Methods of treating Anti-nmdar antibody related disorders

Abstract

The disclosure provides methods for treating a N-methyl-D-aspartate receptor (NMDAR) related pathology using an NMDAR binding antibody. The method of treatment includes using an anti-NMDAR one-arm antibody. The disclosure further provides methods for screening and predicting the potential responsiveness to anti-NMDAR treatment. The disclosure further describes the dosage concentration required for effective treatment with anti-NMDAR treatment.

Description

METHODS OF TREATING ANTI-NMDAR ANTIBODY RELATED DISORDERSCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit and priority of U.S. Provisional Application No. 63 / 673,454, filed on July 19, 2024, which is incorporated by reference herein in its entirety.SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on June 16, 2025, is named 62548-707.601_SL. xml and is 69,983 bytes in size.BACKGROUND

[0003] The N-methyl-D-aspartate receptor (NMD AR) is an ionotropic glutamate receptor that is known to be involved in a variety of functions in the central nervous system. It plays a crucial role in synaptic plasticity, long-term potentiation, and memory formation. NMDARs are activated upon binding of glycine and glutamate. Functional NMDARs are heterotetramers typically consisting of two NR1 subunits with either two of the four NR2 or two NR3 subunits. The glycine-binding modules of the NR1 andNR3 subunits and the glutamate-binding module of the NR2 subunit allow for precise control of ion permeability in physiologic conditions. Overactivation of NMDARs, causing excessive influx of Ca2+into the neurons, can lead to excitotoxicity, which is known to occur in a multitude of neurological disorders such as Alzheimer disease, Parkinson, Epilepsy, and Huntington disease. On the other hand, hypofunction of NMDARs has been known to be associated with neuropsychiatric disorders. NMDARs are also associated with a rare autoimmune disease, anti-NMDAR encephalitis. The anti-NMDAR encephalitis is characterized by psychiatric and neurological symptoms such as memory loss, hallucinations, delusions, and seizures. It is caused by the generation of Immunoglobulin G (IgG) autoantibodies against the NR1 subunit of NMDARs in the blood and in the brain. The anti-NMDAR autoantibodies induce the cross-linking and internalization of NMDARs. The reduced level of cell-surface NMDARs results in reduction of neuronal Ca2+influx and decrease in synaptic currents, which causes several of the neuropsychiatric and neurological symptoms observed in patients.SUMMARY

[0004] Currently, there is no well-established treatment for NMD AR encephalitis and other neurological or neuropsychiatric disorders related to anti -NMD AR encephalitis. It is unclear the extent to which antibodies administered to interfere with pathogenic NMD AR antibodies can obtain access to the central nervous system. Described herein are dosages and routes of administration that achieve therapeutically relevant concentrations of a therapeutic anti -NMD AR antibodies.

[0005] Disclosed herein, in some aspects, a method of treating a central nervous system disease in an individual in need thereof, the method comprising administering a therapeutically effective amount of a therapeutic anti-NMDAR antibody to the individual, wherein the therapeutically effective amount is administered in an amount of about 20 mg / kg (milligram therapeutic anti- NMDAR antibody per kilogram individual) to about 200 mg / kg.

[0006] In some embodiments, the administration of the therapeutic anti-NMDAR antibody to the individual provides a cerebrospinal fluid (CSF) concentration of the therapeutic anti-NMDAR antibody in the individual in an amount of about 0.6 pg / mL to about 2.5 pg / mL.

[0007] Disclosed herein, in some aspects, a method of treating a central nervous system disease in an individual in need thereof, the method comprising administering a therapeutically effective amount of a therapeutic anti-NMDAR antibody to the individual, wherein the therapeutically effective amount provides a cerebrospinal fluid (CSF) concentration of the therapeutic anti- NMDAR antibody in an amount of about 0.6 pg / mL to about 2.5 pg / mL.

[0008] In some embodiments, the therapeutic anti-NMDAR antibody is administered intravenously (IV).

[0009] In some embodiments, the therapeutic anti-NMDAR antibody is administered less frequently than once a day.

[0010] In some embodiments, the therapeutic anti-NMDAR antibody is administered once a week.

[0011] In some embodiments, the therapeutic anti-NMDAR antibody is administered twice a week.

[0012] In some embodiments, the therapeutic anti-NMDAR antibody is administered once every two weeks.

[0013] In some embodiments, the therapeutic anti-NMDAR antibody is administered once every three weeks.

[0014] In some embodiments, the therapeutic anti-NMDAR antibody is administered once every four weeks.

[0015] In some embodiments, the therapeutic anti-NMDAR antibody is administered once every four weeks.

[0016] In some embodiments, the therapeutically effective amount is about 5 mg / kg to about 100 mg / kg.

[0017] In some embodiments, the therapeutically effective amount is about 10 mg / kg to about100 mg / kg.

[0018] In some embodiments, the therapeutically effective amount is about 20 mg / kg to about100 mg / kg.

[0019] In some embodiments, the therapeutically effective amount is about 30 mg / kg to about100 mg / kg.

[0020]

[0021] In some embodiments, the therapeutically effective amount is about 40 mg / kg to about 100 mg / kg.

[0022] In some embodiments, the therapeutically effective amount is about 50 mg / kg to about 90 mg / kg.

[0023] In some embodiments, the therapeutically effective amount is about 60 mg / kg to about 80 mg / kg.

[0024] In some embodiments, the therapeutically effective amount is about 5 mg / kg.

[0025] In some embodiments, the therapeutically effective amount is about 10 mg / kg.

[0026] In some embodiments, the therapeutically effective amount is about 20 mg / kg.

[0027] In some embodiments, the therapeutically effective amount is about 30 mg / kg.

[0028] In some embodiments, the therapeutically effective amount is about 40 mg / kg.

[0029] In some embodiments, the therapeutically effective amount is about 50 mg / kg.

[0030] In some embodiments, the therapeutically effective amount is about 60 mg / kg.

[0031] In some embodiments, the therapeutically effective amount is about 70 mg / kg.

[0032] In some embodiments, the therapeutically effective amount is about 80 mg / kg.

[0033] In some embodiments, the therapeutically effective amount is about 90 mg / kg.

[0034] In some embodiments, the therapeutically effective amount is about 100 mg / kg.

[0035] In some embodiments, the concentration of the therapeutic anti-NMDAR antibody in the CSF of the individual is about 0.8 pg / mL to about 2.0 pg / mL.

[0036] In some embodiments, the concentration of the therapeutic anti-NMDAR antibody in the CSF of the individual is about 1.0 pg / mL to about 1.8 pg / mL.

[0037] In some embodiments, the concentration of the therapeutic anti-NMDAR antibody in the CSF of the individual is about 1.2 pg / mL to about 1.6 pg / mL.

[0038] In some embodiments, the concentration of the therapeutic anti -NMD AR antibody in the CSF of the individual is about 0.6 pg / mL.

[0039] In some embodiments, the concentration of the therapeutic anti-NMD AR antibody in the CSF of the individual is about 0.8 pg / mL.

[0040] In some embodiments, the concentration of the therapeutic anti-NMD AR antibody in the CSF of the individual is about 1.0 pg / mL.

[0041] In some embodiments, the concentration of the therapeutic anti-NMD AR antibody in the CSF of the individual is about 1.2 pg / mL.

[0042] In some embodiments, the concentration of the therapeutic anti-NMD AR antibody in the CSF of the individual is about 1.4 pg / mL.

[0043] In some embodiments, the concentration of the therapeutic anti-NMD AR antibody in the CSF of the individual is about 1.6 pg / mL.

[0044] In some embodiments, the concentration of the therapeutic anti-NMD AR antibody in the CSF of the individual is about 1.8 pg / mL.

[0045] In some embodiments, the concentration of the therapeutic anti-NMD AR antibody in the CSF of the individual is about 2.0 pg / mL.

[0046] In some embodiments, the concentration of the therapeutic anti-NMD AR antibody in the CSF of the individual is about 2.2 pg / mL.

[0047] In some embodiments, the concentration of the therapeutic anti-NMD AR antibody in the CSF of the individual is about 2.4 pg / mL.

[0048] In some embodiments, the therapeutic anti-NMD AR antibody comprises a polypeptide comprising an antigen binding domain that binds to NR1 .

[0049] In some embodiments, the polypeptide is a monospecific polypeptide.

[0050] In some embodiments, the polypeptide does not comprise a second antigen binding domain.

[0051] In some embodiments, the antigen binding domain that binds to NR1 comprises a one- armed antibody.

[0052] In some embodiments, the therapeutic anti-NMD AR antibody is not an NR1 antagonist.

[0053] In some embodiments, the therapeutic anti-NMD AR antibody is not an NR1 agonist.

[0054] In some embodiments, the one-armed antibody comprises: a heavy chain variable region (VH) comprising: a) a heavy chain complementary determining region 1 (HCDR1) comprising an amino acid sequence of SEQ ID NO: 13; b) a heavy chain complementary determining region 2 (HCDR2) comprising an amino acid sequence of SEQ ID NO: 14; and / or c) a heavy chain complementary determining region 3 (HCDR3) comprising an amino acid sequence of SEQ ID NO: 15; and a light chain variable region (VL) comprising: d) a light chaincomplementary determining region 1 (LCDR1) comprising an amino acid sequence of SEQ ID NO: 16; e) a light chain complementary determining region 2 (LCDR2) comprising an amino acid sequence of SEQ ID NO: 17; and / orf) alight chain complementary determining region 3 (LCDR3) comprising an amino acid sequence of SEQ ID NO: 18.

[0055] In some embodiments, the one-armed antibody comprises: a heavy chain variable region (VH) comprising: a) a heavy chain complementary determining region 1 (HCDR1) comprising an amino acid sequence of SEQ ID NO: 23; b) a heavy chain complementary determining region 2 (HCDR2) comprising an amino acid sequence of SEQ ID NO: 24; and / or c) a heavy chain complementary determining region 3 (HCDR3) comprising an amino acid sequence of SEQ ID NO: 25; and a light chain variable region (VL) comprising: d) a light chain complementary determining region 1 (LCDR1) comprising an amino acid sequence of SEQ ID NO: 26; e) a light chain complementary determining region 2 (LCDR2) comprising an amino acid sequence of SEQIDNO: 27; and / orf) alight chain complementary determining region 3 (LCDR3) comprising an amino acid sequence of SEQ ID NO: 28.

[0056] In some embodiments, the one-armed antibody comprises: a heavy chain variable region (VH) comprising: a) a heavy chain complementary determining region 1 (HCDR1) comprising an amino acid sequence of SEQ ID NO: 33; b) a heavy chain complementary determining region 2 (HCDR2) comprising an amino acid sequence of SEQ ID NO: 34; and / or c) a heavy chain complementary determining region 3 (HCDR3) comprising an amino acid sequence of SEQ ID NO: 35; and a light chain variable region (VL) comprising: d) a light chain complementary determining region 1 (LCDR1) comprising an amino acid sequence of SEQ ID NO: 36; e) a light chain complementary determining region 2 (LCDR2) comprising an amino acid sequence of SEQIDNO: 37; and / orf) alight chain complementary determining region 3 (LCDR3) comprising an amino acid sequence of SEQ ID NO: 38.

[0057] In some embodiments, the one-armed antibody comprises: a heavy chain variable region (VH) comprising: a) a heavy chain complementary determining region 1 (HCDR1) comprising an amino acid sequence of SEQ ID NO: 43; b) a heavy chain complementary determining region 2 (HCDR2) comprising an amino acid sequence of SEQ ID NO: 44; and / or c) a heavy chain complementary determining region 3 (HCDR3) comprising an amino acid sequence of SEQ ID NO: 45; and a light chain variable region (VL) comprising: d) a light chain complementary determining region 1 (LCDR1) comprising an amino acid sequence of SEQ ID NO: 46; e) a light chain complementary determining region 2 (LCDR2) comprising an amino acid sequence of SEQIDNO: 47; and / orf) alight chain complementary determini ng region 3 (LCDR3) comprising an amino acid sequence of SEQ ID NO: 48.

[0058] In some embodiments, the one-armed antibody comprises: a heavy chain variable region (VH) comprising: a) a heavy chain complementary determining region 1 (HCDR1) comprising an amino acid sequence of SEQ ID NO: 53; b) a heavy chain complementary determining region 2 (HCDR2) comprising an amino acid sequence of SEQ ID NO: 54; and / or c) a heavy chain complementary determining region 3 (HCDR3) comprising an amino acid sequence of SEQ ID NO: 55; and a light chain variable region (VL) comprising: d) a light chain complementary determining region 1 (LCDR1) comprising an amino acid sequence of SEQ ID NO: 56; e) a light chain complementary determining region 2 (LCDR2) comprising an amino acid sequence ofSEQIDNO: 57; and / or f) a light chain complementary determining region 3 (LCDR3) comprising an amino acid sequence of SEQ ID NO: 58.

[0059] In some embodiments, the one-armed antibody comprises: a heavy chain variable region (VH) comprising: a) a heavy chain complementary determining region 1 (HCDR1) comprising an amino acid sequence of SEQ ID NO: 63; b) a heavy chain complementary determining region 2 (HCDR2) comprising an amino acid sequence of SEQ ID NO: 64; and / or c) a heavy chain complementary determining region 3 (HCDR3) comprising an amino acid sequence of SEQ ID NO: 65; and a light chain variable region (VL) comprising: d) a light chain complementary determining region 1 (LCDR1) comprising an amino acid sequence of SEQ ID NO: 66; e) a light chain complementary determining region 2 (LCDR2) comprising an amino acid sequence of SEQIDNO: 67; and / orf) alight chain complementary determining region 3 (LCDR3) comprising an amino acid sequence of SEQ ID NO: 68.

