SEQ ID NO: 14;

[0381] (a-4) a heavy chain variable region comprising a CDR1 consisting of the amino acid sequence of amino acids 31 to 36 of SEQ ID NO: 18, a CDR2 consisting of the amino acid sequence of amino acids 51 to 66 of SEQ ID NO: 18, and a CDR3 consisting of the amino acid sequence of amino acids 99 to 108 of SEQ ID NO: 18; and / or

[0382] (b) a nucleotide sequence encoding the light chain variable region of a one-armed anti-human NR1 antibody selected from the following (b-1) to (b-4):

[0383] (b-1) a light chain variable region comprising a CDR1 consisting of the amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 8, a CDR2 consisting of the amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 8, and a CDR3 consisting of the amino acid sequence of amino acids 89 to 98 of SEQ ID NO: 8;

[0384] (b-2) a light chain variable region comprising a CDR1 consisting of the amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 12, a CDR2 consisting of the amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 12, and a CDR3 consisting of the amino acid sequence of amino acids 89 to 97 of SEQ ID NO: 12;

[0385] (b-3) a light chain variable region comprising a CDR1 consisting of the amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 16, a CDR2 consisting of the amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 16, and a CDR3 consisting of the amino acid sequence of amino acids 89 to 97 of SEQ ID NO: 16;

[0386] (b-4) A light chain variable region comprising a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 20, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 20, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 98 of SEQ ID NO: 20.

[0387] In one embodiment, the polynucleotide of the present invention is a polynucleotide comprising the nucleotide sequence described in (a) and / or (b) below:

[0388] (a) a nucleotide sequence encoding the heavy chain variable region of a one-armed anti-human NR1 antibody selected from the following (a-1) to (a-4):

[0389] (a-1) a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 6;

[0390] (a-2) a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 10;

[0391] (a-3) a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 14;

[0392] (a-4) a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 18; and / or

[0393] (b) a nucleotide sequence encoding the light chain variable region of a one-armed anti-human NR1 antibody selected from the following (b-1) to (b-4):

[0394] (b-1) a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 8;

[0395] (b-2) a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 12;

[0396] (b-3) a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 16;

[0397] (b-4) A light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 20.

[0398] In one embodiment, the polynucleotide of the present invention is a polynucleotide comprising the nucleotide sequence described in (a) and / or (b) below:

[0399] (a) A nucleotide sequence encoding the heavy chain of a one-armed anti-human NR1 antibody selected from the following (a-1) to (a-4):

[0400] (a-1) a heavy chain comprising a heavy chain variable region comprising a CDR1 consisting of the amino acid sequence of amino acids 31 to 35 of SEQ ID NO: 6, a CDR2 consisting of the amino acid sequence of amino acids 50 to 66 of SEQ ID NO: 6, and a CDR3 consisting of the amino acid sequence of amino acids 99 to 110 of SEQ ID NO: 6;

[0401] (a-2) a heavy chain comprising a heavy chain variable region comprising a CDR1 consisting of the amino acid sequence of amino acids 31 to 35 of SEQ ID NO: 10, a CDR2 consisting of the amino acid sequence of amino acids 50 to 66 of SEQ ID NO: 10, and a CDR3 consisting of the amino acid sequence of amino acids 99 to 111 of SEQ ID NO: 10;

[0402] (a-3) a heavy chain comprising a heavy chain variable region comprising a CDR1 consisting of an amino acid sequence of amino acids 31 to 36 of SEQ ID NO: 14, a CDR2 consisting of an amino acid sequence of amino acids 51 to 66 of SEQ ID NO: 14, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 108 of SEQ ID NO: 14;

[0403] (a-4) a heavy chain comprising a heavy chain variable region comprising a CDR1 consisting of an amino acid sequence of amino acids 31 to 36 of SEQ ID NO: 18, a CDR2 consisting of an amino acid sequence of amino acids 51 to 66 of SEQ ID NO: 18, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 108 of SEQ ID NO: 18; and / or

[0404] (b) a nucleotide sequence encoding the light chain of a one-armed anti-human NR1 antibody selected from the following (b-1) to (b-4):

[0405] (b-1) a light chain comprising a light chain variable region comprising a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 8, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 8, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 98 of SEQ ID NO: 8;

[0406] (b-2) a light chain comprising a light chain variable region comprising a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 12, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 12, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 97 of SEQ ID NO: 12;

[0407] (b-3) a light chain comprising a light chain variable region comprising a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 16, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 16, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 97 of SEQ ID NO: 16;

[0408] (b-4) a light chain comprising a light chain variable region comprising a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 20, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 20, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 97 of SEQ ID NO: 20.

[0409] In one embodiment, the polynucleotide of the present invention comprises the nucleotide sequence described in (a) and / or (b) below:

[0410] (a) a nucleotide sequence encoding the heavy chain variable region of a one-armed anti-human NR1 antibody selected from the following (a-1) to (a-4):

[0411] (a-1) a heavy chain comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 6;

[0412] (a-2) a heavy chain comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 10;

[0413] (a-3) a heavy chain comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 14;

[0414] (a-4) a heavy chain comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 18; and / or

[0415] (b) a nucleotide sequence encoding the light chain variable region of a one-armed anti-human NR1 antibody selected from the following (b-1) to (b-4):

[0416] (b-1) a light chain comprising a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 8;

[0417] (b-2) a light chain comprising a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 12;

[0418] (b-3) a light chain comprising a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 16;

[0419] (b-4) A light chain comprising a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 20.

[0420] In one embodiment, the polynucleotide of the present invention comprises the nucleotide sequence described in (a) and / or (b) below:

[0421] (a) a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 26; and / or

[0422] (b) A nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 28.

[0423] The polynucleotide encoding the heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 26 includes, for example, a polynucleotide comprising the nucleotide sequence shown in SEQ ID NO: 25.

[0424] The polynucleotide encoding the light chain consisting of the amino acid sequence shown in SEQ ID NO: 28 includes, for example, a polynucleotide comprising the nucleotide sequence shown in SEQ ID NO: 27.

[0425] In one embodiment, the polynucleotide of the present invention comprises the nucleotide sequence described in (a) and / or (b) below:

[0426] (a) a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 30; and / or

[0427] (b) A nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 32.

[0428] The polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 30 includes, for example, a polynucleotide comprising the nucleotide sequence shown in SEQ ID NO: 29.

[0429] The polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 32 includes, for example, a polynucleotide comprising the nucleotide sequence shown in SEQ ID NO: 31.

[0430] In one embodiment, the polynucleotide of the present invention comprises the nucleotide sequence described in (a) and / or (b) below:

[0431] (a) a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34; and / or

[0432] (b) A nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 36.

[0433] The polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34 includes, for example, a polynucleotide comprising the nucleotide sequence shown in SEQ ID NO: 33.

[0434] The polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 36 includes, for example, a polynucleotide comprising the nucleotide sequence shown in SEQ ID NO: 35.

[0435] In one embodiment, the polynucleotide of the present invention comprises the nucleotide sequence described in (a) and / or (b) below:

[0436] (a) a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 38; and / or

[0437] (b) A nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 40.

[0438] The polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 38 includes, for example, a polynucleotide comprising the nucleotide sequence shown in SEQ ID NO: 37.

[0439] The polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 40 includes, for example, a polynucleotide comprising the nucleotide sequence shown in SEQ ID NO: 39.

[0440] In one embodiment, the polynucleotide of the present invention may further comprise a nucleotide sequence encoding an Fc polypeptide, and in one embodiment, the polynucleotide of the present invention may comprise a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO:42.

[0441] In one embodiment, the polynucleotide of the present invention comprises the nucleotide sequence described in (a) and / or (b) and (c) below:

[0442] (a) a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 22;

[0443] (b) A nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 24.

[0444] (c) A nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42.

[0445] The polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 22 includes, for example, a polynucleotide comprising the nucleotide sequence shown in SEQ ID NO: 21.

[0446] The polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 24 includes, for example, a polynucleotide comprising the nucleotide sequence shown in SEQ ID NO: 23.

[0447] In one embodiment, the polynucleotide of the present invention is a polynucleotide comprising a nucleotide sequence encoding the heavy chain of a one-armed anti-human NR1 antibody and / or a nucleotide sequence encoding the light chain of a one-armed anti-human NR1 antibody, wherein the antibody competitively binds to human NR1 with an anti-human NR1 antibody comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 2 and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 4, and inhibits NMDAR cellular internalization caused by pathogenic anti-human NR1 antibodies derived from patients with anti-NMDAR encephalitis.

[0448] The polynucleotides of the present invention can be easily produced by those skilled in the art based on their nucleotide sequences and by using methods well known in the art. For example, the polynucleotides of the present invention can be synthesized by utilizing gene synthesis methods known in the art. Such gene synthesis methods that can be used include various methods known to those skilled in the art, such as the method for synthesizing antibody genes described in WO90 / 07861.

[0449] <Expression vector of the present invention>

[0450] The expression vectors of the present invention include an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain variable region of a one-armed anti-human antibody, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain variable region of a one-armed anti-human antibody, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain variable region of a one-armed anti-human antibody of the present invention and a polynucleotide comprising a nucleotide sequence encoding the light chain variable region of the antibody. In addition, the expression vectors of the present invention include an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of a one-armed anti-human antibody of the present invention, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of a one-armed anti-human antibody of the present invention, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of a one-armed anti-human antibody of the present invention and a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody. The expression vectors of the present invention may comprise a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide.

[0451] In one embodiment, the expression vector of the present invention comprises a polynucleotide comprising a nucleotide sequence encoding a heavy chain variable region and / or a polynucleotide comprising a nucleotide sequence encoding a light chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of the amino acid sequence of amino acids 26 to 34 of SEQ ID NO: 2, a CDR2 consisting of the amino acid sequence of amino acids 52 to 58 of SEQ ID NO: 2, and a CDR3 consisting of the amino acid sequence of amino acids 97 to 109 of SEQ ID NO: 2, and the light chain variable region comprises a CDR1 consisting of the amino acid sequence of amino acids 26 to 33 of SEQ ID NO: 4, a CDR2 consisting of the amino acid sequence of amino acids 51 to 53 of SEQ ID NO: 4, and a CDR3 consisting of the amino acid sequence of amino acids 92 to 100 of SEQ ID NO: 4. In one embodiment, the expression vector of the present invention comprises a polynucleotide comprising a nucleotide sequence encoding a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 2 and / or a polynucleotide comprising a nucleotide sequence encoding a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 4. In one embodiment, the expression vector of the present invention comprises a polynucleotide comprising a nucleotide sequence encoding a heavy chain and / or a polynucleotide comprising a nucleotide sequence encoding a light chain, wherein the heavy chain comprises a heavy chain variable region comprising a CDR1 consisting of an amino acid sequence of amino acids 26 to 34 of SEQ ID NO: 2, a CDR2 consisting of an amino acid sequence of amino acids 52 to 58 of SEQ ID NO: 2, and a CDR3 consisting of an amino acid sequence of amino acids 97 to 109 of SEQ ID NO: 2, and the light chain comprises a light chain variable region comprising a CDR1 consisting of an amino acid sequence of amino acids 26 to 33 of SEQ ID NO: 4, a CDR2 consisting of an amino acid sequence of amino acids 51 to 53 of SEQ ID NO: 4, and a CDR3 consisting of an amino acid sequence of amino acids 92 to 100 of SEQ ID NO: 4. In one embodiment, the expression vector of the present invention comprises a polynucleotide comprising a nucleotide sequence encoding a heavy chain and / or a polynucleotide comprising a nucleotide sequence encoding a light chain, wherein the heavy chain comprises a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 2, and the light chain comprises a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 4. In one embodiment, the expression vector of the present invention comprises a polynucleotide comprising a nucleotide sequence encoding a heavy chain and / or a polynucleotide comprising a nucleotide sequence encoding a light chain, wherein the heavy chain consists of the amino acid sequence shown in SEQ ID NO: 22, and the light chain consists of the amino acid sequence shown in SEQ ID NO: 24.