[0060] In some embodiments, the one-armed antibody comprises a heavy chain immunoglobulin variable region and a light chain immunoglobulin variable region selected from: a) SEQ ID NO: 11 and SEQ ID NO: 12, b) SEQ ID NO: 21 and SEQ ID NO: 22, c) SEQ ID NO: 31 and SEQ ID NO: 32, d) SEQ ID NO: 41 and SEQ ID NO: 42, e) SEQ ID NO: 51 and SEQ ID NO: 52, or f) SEQ ID NO: 61 and SEQ ID NO: 62.

[0061] In some embodiments, the one-armed antibody comprises a heavy chain immunoglobulin variable region comprising an amino acid sequence of SEQ ID NO : 11 and a light chain immunoglobulin variable region comprising an amino acid sequence of SEQ ID NO: 12.

[0062] In some embodiments, the therapeutic anti-NMDAR antibody comprises a heavy chain immunoglobulin variable region comprising an amino acid sequence having at least 90% sequence identity to the sequence of SEQ ID NO: 11 and a light chain immunoglobulin variable region comprising an amino acid sequence having at least 90% sequence identity to the sequence of SEQ ID NO: 12.

[0063] In some embodiments, the central nervous systems disease comprises autoimmune encephalitis, dementia, psychosis, schizophrenia, bipolar disorder, seizure, epilepsy, or depression.In some embodiments, the central nervous systems disease comprises dementia, psychosis, schizophrenia, bipolar disorder, seizure, epilepsy, or depression. In some embodiments, the central nervous systems disease comprises autoimmune encephalitis.

[0064] In some embodiments, the therapeutic anti-NMDAR antibody further comprises an Fc region. In some embodiments, the Fc region comprises a LALA mutation (L234A and L235A accordingto EU numbering). In some embodiments, the Fc region comprises a knobs-into-holes mutation. In some embodiments, the Fc region comprises a LALA mutation (L234A and L235A according to EU numbering) and a knobs-into-holes mutation.

[0065] In some embodiments, the therapeutic anti-NMDAR antibody further comprises a pharmaceutically acceptable excipient carrier or diluent comprising an aqueous solution of sodium acetate, polysorbate 80, and L-arginine. In some embodiments, the therapeutic anti-NMDAR antibody further comprises a pharmaceutically acceptable excipient carrier or diluent comprising an aqueous solution of sodium acetate, polysorbate 80, and L-arginine. In some embodiments, 1he aqueous solution comprises about lO mMto about 30mM of sodium acetate, about 0.01% to about 0.03% of polysorbate 80, and about 130 mM to about 150 mM of L-arginine. In some embodiments, the aqueous solution comprises about20 mM of sodium acetate, about 0.02% of polysorbate 80, and about 140 mM of L-arginine. In some embodiments, the aqueous solution further comprises about 40 mg / mL to about 60 mg / mL of the therapeutic anti-NMDAR antibody. In some embodiments, the aqueous solution further comprises about 50 mg / mL of the therapeutic anti-NMDAR antibody.

[0066] In some embodiments disclosed herein is a pharmaceutical composition comprising an aqueous solution of sodium acetate, polysorbate 80, and L-arginine, and a therapeutic anti- NMDAR antibody, wherein the therapeutic anti-NMDAR antibody comprises a heavy chain immunoglobulin variable region and a light chain immunoglobulin variable region selected from: a) SEQ ID NO: 11 and SEQ ID NO: 12, b) SEQ ID NO: 21 and SEQ ID NO: 22, c) SEQ ID NO: 31 and SEQ ID NO: 32, d) SEQ ID NO: 41 and SEQ ID NO: 42, e) SEQ ID NO: 51 and SEQ ID NO: 52, or f) SEQ ID NO: 61 and SEQ ID NO: 62.

[0067] In some embodiments, the aqueous solution comprises about 10 mMto about 30 mM of sodium acetate, about 0.01% to about 0.03% of polysorbate 80, and about 130 mMto about 150 mM of L-arginine. In some embodiments, the aqueous solution comprises about 20 mM of sodium acetate, about 0.02% of polysorbate 80, and about 140 mM of L-arginine. In some embodiments, the aqueous solution further comprises about40 mg / mL to about 60 mg / mL of the therapeutic anti-NMD AR antibody. In some embodiments, the aqueous solution further comprises about 50 mg / mL of the therapeutic anti-NMDAR antibody.

[0068] In some embodiments, the therapeutic anti-NMDAR antibody further comprises an Fc region. In some embodiments, the Fc region comprises a LALA mutation (L234A and L235A accordingto EU numbering). In some embodiments, the Fc region comprises a knobs-into-holes mutation. In some embodiments, the Fc region comprises a LALA mutation (L234A and L235A according to EU numbering) and a knobs-into-holes mutation.BRIEF DESCRIPTION OF THE DRAWINGS

[0069] The novel features described herein are set forth with particularity in the appended claims. A better understanding of the features and advantages of the features described herein will be obtained by reference to the following detailed description that sets forth illustrative examples, in which the principles of the features described herein are utilized, and the accompanying drawings of which:

[0070] FIG. 1A illustrates that ART5803 does not have agonistic activity on NMD AR Ca2+ influx.

[0071] FIG. IB illustrates that ART5803 does not have antagonistic activity on NMD AR Ca2+ influx.

[0072] FIG. 2 demonstrates ART5803 is able to compete with biotinylated anti-NMDAR autoantibody #003-102 Ab binding NMD AR in a competition ELISA.

[0073] FIG. 3 provides a representative experimental design of NMD AR internalization studies using NMD AR-expressing HEK293 cells.

[0074] FIG. 4A compares NMDAR surface expression of HEK cells treated with #003-102 Ab only, which reduced NMDAR surface expression.

[0075] FIG. 4B compares NMDAR surface expression of HEK cells treated with ART5803 only, which maintained NMDAR surface expression.

[0076] FIG. 5A illustrates the blocking effect of ART5803 (#003 -102 Ab and ART5803 coincubation) on NMDAR reduced surface expression induced by #003 -102 Ab.

[0077] FIG. 5B illustrates the rescue effect of ART5803 (#003 -102 Ab pre-treatment, ART5803 post treatment) on NMDAR reduced surface expression induced by #003 -102 Ab.

[0078] FIG. 6 illustrates the blocking activity of ART5803 on #003-102 Ab induced NMDAR hypofunction (Ca2+ influx reduction).

[0079] FIG. 7A compares NMDAR surface expression in CAI pyramidal neurons with isotype control antibody, #003 -102Ab, ART5803, or co-incubation (mix).

[0080] FIG. 7B compares spine size in CAI pyramidal neurons with isotype control antibody, #003-102Ab, ART5803, or co-incubation (mix).

[0081] FIG. 8 A provides a representative image of NMD AR surface expression and synapse morphology in hippocampal CAI pyramidal neurons at baseline (no antibody), after 3 hours incubation with #003-102 Ab only and at 14 hours after co-incubation with ART5803.

[0082] FIG. 8B compares NMD AR surface expression in hippocampal CAI pyramidal neurons at baseline (no antibody), after 3 hours incubation with #003-102 Ab only and at 14 hours after co-incubation with ART5803.

[0083] FIG. 8C compares spine size in hippocampal CAI pyramidal neurons at baseline (no antibody), after 3 hours incubation with #003-102 Ab only and at 14 hours after co-incubation with ART5803.

[0084] FIG. 9A illustrates the experimental design of ART5803 intracerebroventricular (ICV) infusion efficacy study.

[0085] FIG. 9B illustrates the time course of abnormal behaviors via the Abnormal Rating Scale (ARS) in marmosets treated with ART5803 via ICV infusion.

[0086] FIG. 9C compares abnormal behaviors via the ARS between a control antibody ICV infused group and a group treated with ART5803. ARS was compared at baseline, day 14, and day 28.

[0087] FIG. 10A illustrates the experimental design of ART5803 intraperitoneal (IP) injection efficacy study.

[0088] FIG. 10B illustrates abnormal behaviors via ARS in a vehicle treated group at day 0, 6, 14, and 21.

[0089] FIG. 10C illustrates abnormal behaviors via ARS in a ART5803 treated group at day 0, 6, 14, and 21.

[0090] FIG. 10D compares abnormal behaviors between a vehicle IP injected group and a group treated with ART5803 at day 0, 6, 14, and 21.

[0091] FIG. 11A illustrates a patient derived autoantibody simulated mixture induced NMD AR internalization is recovered following treatment with various doses of ART5803.

[0092] FIG. 1 IB illustrates patients 2, 3, 4, 5, and 6 derived autoantibody simulated mixtures induced NMD AR internalization is recovered following treatment with various doses of ART5803.

[0093] FIG. 11C compares NMD AR binding activity of patients’ serum and cerebrospinal fluid (CSF) samples.

[0094] FIG. 12A illustrates the blocking effect of ART5803 on NMD AR internalization induced by patients’ sera.

[0095] FIG. 12B illustrates the blocking effect of ART5803 on NMD AR internalization induced by patients’ CSF.

[0096] FIG. 12C compares ART5803 overlay of serum and CSF concentration in Cynomolgus monkeys following a single IV dose at 100 and 1000 mg / kg.

[0097] FIG 12D compares simulated ART5803 concentrations in human CSF based on Cynomolgus monkey PopPK modeling.

[0098] FIG. 13A illustrates mean ART5803 concentrations in human serum and CSF following single ascending doses ranging from 3 to 100 mg / kg.

[0099] FIG 13B illustrates mean ART5803 concentrations in human serum and CSF following multiple doses of 30 mg / kg.

[0100] FIG. 14 illustrates a schematic diagram of a one-armed antibody.DETAILED DESCRIPTION

[0101] Described herein is a method of treatment for pathologies associated with pathogenic anti-N-methyl-D-aspartate receptor (NMD AR) antigens. The method of treatment includes on a therapeutic anti-NMDAR antibody comprising one-arm antibody ART5803. The disclosure expands the dosage concentration required for effective treatment.Definitions

[0102] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the embodiments provided may be practiced without these details. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and / or” unless the content clearly dictates otherwise. Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed embodiments.

[0103] As used herein the term “NMD AR”, also known as N-methyl-D-aspartate receptor, NMDA receptor, refers to an ionotropic glutamate receptor and ion channel found in neurons. Ionotropic glutamate receptors are ligand-gated ion channels that allow rapid ion influx in response to glutamate. Both hyper- and hypo-functioning of NMD AR has been well documented to be related to neuropsychiatric and neurologic diseases.

[0104] As used herein the term “NR1 ,” or “NR1 subunit” refers to the NMD AR receptor NR1 subunit. For the purposes of this disclosure, the NR1 subunit comprises an amino acid sequence of SEQ ID NO: 6.

[0105] As used herein the term “NTD” refers to the N-terminal domain of the NMD AR receptor subunit. The NTD is an extracellular domain that is involved in assembly and channel modulation. As used herein the NTD is the NTD of the NR1 subunit. For the purposes of this disclosure, the NTD comprises an amino acid sequence set forth in any of SEQ ID NOs: 1 to 5. In certain cases, the NTD lacks an N-terminal signal peptide.

[0106] As used herein the term “autoantibody,” or “autoantibodies” refers to an antibody from an organism, which is directed against a component of the same organism, or its binding site has a sequence that binds to an epitope from a protein from the same organism . As used herein the autoantibody is a human autoantibody. Pathogenic antibodies as described herein refer to antibodies that bind to NMD AR and induce internalization, reducing biological function of NMD AR, and decreasing the amount of NMD AR signaling in neurons. Such normal biological functions include activation by glutamate, glycine, or both and transport of cations including calcium.

[0107] As used herein “pathologic anti-NMDAR antibody” or “pathogenic anti-NMDAR antibody” refers to an antibody that binds to NMD AR and induces a physiological state of disease, or predisposes an individual to develop a physiological state of disease. The physiological state of disease may include anti-NMDAR encephalitis, dementia, psychosis, schizophrenia, bipolar disorder, seizure, epilepsy, or depression. Generally, pathogenic anti- NMDAR antibodies work by binding to and downregulating neuronal surface expression of NMD AR.

[0108] As used herein “therapeutic anti-NMDAR antibody” refers to an antibody that can block binding of a pathologic anti-NMDAR antibody to NMD AR and does not possess a substantial amount of agonistic or antagonistic activity.

[0109] As used herein the term “encephalitis” refers to an inflammation of the brain, with symptoms including reduced or alternation in consciousness, personality changes, psychotic delusions, rigidity, headache, fever, confusion, a stiff neck, and vomiting. Complications may include respiratory failure, seizures, hallucinations, trouble speaking, memory problems, and problems with hearing. As used herein the encephalitis is an anti-NMDAR encephalitis.

[0110] As used herein the term “ART5803” refers to an antibody, whichmay be a one-armed armed antibody, with a heavy and light chain variable region as set forth in SEQ ID NO: 11 and 12, respectively. This antibody is described in PCT Application No. WO2021241616A1.

[0111] As used herein the term “one armed antibody” differs from standard antibodies in that it is monovalent and comprises only a single binding moiety derived from a heavy and light chain variable region. The single binding moiety may comprise an Fv, scFv a single chain Fab, a Fab’ or a Fab. Such one-armed antibodies may still comprise a constant region from either or both heavy and light chains, and further, may pair with a heavy chain that is not further coupled to a heavy chain variable region. A heavy chain constant region of a one-armed anti-human NMD AR antibody of the invention may have mutations that decrease antibody -dependent cellular cytotoxic activity or complement-dependent cytotoxic activity. L234 A indicates a substitution of alanine for leucine at amino acid position 234 according to the EU index in the human Igyl constant region. L235 A indicates a substitution of alanine for leucine at amino acid position 235 according to the EU index in the human Igyl constant region. A human Igyl constant region which has L234A and L235A amino acid mutations is also referred to as a “LALA mutation”. The LALA mutation is known to decrease antibody -dependent cytotoxic activity and complement-dependent cytotoxic activity of the antibody (Mol. Immunol., 1992, Vol. 29, pp. 633-639 / J. Immunol., 2000, Vol. 164, pp. 4178-4184). In addition, in a mouse antibody, D265A amino acid mutation in IgGl is known to decrease antibody -dependent cytotoxic activity and complement-dependent cytotoxic 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 decreased antibody-dependent cytotoxic activity or complement-dependent cytotoxic activity is to be observed in a mouse model, a mouse antibody which has a D265A amino acid mutation antibody can be used in place of a human antibody which has LALA mutations.

[0112] In some embodiments, the one-armed antibody may comprise a monovalent antibody derivative comprising one Fab region and one Fc region, wherein the Fab region is connected to one of two Fc polypeptides in the Fc region. The Fab region and the one Fc polypeptide may be connected via a hinge region or peptide linker. In some embodiments, a one-armed antibody comprises one heavy chain (VH, CHI domain, hinge region, Fc polypeptides (CH2 domain and CH3 domain)), one light chain (VL and CL) andFc polypeptides (FIG. 14). In some embodiments, the one-armed antibody is a one-armed antibody comprising one heavy chain, one light chain, and Fc polypeptides, wherein a hinge region is added to the Fc polypeptides (FIG. 14 - left). In some embodiments, the one-armed antibody is a one-armed antibody consisting of one heavy chain, one light chain, and Fc polypeptides, wherein a CHI domain is connected to the Fc polypeptides via a hinge region (FIG. 14 - center). In some embodiments, the one-armed antibody is a one-armed antibody consisting of one heavy chain, one light chain, and Fc polypeptides (FIG. 14 - right). In some embodiments, the one-armed antibody may have two Fc polypeptides bound by an S-S bond between heavy chains in the hinge region portion (FIG. 14 - left and center), or the two Fcpolypeptides may comprise a modified residue or added cysteine residue in one or both Fc polypeptides to allow them to bind to each other (FIG. 14 - right).

[0113] Other mutations based on known techniques can also be introduced into a heavy chain constant region of a one-armed anti-human NMD AR antibody of the invention. For example, a one-armed anti-human NMD AR antibody of the invention may have a mutation based on the knobs-into-holes technology (hereinafter, referred to as “Knobs-into-holes mutation”). The knob s-into-holes technology is a technology for obtaining the desired heterodimerized antibody molecule efficiently by substituting the amino acid side chain pre sent in the CH3 region of one of the heavy chains with a larger side chain (knob) and by substituting the amino acid side chain present in the CH3 region of the other one of the heavy chains with a smaller side chain (hole) so that the knob is positioned within the hole, thereby promoting heterodimerization of the heavy chains (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).

[0114] In some embodiments, the one-armed anti-human NMD AR antibody of the invention is a one-armed anti-human NMD AR antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 11 , a light chain consisting of the amino acid sequence shown in SEQ ID NO: 12, and an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 19.

[0115] An Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 19 has LALA mutations, and the mutations are located in the alanine residues at amino acid numbers 9 and 10 in SEQ ID NO: 19. The Fc polypeptide comprising the amino acid sequence shown in SEQ ID NO: 19 also has a knobs-into-holes mutation (T366W) and the mutation is located in the tryptophan residue at amino acid number 141.

[0116] In some embodiments, the one-armed anti-human NMD AR antibody of the invention is a one-armed anti-human NMD AR antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 21 , a light chain consisting of the amino acid sequence shown in SEQ ID NO: 22, and an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 19.

[0117] In some embodiments, the one-armed anti-human NMD AR antibody of the invention is a one-armed anti-human NMD AR antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 31 , 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: 19.

[0118] In some embodiments, the one-armed anti-human NMD AR antibody of the invention is a one-armed anti-human NMD AR antibody comprising a heavy chain consisting of the aminoacid sequence shown in SEQ ID NO: 41 , a light chain consisting of the amino acid sequence shown in SEQ ID NO: 42, and an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 19.

[0119] In some embodiments, the one-armed anti-human NMD AR antibody of the invention is a one-armed anti-human NMD AR antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 51 , a light chain consisting of the amino acid sequence shown in SEQ ID NO: 52, and an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 19.

[0120] In some embodiments, the one-armed anti-human NMD AR antibody of the invention is a one-armed anti-human NMD AR antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 61, a light chain consisting of the amino acid sequence shown in SEQ ID NO: 62, and an Fc polypeptide consisting of the amino acid sequence shown in SEQ ID NO: 19.

[0121] As used herein the term “about” refers to an amount that is near the stated amount by 10% or less.

[0122] As used herein the term “individual,” “patient,” or “subject” refers to individuals diagnosed with, suspected of being afflicted with, or at-risk of developing at least one disease for which the described compositions and method are useful for treating. In certain embodiments the individual is a mammal. In certain embodiments, the mammal is a mouse, rat, rabbit, dog, cat, horse, cow, sheep, pig, goat, llama, alpaca, or yak. In certain embodiments, the individual is a human.

[0123] Amongthe provided antibodies are monoclonal antibodies, multispecific antibodies (for example, and polyreactive antibodies), and antibody fragments. The antibodies include antibody-conjugates and molecules comprising the antibodies, such as chimeric molecules. Thus, an antibody includes, but is not limited to, full-length and native antibodies, as well as fragments and portion thereof retaining the binding specificities thereof, such as any specific binding portion thereof including those having any number of, immunoglobulin classes and / or isotypes (e.g., IgGl, IgG2, IgG3, IgG4, IgM, IgA, IgD, IgE and IgM); and biologically relevant (antigen - binding) fragments or specific binding portions thereof, including but not limited to Fab, F(ab ’)2, Fv, and scFv (single chain or related entity). A monoclonal antibody is generally one within a composition of substantially homogeneous antibodies; thus, any individual antibodies comprised within the monoclonal antibody composition are identical except for possible naturally occurring mutations that may be present in minor amounts. The monoclonal antibody can comprise a human IgGl constant region. The monoclonal antibody can comprise a human IgG4 constant region. The term “antibody” herein is used in the broadest sense and includes monoclonalantibodies, and includes intact antibodies and functional (antigen -binding) antibody fragments thereof, including fragment antigen binding (Fab) fragments, F(ab')2fragments, Fab' fragments, Fv fragments, recombinant IgG (rlgG) fragments, single chain antibody fragments, including single chain variable fragments (sFv or scFv), and single domain antibodies (e.g., sdAb, sdFv, nanobody) fragments. The term encompasses genetically engineered and / or otherwise modified forms of immunoglobulins, such as intrabodies, peptibodies, chimeric antibodies, fully human antibodies, humanized antibodies, and heteroconjugate antibodies, multispecific, e.g., bispecific, antibodies, diabodies, triabodies, and tetrabodies, tandem di-scFv, tandem tri-scFv. Unless otherwise stated, the term “antibody” should be understood to encompass functional antibody fragments thereof. The term also encompasses intact or full- length antibodies, including antibodies of any class or sub-class, including IgG and sub-classes thereof, IgM, IgE, IgA, and IgD. The antibody can comprise a human IgGl constant region. The antibody can comprise a human IgG4 constant region. The antibody may comprise an Fc (Fragment, crystallizable) region. The Fc region may comprise two Fc polypeptides. The Fc polypeptide may comprise CH2 and CH3 constant domains of a heavy chain.

[0124] For preparation of suitable antibodies, e.g., recombinant, monoclonal, or polyclonal antibodies, many techniques known in the art can be used (see, e.g., Kohler & Milstein, Nature 256:495-497 (1975); Kozbor et al., Immunology Today 4: 72 (1983); Cole et al ., pp. 77-96 in Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc. (1985); Coligan, Current Protocols in Immunology (1991); Harlow & Lane, Antibodies, A Laboratory Manual (1988); and Goding, Monoclonal Antibodies: Principlesand Practice (2d ed. 1986)). The genes encoding the heavy and light chains of an antibody of interest can be cloned from a cell, e.g., the genes encoding a monoclonal antibody can be cloned from a hybridoma and used to produce a recombinant monoclonal antibody. Gene libraries encoding heavy and light chains of monoclonal antibodies can also be made from hybridoma or plasma cells. Random combinations of the heavy and light chain gene products generate a large pool of antibodies with different antigenic specificity (see, e.g., Kuby, Immunology (3rd ed. 1997)). Techniques for the production of single chain antibodies or recombinant antibodies (U.S. Pat. Nos. 4,946,778, 4,816,567) can be adapted to produce antibodies of this disclosure. Also, transgenic mice, or other organisms such as other mammals, may be used to express humanized or human antibodies (see, e.g., U.S. Pat. Nos.5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; 5,661,016, Marks et al., Bio / Technology 10:779-783 (1992); Lonberg et al., Nature 368:856-859 (1994); Morrison, Nature 368:812-13 (1994); Fishwild et al., Nature Biotechnology 14:845-51 (1996); Neuberger, NatureBiotechnology 14:826 (1996); and Lonberg & Huszar, Intern. Rev. Immunol. 13 :65 -93 (1995)). Alternatively, phage display technology can be used to identify antibodies and heteromeric Fabfragments that specifically bind to selected antigens (see, e.g., McCafferty et al., Nature 348:552- 554 (1990); Marks et al., Biotechnology 10:779-783 (1992)). Antibodies can also be made bispecific, i.e., able to recognize two different antigens (see, e.g., WO 93 / 08829, Traunecker et al., EMBO J. 10:3655-3659 (1991); and Suresh et al., Methods in Enzymology 121 :210 (1986)). Antibodies can also be heteroconjugates, e.g., two covalently joined antibodies, or immunotoxins (see, e.g., U.S. Pat. No. 4,676,980, WO 91 / 00360; WO 92 / 200373; and EP 03089).

[0125] The terms “complementarity determining region,” and “CDR,” which are synonymous with “hypervariable region” or “HVR,” are known in the art to refer to noncontiguous sequences of amino acid within antibody variable regions, which confer antigen specificity and / or binding affinity. In general, there are three CDRs in each heavy chain variable region (CDR-H1, CDR-H2, CDR-H3) and three CDRs in each light chain variable region (CDR- Ll, CDR-L2, CDR-L3). “Framework regions” and “FR” are known in the art to refer to the non- CDR portions of the variable regions of the heavy and light chains. In general, there are four FRs in each full-length heavy chain variable region (FR-H1, FR-H2, FR-H3, and FR-H4), and four FRs in each full-length light chain variable region (FR-L1, FR-L2, FR-L3, and FR-L4). The precise amino acid sequence boundaries of a given CDR or FR can be readily determined using any of a number of well-known schemes, including those described by Kabat et al. (1991), “Sequences of Proteins of Immunological Interest,” 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (“Kabat” numbering scheme), Al-Lazikani etal., (1997) JMB 273,927-948 (“Chothia” numbering scheme); MacCallum et al., J. Mol. Biol. 262:732-745 (1996), “Antibody-antigen interactions: Contact analysis and binding site topography,” J. Mol. Biol. 262, 732-745.” (“Contact” numbering scheme); Lefranc MP et al., “IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains,” Dev Comp Immunol, 2003 Jan;27(l):55-77 (“IMGT” numbering scheme); Honegger A and Pluckthun A, “Yet another numbering scheme for immunoglobulin variable domains: an automatic modeling and analysis tool,” J Mol Biol, 2001 Jun 8;309(3):657-70, (“Aho” numbering scheme); and Whitelegg NR and Rees AR, “WAM: an improved algorithm for modelling antibodies on the WEB,” Protein Eng. 2000Dec;13(12):819-24 (“AbM” numbering scheme. In certain embodiments, the CDRs of the antibodies described herein can be defined by a method selected from Kabat, Chothia, IMGT, Aho, AbM, or combinations thereof.

[0126] The boundaries of a given CDR or FR may vary depending on the scheme used for identification. For example, the Kabat scheme is based on structural alignments, while the Chothia scheme is based on structural information. Numbering for both the Kabat and Chothia schemes is based upon the most common antibody region sequence lengths, with insertions accommodated by insertion letters, for example, “30a,” and deletions appearing in someantibodies. The two schemes place certain insertions and deletions (“indels”) at different positions, resulting in differential numbering. The Contact scheme is based on analysis of complex crystal structures and is similar in many respects to the Chothia numbering scheme.

[0127] The term “variable region” or “variable domain” refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to antigen. The variable domains of the heavy chain and light chain (VHand VL, respectively) of a native antibody generally have similar structures, with each domain comprising four conserved framework regions (FRs) and three CDRs (See e.g., Kindt et al. Kuby Immunology, 6th ed., W.H. Freeman and Co., page 91(2007)). A single VHor VLdomain may be sufficient to confer antigen -binding specificity. Furthermore, antibodies that bind a particular antigen may be isolated using a VHor VLdomain from an antibody that binds the antigen to screen a library of complementary VL or VH domains, respectively (See e.g., Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991)).

[0128] Specific binding or binding of antibody molecules described herein refers to binding mediated by one or more CDR portions of the antibody. Not all CDRs may be required for specific binding. Specific binding can be demonstrated for example by an ELISA against a specific recited target or antigen that shows significant increase in binding compared to an isotype control antibody.