[0452] In one embodiment, the expression vector of the present invention comprises a polynucleotide comprising a nucleotide sequence encoding a heavy chain variable region and / or a polynucleotide comprising a nucleotide sequence encoding a light chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of the amino acid sequence of amino acid numbers 31 to 35 of SEQ ID NO: 6, a CDR2 consisting of the amino acid sequence of amino acid numbers 50 to 66 of SEQ ID NO: 6, and a CDR3 consisting of the amino acid sequence of amino acid numbers 99 to 110 of SEQ ID NO: 6, and the light chain variable region comprises a CDR1 consisting of the amino acid sequence of amino acid numbers 24 to 34 of SEQ ID NO: 8, a CDR2 consisting of the amino acid sequence of amino acid numbers 50 to 56 of SEQ ID NO: 8, and a CDR3 consisting of the amino acid sequence of amino acid numbers 89 to 98 of SEQ ID NO: 8. In one embodiment, the expression vector of the present invention comprises a polynucleotide comprising a nucleotide sequence encoding a heavy chain variable region and / or a polynucleotide comprising a nucleotide sequence encoding a light chain variable region, wherein the heavy chain variable region consists of the amino acid sequence shown in SEQ ID NO: 6, and the light chain variable region consists of the amino acid sequence shown in SEQ ID NO: 8. In one embodiment, the expression vector of the present invention comprises a polynucleotide comprising a nucleotide sequence encoding a heavy chain and / or a polynucleotide comprising a nucleotide sequence encoding a light chain, wherein the heavy chain comprises a heavy chain variable region comprising a CDR1 consisting of an amino acid sequence numbered 31 to 35 of SEQ ID NO: 6, a CDR2 consisting of an amino acid sequence numbered 50 to 66 of SEQ ID NO: 6, and a CDR3 consisting of an amino acid sequence numbered 99 to 110 of SEQ ID NO: 6, and the light chain comprises a light chain variable region comprising a CDR1 consisting of an amino acid sequence numbered 24 to 34 of SEQ ID NO: 8, a CDR2 consisting of an amino acid sequence numbered 50 to 56 of SEQ ID NO: 8, and a CDR3 consisting of an amino acid sequence numbered 89 to 98 of SEQ ID NO: 8. In one embodiment, the expression vector of the present invention comprises a polynucleotide comprising a nucleotide sequence encoding a heavy chain and / or a polynucleotide comprising a nucleotide sequence encoding a light chain, wherein the heavy chain comprises a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 6, and the light chain comprises a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 8. In one embodiment, the expression vector of the present invention comprises a polynucleotide comprising a nucleotide sequence encoding a heavy chain and / or a polynucleotide comprising a nucleotide sequence encoding a light chain, wherein the heavy chain consists of the amino acid sequence shown in SEQ ID NO: 26, and the light chain consists of the amino acid sequence shown in SEQ ID NO: 28.

[0453] In one embodiment, the expression vector of the present invention comprises a polynucleotide comprising a nucleotide sequence encoding a heavy chain variable region and / or a polynucleotide comprising a nucleotide sequence encoding a light chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 31 to 35 of SEQ ID NO: 10, a CDR2 consisting of an amino acid sequence of amino acids 50 to 66 of SEQ ID NO: 10, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 111 of SEQ ID NO: 10, and the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 12, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 12, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 97 of SEQ ID NO: 12. In one embodiment, the expression vector of the present invention comprises a polynucleotide comprising a nucleotide sequence encoding a heavy chain variable region and / or a polynucleotide comprising a nucleotide sequence encoding a light chain variable region, wherein the heavy chain variable region consists of the amino acid sequence shown in SEQ ID NO: 10, and the light chain variable region consists of the amino acid sequence shown in SEQ ID NO: 12. In one embodiment, the expression vector of the present invention comprises a polynucleotide comprising a nucleotide sequence encoding a heavy chain and / or a polynucleotide comprising a nucleotide sequence encoding a light chain, wherein the heavy chain comprises a heavy chain variable region comprising a CDR1 consisting of an amino acid sequence of amino acids 31 to 35 of SEQ ID NO: 10, a CDR2 consisting of an amino acid sequence of amino acids 50 to 66 of SEQ ID NO: 10, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 111 of SEQ ID NO: 10, and the light chain comprises a light chain variable region comprising a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 12, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 12, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 97 of SEQ ID NO: 12. In one embodiment, the expression vector of the present invention comprises a polynucleotide comprising a nucleotide sequence encoding a heavy chain and / or a polynucleotide comprising a nucleotide sequence encoding a light chain, wherein the heavy chain comprises a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 10, and the light chain comprises a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 12.In one embodiment, the expression vector of the present invention comprises a polynucleotide comprising a nucleotide sequence encoding a heavy chain and / or a polynucleotide comprising a nucleotide sequence encoding a light chain, wherein the heavy chain consists of the amino acid sequence shown in SEQ ID NO: 30, and the light chain consists of the amino acid sequence shown in SEQ ID NO: 32.

[0454] In one embodiment, the expression vector of the present invention comprises a polynucleotide comprising a nucleotide sequence encoding a heavy chain variable region and / or a polynucleotide comprising a nucleotide sequence encoding a light chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acid numbers 31 to 36 of SEQ ID NO: 14, a CDR2 consisting of an amino acid sequence of amino acid numbers 51 to 66 of SEQ ID NO: 14, and a CDR3 consisting of an amino acid sequence of amino acid numbers 99 to 108 of SEQ ID NO: 14, and the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acid numbers 24 to 34 of SEQ ID NO: 16, a CDR2 consisting of an amino acid sequence of amino acid numbers 50 to 56 of SEQ ID NO: 16, and a CDR3 consisting of an amino acid sequence of amino acid numbers 89 to 97 of SEQ ID NO: 16. In one embodiment, the expression vector of the present invention comprises a polynucleotide comprising a nucleotide sequence encoding a heavy chain variable region and / or a polynucleotide comprising a nucleotide sequence encoding a light chain variable region, wherein the heavy chain variable region consists of the amino acid sequence shown in SEQ ID NO: 14, and the light chain variable region consists of the amino acid sequence shown in SEQ ID NO: 16. In one embodiment, the expression vector of the present invention comprises a polynucleotide comprising a nucleotide sequence encoding a heavy chain and / or a polynucleotide comprising a nucleotide sequence encoding a light chain, wherein the heavy chain comprises a heavy chain variable region comprising a CDR1 consisting of an amino acid sequence numbered 31 to 36 of SEQ ID NO: 14, a CDR2 consisting of an amino acid sequence numbered 51 to 66 of SEQ ID NO: 14, and a CDR3 consisting of an amino acid sequence numbered 99 to 108 of SEQ ID NO: 14, and the light chain comprises a light chain variable region comprising a CDR1 consisting of an amino acid sequence numbered 24 to 34 of SEQ ID NO: 16, a CDR2 consisting of an amino acid sequence numbered 50 to 56 of SEQ ID NO: 16, and a CDR3 consisting of an amino acid sequence numbered 89 to 97 of SEQ ID NO: 16. In one embodiment, the expression vector of the present invention comprises a polynucleotide comprising a nucleotide sequence encoding a heavy chain and / or a polynucleotide comprising a nucleotide sequence encoding a light chain, wherein the heavy chain comprises a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 14, and the light chain comprises a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 16.In one embodiment, the expression vector of the present invention comprises a polynucleotide comprising a nucleotide sequence encoding a heavy chain and / or a polynucleotide comprising a nucleotide sequence encoding a light chain, wherein the heavy chain consists of the amino acid sequence shown in SEQ ID NO: 34, and the light chain consists of the amino acid sequence shown in SEQ ID NO: 36.

[0455] In one embodiment, the expression vector of the present invention comprises a polynucleotide comprising a nucleotide sequence encoding a heavy chain variable region and / or a polynucleotide comprising a nucleotide sequence encoding a light chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 31 to 36 of SEQ ID NO: 18, a CDR2 consisting of an amino acid sequence of amino acids 51 to 66 of SEQ ID NO: 18, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 108 of SEQ ID NO: 18, and the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 20, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 20, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 97 of SEQ ID NO: 20. In one embodiment, the expression vector of the present invention comprises a polynucleotide comprising a nucleotide sequence encoding a heavy chain variable region and / or a polynucleotide comprising a nucleotide sequence encoding a light chain variable region, wherein the heavy chain variable region consists of the amino acid sequence shown in SEQ ID NO: 18, and the light chain variable region consists of the amino acid sequence shown in SEQ ID NO: 20. In one embodiment, the expression vector of the present invention comprises a polynucleotide comprising a nucleotide sequence encoding a heavy chain and / or a polynucleotide comprising a nucleotide sequence encoding a light chain, wherein the heavy chain comprises a heavy chain variable region comprising a CDR1 consisting of an amino acid sequence numbered 31 to 36 of SEQ ID NO: 18, a CDR2 consisting of an amino acid sequence numbered 51 to 66 of SEQ ID NO: 18, and a CDR3 consisting of an amino acid sequence numbered 99 to 108 of SEQ ID NO: 18, and the light chain comprises a light chain variable region comprising a CDR1 consisting of an amino acid sequence numbered 24 to 34 of SEQ ID NO: 20, a CDR2 consisting of an amino acid sequence numbered 50 to 56 of SEQ ID NO: 20, and a CDR3 consisting of an amino acid sequence numbered 89 to 97 of SEQ ID NO: 20. In one embodiment, the expression vector of the present invention comprises a polynucleotide comprising a nucleotide sequence encoding a heavy chain and / or a polynucleotide comprising a nucleotide sequence encoding a light chain, wherein the heavy chain comprises a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 18, and the light chain comprises a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 20.In one embodiment, the expression vector of the present invention comprises a polynucleotide comprising a nucleotide sequence encoding a heavy chain and / or a polynucleotide comprising a nucleotide sequence encoding a light chain, wherein the heavy chain consists of the amino acid sequence shown in SEQ ID NO: 38, and the light chain consists of the amino acid sequence shown in SEQ ID NO: 40.

[0456] In one embodiment, the expression vector of the present invention may further comprise a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide. In one embodiment, the expression vector of the present invention may further comprise a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide shown in SEQ ID NO: 42.

[0457] In one embodiment, the expression vector of the present invention is an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of a one-armed anti-human NR1 antibody and / or a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody, wherein the antibody competitively binds to human NR1 with an anti-human NR1 antibody comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 2 and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 4, and inhibits NMDAR cellular internalization caused by pathogenic anti-human NR1 antibodies derived from patients with anti-NMDAR encephalitis.

[0458] In one embodiment, the expression vector of the present invention is an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of a one-armed anti-human NR1 antibody and / or a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody and an Fc polypeptide of the antibody, wherein the antibody competitively binds to human NR1 with an anti-human NR1 antibody comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 2 and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 4, and inhibits NMDAR cellular internalization caused by pathogenic anti-human NR1 antibodies derived from patients with anti-NMDAR encephalitis.

[0459] Expression vectors for expressing the polynucleotides of the present invention include, but are not limited to, polynucleotides comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody of the present invention, a polynucleotide comprising a nucleotide sequence encoding the light chain of the one-armed anti-human NR1 antibody of the present invention, or a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide that can be expressed in various host cells such as eukaryotic cells (e.g., animal cells, insect cells, plant cells, and yeast) and / or prokaryotic cells (e.g., E. coli), wherein the Fc polypeptide is combined with the heavy chain to form an Fc region and produce the polypeptides encoded by them. Such expression vectors include, for example, plasmid vectors, viral vectors (e.g., adenovirus and retrovirus), etc. In one embodiment, pEE6.4 or pEE12.4 (Lonza) can be used as an expression vector.

[0460] The expression vector of the present invention may comprise a promoter operably coupled to the polynucleotide of the present invention. Promoters used to express the polynucleotide of the present invention in animal cells include, for example, promoters of viral origin (such as CMV, RSV and SV40), actin promoters, EF (elongation factor) 1α promoters, heat shock promoters, etc. Promoters used to express the polynucleotide of the present invention in bacteria (e.g., Escherichia coli) include, for example, trp promoters, lac promoters, λPL promoters, tac promoters, etc. Promoters used to express the polynucleotide of the present invention in yeast include, for example, GAL 1 promoters, GAL 10 promoters, PH05 promoters, PGK promoters, GAP promoters, ADH promoters, etc.

[0461] When animal cells, insect cells or yeast are used as host cells, the expression vector of the present invention may include a start codon, a stop codon, an enhancer sequence, 5' and 3' untranslated regions of the gene encoding the one-armed anti-human NR1 antibody of the present invention or its heavy chain or light chain, a secretion signal sequence, a splice junction, a polyadenylation site or a replicable unit, etc. When Escherichia coli is used as a host cell, the expression vector of the present invention may include a start codon, a stop codon, a terminator region and a replicable unit. Depending on the purpose, the expression vector of the present invention may include a commonly used selective marker (e.g., a tetracycline resistance gene, an ampicillin resistance gene, a kanamycin resistance gene, a neomycin resistance gene and a dihydrofolate reductase gene).

[0462] <Transformed host cell of the present invention>

[0463] The transformed host cells of the present invention include transformed host cells having the expression vector of the present invention. The transformed host cells of the present invention include host cells selected from the following (1)-(4):

[0464] (1) A transformed host cell having an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain variable region of the one-armed anti-human NR1 antibody of the present invention;

[0465] (2) a transformed host cell having an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain variable region of the one-armed anti-human NR1 antibody of the present invention;

[0466] (3) a transformed host cell having an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain variable region of the one-armed anti-human NR1 antibody of the present invention and a polynucleotide comprising a nucleotide sequence encoding the light chain variable region of the antibody;

[0467] (4) A transformed host cell having an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain variable region of the one-armed anti-human NR1 antibody of the present invention, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain variable region of the antibody.

[0468] The transformed host cells of the present invention also include host cells selected from the following (a)-(d):

[0469] (a) a transformed host cell having an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of a one-armed anti-human NR1 antibody of the present invention;

[0470] (b) a transformed host cell having an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the one-armed anti-human NR1 antibody of the present invention;

[0471] (c) a transformed host cell having an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody of the present invention and a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody;

[0472] (d) A transformed host cell having an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody of the present invention and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody.

[0473] In one embodiment, the expression vector contained in the host cell of (a)-(d) above may further contain a polynucleotide containing a nucleotide sequence encoding an Fc polypeptide. In one embodiment, the host cell of (a)-(d) above may further contain an expression vector containing a polynucleotide containing a nucleotide sequence encoding an Fc polypeptide.

[0474] Examples of transformed host cells of the present invention include transformed host cells having an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody of the present invention, a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody, and a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody; transformed host cells having an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody of the present invention, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody, and a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody; and transformed host cells having an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody of the present invention, a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody.

[0475] In one embodiment, the host cell of the present invention is a transformed host cell having an expression vector selected from the group consisting of (a) to (d):

[0476] (a) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain variable region of the one-armed anti-human NR1 antibody of the present invention as listed in any one of (1) to (8) below;

[0477] (b) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain variable region of the one-armed anti-human NR1 antibody of the present invention as listed in any one of (1) to (8) below; (c) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain variable region of the one-armed anti-human NR1 antibody of the present invention as listed in any one of (1) to (8) below and a polynucleotide comprising a nucleotide sequence encoding the light chain variable region of the antibody;

[0478] (d) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain variable region of the one-armed anti-human NR1 antibody of the present invention as set forth in any one of (1) to (8) below, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain variable region of the antibody:

[0479] (1) A one-armed anti-human NR1 antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 31 to 35 of SEQ ID NO: 6, a CDR2 consisting of an amino acid sequence of amino acids 50 to 60 of SEQ ID NO: 6, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 110 of SEQ ID NO: 6, and the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 8, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 8, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 98 of SEQ ID NO: 8;

[0480] (2) a one-armed anti-human NR1 antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 31 to 35 of SEQ ID NO: 10, a CDR2 consisting of an amino acid sequence of amino acids 50 to 66 of SEQ ID NO: 10, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 111 of SEQ ID NO: 10, and the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 12, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 12, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 97 of SEQ ID NO: 12;

[0481] (3) a one-armed anti-human NR1 antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 31 to 36 of SEQ ID NO: 14, a CDR2 consisting of an amino acid sequence of amino acids 51 to 66 of SEQ ID NO: 14, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 108 of SEQ ID NO: 14, and the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 16, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 16, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 97 of SEQ ID NO: 16;

[0482] (4) a one-armed anti-human NR1 antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 31 to 36 of SEQ ID NO: 18, a CDR2 consisting of an amino acid sequence of amino acids 51 to 66 of SEQ ID NO: 18, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 108 of SEQ ID NO: 18, and the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 20, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 20, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 97 of SEQ ID NO: 20;

[0483] (5) a one-armed anti-human NR1 antibody comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 6, and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 8;

[0484] (6) a one-armed anti-human NR1 antibody comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 10, and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 12;

[0485] (7) a one-armed anti-human NR1 antibody comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 14, and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 16;

[0486] (8) A one-armed anti-human NR1 antibody comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 18, and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 20.

[0487] In one embodiment, the host cell of the present invention is a transformed host cell having an expression vector selected from the group consisting of:

[0488] (a) an expression vector comprising a polynucleotide encoding a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody of the present invention as listed in any one of (1) to (8) below;

[0489] (b) an expression vector comprising a polynucleotide encoding a nucleotide sequence encoding the light chain of the one-armed anti-human NR1 antibody of the present invention as listed in any one of (1) to (8) below;

[0490] (c) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody of the present invention as set forth in any one of (1) to (8) below and a polynucleotide comprising a nucleotide sequence encoding the light chain variable region of the antibody;

[0491] (d) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody of the present invention as listed in any one of (1) to (8) below and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody:

[0492] (1) A one-armed anti-human NR1 antibody comprising a heavy chain, a light chain, and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region comprising a CDR1 consisting of an amino acid sequence of amino acids 31 to 35 of SEQ ID NO: 6, a CDR2 consisting of an amino acid sequence of amino acids 50 to 66 of SEQ ID NO: 6, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 110 of SEQ ID NO: 6, and the light chain comprises a light chain variable region comprising a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 8, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 8, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 98 of SEQ ID NO: 8;

[0493] (2) A one-armed anti-human NR1 antibody comprising a heavy chain, a light chain, and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 31 to 35 of SEQ ID NO: 10, a CDR2 consisting of an amino acid sequence of amino acids 50 to 66 of SEQ ID NO: 10, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 111 of SEQ ID NO: 10; and the light chain comprises a light chain variable region, wherein the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 12, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 12, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 97 of SEQ ID NO: 12;

[0494] (3) A one-armed anti-human NR1 antibody comprising a heavy chain, a light chain, and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 31 to 36 of SEQ ID NO: 14, a CDR2 consisting of an amino acid sequence of amino acids 51 to 66 of SEQ ID NO: 14, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 108 of SEQ ID NO: 14; and the light chain comprises a light chain variable region, wherein the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 16, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 16, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 97 of SEQ ID NO: 16;

[0495] (4) A one-armed anti-human NR1 antibody comprising a heavy chain, a light chain, and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 31 to 36 of SEQ ID NO: 18, a CDR2 consisting of an amino acid sequence of amino acids 51 to 66 of SEQ ID NO: 18, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 108 of SEQ ID NO: 18; and the light chain comprises a light chain variable region, wherein the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 20, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 20, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 97 of SEQ ID NO: 20;

[0496] (5) A one-armed anti-human NR1 antibody comprising a heavy chain, a light chain, and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 6, and the light chain comprises a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 8;

[0497] (6) an anti-human NR1 antibody comprising a heavy chain, a light chain, and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 10, and the light chain comprises a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 12;

[0498] (7) A one-armed anti-human NR1 antibody comprising a heavy chain, a light chain, and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 14, and the light chain comprises a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 16;

[0499] (8) An anti-human NR1 antibody comprising a heavy chain, a light chain, and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region, and the heavy chain variable region consists of the amino acid sequence shown in SEQ ID NO: 18; and the light chain comprises a light chain variable region, and the light chain variable region consists of the amino acid sequence shown in SEQ ID NO: 20.

[0500] In one embodiment, the host cell of the present invention is a transformed host cell having an expression vector selected from the group consisting of (a)-(i) below:

[0501] (a) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody of the present invention as listed in any one of the following (1) to (10) and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody; (b) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the one-armed anti-human NR1 antibody of the present invention as listed in any one of the following (1) to (10) and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody; (c) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody of the present invention as listed in any one of the following (1) to (10) and a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody;

[0502] (d) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody of the present invention as listed in any one of (1) to (10) below, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody;

[0503] (e) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody of the present invention as set forth in any one of (1) to (10) below and a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody;

[0504] (f) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the one-armed anti-human NR1 antibody of the present invention as listed in any one of (1) to (10) below and a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody;

[0505] (g) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody of the present invention as set forth in any one of (1) to (10) below and a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody;

[0506] (h) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody of the present invention as set forth in any one of (1) to (10) below, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody and a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody;

[0507] (i) An expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody of the present invention as listed in any one of (1) to (10) below, a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody, and a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody:

[0508] (1) A one-armed anti-human NR1 antibody comprising a heavy chain, a light chain, and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 26 to 34 of SEQ ID NO: 2, a CDR2 consisting of an amino acid sequence of amino acids 52 to 58 of SEQ ID NO: 2, and a CDR3 consisting of an amino acid sequence of amino acids 97 to 109 of SEQ ID NO: 2; and the light chain comprises a light chain variable region, wherein the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 26 to 33 of SEQ ID NO: 4, a CDR2 consisting of an amino acid sequence of amino acids 51 to 53 of SEQ ID NO: 4, and a CDR3 consisting of an amino acid sequence of amino acids 92 to 100 of SEQ ID NO: 4;

[0509] (2) A one-armed anti-human NR1 antibody comprising a heavy chain, a light chain, and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 31 to 35 of SEQ ID NO: 6, a CDR2 consisting of an amino acid sequence of amino acids 50 to 66 of SEQ ID NO: 6, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 110 of SEQ ID NO: 6; and the light chain comprises a light chain variable region, wherein the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 8, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 8, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 98 of SEQ ID NO: 8;

[0510] (3) A one-armed anti-human NR1 antibody comprising a heavy chain, a light chain, and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 31 to 35 of SEQ ID NO: 10, a CDR2 consisting of an amino acid sequence of amino acids 50 to 66 of SEQ ID NO: 10, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 111 of SEQ ID NO: 10; and the light chain comprises a light chain variable region, wherein the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 12, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 12, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 97 of SEQ ID NO: 12;

[0511] (4) A one-armed anti-human NR1 antibody comprising a heavy chain, a light chain, and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 31 to 36 of SEQ ID NO: 14, a CDR2 consisting of an amino acid sequence of amino acids 51 to 66 of SEQ ID NO: 14, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 108 of SEQ ID NO: 14; and the light chain comprises a light chain variable region, wherein the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 16, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 16, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 97 of SEQ ID NO: 16;

[0512] (5) A one-armed anti-human NR1 antibody comprising a heavy chain, a light chain, and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 31 to 36 of SEQ ID NO: 18, a CDR2 consisting of an amino acid sequence of amino acids 51 to 66 of SEQ ID NO: 18, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 108 of SEQ ID NO: 18; and the light chain comprises a light chain variable region, wherein the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 20, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 20, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 97 of SEQ ID NO: 20;

[0513] (6) A one-armed anti-human NR1 antibody comprising a heavy chain, a light chain, and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 2, and the light chain comprises a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 4;

[0514] (7) A one-armed anti-human NR1 antibody comprising a heavy chain, a light chain, and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 6, and the light chain comprises a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 8;

[0515] (8) A one-armed anti-human NR1 antibody comprising a heavy chain, a light chain, and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 10, and the light chain comprises a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 12;

[0516] (9) A one-armed anti-human NR1 antibody comprising a heavy chain, a light chain, and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 14, and the light chain comprises a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 16;

[0517] (10) A single-armed anti-human NR1 antibody comprising a heavy chain, a light chain, and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region, and the heavy chain variable region consists of the amino acid sequence shown in SEQ ID NO: 18; and the light chain comprises a light chain variable region, and the light chain variable region consists of the amino acid sequence shown in SEQ ID NO: 20.