[0129] As described herein an “epitope” refers to the binding determinant of an antibody or fragment described herein minimally necessary for specific binding of the antibody or fragment thereof to a target antigen. When the target antigen is a polypeptide the epitope will be a continuous or discontinuous epitope. A continuous epitope is formed by one region of the target antigen, while a discontinuous epitope may be formed from two or more separate regions. A discontinuous epitope, for example, may form when a target antigen adopts a tertiary structure that brings two amino acid sequences together and forms a three-dimensional structure bound by the antibody. When the target antigen is a polypeptide the epitope will generally be a plurality of amino acid linked into a polypeptide chain. A continuous epitope may comprise 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 contiguous amino acid. While an epitopemay comprise a contiguous polymer of amino acid, not every amino acid of the polymer may be contacted by an amino acid residue of the antibody. Such non-contacted amino acids will still comprise part of the epitope as they may be important for the structure and linkage of the contacted amino acid. The skilled artisan may determine if any given antibody binds an epitope of a reference antibody, for example, by cross-blocking experiments with a reference antibody. In certain embodiments, described herein, are antibodies that bind the same epitope of the described antibodies. In certain embodiments, described herein, are antibodies that are competitively blocked by the describedantibodies. In certain embodiments, described herein, are antibodies that compete for binding with the described antibodies.

[0130] Among the provided antibodies are antibody fragments. An “antibody fragment” refers to a molecule other than an intact antibody that comprises a portion of an intact antibody that binds the antigen to which the intact antibody binds. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab ’, Fab’-SH, F(ab’)2; diabodies; linear antibodies; single-chain antibody molecules (e.g. scFv or sFv); and multispecific antibodies formed from antibody fragments. In particular embodiments, the antibodies are single-chain antibody fragments comprising a variable heavy chain region and / or a variable light chain region, such as scFvs.

[0131] Antibody fragments can be made by various techniques, including but not limited to proteolytic digestion of an intact antibody as well as production by recombinant host cells. In some embodiments, the antibodies are recombinantly -produced fragments, such as fragments comprising arrangements that do not occur naturally, such as those with two or more antibody regions or chains joined by synthetic linkers, e.g., polypeptide linkers, and / or those that are not produced by enzyme digestion of a naturally -occurring intact antibody. In some aspects, the antibody fragments are scFvs.

[0132] A “humanized” antibody is an antibody in which all or substantially all CDR amino acid residues are derived from non-human CDRs and all or substantially all FR amino acid residues are derived from human FRs. A humanized antibody optionally may include at least a portion of an antibody constant region derived from a human antibody. A “humanized form” of a non-human antibody refers to a variant of the non-human antibody that has undergone humanization, typically to reduce immunogenicity to humans, while retaining the specificity and affinity of the parental non-human antibody. In some embodiments, some FR residues in a humanized antibody are substituted with corresponding residues from a non-human antibody (e.g., the antibody from which the CDR residues are derived), e.g., to restore or improve antibody specificity or affinity.

[0133] Among the provided antibodies are human antibodies. A “human antibody” is an antibody with an amino acid sequence corresponding to that of an antibody produced by a human or a human cell, or non-human source that utilizes human antibody repertoires or other human antibody-encoding sequences, including human antibody libraries. The term excludes humanized forms of non-human antibodies comprising non-human antigen-binding regions, such as those in which all or substantially all CDRs are non-human.

[0134] Human antibodies may be prepared by administering an immunogen to a transgenic animal that has been modified to produce intact human antibodies or intact antibodies withhuman variable regions in response to antigenic challenge. Such animals typically contain all or a portion of the human immunoglobulin loci, which replace the endogenous immunoglobulin loci, or which are present extrachromosomally or integrated randomly into the animal’s chromosomes. In such transgenic animals, the endogenous immunoglobulin loci have generally been inactivated. Human antibodies also may be derived from human antibody libraries, including phage display and cell-free libraries, containing antibody -encoding sequences derived from a human repertoire.

[0135] The terms “polypeptide” and “protein” are used interchangeably to refer to a polymer of amino acid residues, and are not limited to a minimum length. Polypeptides, including the provided antibodies and antibody chains and other peptides, e.g., linkers and binding peptides, may include amino acid residues including natural and / or non -natural amino acid residues. The terms also include post-expression modifications of the polypeptide, for example, glycosylation, sialylation, acetylation, phosphorylation, and the like. In some aspects, the polypeptides may contain modifications with respect to a native or natural sequence, as long as the protein maintains the desired activity. These modifications may be deliberate, as through site -directed mutagenesis, or may be accidental, such as through mutations of hosts which produce the proteins or errors due to PCR amplification”. In some embodiments, amino acid sequence variants of the antibodies provided herein are contemplated. A variant typically differs from a polypeptide specifically disclosed herein in one or more substitutions, deletions, additions and / or insertions. Such variants can be naturally occurring or can be synthetically generated, for example, by modifying one or more of the above polypeptide sequences of the invention and evaluating one or more biological activities of the polypeptide as described herein and / or using any of a number of known techniques. For example, it may be desirable to improve the binding affinity and / or other biological properties of the antibody Amino acid sequence variants of an antibody may be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody, or by peptide synthesis. Such modifications include, for example, deletions from, and / or insertions into and / or substitutions of residues within the amino acid sequences of the antibody. Any combination of deletion, insertion, and sub stitution can be made to arrive at the final construct, provided that the final construct possesses the desired characteristics, e.g., antigen-binding.

[0136] Percent (%) sequence identity with respect to a reference polypeptide sequence is the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes ofdetermining percent amino acid sequence identity can be achieved in various ways that are known for instance, using publicly available computer software such as BLAST, BLAST -2, ALIGN or Megalign (DNASTAR) software. Appropriate parameters for aligning sequences are able to be determined, including algorithms needed to achieve maximal alignment over the full length of the sequences being compared. For purposes herein, however, % amino acid sequence identity values are generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was authored by Genentech, Inc., and the source code has been filed with user documentation in the U.S. Copyright Office, Washington D.C., 20559, where it is registered under U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc., South San Francisco, Calif., or may be compiled from the source code. The ALIGN-2 program should be compiled for use on a UNIX operating system, including digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary.

[0137] In situations where ALIGN-2 is employed for amino acid sequence comparisons, the % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B (which can alternatively be phrased as a given amino acid sequence A that has or comprises a certain % amino acid sequence identity to, with, or against a given amino acid sequence B) is calculated as follows: lOOtimes the fraction X / Y, where X is the number of amino acid residues scored as identical matches by the sequence alignment program ALIGN-2 in that program's alignment of A and B, and where Y is the total number of amino acid residues in B. It will be appreciated that where the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % amino acid sequence identity of A to B will not equal the % amino acid sequence identity of B to A. Unless specifically stated otherwise, all % amino acid sequence identity values used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program.

[0138] In some embodiments, an antibody provided herein has a dissociation constant (KD) of about 1 pM, 100 nM, 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, 5 nM, 2 nM, 1 nM, 0.5 nM, 0.1 nM, 0.05 nM, 0.01 nM or less (e.g., 10xM or less, e.g., from 10xM to 1013M, e.g., from 109M to 1013M) for the antibody target. In some embodiments, an antibody provided herein has a dissociation constant (KD) of about 100 nM, 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, 5 nM, 2 nM, 1 nM, 0.5 nM, 0.1 nM, 0.05 nM, 0.01 nM, or 0.001 nM or greater (e.g., 10xM or less, e.g., from 10xMto 1013M, e.g., from 109Mto 1013M) for the antibody target. The antibody target can be an NR1 target. KDcan be measured by any suitable assay. In certain embodiments, KD can be measured using surface plasmon resonance assays (e.g., using a BIACORE®-2000, a BIACORE®-3000 or Octet).

[0139] In some embodiments, an antibody provided herein may be further modified to contain additional nonproteinaceous moieties that are known and available. The moieties suitable for derivatization of the antibody include but are not limited to water soluble polymers. Non- limiting examples of water soluble polymers include, but are not limited to, polyethylene glycol (PEG), copolymers of ethylene glycol / propylene glycol, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone, poly-1, 3-dioxolane, poly-1, 3, 6-trioxane, ethylene / maleic anhydride copolymer, polyaminoacids (either homopolymers or random copolymers), and dextran or poly(n vinyl pyrrolidone)poly ethylene glycol, polypropylene glycol homopolymers, polypropylene oxide / ethylene oxide co-polymers, poly oxy ethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde may have advantages in manufacturing due to its stability in water. The polymer may be of any molecular weight, and may be branched or unbranched. The number of polymers attached to the antibody may vary, and if two or more polymers are attached, they can be the same or different molecules.

[0140] “Treat,” “treatment,” or “treating,” as used herein refers to, e.g., a deliberate intervention to a physiological disease state resulting in the reduction in severity of a disease or condition; the reduction in the duration of a condition course; the amelioration or elimination of one or more symptoms associated with a disease or condition; or the provision of beneficial effects to a subject with a disease or condition. Treatment does not require curing the underlying disease or condition.

[0141] A “therapeutically effective amount,” “effective dose,” “effective amount,” or “therapeutically effective dosage” of a drug or therapeutic agent is any amount of the drug that, when used alone or in combination with another therapeutic agent, protects a subject against the onset of a disease or promotes disease regression evidenced by a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom -free periods, or a prevention of impairment or disability due to the disease affliction. The ability of a therapeutic agent to promote disease regression can be evaluated using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by assaying the activity of the agent in in vitro assays.

[0142] As used herein, “pharmaceutically acceptable” with reference to a carrier” “excipienf’ or “diluent” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. In some aspects, the carrier is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (e.g., by injection or infusion). Depending on the route of administration, the active compound, i.e., antibody, can be coated in a material to protect thecompound from the action of acids and other natural conditions that can inactivate the compound.

[0143] The pharmaceutical compounds described herein can include one or more pharmaceutically acceptable salts. A “pharmaceutically acceptable salt” refers to a salt that retains the desired biological activity of the parent compound and does not impart any undesired toxicological effects (see e.g., Berge, S.M., et al. (1977) J. Pharm. Sci. 66: 1 -19). Examples of such salts include acid addition salts and base addition salts. Acid addition salts include those derived from nontoxic inorganic acids, such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorous and the like, as well as from nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl- substituted alkanoic acids, hydroxy alkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like. Base addition salts include those derived from alkaline earth metals, such as sodium, potassium, magnesium, calcium and the like, as well as from nontoxic organic amines, such as N,N'- dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine and the like.Therapeutically effective dose of anti-NMDAR antibody

[0144] In some embodiments, the therapeutically effective amount is at least about 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, about 20 mg / kg, 21 mg / kg, 22 mg / kg, 23 mg / kg, 24 mg / kg, 25 mg / kg, 26 mg / kg, 27 mg / kg, 28 mg / kg, 29 mg / kg, 30 mg / kg, 31 mg / kg, 32 mg / kg, 33 mg / kg, 34 mg / kg, 35 mg / kg, 36 mg / kg, 37 mg / kg, 38 mg / kg, 39 mg / kg, 40 mg / kg, 41 mg / kg, 42 mg / kg, 43 mg / kg, 44 mg / kg, 45 mg / kg, 46 mg / kg, 47 mg / kg, 48 mg / kg, 49 mg / kg, 50 mg / kg, 51 mg / kg, 52 mg / kg, 53 mg / kg, 54 mg / kg, 55 mg / kg, 56 mg / kg, 57 mg / kg, 58 mg / kg, 59 mg / kg, 60 mg / kg, 61 mg / kg, 62 mg / kg, 63 mg / kg, 64 mg / kg, 65 mg / kg, 66 mg / kg, 67 mg / kg, 68 mg / kg, 69 mg / kg, 70 mg / kg, 71 mg / kg, 72 mg / kg, 73 mg / kg, 74 mg / kg, 75 mg / kg, 76 mg / kg, 77 mg / kg, 78 mg / kg, 79 mg / kg, 80 mg / kg, 81, mg / kg, 82 mg / kg, 83 mg / kg, 84 mg / kg, 85 mg / kg, 86 mg / kg, 87 mg / kg, 88 mg / kg, 89 mg / kg, 90 mg / kg, 91 mg / kg, 92 mg / kg, 93 mg / kg, 94 mg / kg, 95 mg / kg, 96 mg / kg, 97 mg / kg, 98 mg / kg, 99 mg / kg, 100 mg / kg, 101 mg / kg 102 mg / kg, 103 mg / kg, 104 mg / kg, 105 mg / kg, 106 mg / kg, 107 mg / kg, 108 mg / kg, 109 mg / kg,110 mg / kg, 111 mg / kg, 112 mg / kg, 113 mg / kg, 114 mg / kg, 115 mg / kg, 116 mg / kg, 117 mg / kg,118 mg / kg, 119 mg / kg, 120 mg / kg, 121 mg / kg, 122 mg / kg, 123 mg / kg, 124 mg / kg, 125 mg / kg,126 mg / kg, 127 mg / kg, 128 mg / kg, 129 mg / kg, 130 mg / kg, 131 mg / kg, 132 mg / kg, 133 mg / kg,134 mg / kg, 135 mg / kg, 136 mg / kg, 137 mg / kg, 138 mg / kg, 139 mg / kg, 140 mg / kg, 141 mg / kg,142 mg / kg, 143 mg / kg, 144 mg / kg, 145 mg / kg, 146 mg / kg, 147 mg / kg, 148 mg / kg, 149 mg / kg,150 mg / kg, 151 mg / kg, 152 mg / kg, 153 mg / kg, 154 mg / kg, 155 mg / kg, 156 mg / kg, 157 mg / kg, 158 mg / kg, 159 mg / kg, 160 mg / kg, 161 mg / kg, 162 mg / kg, 163 mg / kg, 164 mg / kg, 165 mg / kg, 166 mg / kg, 167 mg / kg, 168 mg / kg, 169 mg / kg, 170 mg / kg, 171 mg / kg, 172 mg / kg, 173 mg / kg, 174 mg / kg, 175 mg / kg, 176 mg / kg, 177 mg / kg, 178 mg / kg, 179 mg / kg, 180 mg / kg, 181 mg / kg, 182 mg / kg, 183 mg / kg, 184 mg / kg, 185 mg / kg, 186 mg / kg, 187 mg / kg, 188 mg / kg, 189 mg / kg, 190 mg / kg, 191 mg / kg, 192 mg / kg, 193 mg / kg, 194 mg / kg, 195 mg / kg, 196 mg / kg, 197 mg / kg, 198 mg / kg, 199 mg / kg, or 200 mg / kg.

[0145] In some embodiments, the therapeutically effective amount is at most about 1 mg / kg 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 21 mg / kg, 22 mg / kg, 23 mg / kg, 24 mg / kg, 25 mg / kg, 26 mg / kg, 27 mg / kg, 28 mg / kg, 29 mg / kg, 30 mg / kg, 31 mg / kg, 32 mg / kg, 33 mg / kg, 34 mg / kg, 35 mg / kg, 36 mg / kg, 37 mg / kg, 38 mg / kg, 39 mg / kg, 40 mg / kg, 41 mg / kg, 42 mg / kg, 43 mg / kg, 44 mg / kg, 45 mg / kg, 46 mg / kg, 47 mg / kg, 48 mg / kg, 49 mg / kg, 50 mg / kg, 51 mg / kg, 52 mg / kg, 53 mg / kg, 54 mg / kg, 55 mg / kg, 56 mg / kg, 57 mg / kg, 58 mg / kg, 59 mg / kg, 60 mg / kg, 61 mg / kg, 62 mg / kg, 63 mg / kg, 64 mg / kg, 65 mg / kg, 66 mg / kg, 67 mg / kg, 68 mg / kg, 69 mg / kg, 70 mg / kg, 71 mg / kg, 72 mg / kg, 73 mg / kg, 74 mg / kg, 75 mg / kg, 76 mg / kg, 77 mg / kg, 78 mg / kg, 79 mg / kg, 80 mg / kg, 81, mg / kg, 82 mg / kg, 83 mg / kg, 84 mg / kg, 85 mg / kg, 86 mg / kg, 87 mg / kg, 88 mg / kg, 89 mg / kg, 90 mg / kg, 91 mg / kg, 92 mg / kg, 93 mg / kg, 94 mg / kg, 95 mg / kg, 96 mg / kg, 97 mg / kg, 98 mg / kg, 99 mg / kg, 100 mg / kg, 101 mg / kg, 102 mg / kg, 103 mg / kg, 104 mg / kg, 105 mg / kg, 106 mg / kg, 107 mg / kg, 108 mg / kg, 109 mg / kg, 110 mg / kg, 111 mg / kg, 112 mg / kg, 113 mg / kg, 114 mg / kg, 115 mg / kg, 116 mg / kg, 117 mg / kg, 118 mg / kg, 119 mg / kg, 120 mg / kg, 121 mg / kg, 122 mg / kg, 123 mg / kg, 124 mg / kg, 125 mg / kg, 126 mg / kg, 127 mg / kg, 128 mg / kg, 129 mg / kg, 130 mg / kg, 131 mg / kg, 132 mg / kg, 133 mg / kg, 134 mg / kg, 135 mg / kg, 136 mg / kg, 137 mg / kg, 138 mg / kg, 139 mg / kg, 140 mg / kg, 141 mg / kg, 142 mg / kg, 143 mg / kg, 144 mg / kg, 145 mg / kg, 146 mg / kg, 147 mg / kg, 148 mg / kg, 149 mg / kg, 150 mg / kg, 151 mg / kg, 152 mg / kg, 153 mg / kg, 154 mg / kg, 155 mg / kg, 156 mg / kg, 157 mg / kg, 158 mg / kg, 159 mg / kg, 160 mg / kg, 161 mg / kg, 162 mg / kg, 163 mg / kg, 164 mg / kg, 165 mg / kg, 166 mg / kg, 167 mg / kg, 168 mg / kg, 169 mg / kg, 170 mg / kg, 171 mg / kg, 172 mg / kg, 173 mg / kg, 174 mg / kg, 175 mg / kg, 176 mg / kg, 177 mg / kg, 178 mg / kg, 179 mg / kg, 180 mg / kg, 181 mg / kg, 182 mg / kg, 183 mg / kg, 184 mg / kg, 185 mg / kg, 186 mg / kg, 187 mg / kg, 188 mg / kg, 189 mg / kg, 190 mg / kg, 191 mg / kg, 192 mg / kg, 193 mg / kg, 194 mg / kg, 195 mg / kg, 196 mg / kg, 197 mg / kg, 198 mg / kg, 199 mg / kg, or 200 mg / kg.

[0146] In some embodiments, the therapeutically effective amount ranges from 20 mg / kg to200 mg / kg, 21 mg / kgto 200 mg / kg, 22 mg / kgto 200 mg / kg, 23 mg / kgto 200 mg / kg, 24 mg / kgto200 mg / kg, 25 mg / kgto 200 mg / kg, 26 mg / kgto 200 mg / kg, 27 mg / kgto 200 mg / kg, 28 mg / kgto200 mg / kg, 29 mg / kgto 200 mg / kg, 30 mg / kgto 200 mg / kg, 31 mg / kgto 200 mg / kg, 32 mg / kgto 200 mg / kg, 33 mg / kgto 200 mg / kg, 34 mg / kgto 200 mg / kg, 35 mg / kgto 200 mg / kg, 36 mg / kgto 200 mg / kg, 37 mg / kgto 200 mg / kg, 38 mg / kgto 200 mg / kg, 39 mg / kgto 200 mg / kg, 40 mg / kgto 200 mg / kg, 41 mg / kgto 200 mg / kg, 42 mg / kgto 200 mg / kg, 43 mg / kgto 200 mg / kg, 44 mg / kgto 200 mg / kg, 45 mg / kgto 200 mg / kg, 46 mg / kgto 200 mg / kg, 47 mg / kgto 200 mg / kg, 48 mg / kgto 200 mg / kg, 49 mg / kgto 200 mg / kg, 50 mg / kgto 200 mg / kg, 51 mg / kgto 200 mg / kg, 52 mg / kgto 200 mg / kg, 53 mg / kgto 200 mg / kg, 54 mg / kgto 200 mg / kg, 55 mg / kgto 200 mg / kg, 56 mg / kgto 200 mg / kg, 57 mg / kgto 200 mg / kg, 58 mg / kgto 200 mg / kg, 59 mg / kgto 200 mg / kg, 60 mg / kgto 200 mg / kg, 61 mg / kgto 200 mg / kg, 62 mg / kgto 200 mg / kg, 63 mg / kgto 200 mg / kg, 64 mg / kgto 200 mg / kg, 65 mg / kgto 200 mg / kg, 66 mg / kgto 200 mg / kg, 67 mg / kgto 200 mg / kg, 68 mg / kgto 200 mg / kg, 69 mg / kgto 200 mg / kg, 70 mg / kgto 200 mg / kg, 71 mg / kgto 200 mg / kg, 72 mg / kgto 200 mg / kg, 73 mg / kgto 200 mg / kg, 74 mg / kgto 200 mg / kg, 75 mg / kgto 200 mg / kg, 76 mg / kgto 200 mg / kg, 77 mg / kgto 200 mg / kg, 78 mg / kgto 200 mg / kg, 79 mg / kgto 200 mg / kg, 80 mg / kgto 200 mg / kg, 81 mg / kg to 200 mg / kg, 82 mg / kg to 200 mg / kg, 83 mg / kg to 200 mg / kg, 84 mg / kg to 200 mg / kg, 85 mg / kg to 200 mg / kg, 86 mg / kgto 200 mg / kg, 87 mg / kg to 200 mg / kg, 88 mg / kg to 200 mg / kg, 89 mg / kg to 200 mg / kg, 90 mg / kgto 200 mg / kg, 91 mg / kg to 200 mg / kg, 92 mg / kg to 200 mg / kg, 93 mg / kg to 200 mg / kg, 94 mg / kgto 200 mg / kg, 95 mg / kg to 200 mg / kg, 96 mg / kg to 200 mg / kg, 97 mg / kg to 200 mg / kg, 98 mg / kg to 200 mg / kg, 99 mg / kg to 200 mg / kg, 100 mg / kg to 200 mg / kg, 101 mg / kg to 200 mg / kg, 102 mg / kg to 200 mg / kg, 103 mg / kg to 200 mg / kg, 104 mg / kg to 200 mg / kg, 105 mg / kg to 200 mg / kg, 106 mg / kg to 200 mg / kg, 107 mg / kg to 200 mg / kg 108 mg / kg to 200 mg / kg, 109 mg / kg to 200 mg / kg, 110 mg / kg to 200 mg / kg, 111 mg / kg to 200 mg / kg, 112 mg / kg to 200 mg / kg, 113 mg / kg to 200 mg / kg, 114 mg / kg to 200 mg / kg, 115 mg / kg to 200 mg / kg, 116 mg / kg to 200 mg / kg, 117 mg / kg to 200 mg / kg, 118 mg / kg to 200 mg / kg, 119 mg / kg to 200 mg / kg, 120 mg / kgto 200 mg / kg, 121 mg / kgto 200 mg / kg, 122 mg / kgto 200 mg / kg 123 mg / kg to 200 mg / kg, 124 mg / kg to 200 mg / kg, 125 mg / kg to 200 mg / kg, 126 mg / kg to 200 mg / kg, 127 mg / kg to 200 mg / kg, 128 mg / kg to 200 mg / kg, 129 mg / kg to 200 mg / kg, 130 mg / kg to 200 mg / kg, 131 mg / kg to 200 mg / kg, 132 mg / kg to 200 mg / kg, 133 mg / kg to 200 mg / kg, 134 mg / kg to 200 mg / kg, 135 mg / kg to 200 mg / kg, 136 mg / kg to 200 mg / kg, 137 mg / kg to 200 mg / kg 138 mg / kg to 200 mg / kg, 139 mg / kg to 200 mg / kg, 140 mg / kg to 200 mg / kg, 141 mg / kg to 200 mg / kg, 142 mg / kg to 200 mg / kg, 143 mg / kg to 200 mg / kg, 144 mg / kg to 200 mg / kg, 145 mg / kg to 200 mg / kg, 146 mg / kg to 200 mg / kg, 147 mg / kg to 200 mg / kg, 148 mg / kg to 200 mg / kg, 149 mg / kg to 200 mg / kg, 150 mg / kg to 200 mg / kg, 151 mg / kg to 200 mg / kg, 152 mg / kg to 200 mg / kg 153 mg / kg to 200 mg / kg, 154 mg / kg to 200 mg / kg, 155 mg / kg to 200 mg / kg, 156 mg / kg to 200 mg / kg, 157 mg / kg to 200 mg / kg, 158 mg / kg to 200 mg / kg, 159 mg / kg to 200 mg / kg, 160 mg / kg to 200 mg / kg, 161 mg / kg to 200 mg / kg, 162 mg / kg to 200 mg / kg, 163 mg / kg to 200 mg / kg, 164mg / kg to 200 mg / kg, 165 mg / kg to 200 mg / kg, 166 mg / kg to 200 mg / kg, 167 mg / kg to 200 mg / kg, 168 mg / kg to 200 mg / kg, 169 mg / kg to 200 mg / kg, 170 mg / kg to 200 mg / kg, 171 mg / kg to 200 mg / kg, 172 mg / kg to 200 mg / kg, 173 mg / kg to 200 mg / kg, 174 mg / kg to 200 mg / kg, 175 mg / kg to 200 mg / kg, 176 mg / kg to 200 mg / kg, 177 mg / kg to 200 mg / kg, 178 mg / kg to 200 mg / kg, 179 mg / kg to 200 mg / kg, 180 mg / kg to 200 mg / kg, 181 mg / kg to 200 mg / kg, 182 mg / kg to 200 mg / kg 183 mg / kg to 200 mg / kg, 184 mg / kg to 200 mg / kg, 185 mg / kg to 200 mg / kg, 186 mg / kg to 200 mg / kg, 187 mg / kg to 200 mg / kg, 188 mg / kg to 200 mg / kg, 189 mg / kg to 200 mg / kg, 190 mg / kg to 200 mg / kg, 191 mg / kg to 200 mg / kg, 192 mg / kg to 200 mg / kg, 193 mg / kg to 200 mg / kg, 194 mg / kg to 200 mg / kg, 195 mg / kg to 200 mg / kg, 196 mg / kg to 200 mg / kg, 197 mg / kg to 200 mg / kg 198 mg / kg to 200 mg / kg, or 199 mg / kg to 200 mg / kg.