[0518] In one embodiment, the host cell of the present invention is a transformed host cell having an expression vector selected from the group consisting of (a)-(i) below:

[0519] (a) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 22, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0520] (b) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 22 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0521] (c) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 24, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0522] (d) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 24 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0523] (e) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 22 and a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 24, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0524] (f) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 22 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 24;

[0525] (g) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 22, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 24, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0526] (h) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 22, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 24, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0527] (i) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 22, a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 24, and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42.

[0528] In one embodiment, the host cell of the present invention is a transformed host cell having one or more expression vectors selected from the group consisting of:

[0529] (a) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 26;

[0530] (b) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 28;

[0531] (c) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 26 and a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 28;

[0532] (d) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 26, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 28;

[0533] (e) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 26 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0534] (f) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 28 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0535] (g) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 26, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0536] (h) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 28, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0537] (i) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 26 and a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 28, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0538] (j) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 26 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 28;

[0539] (k) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 26, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 28, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0540] (1) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 26, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 28, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0541] (m) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 26, a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 28, and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42.

[0542] In one embodiment, the host cell of the present invention is a transformed host cell having one or more expression vectors selected from the group consisting of:

[0543] (a) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 30;

[0544] (b) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 32;

[0545] (c) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 30 and a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 32;

[0546] (d) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 30, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 32;

[0547] (e) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 30 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0548] (f) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 32 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0549] (g) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 30, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0550] (h) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 32, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0551] (i) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 30 and a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 32, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0552] (j) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 30 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 32;

[0553] (k) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 30, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 32, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0554] (1) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 30, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 32, and an expression vector comprising a polynucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0555] (m) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 30, a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 32, and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42.

[0556] In one embodiment, the host cell of the present invention is a transformed host cell having one or more expression vectors selected from the group consisting of:

[0557] (a) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34;

[0558] (b) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 36;

[0559] (c) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34 and a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 36;

[0560] (d) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 36;

[0561] (e) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0562] (f) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 36 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0563] (g) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0564] (h) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 36, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0565] (i) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34 and a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 36, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0566] (j) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34 and a polynucleotide comprising a nucleotide sequence comprising an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 36;

[0567] (k) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 36, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0568] (1) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 36, and an expression vector comprising a polynucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0569] (m) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34, a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 36, and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42.

[0570] In one embodiment, the host cell of the present invention is a transformed host cell having one or more expression vectors selected from the group consisting of:

[0571] (a) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 38;

[0572] (b) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 40;

[0573] (c) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 38 and a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 40;

[0574] (d) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 38, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 40;

[0575] (e) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 38 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0576] (f) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 40 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0577] (g) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 38, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0578] (h) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 40, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0579] (i) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 38 and a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 40, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0580] (j) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 38 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 40;

[0581] (k) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 38, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 40, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0582] (1) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 38, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 40, and an expression vector comprising a polynucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0583] (m) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 38, a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 40, and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42.

[0584] In one embodiment, the host cell of the present invention is a transformed host cell having an expression vector encoding the heavy chain and / or light chain of a one-armed anti-human NR1 antibody, wherein the one-armed anti-human NR1 antibody competitively binds to human NR1 with an anti-human NR1 antibody comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 2 and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 4, and inhibits NMDAR cellular internalization caused by pathogenic anti-human NR1 antibodies derived from patients with anti-NMDAR encephalitis, wherein the host cell of the present invention is a transformed host cell having one or more expression vectors selected from the following:

[0585] (a) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the antibody;

[0586] (b) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody;

[0587] (c) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the antibody and a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody;

[0588] (d) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the antibody, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody;

[0589] (e) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the antibody and a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody;

[0590] (f) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody and a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody;

[0591] (g) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the antibody, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody;

[0592] (h) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody;

[0593] (i) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the antibody and a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody; (j) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the antibody and a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody; (k) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the antibody, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody and a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody;

[0594] (1) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the antibody, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody;

[0595] (m) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the antibody, a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody, and a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody.

[0596] There are no particular limitations on the host cell for transformation, as long as it is compatible with the expression vector used and can be transformed with one or more expression vectors and express the antibody. The host cell for transformation includes, for example, various cells, such as natural cells or artificially established cells commonly used in the technical field of the present invention (e.g., animal cells (e.g., CHOK1SV1 cells), incest cells (e.g., Sf9), cells (e.g., Escherichia coli, etc.), yeast (Saccharomyces, Pichia, etc.), etc.). In one embodiment, cultured cells such as CHOK1SV cells, CHO-DG44 cells, HEK293 cells, and NS0 cells can be used as host cells.

[0597] Methods for transforming host cells include the calcium phosphate method, electroporation, and the like.

[0598] <Method for producing the one-armed anti-human NR1 antibody of the present invention, and the one-armed anti-human NR1 antibody produced thereby>

[0599] The method for producing a one-armed anti-human NR1 antibody comprises culturing a transformed host cell of the present invention, expressing a one-armed anti-human NR1 antibody, and producing a one-armed anti-human NR1 antibody. In one embodiment, the method for producing a one-armed anti-human NR1 antibody of the present invention comprises culturing a host cell selected from the following (a)-(e), and expressing the one-armed anti-human NR1 antibody:

[0600] (a) a host cell transformed with an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody of the present invention, a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody, and a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody;

[0601] (b) a host cell transformed with an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of a one-armed anti-human NR1 antibody and a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody;

[0602] (c) a host cell transformed with an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of a one-armed anti-human NR1 antibody and a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody;

[0603] (d) a host cell transformed with an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of a one-armed anti-human NR1 antibody and a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the antibody;

[0604] (e) A host cell transformed with an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody of the present invention, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody.

[0605] The method for producing the one-armed anti-human NR1 antibody of the present invention is not particularly limited, as long as the method comprises culturing the transformed host cell of the present invention and expressing the one-armed anti-human NR1 antibody.

[0606] The transformed host cells can be cultured by known methods. Culture conditions, for example, temperature, pH of the culture medium, and culture time are appropriately selected. If the host cells are animal cells, culture medium such as MEM medium (Science, 1959, Vol. 130, pp. 432-437), DMEM medium (Virology, 1959, Vol. 8, p. 396), RPMI1640 medium (J. Am. Med. Assoc., 1967, Vol. 199, p. 519), 199 medium (Exp. Biol. Med., 1950, Vol. 73, pp. 1-8) containing about 5-20% fetal bovine serum can be used as culture medium. The pH of the culture medium is, for example, about 6-8, and culture is performed regularly at about 30-40° C. for about 15-336 hours, with ventilation and stirring as needed. If the host cell is an insect cell, a culture medium such as Grace medium (Proc. Natl. Acad. Sci. USA., 1985, Vol. 82, p. 8404) containing fetal bovine serum can be used as a culture medium. The pH of the culture medium is, for example, about 5-8, and culture is carried out regularly at about 20-40° C. for about 15-100 hours, with ventilation and stirring if necessary. If the host cell is Escherichia coli or yeast, a liquid culture medium containing, for example, a nutrient source is suitable as a culture medium. The nutrient medium contains, for example, a carbon source, an inorganic or organic nitrogen source required for the growth of the transformed host cells. Carbon sources include, for example, glucose, dextran, soluble starch, and sucrose, and inorganic or organic nitrogen sources include, for example, ammonium salts, nitrates, amino acids, corn steep liquor, peptone, casein, meat extract, soy flour, and potato extract. If necessary, it may contain other nutrients (e.g., inorganic salts (e.g., calcium chloride, sodium dihydrogen phosphate, magnesium chloride) and vitamins), antibiotics (e.g., tetracycline, neomycin, ampicillin, kanamycin), etc. The pH of the culture medium is, for example, about 5-8. If the host cell is Escherichia coli, LB medium and M9 medium (Molecular Cloning, Cold Spring Harbor Laboratory, Vol. 3, A2.2) and the like can be used as culture medium. The culture medium is regularly cultured at about 14-43° C. for about 3-24 hours, and is ventilated and stirred when necessary. If the host cell is yeast, Burkholder minimal medium (Proc. Natl. Acad. Sci. USA., 1980, Vol. 77, p. 4505) and the like can be used as culture medium. Culture is regularly carried out at about 20-35° C. for about 14-144 hours, and is ventilated and stirred when necessary. The one-armed anti-human NR1 antibody of the present invention can be expressed by the above-mentioned culture.

[0607] In addition to culturing transformed host cells and expressing the one-armed anti-human NR1 antibody of the present invention, the method for producing the one-armed anti-human NR1 antibody of the present invention may also include recovering, isolating or purifying the one-armed anti-human NR1 antibody from the transformed host cells. The method of separation or purification includes, for example, methods utilizing solubility, such as salting out and solvent precipitation; methods utilizing molecular weight differences, such as dialysis, ultrafiltration and gel filtration; methods utilizing charge, such as ion exchange chromatography and hydroxyapatite chromatography; methods utilizing specific affinity, such as affinity chromatography; methods utilizing hydrophobicity differences, such as reversed-phase high-performance liquid chromatography; and methods utilizing isoelectric point differences, such as isoelectric point electrophoresis. In one embodiment, the antibodies accumulated in the culture supernatant can be purified by various chromatographic methods, such as column chromatography using a protein A column or a protein G column.

[0608] In the method for producing the one-armed anti-human NR1 antibody of the present invention, the one-armed anti-human NR1 antibody can be effectively obtained by introducing knob-to-hole mutations in the CH3 of the heavy chain of the one-armed anti-human NR1 antibody and the CH3 of the Fc polypeptide that combines with the heavy chain to form the Fc region, respectively.

[0609] The one-armed anti-human NR1 antibody of the present invention also includes a one-armed anti-human NR1 antibody produced by the method for producing the one-armed anti-human NR1 antibody of the present invention.

[0610] <Pharmaceutical Compositions, Etc. of the Present Invention>

[0611] The pharmaceutical composition of the present invention comprises a composition containing the one-armed anti-human NR1 antibody of the present invention and a pharmaceutically acceptable excipient. The pharmaceutical composition of the present invention can be prepared by conventional methods using excipients commonly used in the art, i.e., pharmaceutical excipients or pharmaceutical carriers. The dosage forms of these pharmaceutical compositions include, for example, parenteral dosage forms such as injections, drips, etc., and the pharmaceutical compositions can be administered by intravenous administration, subcutaneous administration, etc. When preparing the pharmaceutical composition, the excipients, carriers, additives, etc. according to these dosage forms can be used within a pharmaceutically acceptable range.

[0612] The pharmaceutical composition of the present invention may comprise a plurality of one-armed anti-human NR1 antibodies of the present invention. For example, the present invention comprises one-armed anti-human NR1 antibodies without C-terminal lysine deletion and N-terminal pyroglutamylation, and / or one-armed anti-human NR1 antibodies with C-terminal lysine deletion and N-terminal pyroglutamylation.