[0147] In some embodiments, the therapeutically effective amount ranges from 20 mg / kg to 21 mg / kg, 20 mg / kg to 22 mg / kg, 20 mg / kg to 23 mg / kg, 20 mg / kg to 24 mg / kg, 20 mg / kg to 25 mg / kg, 20 mg / kg to 26 mg / kg, 20 mg / kg to 27 mg / kg, 20 mg / kg to 28 mg / kg, 20 mg / kg to 29 mg / kg, 20 mg / kg to 30 mg / kg, 20 mg / kg to 31 mg / kg, 20 mg / kg to 32 mg / kg, 20 mg / kg to 33 mg / kg, 20 mg / kg to 34 mg / kg, 20 mg / kg to 35 mg / kg, 20 mg / kg to 36 mg / kg, 20 mg / kg to 37 mg / kg, 20 mg / kg to 38 mg / kg, 20 mg / kg to 39 mg / kg, 20 mg / kg to 40 mg / kg, 20 mg / kg to 41 mg / kg, 20 mg / kg to 42 mg / kg, 20 mg / kg to 43 mg / kg, 20 mg / kg to 44 mg / kg, 20 mg / kg to 45 mg / kg, 20 mg / kg to 46 mg / kg, 20 mg / kg to 47 mg / kg, 20 mg / kg to 48 mg / kg, 20 mg / kg to 49 mg / kg, 20 mg / kg to 50 mg / kg, 20 mg / kg to 51 mg / kg, 20 mg / kg to 52 mg / kg, 20 mg / kg to 53 mg / kg, 20 mg / kg to 54 mg / kg, 20 mg / kg to 55 mg / kg, 20 mg / kg to 56 mg / kg, 20 mg / kg to 57 mg / kg, 20 mg / kg to 58 mg / kg, 20 mg / kg to 59 mg / kg, 20 mg / kg to 60 mg / kg, 20 mg / kg to 61 mg / kg, 20 mg / kg to 62 mg / kg, 20 mg / kg to 63 mg / kg, 20 mg / kg to 64 mg / kg, 20 mg / kg to 65 mg / kg, 20 mg / kg to 66 mg / kg, 20 mg / kg to 67 mg / kg, 20 mg / kg to 68 mg / kg, 20 mg / kg to 69 mg / kg, 20 mg / kg to 70 mg / kg, 20 mg / kg to 71 mg / kg, 20 mg / kg to 72 mg / kg, 20 mg / kg to 73 mg / kg, 20 mg / kg to 74 mg / kg, 20 mg / kg to 75 mg / kg, 20 mg / kg to 76 mg / kg, 20 mg / kg to 77 mg / kg, 20 mg / kg to 78 mg / kg, 20 mg / kg to 79 mg / kg, 20 mg / kg to 80 mg / kg, 20 mg / kg to 81 mg / kg, 20 mg / kg to 82 mg / kg, 20 mg / kg to 83 mg / kg, 20 mg / kg to 84 mg / kg, 20 mg / kg to 85 mg / kg, 20 mg / kg to 86 mg / kg, 20 mg / kg to 87 mg / kg, 20 mg / kg to 88 mg / kg, 20 mg / kg to 89 mg / kg, 20 mg / kg to 90 mg / kg, 20 mg / kg to 91 mg / kg, 20 mg / kg to 92 mg / kg, 20 mg / kg to 93 mg / kg, 20 mg / kg to 94 mg / kg, 20 mg / kg to 95 mg / kg, 20 mg / kg to 96 mg / kg, 20 mg / kg to 97 mg / kg, 20 mg / kg to 98 mg / kg, 20 mg / kg to 99 mg / kg, 20 mg / kg to 100 mg / kg, 20 mg / kg to 101 mg / kg, 20 mg / kg to 102 mg / kg, 20 mg / kg to 103 mg / kg, 20 mg / kg to 104 mg / kg, 20 mg / kg to 105 mg / kg, 20 mg / kg to 106 mg / kg, 20 mg / kg to 107 mg / kg, 20 mg / kg to 108 mg / kg, 20 mg / kg to 109 mg / kg, 20 mg / kg to 110 mg / kg, 20 mg / kg to 111 mg / kg, 20 mg / kg to 112 mg / kg, 20 mg / kg to 113 mg / kg, 20 mg / kg to 114 mg / kg, 20 mg / kg to 115 mg / kg, 20 mg / kg to 116 mg / kg, 20 mg / kg to 117mg / kg, 20 mg / kgto 118 mg / kg, 20 mg / kg to 119 mg / kg, 20 mg / kgto 120 mg / kg, 20 mg / kgto 121 mg / kg, 20 mg / kgto 122 mg / kg, 20 mg / kg to 123 mg / kg, 20 mg / kgto 124 mg / kg, 20 mg / kgto 125 mg / kg, 20 mg / kgto 126 mg / kg, 20 mg / kg to 127 mg / kg, 20 mg / kgto 128 mg / kg, 20 mg / kgto 129 mg / kg, 20 mg / kgto 130 mg / kg, 20 mg / kg to 131 mg / kg, 20 mg / kgto 132 mg / kg, 20 mg / kgto 133 mg / kg, 20 mg / kgto 134 mg / kg, 20 mg / kg to 135 mg / kg, 20 mg / kgto 136 mg / kg, 20 mg / kgto 137 mg / kg, 20 mg / kgto 138 mg / kg, 20 mg / kg to 139 mg / kg, 20 mg / kgto 140 mg / kg, 20 mg / kgto 141 mg / kg, 20 mg / kgto 142 mg / kg, 20 mg / kg to 143 mg / kg, 20 mg / kgto 144 mg / kg, 20 mg / kgto 145 mg / kg, 20 mg / kgto 146 mg / kg, 20 mg / kg to 147 mg / kg, 20 mg / kgto 148 mg / kg, 20 mg / kgto 149 mg / kg, 20 mg / kgto 150 mg / kg, 20 mg / kg to 151 mg / kg, 20 mg / kgto 152 mg / kg, 20 mg / kgto 153 mg / kg, 20 mg / kgto 154 mg / kg, 20 mg / kg to 155 mg / kg, 20 mg / kgto 156 mg / kg, 20 mg / kgto 157 mg / kg, 20 mg / kgto 158 mg / kg, 20 mg / kg to 159 mg / kg, 20 mg / kgto 160 mg / kg, 20 mg / kgto 161 mg / kg, 20 mg / kgto 162 mg / kg, 20 mg / kg to 163 mg / kg, 20 mg / kgto 164 mg / kg, 20 mg / kgto 165 mg / kg, 20 mg / kgto 166 mg / kg, 20 mg / kg to 167 mg / kg, 20 mg / kgto 168 mg / kg, 20 mg / kgto 169 mg / kg, 20 mg / kgto 170 mg / kg, 20 mg / kg to 171 mg / kg, 20 mg / kgto 172 mg / kg, 20 mg / kgto 173 mg / kg, 20 mg / kgto 174 mg / kg, 20 mg / kg to 175 mg / kg, 20 mg / kgto 176 mg / kg, 20 mg / kgto 177 mg / kg, 20 mg / kgto 178 mg / kg, 20 mg / kg to 179 mg / kg, 20 mg / kgto 180 mg / kg, 20 mg / kgto 181 mg / kg, 20 mg / kgto 182 mg / kg, 20 mg / kg to 183 mg / kg, 20 mg / kgto 184 mg / kg, 20 mg / kgto 185 mg / kg, 20 mg / kgto 186 mg / kg, 20 mg / kg to 187 mg / kg, 20 mg / kgto 188 mg / kg, 20 mg / kgto 189 mg / kg, 20 mg / kgto 190 mg / kg, 20 mg / kg to 191 mg / kg, 20 mg / kgto 192 mg / kg, 20 mg / kgto 193 mg / kg, 20 mg / kgto 194 mg / kg, 20 mg / kg to 195 mg / kg, 20 mg / kgto 196 mg / kg, 20 mg / kgto 197 mg / kg, 20 mg / kg to 198 mg / kg, 20 mg / kg to 199 mg / kg, or 20 mg / kg to 200 mg / kg.

[0148] In some embodiments, the therapeutically effective amount provides a cerebrospinal fluid (CSF) concentration of the therapeutic anti-NMDAR antibody in an amount of about 0.6 pg / mL to about2.5 pg / mL, about 0.7 pg / mL to about2.5 pg / mL, about0.8 pg / mL to about2.5 pg / mL, about 0.9 pg / mL to about 2.5 pg / mL, about 1.0 pg / mL to about 2.5 pg / mL, about 1.1 pg / mL to about2.5 pg / mL, about 1.2 pg / mL to about2.5 pg / mL, about 1.3 pg / mL to about2.5 pg / mL, about 1.4 pg / mL to about 2.5 pg / mL, about 1.5 pg / mL to about 2.5 pg / mL, about 1.6 pg / mL to about 2.5 pg / mL, about 1.7pg / mLto about 2.5 pg / mL, about 1.8 pg / mL to about 2.5 pg / mL, about 1.9 pg / mL to about 2.5 pg / mL, about 2.1 pg / mL to about 2.5 pg / mL, about 2.2 pg / mL to about 2.5 pg / mL, about 2.3 pg / mL to about 2.5 pg / mL, or about 2.4 pg / mL to about 2.5 pg / mL.

[0149] In some embodiments, the therapeutically effective amount provides a cerebrospinal fluid (CSF) concentration of the therapeutic anti-NMDAR antibody in an amount of about 0.6 pg / mL to about 0.7 pg / mL, about 0.6 pg / mL to about 0.8 pg / mL, about 0.6 pg / mL to about 0.9 pg / mL, about 0.6 pg / mL to about 1.0 pg / mL, about 0.6 pg / mL to about 1.1 pg / mL, about 0.6pg / mL to about 1 .2 pg / mL, about 0.6 pg / mL to about 1 .3 pg / mL, about 0.6 pg / mL to about 1 .4 pg / mL, about 0.6 pg / mL to about 1.5 pg / mL, about 0.6 pg / mL to about 1.6 pg / mL, about 0.6 pg / mL to about 1 .7 pg / mL, about 0.6 pg / mL to about 1.8 pg / mL, about 0.6 pg / mL to about 1 .9 pg / mL, about 0.6 pg / mL to about 2.0 pg / mL, about 0.6 pg / mL to about 2.1 pg / mL, about 0.6 pg / mL to about 2.2 pg / mL, about 0.6 pg / mL to about 2.3 pg / mL, about 0.6 pg / mL to about 2.4 pg / mL, or about 0.6 pg / mL to about 2.5 pg / mL.

[0150] In some embodiments, the therapeutically effective amount provides a cerebrospinal fluid (CSF) concentration of the therapeutic anti-NMDAR antibody in an amount of at least 0.6 pg / mL, 0.7 pg / mL, 0.8 pg / mL, 0.9 pg / mL, 1.0 pg / mL, 1.1 pg / mL, 1.2 pg / mL, 1.3 pg / mL, 1.4 pg / mL, 1.5 pg / mL, 1.6 pg / mL, 1.7 pg / mL, 1.8 pg / mL, 1.9 pg / mL, 2.0 pg / mL, 2.1 pg / mL, 2.2 pg / mL, 2.3 pg / mL, 2.4 pg / mL, or 2.5 pg / mL.

[0151] In some embodiments, the therapeutically effective amount provides a cerebrospinal fluid (CSF) concentration of the therapeutic anti-NMDAR antibody in an amount of at most 0.6 pg / mL, 0.7 pg / mL, 0.8 pg / mL, 0.9 pg / mL, 1.0 pg / mL, 1.1 pg / mL, 1.2 pg / mL, 1.3 pg / mL, 1.4 pg / mL, 1.5 pg / mL, 1.6 pg / mL, 1.7 pg / mL, 1.8 pg / mL, 1.9 pg / mL, 2.0 pg / mL, 2.1 pg / mL, 2.2 pg / mL, 2.3 pg / mL, 2.4 pg / mL, or 2.5 pg / mL.

[0152] In some embodiments, the therapeutic anti-NMDAR antibody is administered less frequently than once a day.

[0153] In some embodiments, the therapeutic anti-NMDAR antibody is administered once a week, twice a week, every two weeks, every three weeks, or every four weeks.

[0154] In some embodiments, the therapeutic anti-NMDAR antibody binds an antigen comprising a single epitope, a single NMD AR epitope, or a single NTD-NR1 epitope. In some embodiments, the NTD-NR1 epitope lacks an N-terminal signal peptide.

[0155] In some embodiments, the NTD-NRl epitope comprises an amino acid sequence with at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98 %, at least about 99%, or about 100% sequence identity or sequence similarity to SEQ ID NO: 1.

[0156] In some embodiments, the NTD-NR1 epitope comprises an amino acid sequence of SEQ ID NO: 1. In some embodiments, the NTD-NRl epitope lacks an N-terminal signal peptide.

[0157] In some embodiments, the NTD-NR1 epitope comprises an amino acid sequence with one or more insertions, deletions, and / or substitutions relative to SEQ ID NO: 1.

[0158] In some embodiments, the NTD-NRl epitope comprises an amino acid sequence with at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, atleast 11, at least 12, atleast 13, at least 14, at least 15, at least 16, at least 17, at least18, at least 19, at least 20, at least 25, at least 30, at least 35, or at least 40 amino acid insertions, deletions, and / or substitutions relative to SEQ ID NO: 1.

[0159] In some embodiments, the NTD-NRl epitope comprises an amino acid sequence with at most 1, atmost2, at most 3, atmost4, at most 5, at most 6, at most 7, at most 8, at most 9, at most 10, at most 11, at most 12, at most 13, at most 14, at most 15, at most 16, at most 17, at most 18, at most 19, at most 20, at most 25, at most 30, at most 35, or at most 40 amino acid insertions, deletions, and / or substitutions relative to SEQ ID NO: 1.

[0160] In some embodiments, the NTD-NRl epitope comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, or 40 amino acid insertions, deletions, and / or substitutions relative to SEQ ID NO: 1.

[0161] The one or more insertions, deletions, and / or substitutions can be at the N-terminus, the C-terminus, within the amino acid sequence, or a combination thereof. The one or more insertions can be contiguous, non -contiguous, or a combination thereof.

[0162] In certain embodiments, the NTD-NR1 epitope comprises 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, or 40 contiguous amino acids from SEQ ID NO: 1.

[0163] In some embodiments, the NTD-NRl epitope comprises an amino acid sequence with at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98 %, at least about 99%, or about 100% sequence identity or sequence similarity to SEQ ID NO: 2.

[0164] In some embodiments, the NTD-NR1 epitope comprises an amino acid sequence of SEQ ID NO: 2.

[0165] In some embodiments, the NTD-NR1 epitope comprises an amino acid sequence with one or more insertions, deletions, and / or substitutions relative to SEQ ID NO: 2.

[0166] In some embodiments, the NTD-NRl epitope comprises an amino acid sequence with at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, atleast 11, at least 12, atleast 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 25, or at least 30 amino acid insertions, deletions, and / or substitutions relative to SEQ ID NO: 2.