[0613] In one embodiment, the pharmaceutical composition of the present invention comprises a one-armed anti-human NR1 antibody selected from any one of the following (1) to (5) and / or a one-armed anti-human NR1 antibody produced by post-translational modification of the one-armed anti-human NR1 antibody:

[0614] (1) A one-armed anti-human NR1 antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 26 to 34 of SEQ ID NO: 2, a CDR2 consisting of an amino acid sequence of amino acids 52 to 58 of SEQ ID NO: 2, and a CDR3 consisting of an amino acid sequence of amino acids 97 to 109 of SEQ ID NO: 2, and the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 26 to 33 of SEQ ID NO: 4, a CDR2 consisting of an amino acid sequence of amino acids 51 to 53 of SEQ ID NO: 4, and a CDR3 consisting of an amino acid sequence of amino acids 92 to 100 of SEQ ID NO: 4;

[0615] (2) a one-armed anti-human NR1 antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 31 to 35 of SEQ ID NO: 6, a CDR2 consisting of an amino acid sequence of amino acids 50 to 60 of SEQ ID NO: 6, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 110 of SEQ ID NO: 6, and the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 8, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 8, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 98 of SEQ ID NO: 8;

[0616] (3) a one-armed anti-human NR1 antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 31 to 35 of SEQ ID NO: 10, a CDR2 consisting of an amino acid sequence of amino acids 50 to 66 of SEQ ID NO: 10, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 111 of SEQ ID NO: 10, and the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 12, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 12, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 97 of SEQ ID NO: 12;

[0617] (4) a one-armed anti-human NR1 antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 31 to 36 of SEQ ID NO: 14, a CDR2 consisting of an amino acid sequence of amino acids 51 to 66 of SEQ ID NO: 14, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 108 of SEQ ID NO: 14, and the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 16, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 16, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 97 of SEQ ID NO: 16;

[0618] (5) A one-armed anti-human NR1 antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acid numbers 31 to 36 of SEQ ID NO: 18, a CDR2 consisting of an amino acid sequence of amino acid numbers 51 to 66 of SEQ ID NO: 18, and a CDR3 consisting of an amino acid sequence of amino acid numbers 99 to 108 of SEQ ID NO: 18, and the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acid numbers 24 to 34 of SEQ ID NO: 20, a CDR2 consisting of an amino acid sequence of amino acid numbers 50 to 56 of SEQ ID NO: 20, and a CDR3 consisting of an amino acid sequence of amino acid numbers 89 to 97 of SEQ ID NO: 20.

[0619] In one embodiment, the pharmaceutical composition of the present invention comprises a one-armed anti-human NR1 antibody selected from any one of the following (1) to (5) and / or a one-armed anti-human NR1 antibody produced by post-translational modification of the one-armed anti-human NR1 antibody:

[0620] (1) A one-armed anti-human NR1 antibody comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 2, and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 4;

[0621] (2) a one-armed anti-human NR1 antibody comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 6, and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 8;

[0622] (3) a one-armed anti-human NR1 antibody comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 10, and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 12;

[0623] (4) a one-armed anti-human NR1 antibody comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 14, and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 16;

[0624] (5) A one-armed anti-human NR1 antibody comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 18, and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 20.

[0625] In one embodiment, the pharmaceutical composition of the present invention comprises a one-armed anti-human NR1 antibody selected from any one of the following (1) to (5) and / or a one-armed anti-human NR1 antibody produced by post-translational modification of the one-armed anti-human NR1 antibody:

[0626] (1) A one-armed anti-human NR1 antibody comprising a heavy chain, a light chain, and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region comprising a CDR1 consisting of an amino acid sequence of amino acids 26 to 34 of SEQ ID NO: 2, a CDR2 consisting of an amino acid sequence of amino acids 52 to 58 of SEQ ID NO: 2, and a CDR3 consisting of an amino acid sequence of amino acids 97 to 109 of SEQ ID NO: 2, and the light chain comprises a light chain variable region comprising a CDR1 consisting of an amino acid sequence of amino acids 26 to 33 of SEQ ID NO: 4, a CDR2 consisting of an amino acid sequence of amino acids 51 to 53 of SEQ ID NO: 4, and a CDR3 consisting of an amino acid sequence of amino acids 92 to 100 of SEQ ID NO: 4;

[0627] (2) A one-armed anti-human NR1 antibody comprising a heavy chain, a light chain, and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 31 to 35 of SEQ ID NO: 6, a CDR2 consisting of an amino acid sequence of amino acids 50 to 66 of SEQ ID NO: 6, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 110 of SEQ ID NO: 6, and the light chain comprises a light chain variable region, wherein the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 8, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 8, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 98 of SEQ ID NO: 8;

[0628] (3) a one-armed anti-human NR1 antibody comprising a heavy chain variable region, a light chain, and an Fc polypeptide, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 31 to 35 of SEQ ID NO: 10, a CDR2 consisting of an amino acid sequence of amino acids 50 to 66 of SEQ ID NO: 10, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 111 of SEQ ID NO: 10, and the light chain comprises a light chain variable region comprising a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 12, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 12, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 97 of SEQ ID NO: 12;

[0629] (4) a one-armed anti-human NR1 antibody comprising a heavy chain and a light chain and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region comprising a CDR1 consisting of an amino acid sequence of amino acids 31 to 36 of SEQ ID NO: 14, a CDR2 consisting of an amino acid sequence of amino acids 51 to 66 of SEQ ID NO: 14, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 108 of SEQ ID NO: 14, and the light chain comprises a light chain variable region comprising a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 16, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 16, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 97 of SEQ ID NO: 16;

[0630] (5) A one-armed anti-human NR1 antibody comprising a heavy chain, a light chain and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 31 to 36 of SEQ ID NO: 18, a CDR2 consisting of an amino acid sequence of amino acids 51 to 66 of SEQ ID NO: 18, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 108 of SEQ ID NO: 18, and the light chain comprises a light chain variable region, wherein the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 20, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 20, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 97 of SEQ ID NO: 20.

[0631] In one embodiment, the pharmaceutical composition of the present invention comprises a one-armed anti-human NR1 antibody selected from any one of the following (1) to (5) and / or a one-armed anti-human NR1 antibody produced by post-translational modification of the one-armed anti-human NR1 antibody:

[0632] (1) A one-armed anti-human NR1 antibody comprising a heavy chain having a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 2, a light chain having a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 4, and an Fc polypeptide;

[0633] (2) a one-armed anti-human NR1 antibody comprising a heavy chain having a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 6, a light chain having a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 8, and an Fc polypeptide;

[0634] (3) a one-armed anti-human NR1 antibody comprising a heavy chain having a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 10, a light chain having a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 12, and an Fc polypeptide;

[0635] (4) a one-armed anti-human NR1 antibody comprising a heavy chain having a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 14, a light chain having a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 16, and an Fc polypeptide;

[0636] (5) A one-armed anti-human NR1 antibody comprising a heavy chain having a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 18, a light chain having a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 20, and an Fc polypeptide.

[0637] In one embodiment, the pharmaceutical composition of the present invention comprises a one-armed anti-human NR1 antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 22, a light chain consisting of the amino acid sequence shown in SEQ ID NO: 24, and an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42, and / or a one-armed anti-human NR1 antibody produced by post-translational modification of the one-armed anti-human NR1 antibody.

[0638] In one embodiment, the pharmaceutical composition of the present invention comprises a one-armed anti-human NR1 antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 26, a light chain consisting of the amino acid sequence shown in SEQ ID NO: 28, and an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42, and / or a one-armed anti-human NR1 antibody produced by post-translational modification of the one-armed anti-human NR1 antibody.

[0639] In one embodiment, the pharmaceutical composition of the present invention comprises a one-armed anti-human NR1 antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 30, a light chain consisting of the amino acid sequence shown in SEQ ID NO: 32, and an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42, and / or a one-armed anti-human NR1 antibody produced by post-translational modification of the one-armed anti-human NR1 antibody.

[0640] In one embodiment, the pharmaceutical composition of the present invention comprises a one-armed anti-human NR1 antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34, a light chain consisting of the amino acid sequence shown in SEQ ID NO: 36, and an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42, and / or a one-armed anti-human NR1 antibody produced by post-translational modification of the one-armed anti-human NR1 antibody.

[0641] In one embodiment, the pharmaceutical composition of the present invention comprises a one-armed anti-human NR1 antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 38, a light chain consisting of the amino acid sequence shown in SEQ ID NO: 40, and an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42, and / or a one-armed anti-human NR1 antibody produced by post-translational modification of the one-armed anti-human NR1 antibody.

[0642] In one embodiment, the pharmaceutical composition of the present invention comprises a single-armed anti-human NR1 antibody that competitively binds to human NR1 with an anti-human NR1 antibody comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 2 and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 4, and inhibits NMDAR cellular internalization caused by pathogenic anti-human NR1 antibodies derived from patients with anti-NMDAR encephalitis, and / or a single-armed anti-human NR1 antibody produced by post-translational modification of the single-armed anti-human NR1 antibody.

[0643] The dosage of the one-armed anti-human NR1 antibody of the present invention varies depending on the disease condition, patient age, or dosage form to be used. For example, a dosage of about 0.001 mg / kg to 100 mg / kg can be used. In addition, the dosage of the one-armed anti-human NR1 antibody of the present invention can be adjusted and formulated to correspond to such a dosage.

[0644] The pharmaceutical composition of the present invention can be used as a therapeutic agent for anti-NMDAR encephalitis.

[0645] The present invention includes a pharmaceutical composition of a one-armed anti-human NR1 antibody for use in treatment, comprising the one-armed anti-human NR1 antibody of the present invention and a pharmaceutically acceptable excipient. In addition, the present invention includes a method for treating anti-NMDAR encephalitis, comprising administering a therapeutically effective amount of the one-armed anti-human NR1 antibody of the present invention. In addition, the present invention includes the one-armed anti-human NR1 antibody of the present invention for use in treating anti-NMDAR encephalitis. In addition, the present invention includes the use of the one-armed anti-human NR1 antibody of the present invention in the manufacture of a pharmaceutical composition for treating anti-NMDAR encephalitis.

[0646] <Monovalent anti-human NR1 antibody derivatives of the present invention>

[0647] In the present specification, a "monovalent anti-human NR1 antibody derivative" is a monovalent antibody derivative that binds to human NR1 and comprises a human NR1 antigen-binding site derived from an anti-human NR1 antibody. The monovalent anti-human NR1 antibody derivative of the present invention includes, for example, scFc, Fab fragments, F(ab')2 fragments, and the like derived from anti-human NR1 antibodies.

[0648] The monovalent anti-human NR1 antibody derivative of the present invention is a monovalent anti-human NR1 antibody derivative comprising a heavy chain variable region and a light chain variable region selected from any one of the following (1) to (4): (1) a monovalent anti-human NR1 antibody derivative comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 31 to 35 of SEQ ID NO: 6, a CDR2 consisting of an amino acid sequence of amino acids 50 to 66 of SEQ ID NO: 6, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 110 of SEQ ID NO: 6, and the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 8, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 8, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 98 of SEQ ID NO: 8;

[0649] (2) a monovalent anti-human NR1 antibody derivative comprising a heavy chain variable region comprising a CDR1 consisting of an amino acid sequence of amino acids 31 to 35 of SEQ ID NO: 10, a CDR2 consisting of an amino acid sequence of amino acids 50 to 66 of SEQ ID NO: 10, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 111 of SEQ ID NO: 10, and a light chain variable region comprising a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 12, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 12, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 97 of SEQ ID NO: 12;

[0650] (3) A monovalent anti-human NR1 antibody derivative comprising a heavy chain variable region comprising a CDR1 consisting of an amino acid sequence of amino acids 31 to 36 of SEQ ID NO: 14, a CDR2 consisting of an amino acid sequence of amino acids 51 to 66 of SEQ ID NO: 14, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 108 of SEQ ID NO: 14, and a light chain variable region comprising a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 16, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 16, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 97 of SEQ ID NO: 16;

[0651] (4) A monovalent anti-human NR1 antibody derivative comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acid numbers 31 to 36 of SEQ ID NO: 18, a CDR2 consisting of an amino acid sequence of amino acid numbers 51 to 66 of SEQ ID NO: 18, and a CDR3 consisting of an amino acid sequence of amino acid numbers 99 to 108 of SEQ ID NO: 18, and the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acid numbers 24 to 34 of SEQ ID NO: 20, a CDR2 consisting of an amino acid sequence of amino acid numbers 50 to 56 of SEQ ID NO: 20, and a CDR3 consisting of an amino acid sequence of amino acid numbers 89 to 97 of SEQ ID NO: 20.

[0652] In one embodiment, the monovalent anti-human NR1 antibody derivative of the present invention is a monovalent anti-human NR1 antibody derivative comprising a heavy chain variable region and a light chain variable region selected from any one of the following (5) to (8):

[0653] (5) A monovalent anti-human NR1 antibody derivative comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 6, and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 8;

[0654] (6) A monovalent anti-human NR1 antibody derivative comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 10, and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 12;

[0655] (7) A monovalent anti-human NR1 antibody derivative comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 14, and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 16;

[0656] (8) A monovalent anti-human NR1 antibody derivative comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 18, and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 20.