[0167] In some embodiments, the NTD-NRl epitope comprises an amino acid sequence with at most 1, atmost2, at most 3, atmost4, at most 5, at most 6, at most 7, at most 8, at most 9, at most 10, at most 11, at most 12, at most 13, at most 14, at most 15, at most 16, at most 17, at most 18, at most 19, atmost 20, atmost25, or at most 30 amino acid insertions, deletions, and / or substitutions relative to SEQ ID NO: 2.

[0168] In some embodiments, the NTD-NRl epitope comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, or 30 amino acid insertions, deletions, and / or substitutions relative to SEQ ID NO: 2.

[0169] The one or more insertions, deletions, and / or substitutions can be at the N-terminus, the C-terminus, within the amino acid sequence, or a combination thereof. The one or more insertions can be contiguous, non -contiguous, or a combination thereof.

[0170] In certain embodiments, the NTD-NR1 epitope comprises 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, or 30 contiguous amino acids from SEQ ID NO: 2.

[0171] In some embodiments, the NTD-NRl epitope comprises an amino acid sequence with at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98 %, at least about 99%, or about 100% sequence identity or sequence similarity to SEQ ID NO: 3.

[0172] In some embodiments, the NTD-NR1 epitope comprises an amino acid sequence of SEQ ID NO: 3.

[0173] In some embodiments, the NTD-NR1 epitope comprises an amino acid sequence with one or more insertions, deletions, and / or substitutions relative to SEQ ID NO: 3.

[0174] In some embodiments, the NTD-NRl epitope comprises an amino acid sequence with at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, atleast 11, at least 12, atleast 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or at least 25 amino acid insertions, deletions, and / or substitutions relative to SEQ ID NO: 3.

[0175] In some embodiments, the NTD-NRl epitope comprises an amino acid sequence with at most 1, atmost2, at most 3, atmost4, at most 5, at most 6, at most 7, at most 8, at most 9, at most 10, at most 11, at most 12, at most 13, at most 14, at most 15, at most 16, at most 17, at most 18, at most 19, at most 20, or at most 25 amino acid insertions, deletions, and / or substitutions relative to SEQ ID NO: 3.

[0176] In some embodiments, the NTD-NRl epitope comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 25 amino acid insertions, deletions, and / or substitutions relative to SEQ ID NO: 3.

[0177] The one or more insertions, deletions, and / or substitutions can be at the N-terminus, the C-terminus, within the amino acid sequence, or a combination thereof. The one or more insertions can be contiguous, non -contiguous, or a combination thereof.

[0178] In certain embodiments, the NTD-NR1 epitope comprises 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 25 contiguous amino acids from SEQ ID NO: 3.

[0179] In some embodiments, the NTD-NRl epitope comprises an amino acid sequence with at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98 %, at least about 99%, or about 100% sequence identity or sequence similarity to SEQ ID NO: 4.

[0180] In some embodiments, the NTD-NR1 epitope comprises an amino acid sequence of SEQ ID NO: 4.

[0181] In some embodiments, the NTD-NR1 epitope comprises an amino acid sequence with one or more insertions, deletions, and / or substitutions relative to SEQ ID NO: 4.

[0182] In some embodiments, the NTD-NRl epitope comprises an amino acid sequence with at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, atleast 11, at least 12, atleast 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 amino acid insertions, deletions, and / or substitutions relative to SEQ ID NO: 4.

[0183] In some embodiments, the NTD-NRl epitope comprises an amino acid sequence with at most 1, atmost2, at most 3, atmost4, at most 5, at most 6, at most 7, at most 8, at most 9, at most 10, at most 11, at most 12, at most 13, at most 14, at most 15, at most 16, at most 17, at most 18, at most 19, or atmost 20 amino acid insertions, deletions, and / or substitutions relative to SEQ ID NO: 4.

[0184] In some embodiments, the NTD-NRl epitope comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid insertions, deletions, and / or substitutions relative to SEQ ID NO: 4.

[0185] The one or more insertions, deletions, and / or substitutions can be at the N-terminus, the C-terminus, within the amino acid sequence, or a combination thereof. The one or more insertions can be contiguous, non -contiguous, or a combination thereof.

[0186] In certain embodiments, the NTD-NR1 epitope comprises 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 contiguous amino acids from SEQ ID NO: 4.

[0187] In some embodiments, the NTD-NRl epitope comprises an amino acid sequence with at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98 %, at least about 99%, or about 100% sequence identity or sequence similarity to SEQ ID NO: 5.

[0188] In some embodiments, the NTD-NR1 epitope comprises an amino acid sequence of SEQ ID NO: 5.

[0189] In some embodiments, the NTD-NR1 epitope comprises an amino acid sequence with one or more insertions, deletions, and / or substitutions relative to SEQ ID NO: 5.

[0190] In some embodiments, the NTD-NRl epitope comprises an amino acid sequence with at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, atleast 11, at least 12, atleast 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 amino acid insertions, deletions, and / or substitutions relative to SEQ ID NO: 5.

[0191] In some embodiments, the NTD-NRl epitope comprises an amino acid sequence with at most 1, atmost2, at most 3, atmost4, at most 5, at most 6, at most 7, at most 8, at most 9, at most 10, at most 11, at most 12, at most 13, at most 14, at most 15, at most 16, at most 17, at most 18, at most 19, or atmost 20 amino acid insertions, deletions, and / or substitutions relative to SEQ ID NO: 5.

[0192] In some embodiments, the NTD-NRl epitope comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid insertions, deletions, and / or substitutions relative to SEQ ID NO: 5.

[0193] The one or more insertions, deletions, and / or substitutions can be at the N-terminus, the C-terminus, within the amino acid sequence, or a combination thereof. The one or more insertions can be contiguous, non -contiguous, or a combination thereof.

[0194] In certain embodiments, the NTD-NR1 epitope comprises 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 contiguous amino acids from SEQ ID NO: 5.

[0195] In one aspect, the disclosure provides a method of detecting a pathologic anti- NMDAR antibody in a biological sample of an individual, wherein the method comprises contacting a biological sample of the individual to and detecting the binding of a pathologic anti- NMDAR antibody in the biological sample of the individual.

[0196] In some embodiments, the biological sample comprises blood, plasma, serum, saliva, cell lysate, lymph, amniotic fluid, cerebral -spinal fluid, lachrymal fluid, mucus, urine, sputum, amniotic fluid, or sweat. In some embodiments, the biological sample comprises plasma, serum, or cerebral spinal fluid. In some embodiments, the biological sample comprises blood, plasma, serum, lymph, cerebral-spinal fluid. In some embodiments, the biological sample comprises amniotic fluid. In some embodiments, the biological sample comprises blood. In some embodiments, the biological sample comprises plasma. In some embodiments, the biological sample comprises serum. In some embodiments, the biological sample comprises lymph. In some embodiments, the biological sample comprises cerebral-spinal fluid. In certain embodiments, the biological sample further comprises a diluent. In some embodiments, the biological sample comprises any suitable amount of a bodily fluid or tissue (e.g., blood, saliva, urine, skin or other tissues) that may be collected from an individual. In some embodiments, the biological sample comprises a portion of an undiluted sample in a suitable diluent, for example, up to 50%, 40%,30%, 20%, 10%, 5%, or 1 % weight or volume of a sample included in an assay for anti-NMDAR antibodies.

[0197] In some embodiments, the binding of the pathologic anti-NMDAR antibody in the biological sample to the plurality of NMD AR antigens can be detected by an immunoassay. In some embodiments, the immunoassay comprises an enzyme immunoassay, a radioimmunoassay, a fluoroimmunoassay, a chemiluminescent immunoassay, a counting immunoassay, an immunoenzymometric assay, an enzyme multiplied immunoassay technique, a photoacoustic Immunoassayreal-time immunoquantitative PCR, or an enzyme-linked immunosorbent assay (ELISA). In some embodiments, the immunoassay comprises an ELISA.

[0198] In some embodiments, the ELISA comprises contacting the biological sample of the individual to the plurality of NMD AR antigens to produce a pathologic anti-NMDAR antibody / NMD AR antigen complex; and contacting the pathologic anti-NMDAR antibody / NMD AR antigen complex to a detection agent that binds to the pathologic anti- NMDAR antibody.

[0199] In some embodiments, the detection agent comprises an antibody. In some embodiments, the antibody targets ART5803. In some embodiments, the antibody comprises an anti-isotype antibody. In some embodiments, the anti-isotype antibody comprises an antibody targeting IgA, IgD, IgG, IgE, orlgM. In some embodiments, the anti -isotype antibody comprises an antibody targeting IgAl, IgA2, IgD, IgGl, IgG2, IgG3, IgG4, IgE, or IgM. In some embodiments, the anti-isotype antibody comprises an antibody targeting IgA, IgG, or IgM. In some embodiments, the anti-isotype antibody comprises an antibody targeting IgG. In some embodiments, the anti-isotype antibody comprises an antibody targeting IgGl . In some embodiments, the anti-isotype antibody comprises an antibody targeting IgG2. In some embodiments, the anti-isotype antibody comprises an antibody targeting IgG3. In some embodiments, the anti-isotype antibody comprises an antibody targeting IgG4. In some embodiments, the anti-isotype antibody comprises an antibody targeting IgA. In some embodiments, the anti-isotype antibody comprises an antibody targeting IgAl . In some embodiments, the anti-isotype antibody comprises an antibody targeting IgA2. In some embodiments, the anti-isotype antibody comprises an antibody targeting IgM.

[0200] In some embodiments, the detection agent is labelled with a fluorescent tag, a radioactive tag, or an enzyme.

[0201] In some embodiments, the fluorescent tag comprises a fluorescent protein, wherein the fluorescent protein comprises a yellow fluorescent protein (YFP), a green fluorescent protein (GFP), a cyan fluorescent protein (CFP), a red fluorescent protein (RFP), umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine, fluorescein, cyanines,dansyl chloride, phycocyanin, Venus, Citrine, mRuby3, mCherry, tdTomato, dsRed, phycoerythrin, or combinations thereof . In some embodiments, the fluorescent tag comprises a fluorophore disclosed herein.

[0202] In some embodiments, the radioactive tag comprises32P,33P,47Sc,59Fe,64Cu,67Cu, 75 Se,77As,89Sr,90Y,99Mo,105Rh,109Pd,111Ag,125I,131I,142Pr,143Pr,149Pm.153Sm,161Tb,166Ho,169Er.177Lu,186Re,188Re,189Re,194Ir,198Au,199Au,211Pb,213Bi,58Co,67Ga,80mBr,99mTc,193mRh,io9pt, mIn?ii9Sb, i25i,161Ho,189mOs,192Ir,152Dy,211At,212Bi,223Ra,219Rn,215Po,211Bi,225Ac,221Fr,217At,213Bi,225Fm, or combinations thereof.

[0203] In some embodiments, the enzyme comprises horseradish peroxidase enzyme (HRP), alkaline phosphatase (AP), beta -galactosidase (Gal), glucose oxidase, luciferase, beta-lactamase, urease, or lysozyme. In some embodiments, the enzyme comprises HRP. In some embodiments, the enzyme comprises HRP and AP.

[0204] In some embodiments, the binding of a pathologic anti-NMDAR antibody is detected by fluorescently activated cell sorting (FACS). In some embodiments, the FACS comprises contacting biological sample of the individual to the plurality of NMD AR antigens expressed in HEK cells to produce a pathologic anti-NMDAR antib ody / NMD AR antigen complex; contacting the pathologic anti-NMDAR antib ody / NMD AR antigen complex to a detection agent that binds to the pathologic anti-NMDAR antibody. In some embodiments, the detection agent is disclosed herein.

[0205] In some embodiments, the pathologic anti-NMDAR antibody present in the biological sample is detected at a concentration of at most about 500 pg / ml, at most about 400 pg / ml, at most about 300 pg / ml, at most about 200 pg / ml, at most about 100 pg / ml, at most about 90 pg / ml, at most about 80 pg / ml, at most about 70 pg / ml, at most about 60 pg / ml, at most about 50 pg / ml, at most about 40 pg / ml, at most about 30 pg / ml, at most about 20 pg / ml, at most about 10 pg / ml, at most about 5 pg / ml, at most about 2 pg / ml, or at most about 1 pg / ml or more. In some embodiments, the pathologic anti-NMDAR antibody present in the biological sample is detected at a concentration of at most about 500 ng / ml, at most about 400 ng / ml, at most about 300 ng / ml, at most about 200 ng / ml, at most about 100 ng / ml, at most about 90 ng / ml, at most about 80 ng / ml, at most about 70 ng / ml, at most about 60 ng / ml, at most about 50 ng / ml, at most about 40 ng / ml, at most about 30 ng / ml, at most about 20 ng / ml, at most about 10 ng / ml, at most about 5 ng / ml, at most about 2 ng / ml, or at most about 1 ng / ml or more.

[0206] In some embodiments, the pathologic anti-NMDAR antibody present in the biological sample is detected at a concentration of at least about 500 ng / ml, at least about 400 ng / ml, at least about 300 ng / ml, at least about 200 ng / ml, at least about 100 ng / ml, at least about 90 ng / ml, at least about 80 ng / ml, at least about 70 ng / ml, at least about 60 ng / ml, at least about 50 ng / ml, atleast about 40 ng / ml, at least about 30 ng / ml, at least about 20 ng / ml, at least about 10 ng / ml, at least about 5 ng / ml, at least about 2 ng / ml, or at least about 1 ng / ml.