[0657] The monovalent anti-human NR1 antibody derivatives of the present invention include monovalent anti-human NR1 antibody derivatives that competitively bind to human NR1 with an anti-human NR1 antibody comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 2 and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 4, and inhibit NMDAR internalization caused by pathogenic anti-human NR1 antibodies derived from patients with anti-NMDA receptor encephalitis. As described in the section "Single-armed anti-human NR1 antibodies of the present invention," the monovalent anti-human NR1 antibody derivatives of the present invention can be obtained by those skilled in the art.

[0658] The monovalent anti-human NR1 antibody derivatives of the present invention can be modified to improve their in vivo stability, such as by pegylation.

[0659] The present invention further includes polynucleotides encoding the antibody derivatives, expression vectors comprising the polynucleotides, host cells transformed by the expression vectors, methods for producing the antibody derivatives, pharmaceutical compositions comprising the antibody derivatives, uses of the antibody derivatives in the manufacture of the pharmaceutical compositions, and methods for treating patients with anti-NMDAR encephalitis using the antibody derivatives.

[0660] Specific examples are provided herein to provide a further understanding of the present invention; however, these examples are provided for illustrative purposes only and are not intended to limit the present invention.

[0661] The present invention provides embodiments including but not limited to the following:

[0662] 1. A one-armed anti-human NR1 antibody selected from any one of the following (1) to (5):

[0663] (1) A one-armed anti-human NR1 antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 26 to 34 of SEQ ID NO: 2, a CDR2 consisting of an amino acid sequence of amino acids 52 to 58 of SEQ ID NO: 2, and a CDR3 consisting of an amino acid sequence of amino acids 97 to 109 of SEQ ID NO: 2, and the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 26 to 33 of SEQ ID NO: 4, a CDR2 consisting of an amino acid sequence of amino acids 51 to 53 of SEQ ID NO: 4, and a CDR3 consisting of an amino acid sequence of amino acids 92 to 100 of SEQ ID NO: 4;

[0664] (2) a one-armed anti-human NR1 antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 31 to 35 of SEQ ID NO: 6, a CDR2 consisting of an amino acid sequence of amino acids 50 to 60 of SEQ ID NO: 6, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 110 of SEQ ID NO: 6, and the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 8, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 8, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 98 of SEQ ID NO: 8;

[0665] (3) a one-armed anti-human NR1 antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 31 to 35 of SEQ ID NO: 10, a CDR2 consisting of an amino acid sequence of amino acids 50 to 66 of SEQ ID NO: 10, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 111 of SEQ ID NO: 10, and the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 12, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 12, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 97 of SEQ ID NO: 12;

[0666] (4) a one-armed anti-human NR1 antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 31 to 36 of SEQ ID NO: 14, a CDR2 consisting of an amino acid sequence of amino acids 51 to 66 of SEQ ID NO: 14, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 108 of SEQ ID NO: 14, and the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 16, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 16, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 97 of SEQ ID NO: 16;

[0667] (5) A one-armed anti-human NR1 antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acid numbers 31 to 36 of SEQ ID NO: 18, a CDR2 consisting of an amino acid sequence of amino acid numbers 51 to 66 of SEQ ID NO: 18, and a CDR3 consisting of an amino acid sequence of amino acid numbers 99 to 108 of SEQ ID NO: 18, and the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acid numbers 24 to 34 of SEQ ID NO: 20, a CDR2 consisting of an amino acid sequence of amino acid numbers 50 to 56 of SEQ ID NO: 20, and a CDR3 consisting of an amino acid sequence of amino acid numbers 89 to 97 of SEQ ID NO: 20.

[0668] 2. A one-armed anti-human NR1 antibody according to embodiment 1, selected from any one of the following (1) to (5):

[0669] (1) A one-armed anti-human NR1 antibody comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 2, and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 4;

[0670] (2) a one-armed anti-human NR1 antibody comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 6, and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 8;

[0671] (3) a one-armed anti-human NR1 antibody comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 10, and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 12;

[0672] (4) a one-armed anti-human NR1 antibody comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 14, and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 16;

[0673] (5) A one-armed anti-human NR1 antibody comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 18, and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 20.

[0674] 3. The one-armed anti-human NR1 antibody according to embodiment 1, selected from any one of the following (1) to (5):

[0675] (1) A one-armed anti-human NR1 antibody comprising a heavy chain, a light chain, and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region comprising a CDR1 consisting of an amino acid sequence of amino acids 26 to 34 of SEQ ID NO: 2, a CDR2 consisting of an amino acid sequence of amino acids 52 to 58 of SEQ ID NO: 2, and a CDR3 consisting of an amino acid sequence of amino acids 97 to 109 of SEQ ID NO: 2, and the light chain comprises a light chain variable region comprising a CDR1 consisting of an amino acid sequence of amino acids 26 to 33 of SEQ ID NO: 4, a CDR2 consisting of an amino acid sequence of amino acids 51 to 53 of SEQ ID NO: 4, and a CDR3 consisting of an amino acid sequence of amino acids 92 to 100 of SEQ ID NO: 4;

[0676] (2) A one-armed anti-human NR1 antibody comprising a heavy chain, a light chain, and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 31 to 35 of SEQ ID NO: 6, a CDR2 consisting of an amino acid sequence of amino acids 50 to 66 of SEQ ID NO: 6, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 110 of SEQ ID NO: 6, and the light chain comprises a light chain variable region, wherein the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 8, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 8, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 98 of SEQ ID NO: 8;

[0677] (3) a one-armed anti-human NR1 antibody comprising a heavy chain, a light chain, and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 31 to 35 of SEQ ID NO: 10, a CDR2 consisting of an amino acid sequence of amino acids 50 to 66 of SEQ ID NO: 10, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 111 of SEQ ID NO: 10, and the light chain comprises a light chain variable region, wherein the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 12, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 12, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 97 of SEQ ID NO: 12;

[0678] (4) A one-armed anti-human NR1 antibody comprising a heavy chain, a light chain, and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region comprising a CDR1 consisting of an amino acid sequence of amino acids 31 to 36 of SEQ ID NO: 14, a CDR2 consisting of an amino acid sequence of amino acids 51 to 66 of SEQ ID NO: 14, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 108 of SEQ ID NO: 14, and the light chain comprises a light chain variable region comprising a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 16, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 16, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 97 of SEQ ID NO: 16;

[0679] (5) A one-armed anti-human NR1 antibody comprising a heavy chain, a light chain and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 31 to 36 of SEQ ID NO: 18, a CDR2 consisting of an amino acid sequence of amino acids 51 to 66 of SEQ ID NO: 18, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 108 of SEQ ID NO: 18, and the light chain comprises a light chain variable region, wherein the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 20, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 20, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 97 of SEQ ID NO: 20.

[0680] 4. The one-armed anti-human NR1 antibody according to embodiment 3, selected from any one of the following (1) to (5):

[0681] (1) A one-armed anti-human NR1 antibody comprising a heavy chain, a light chain, and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 2, and the light chain comprises a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 4;

[0682] (2) A one-armed anti-human NR1 antibody comprising a heavy chain, a light chain, and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 6, and the light chain comprises a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 8;

[0683] (3) A one-armed anti-human NR1 antibody comprising a heavy chain, a light chain, and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 10, and the light chain comprises a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 12;

[0684] (4) A one-armed anti-human NR1 antibody comprising a heavy chain, a light chain, and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 14, and the light chain comprises a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 16;

[0685] (5) A one-armed anti-human NR1 antibody comprising a heavy chain, a light chain, and an Fc polypeptide, wherein the heavy chain comprises a heavy chain variable region, and the heavy chain variable region consists of the amino acid sequence shown in SEQ ID NO: 18; and the light chain comprises a light chain variable region, and the light chain variable region consists of the amino acid sequence shown in SEQ ID NO: 20.

[0686] 5. The one-armed anti-human NR1 antibody of any one of embodiments 1 to 4, comprising an Fc region comprising the LALA mutation (L234A and L235A).

[0687] 6. The one-armed anti-human NR1 antibody of any one of embodiments 1 to 4, comprising an Fc region comprising a knob-to-hole mutation.

[0688] 7. The one-armed anti-human NR1 antibody of any one of embodiments 1 to 4, comprising an Fc region comprising a LALA mutation (L234A and L235A) and a knob-to-hole mutation.

[0689] 8. The one-armed anti-human NR1 antibody of embodiment 6 or 7, wherein the knob-to-hole mutation is a T366W mutation in one Fc polypeptide forming the Fc region, and T366S, L368A, and Y407V mutations in another Fc polypeptide forming the Fc region.

[0690] 9. The one-armed anti-human NR1 antibody of any one of embodiments 1 to 8, wherein the one-armed anti-human NR1 antibody is a human antibody or a humanized antibody.

[0691] 10. A one-armed anti-human NR1 antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 22, a light chain consisting of the amino acid sequence shown in SEQ ID NO: 24, and an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42.

[0692] 11. A one-armed anti-human NR1 antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 26, a light chain consisting of the amino acid sequence shown in SEQ ID NO: 28, and an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42.

[0693] 12. A one-armed anti-human NR1 antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 30, a light chain consisting of the amino acid sequence shown in SEQ ID NO: 32, and an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42.

[0694] 13. A one-armed anti-human NR1 antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34, a light chain consisting of the amino acid sequence shown in SEQ ID NO: 36, and an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42.

[0695] 14. A one-armed anti-human NR1 antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 38, a light chain consisting of the amino acid sequence shown in SEQ ID NO: 40, and an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42.

[0696] 15. A one-armed anti-human NR1 antibody, wherein the one-armed anti-human NR1 antibody

[0697] competitively binds to human NR1 with an anti-human NR1 antibody comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 2 and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 4, and

[0698] Inhibits NMDAR cellular internalization induced by pathogenic anti-human NR1 antibodies derived from patients with anti-NMDAR encephalitis.

[0699] 16. The one-armed anti-human NR1 antibody of any one of embodiments 1 to 15, which is produced by post-translational modification.

[0700] 17. The one-armed anti-human NR1 antibody of embodiment 16, wherein the post-translational modification is pyroglutamylation of the N-terminal heavy chain variable region and / or deletion of the C-terminal heavy chain lysine.

[0701] 18. A polynucleotide comprising the nucleotide sequence listed in (a) and / or (b) below:

[0702] (a) a nucleotide sequence encoding the heavy chain variable region of the one-armed anti-human NR1 antibody according to any one of (2) to (5) of embodiment 1 and (2) to (5) of embodiment 2;

[0703] (b) A nucleotide sequence encoding the light chain variable region of the one-armed anti-human NR1 antibody according to any one of (2) to (5) of embodiment 1 and (2) to (5) of embodiment 2.

[0704] 19. A polynucleotide comprising the nucleotide sequence listed in (a) and / or (b) below:

[0705] (a) a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody according to any one of (2) to (5) of embodiment 3 and (2) to (5) of embodiment 4;

[0706] (b) A nucleotide sequence encoding the light chain of the one-armed anti-human NR1 antibody according to any one of (2) to (5) of embodiment 3 and (2) to (5) of embodiment 4.

[0707] 20. A polynucleotide comprising the nucleotide sequence listed in (a) and / or (b) below:

[0708] (a) a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 26;

[0709] (b) A nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 28.

[0710] 21. A polynucleotide comprising the nucleotide sequence listed in (a) and / or (b) below:

[0711] (a) a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 30;

[0712] (b) A nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 32.

[0713] 22. A polynucleotide comprising the nucleotide sequence listed in (a) and / or (b) below:

[0714] (a) a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34;

[0715] (b) A nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 36.

[0716] 23. A polynucleotide comprising the nucleotide sequence listed in (a) and / or (b) below:

[0717] (a) a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 38;

[0718] (b) A nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 40.

[0719] 24. A polynucleotide comprising the nucleotide sequence listed in (a) and / or (b) below:

[0720] (a) a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody according to embodiment 15;

[0721] (b) The nucleotide sequence encoding the light chain of the one-armed anti-human NR1 antibody as described in embodiment 15.

[0722] 25. An expression vector comprising a polynucleotide comprising the nucleotide sequence listed in (a) and / or (b) below:

[0723] (a) a polynucleotide comprising a nucleotide sequence encoding the heavy chain variable region of the one-armed anti-human NR1 antibody as set forth in any one of (2) to (5) of Embodiment 1 and (2) to (5) of Embodiment 2;

[0724] (b) A polynucleotide comprising a nucleotide sequence encoding the light chain variable region of the one-armed anti-human NR1 antibody as set forth in any one of (2) to (5) of Embodiment 1 and (2) to (5) of Embodiment 2.

[0725] 26. An expression vector comprising a polynucleotide comprising the nucleotide sequence listed in (a) and / or (b) below:

[0726] (a) a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as set forth in any one of (2) to (5) of Embodiment 3 and (2) to (5) of Embodiment 4;

[0727] (b) A polynucleotide comprising a nucleotide sequence encoding the light chain of the one-armed anti-human NR1 antibody as set forth in any one of (2) to (5) of Embodiment 3 and (2) to (5) of Embodiment 4.

[0728] 27. The expression vector of embodiment 25 or 26, further comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide.

[0729] 28. An expression vector comprising the polynucleotide listed in (a) and / or (b) below, and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42:

[0730] (a) a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 22;

[0731] (b) A polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 24.

[0732] 29. An expression vector comprising the polynucleotide listed in (a) and / or (b) below:

[0733] (a) a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 26;

[0734] (b) A polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 28.

[0735] 30. An expression vector comprising the polynucleotide listed in (a) and / or (b) below:

[0736] (a) a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 30;

[0737] (b) A polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 32.

[0738] 31. An expression vector comprising the polynucleotide listed in (a) and / or (b) below:

[0739] (a) a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34;

[0740] (b) A polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 36.

[0741] 32. An expression vector comprising the polynucleotide listed in (a) and / or (b) below:

[0742] (a) a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 38;

[0743] (b) A polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 40.

[0744] 33. The expression vector of any one of embodiments 29-32, further comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42.

[0745] 34. An expression vector comprising a polynucleotide comprising the amino acids listed in (a) to (f) below:

[0746] (a) a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody according to embodiment 15;

[0747] (b) a polynucleotide comprising a nucleotide sequence encoding the light chain of the one-armed anti-human NR1 antibody according to embodiment 15;

[0748] (c) a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody according to embodiment 15, and a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody;

[0749] (d) a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody according to embodiment 15, and a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody;

[0750] (e) a polynucleotide comprising a nucleotide sequence encoding the light chain of the one-armed anti-human NR1 antibody according to embodiment 15, and a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody;

[0751] (f) A polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as described in embodiment 15, a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody, and a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody.

[0752] 35. A host cell transformed with one or more expression vectors selected from the following (a) to (d):

[0753] (a) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain variable region of the one-armed anti-human NR1 antibody as set forth in any one of (2) to (5) of Embodiment 1 and (2) to (5) of Embodiment 2;

[0754] (b) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain variable region of the one-armed anti-human NR1 antibody as set forth in any one of (2) to (5) of Embodiment 1 and (2) to (5) of Embodiment 2;

[0755] (c) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain variable region of the one-armed anti-human NR1 antibody as set forth in any one of (2) to (5) of Embodiment 1 and (2) to (5) of Embodiment 2, and a polynucleotide comprising a nucleotide sequence encoding the light chain variable region of the antibody;

[0756] (d) An expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain variable region of the one-armed anti-human NR1 antibody as listed in any one of (2) to (5) of Embodiment 1 and (2) to (5) of Embodiment 2, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain variable region of the antibody.

[0757] 36. A host cell transformed with one or more expression vectors selected from the following (a) to (d):

[0758] (a) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as set forth in any one of (2) to (5) of Embodiment 3 and (2) to (5) of Embodiment 4;

[0759] (b) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the one-armed anti-human NR1 antibody as set forth in any one of (2) to (5) of Embodiment 3 and (2) to (5) of Embodiment 4;

[0760] (c) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as set forth in any one of (2) to (5) of Embodiment 3 and (2) to (5) of Embodiment 4, and a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody;

[0761] (d) An expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as set forth in any one of (2) to (5) of Embodiment 3 and (2) to (5) of Embodiment 4, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody.

[0762] 37. A host cell transformed with one or more expression vectors selected from the following (a) to (i):

[0763] (a) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as set forth in any one of (1) to (5) of Embodiment 3 and (1) to (5) of Embodiment 4, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody;

[0764] (b) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the one-armed anti-human NR1 antibody as set forth in any one of (1) to (5) of Embodiment 3 and (1) to (5) of Embodiment 4, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody;

[0765] (c) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as set forth in any one of (1) to (5) of Embodiment 3 and (1) to (5) of Embodiment 4 and a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody;

[0766] (d) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as set forth in any one of (1) to (5) of Embodiment 3 and (1) to (5) of Embodiment 4, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody;

[0767] (e) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as set forth in any one of (1) to (5) of Embodiment 3 and (1) to (5) of Embodiment 4 and a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody;

[0768] (f) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the one-armed anti-human NR1 antibody as set forth in any one of (1) to (5) of Embodiment 3 and (1) to (5) of Embodiment 4, and a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody;

[0769] (g) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as set forth in any one of (1) to (5) of Embodiment 3 and (1) to (5) of Embodiment 4 and a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody;

[0770] (h) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as set forth in any one of (1) to (5) of Embodiment 3 and (1) to (5) of Embodiment 4, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody and a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody;

[0771] (i) An expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as set forth in any one of (1) to (5) of Embodiment 3 and (1) to (5) of Embodiment 4, a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody, and a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody.

[0772] 38. A host cell transformed with one or more expression vectors selected from the following (a) to (i):

[0773] (a) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 22, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0774] (b) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 22 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0775] (c) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 24, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0776] (d) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 24 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0777] (e) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 22 and a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 24, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0778] (f) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 22 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 24;

[0779] (g) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 22, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 24, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0780] (h) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 22, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 24, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0781] (i) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 22, a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 24, and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42.

[0782] 39. A host cell transformed with one or more expression vectors selected from the following (a) to (m):

[0783] (a) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 26;

[0784] (b) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 28;

[0785] (c) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 26 and a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 28;

[0786] (d) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 26, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 28;

[0787] (e) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 26 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0788] (f) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 28 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0789] (g) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 26, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0790] (h) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 28, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0791] (i) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 26 and a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 28, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0792] (j) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 26 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 28;

[0793] (k) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 26, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 28, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0794] (1) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 26, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 28, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0795] (m) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 26, a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 28, and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42.

[0796] 40. A host cell transformed with one or more expression vectors selected from the following (a) to (m):

[0797] (a) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 30;

[0798] (b) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 32;

[0799] (c) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 30 and a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 32;

[0800] (d) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 30, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 32;

[0801] (e) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 30 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0802] (f) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 32 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0803] (g) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 30, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0804] (h) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 32, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0805] (i) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 30 and a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 32, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0806] (j) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 30 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 32;

[0807] (k) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 30, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 32, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0808] (1) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 30, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 32, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0809] (m) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 30, a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 32, and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42.

[0810] 41. A host cell transformed with one or more expression vectors selected from the following (a) to (m):

[0811] (a) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34;

[0812] (b) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 36;

[0813] (c) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34 and a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 36;

[0814] (d) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 36;

[0815] (e) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0816] (f) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 36 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0817] (g) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0818] (h) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 36, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0819] (i) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34 and a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 36, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0820] (j) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34 and a polynucleotide comprising a nucleotide sequence comprising an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 36;

[0821] (k) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 36, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0822] (1) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 36, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0823] (m) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34, a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 36, and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42.

[0824] 42. A host cell transformed with one or more expression vectors selected from the following (a) to (m):

[0825] (a) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 38;

[0826] (b) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 40;

[0827] (c) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 38 and a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 40;

[0828] (d) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 38, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 40;

[0829] (e) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 38 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0830] (f) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 40 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0831] (g) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 38, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0832] (h) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 40, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0833] (i) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 38 and a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 40, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0834] (j) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 38 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 40;

[0835] (k) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 38, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 40, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0836] (1) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 38, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 40, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42;

[0837] (m) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 38, a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 40, and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42.

[0838] 43. A host cell transformed with one or more expression vectors selected from the following (a) to (m):

[0839] (a) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody according to embodiment 15;

[0840] (b) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the one-armed anti-human NR1 antibody according to embodiment 15;

[0841] (c) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody according to embodiment 15 and a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody;

[0842] (d) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody according to embodiment 15, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody;

[0843] (e) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody according to embodiment 15 and a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody;

[0844] (f) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the one-armed anti-human NR1 antibody according to embodiment 15 and a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody;

[0845] (g) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody according to embodiment 15, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody;

[0846] (h) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the one-armed anti-human NR1 antibody according to embodiment 15, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody;

[0847] (i) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as described in embodiment 15 and a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody;

[0848] (j) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as described in embodiment 15 and a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody;

[0849] (k) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as described in embodiment 15, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody and a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody;

[0850] (1) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as described in embodiment 15, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody;

[0851] (m) An expression vector comprising a polynucleotide containing a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as described in embodiment 15, a polynucleotide containing a nucleotide sequence encoding the light chain of the antibody, and a polynucleotide containing a nucleotide sequence encoding the Fc polypeptide of the antibody.

[0852] 44. A method for producing a one-armed anti-human NR1 antibody, comprising culturing the host cell according to any one of claims 35 to 43, and expressing a polypeptide constituting the one-armed anti-human NR1 antibody.

[0853] 45. A pharmaceutical composition comprising the one-armed anti-human NR1 antibody of any one of embodiments 1 to 17 and a pharmaceutically acceptable excipient.

[0854] 46. ​​The pharmaceutical composition of embodiment 45, wherein the pharmaceutical composition is used to treat anti-NMDAR encephalitis.

[0855] 47. A method for treating anti-NMDAR encephalitis, comprising administering a therapeutically effective amount of the one-armed anti-human NR1 antibody of any one of embodiments 1 to 17.

[0856] 48. The one-armed anti-human NR1 antibody of any one of embodiments 1 to 17, for use in treating anti-NMDAR encephalitis.

[0857] 49. Use of the one-armed anti-human NR1 antibody of any one of embodiments 1 to 17 in the production of a pharmaceutical composition for treating anti-NMDAR encephalitis.

[0858] Example

[0859] Unless otherwise specified, the steps described in the following examples were performed according to well-known methods. In addition, regarding the examples using commercially available kits or reagents, the experiments were performed according to the attached protocols unless otherwise specified.

[0860] (Example 1: Obtaining Antibodies from Patients with Anti-NMDAR Encephalitis)

[0861] Based on the sequence information described in Patent Document 2 (see claim 1 and the description of the Examples of the document), anti-human NR1 monoclonal antibodies (003-109, 007-168, 007-169, 007-124, 007-142, 008-218, P003-102, hereinafter referred to as "pathogenic anti-human NR1 antibodies") having the same heavy chain variable region and light chain variable region as the antibodies isolated from anti-NMDAR encephalitis patients described in the patent document were prepared according to conventional methods. In particular, a polynucleotide encoding a heavy chain polypeptide containing a signal sequence added to the N-terminal portion of the heavy chain variable region sequence of the pathogenic anti-human NR1 antibody, and a CH1 sequence, hinge sequence, and Fc sequence added to its C-terminal portion were inserted into pcDNA3.4 (Thermo Fisher Scientific) to prepare an expression vector. Similarly, a polynucleotide encoding a polypeptide containing a signal sequence added to the N-terminal portion of a pathogenic anti-human NR1 antibody and a CH1 sequence added to the C-terminal portion thereof was inserted into pcDNA3.4 to prepare an expression vector. The expression vector was transfected into ExpiCHO-S cells (Thermo Fisher Scientific, A29127), and the antibody was obtained according to conventional methods.

[0862] The binding activity of the above-mentioned seven pathogenic anti-human NR1 antibodies was evaluated by flow cytometry measurement. The flow cytometry test (Becton, Dickinson and Company, FACS Verse) was carried out in HEK cells expressing NMDAR (as described below) (same as in Example 7). As a result, all seven pathogenic anti-human NR1 antibodies showed high binding activity in HEK cells expressing NMDAR. P003-102 (having a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 2, and a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 4) showed the highest binding activity (data not shown) in HEK cells expressing NMDAR.

[0863] Note that the NMDAR-expressing HEK cells used in the Examples are HEK cell lines expressing human NMDAR (NR1 / NR2B) (Charles River Laboratories, CTN6121), and, unless otherwise stated, were cultured at 37° C. and 50% CO 2 using DMEM / F12 (Thermo Fisher Scientific, R25001) containing 10% FBS (GE Healthcare Life Sciences, SH30070.03), 50 units / mL penicillin-streptomycin (Penicillin-Streptomycin, Thermo Fisher Scientific, 15070063), 0.5 mg / mL Geneticin (Geneticin, Thermo Fisher Scientific, 10131027), 0.005 mg / mL Blasticidin (Blasticidin, InvivoGen, ant-bl-05), and 0.1 mg / mL Zeocin (Zeocin, Thermo Fisher Scientific, R25001). Scientific, 11320033) (hereinafter referred to as "NMDAR-expressing HEK cell culture medium").

[0864] (Example 2: Confirmation of NMDAR Binding Activity of the One-armed Pathogenic Anti-human NR1 Antibody P003-102)

[0865] A monovalent anti-human NR1 antibody derivative derived from P003-102 was prepared, which showed high stability and the highest binding activity to NMDAR-expressing HEK cells.

[0866] A monovalent anti-human NR1 antibody derived from P003-102 was prepared based on the description of a prior patent document (WO1998 / 050431). Specifically, an antibody heavy chain expression vector was prepared, wherein a polynucleotide (SEQ ID NO: 21) encoding a heavy chain polypeptide (SEQ ID NO: 22) having a knob-in-hole mutation (hereinafter referred to as a "KIH mutation") in the constant region of the heavy chain of P003-102 was inserted into pcDNA3.4. An FC expression vector was prepared, wherein a polynucleotide (SEQ ID NO: 41) encoding an FC polypeptide (SEQ ID NO: 42) was inserted into pcDNA3.4 with the KIH mutation and the above-mentioned KIH mutation. An antibody light chain expression vector was prepared, wherein a polynucleotide (SEQ ID NO: 23) encoding the light chain polypeptide (SEQ ID NO: 24) of P003-102 was inserted into pcDNA3.4. According to conventional methods, by transfecting three vectors, namely, an antibody heavy chain expression vector, an antibody light chain expression vector, and an FC expression vector, into ExpiCHO-S cells, and purifying the antibody molecules expressed in the cells, a monovalent antibody (one-armed antibody) (hereinafter referred to as "ABN-5") having an antigen-binding site derived from P003-102 was obtained.

[0867] The binding activity of ABN-5 to human NMDAR was evaluated by flow cytometry in HEK cells expressing NMDAR as described in Example 1. ABN-5 (a one-armed antibody) showed binding activity to NMDAR expressed in HEK cells, although it was weaker than that of P003-102 (a bivalent antibody) ( Figure 1 In addition, ABN-5 showed higher binding activity to human NMDAR than the other six pathogenic anti-human NR1 antibodies (data not shown).

[0868] (Example 3: Internalization of NMDAR into cells by pathogenic anti-human NR1 antibodies) Pathogenic anti-human NR1 antibodies induce internalization of NMDAR by cross-linking NMDAR on the cell...

Claims

1. A one-armed anti-human NR1 antibody selected from any one of the following (1) to (5): (1) A one-armed anti-human NR1 antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 26 to 34 of SEQ ID NO: 2, a CDR2 consisting of an amino acid sequence of amino acids 52 to 58 of SEQ ID NO: 2, and a CDR3 consisting of an amino acid sequence of amino acids 97 to 109 of SEQ ID NO: 2, and the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 26 to 33 of SEQ ID NO: 4, a CDR2 consisting of an amino acid sequence of amino acids 51 to 53 of SEQ ID NO: 4, and a CDR3 consisting of an amino acid sequence of amino acids 92 to 100 of SEQ ID NO: 4; (2) a one-armed anti-human NR1 antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 31 to 35 of SEQ ID NO: 6, a CDR2 consisting of an amino acid sequence of amino acids 50 to 60 of SEQ ID NO: 6, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 110 of SEQ ID NO: 6, and the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 8, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 8, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 98 of SEQ ID NO: 8; (3) a one-armed anti-human NR1 antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 31 to 35 of SEQ ID NO: 10, a CDR2 consisting of an amino acid sequence of amino acids 50 to 66 of SEQ ID NO: 10, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 111 of SEQ ID NO: 10, and the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 12, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 12, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 97 of SEQ ID NO: 12; (4) a one-armed anti-human NR1 antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 31 to 36 of SEQ ID NO: 14, a CDR2 consisting of an amino acid sequence of amino acids 51 to 66 of SEQ ID NO: 14, and a CDR3 consisting of an amino acid sequence of amino acids 99 to 108 of SEQ ID NO: 14, and the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acids 24 to 34 of SEQ ID NO: 16, a CDR2 consisting of an amino acid sequence of amino acids 50 to 56 of SEQ ID NO: 16, and a CDR3 consisting of an amino acid sequence of amino acids 89 to 97 of SEQ ID NO: 16; (5) A one-armed anti-human NR1 antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acid numbers 31 to 36 of SEQ ID NO: 18, a CDR2 consisting of an amino acid sequence of amino acid numbers 51 to 66 of SEQ ID NO: 18, and a CDR3 consisting of an amino acid sequence of amino acid numbers 99 to 108 of SEQ ID NO: 18, and the light chain variable region comprises a CDR1 consisting of an amino acid sequence of amino acid numbers 24 to 34 of SEQ ID NO: 20, a CDR2 consisting of an amino acid sequence of amino acid numbers 50 to 56 of SEQ ID NO: 20, and a CDR3 consisting of an amino acid sequence of amino acid numbers 89 to 97 of SEQ ID NO:

20.

2. A host cell transformed with one or more expression vectors selected from the following (a) to (d): (a) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain variable region of the one-armed anti-human NR1 antibody as set forth in any one of (2) to (5) of claim 1 and (2) to (5) of claim 2; (b) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain variable region of the one-armed anti-human NR1 antibody as set forth in any one of (2) to (5) of claim 1 and (2) to (5) of claim 2; (c) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain variable region of the one-armed anti-human NR1 antibody as set forth in any one of (2) to (5) of claim 1 and (2) to (5) of claim 2, and a polynucleotide comprising a nucleotide sequence encoding the light chain variable region of the antibody; (d) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain variable region of the one-armed anti-human NR1 antibody as set forth in any one of (2) to (5) of claim 1 and (2) to (5) of claim 2, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain variable region of the antibody.

3. A host cell transformed with one or more expression vectors selected from the following (a) to (d): (a) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as set forth in any one of (2) to (5) of claim 3 and (2) to (5) of claim 4; (b) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the one-armed anti-human NR1 antibody as set forth in any one of (2) to (5) of claim 3 and (2) to (5) of claim 4; (c) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as set forth in any one of (2) to (5) of claim 3 and (2) to (5) of claim 4, and a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody; (d) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as set forth in any one of (2) to (5) of claim 3 and (2) to (5) of claim 4, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody.

4. A host cell transformed with one or more expression vectors selected from the following (a) to (i): (a) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as set forth in any one of (1) to (5) of claim 3 and (1) to (5) of claim 4, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody; (b) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the one-armed anti-human NR1 antibody as set forth in any one of (1) to (5) of claim 3 and (1) to (5) of claim 4, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody; (c) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as set forth in any one of (1) to (5) of claim 3 and (1) to (5) of claim 4 and a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody; (d) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as set forth in any one of (1) to (5) of claim 3 and (1) to (5) of claim 4, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody; (e) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as set forth in any one of (1) to (5) of claim 3 and (1) to (5) of claim 4 and a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody; (f) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the one-armed anti-human NR1 antibody as set forth in any one of (1) to (5) of claim 3 and (1) to (5) of claim 4, and a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody; (g) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as set forth in any one of (1) to (5) of claim 3 and (1) to (5) of claim 4 and a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody; (h) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as set forth in any one of (1) to (5) of claim 3 and (1) to (5) of claim 4, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody and a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody; (i) An expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody as set forth in any one of (1) to (5) of claim 3 and (1) to (5) of claim 4, a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody, and a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody.

5. A host cell transformed with one or more expression vectors selected from the following (a) to (i): (a) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 22, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42; (b) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 22 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42; (c) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 24, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42; (d) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 24 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42; (e) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 22 and a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 24, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42; (f) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 22 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 24; (g) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 22, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 24, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42; (h) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 22, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 24, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42; (i) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 22, a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 24, and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO:

42.

6. A host cell transformed with one or more expression vectors selected from the following (a) to (m): (a) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 26; (b) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 28; (c) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 26 and a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 28; (d) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 26, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 28; (e) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 26 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42; (f) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 28 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42; (g) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 26, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42; (h) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 28, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42; (i) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 26 and a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 28, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42; (j) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 26 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 28; (k) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 26, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 28, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42; (1) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 26, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 28, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42; (m) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 26, a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 28, and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO:

42.

7. A host cell transformed with one or more expression vectors selected from the following (a) to (m): (a) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 30; (b) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 32; (c) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 30 and a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 32; (d) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 30, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 32; (e) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 30 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42; (f) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 32 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42; (g) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 30, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42; (h) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 32, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42; (i) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 30 and a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 32, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42; (j) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 30 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 32; (k) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 30, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 32, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42; (1) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 30, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 32, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42; (m) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 30, a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 32, and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO:

42.

8. A host cell transformed with one or more expression vectors selected from the following (a) to (m): (a) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34; (b) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 36; (c) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34 and a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 36; (d) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 36; (e) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42; (f) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 36 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42; (g) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42; (h) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 36, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42; (i) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34 and a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 36, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42; (j) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34 and a polynucleotide comprising a nucleotide sequence comprising an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 36; (k) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 36, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42; (1) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 36, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42; (m) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 34, a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 36, and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO:

42.

9. A host cell transformed with one or more expression vectors selected from the following (a) to (m): (a) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 38; (b) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 40; (c) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 38 and a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 40; (d) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 38, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 40; (e) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 38 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42; (f) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 40 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42; (g) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 38, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42; (h) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 40, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42; (i) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 38 and a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 40, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42; (j) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 38 and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 40; (k) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 38, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 40, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42; (1) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 38, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 40, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 42; (m) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 38, a polynucleotide comprising a nucleotide sequence encoding a light chain consisting of the amino acid sequence shown in SEQ ID NO: 40, and a polynucleotide comprising a nucleotide sequence encoding an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO:

42.

10. A host cell transformed with one or more expression vectors selected from the following (a) to (m): (a) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody according to claim 15; (b) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the one-armed anti-human NR1 antibody according to claim 15; (c) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody of claim 15 and a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody; (d) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody of claim 15, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody; (e) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody of claim 15 and a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody; (f) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the one-armed anti-human NR1 antibody of claim 15 and a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody; (g) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody of claim 15, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody; (h) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the one-armed anti-human NR1 antibody of claim 15, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody; (i) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody of claim 15 and a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody; (j) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody of claim 15 and a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody; (k) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody of claim 15 , and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody and a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody; (1) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody of claim 15, an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody, and an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody; (m) an expression vector comprising a polynucleotide comprising a nucleotide sequence encoding the heavy chain of the one-armed anti-human NR1 antibody according to claim 15, a polynucleotide comprising a nucleotide sequence encoding the light chain of the antibody, and a polynucleotide comprising a nucleotide sequence encoding the Fc polypeptide of the antibody.

Images