[0207] In some embodiments, the pathologic anti-NMDAR antibody present in the biological sampleis detected ata concentration ofab out 500 ng / ml orless, about400 ng / ml, about 300 ng / ml, about 200 ng / ml, about 100 ng / ml, about 90 ng / ml, about 80 ng / ml, about 70 ng / ml, about 60 ng / ml, about 50 ng / ml, about40 ng / ml, about 30 ng / ml, about 20 ng / ml, about 10 ng / ml, about 5 ng / ml, about 2 ng / ml, or about 1 ng / ml. In some embodiments, the pathologic anti-NMDAR antibody present in the biological sample is detected at a concentration of about 500 pg / ml or less, about 400 pg / ml, about 300 pg / ml, about 200 pg / ml, about 100 pg / ml, about 90 pg / ml, about 80 pg / ml, about 70 pg / ml, about 60 pg / ml, about 50 pg / ml, about 40 pg / ml, about 30 pg / ml, about 20 pg / ml, about 10 pg / ml, about 5 pg / ml, about 2 pg / ml, or about 1 pg / ml.

[0208] In some embodiments, the pathologic anti-NMDAR antibody present in the biological sample is detected at a concentration ranging from 1 ng / ml to 500 pg / ml, 2 ng / ml to 500 pg / ml, 5 ng / ml to 500 pg / ml, 10 ng / ml to 500 pg / ml, 20 ng / ml to 500 pg / ml, 30 ng / ml to 500 pg / ml, 40 ng / ml to 500 pg / ml, 50 ng / ml to 500 pg / ml, 60 ng / ml to 500 pg / ml, 70 ng / ml to 500 pg / ml, 80 ng / ml to 500 pg / ml, 90 ng / ml to 500 pg / ml, 100 ng / ml to 500 pg / ml, or 200 ng / ml to 500 pg / ml. In some embodiments, the pathologic anti-NMDAR antibody present in the biological sample is detected at a concentration ranging from 1 to 500 ng / ml, 2 to 500 ng / ml, 5 to 500 ng / ml, 10 to 500 ng / ml, 20 to 500 ng / ml, 30 to 500 ng / ml, 40 to 500 ng / ml, 50 to 500 ng / ml, 60 to 500 ng / ml, 70 to 500 ng / ml, 80 to 500 ng / ml, 90 to 500 ng / ml, 100 to 500 ng / ml, 200 to 500 ng / ml, 300 to 500 ng / ml, 400 to 500 ng / ml, 1 to 400 ng / ml, 2 to 400 ng / ml, 5 to 400 ng / ml, 10 to 400 ng / ml 20 to 400 ng / ml, 30 to 400 ng / ml, 40 to 400 ng / ml, 50 to 400 ng / ml, 60 to 400 ng / ml, 70 to 400 ng / ml, 80 to 400 ng / ml, 90 to 400 ng / ml, 100 to 400 ng / ml, 200 to 400 ng / ml, 300 to 400 ng / ml, 1 to 300 ng / ml, 2 to 300 ng / ml, 5 to 300 ng / ml, 10 to 300 ng / ml, 20 to 300 ng / ml, 30 to 300 ng / ml, 40 to 300 ng / ml, 50 to 300 ng / ml, 60 to 300 ng / ml, 70 to 300 ng / ml, 80 to 300 ng / ml, 90 to 300 ng / ml, 100 to 300 ng / ml, 200 to 300 ng / ml, 1 to 200 ng / ml, 2 to 200 ng / ml, 5 to 200 ng / ml, 10 to 200 ng / ml, 20 to 200 ng / ml, 30 to 200 ng / ml, 40 to 200 ng / ml, 50 to 200 ng / ml, 60 to 200 ng / ml, 70 to 200 ng / ml, 80 to 200 ng / ml, 90 to 200 ng / ml, 100 to 200 ng / ml, 1 to 100 ng / ml, 2 to 100 ng / ml, 5 to 100 ng / ml, 10 to 100 ng / ml, 20 to 100 ng / ml, 30 to 100 ng / ml, 40 to 100 ng / ml, 50 to 100 ng / ml, 60 to 100 ng / ml, 70 to 100 ng / ml, 80 to 100 ng / ml, 90 to 100 ng / ml, 1 to 90 ng / ml, 2 to 90 ng / ml, 5 to 90 ng / ml, 10 to 90 ng / ml, 20 to 90 ng / ml, 30 to 90 ng / ml, 40 to 90 ng / ml, 50 to 90 ng / ml, 60 to 90 ng / ml, 70 to 90 ng / ml, 80 to 90 ng / ml, 1 to 80 ng / ml, 2 to 80 ng / ml, 5 to 80 ng / ml, 10 to 80 ng / ml, 20 to 80 ng / ml, 30 to 80 ng / ml, 40 to 80 ng / ml, 50 to 80 ng / ml, 60 to 80 ng / ml, 70 to 80 ng / ml, 1 to 70 ng / ml, 2 to 70 ng / ml, 5 to 70 ng / ml, 10 to 70 ng / ml, 20 to 70 ng / ml, 30 to 70 ng / ml, 40 to 70 ng / ml, 50 to 70 ng / ml, 60 to 70 ng / ml, 1 to 60ng / ml, 2 to 60 ng / ml, 5 to 60 ng / ml, 10 to 60 ng / ml, 20 to 60 ng / ml, 30 to 60 ng / ml, 40 to 60 ng / ml, 50 to 60 ng / ml, 1 to 50 ng / ml, 2 to 50 ng / ml, 5 to 50 ng / ml, 10 to 50 ng / ml, 20 to 50 ng / ml, 30 to 50 ng / ml, 40 to 50 ng / ml, 1 to 40 ng / ml, 2 to 40 ng / ml, 5 to 40 ng / ml, 10 to 40 ng / ml, 20 to 40 ng / ml, 30 to 40 ng / ml, 1 to 30 ng / ml, 2 to 30 ng / ml, 5 to 30 ng / ml, 10 to 30 ng / ml , 20 to 30 ng / ml, 1 to 20 ng / ml, 2 to 20 ng / ml, 5 to 20 ng / ml, 10 to 20 ng / ml, 1 to 10 ng / ml, 2 to 10 ng / ml, 5 to 10 ng / ml, 1 to 5 ng / ml, 2 to 5 ng / ml, or 1 to 2 ng / ml.

[0209] In some embodiments, the detection of the pathologic anti-NMDAR antibody indicates a diagnosis of an anti-NMDAR pathology. In some embodiments, the anti-NMDAR pathology comprises autoimmune encephalitis, anti-NMDAR autoimmune encephalitis, dementia, psychosis, schizophrenia, bipolar disorder, seizure, epilepsy, or depression. In some embodiments, the anti-NMDAR pathology comprises anti-NMDAR autoimmune encephalitis. In some embodiments, the anti-NMDAR pathology comprises dementia, psychosis, schizophrenia, bipolar disorder, seizure, epilepsy, or depression. In some embodiments, anti-NMDAR pathology comprises dementia. In some embodiments, anti-NMDAR pathology comprises psychosis. In some embodiments, anti-NMDAR pathology comprises schizophrenia. In some embodiments, anti-NMDAR pathology comprises bipolar disorder. In some embodiments, anti-NMDAR pathology comprises seizure. In some embodiments, anti-NMDAR pathology comprises epilepsy. In some embodiments, anti-NMDAR pathology comprises depression.

[0210] In some embodiments, the detection of the pathologic anti-NMDAR antibody is followed by administration of atherapeutic agent that treats an anti -NMD AR pathology. In some embodiments, the detection of the pathologic anti-NMDAR antibody is followed by administration of a one-arm antibody that treats an anti-NMDAR pathology. In some embodiments, the detection of the pathologic anti-NMDAR antibody is followed by administration of a therapeutic anti-NMDAR antibody.Therapeutic methods for disease associated with anti-NMDAR Autoantibody

[0211] The methods of detecting anti-NMDAR autoantibodies described herein can be combined with steps taken to treat an anti-NMDAR pathology.

[0212] In one aspect, disclosed herein is a therapeutic anti-NMDAR antibody or an anti- NMDAR binding fragment thereof that prevents binding of the pathologic anti-NMDAR autoantibody to an NMDA receptor of the individual, based upon detecting the presence of the pathologic anti-NMDAR antibody.

[0213] In some embodiments, the anti-NMDAR pathology comprises autoimmune encephalitis, anti-NMDAR autoimmune encephalitis, dementia, psychosis, schizophrenia, bipolar disorder, seizure, epilepsy, or depression. In some embodiments, the anti-NMDAR pathologycomprises anti-NMDAR autoimmune encephalitis. In some embodiments, the anti-NMDAR pathology comprises dementia, psychosis, schizophrenia, bipolar disorder, seizure, epilepsy, or depression. In some embodiments, anti-NMDAR pathology comprises dementia. In some embodiments, anti-NMDAR pathology comprises psychosis. In some embodiments, anti- NMDAR pathology comprises schizophrenia. In some embodiments, anti-NMDAR pathology comprises bipolar disorder. In some embodiments, anti-NMDAR pathology comprises seizure. In some embodiments, anti-NMDAR pathology comprises epilepsy. In some embodiments, anti- NMDAR pathology comprises depression. In some embodiments, anti-NMDAR pathology comprises poor quality of life. In some embodiments, anti-NMDAR pathology comprises neurological disability.

[0214] Treatment refers to a method that seeks to partially or completely alleviating, ameliorating, relieving, delaying onset of, inhibiting, or slowing progression of, reducing severity of, and / or reducing incidence of one or more symptoms or features of a particular disease, disorder, and / or condition being treated. The treatment of anti-NMDAR autoimmune encephalitis by a therapeutic anti-NMDAR antibody or an anti-NMDAR binding fragment thereof is expected to produce significant improvement in one or more of the typical clinical presentations such as improvement in acute psychiatric symptoms, improved memory function, reductions in seizures or dyskinesias, and improvement in consciousness and awareness. Various measures and tools for assessing psychiatric states are well-known to a clinician trained in the field. In some embodiments, clinical improvement before and / or after treatment is determined by the treating physician using the clinical global impression (CGI) generally as a summary measure for severity (CGI-S) and improvement (CGI-I). In some embodiments, after treatment, CGI reflects improvement on mental state. In some embodiments, after treatment, CGI is much improved. In some embodiments, after treatment, CGI is very much improved.

[0215] In some embodiments, clinical improvement in terms of functional recovery before and / or after treatment is evaluated using the modified Rankin Scale (mRS), with improvement in mRS scores obtained after treatment. In some embodiments, after treatment, mRS is 4 or lower. In some embodiments, after treatment, mRS is 3 or lower. In some embodiments, after treatment, mRS is 2 or lower. In some embodiments, after treatment, mRS is 1 or lower. In some embodiments, after treatment, mRS is 0. In some embodiments, an individual receiving treatment will score 1, 2, 3, 4, 5, or 6 points lower compared to a pretreatment assessment.

[0216] In some embodiments, clinical improvement for cognitive assessment before and / or after treatment is conducted by monitoring Montreal Cognitive Assessment scores (MOCA), with increases in MOCA scores obtained with treatment. In some embodiments, after treatment, MOCA reflects normal cognitive function. In some embodiments after treatment, MOCA is 27 orhigher. In some embodiments, after treatment, MOCA is 26 or higher. In some embodiments after treatment, MOCA is 25 or higher. In some embodiments, after treatment, MOCA is 24 or higher. In some embodiments, after treatment, MOCA is 23 or higher. In some embodiments, after treatment, MOCA is 22 or higher. In some embodiments, after treatment, MOCA is 21 or higher. In some embodiments, after treatment, MOCA is 20 or higher. In some embodiments, after treatment, MOCA is 19 or higher. In some embodiments, after treatment, MOCA is 18 or higher. In some embodiments, an individual receiving treatment will score 1, 2, 3, 4, 5 ,6, 7, 8, 9, or 10 points higher compared to a pretreatment assessment.

[0217] In some embodiments, clinical improvement for cognitive assessment before and / or after treatment is evaluated using a Clinical Assessment Scales for the Elderly (CASE) score. In some embodiments, the CASE score is normalized to patient age. In some embodiments after administration of the therapeutic anti-NMDAR antibody, the CASE score is improved to about 3 standard deviations (SD) below the normative mean. In some embodiments after administration of the therapeutic anti-NMDAR antibody, the CASE score is improved to about 2.5 SD below the normative mean. In some embodiments after administration of the therapeutic anti-NMDAR antibody, the CASE score is improved to about 2 SD below the normative mean. In some embodiments after administration of the therapeutic anti-NMDAR antibody, the CASE score is improved to about 1.5 SD below the normative mean. In some embodiments after administration of the therapeutic anti-NMDAR antibody, the CASE score is improved to about 1 SD below the normative mean. In some embodiments after administration of the therapeutic anti-NMDAR antibody, the CASE score is improved to about 0.5 SD below the normative mean. In some embodiments after administration of the therapeutic anti-NMDAR antibody, the CASE score is improved to about the normative mean.

[0218] In some embodiments, clinical improvement for cognitive assessment before and / or after treatment is evaluated using a Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) score. In some embodiments, the RBANS score is normalized to patient age. In some embodiments after administration of the therapeutic anti-NMDAR antibody, the RBANS score is improved to about 3 standard deviations (SD) below the normative mean. In some embodiments after administration of the therapeutic anti-NMDAR antibody, the RBANS score is improved to about 2.5 SD below the normative mean. In some embodiments after administration of the therapeutic anti-NMDAR antibody, the RBANS score is improved to about 2 SD below the normative mean. In some embodiments after administration of the therapeutic anti-NMDAR antibody, the RBANS score is improved to about 1.5 SD below the normative mean. In some embodiments after administration of the therapeutic anti-NMDAR antibody, the RBANS score is improved to about 1 SD below the normative mean. In some embodiments after administration ofthe therapeutic anti-NMDAR antibody, the RBANS score is improved to about 0.5 SD below the normative mean. In some embodiments after administration of the therapeutic anti-NMDAR antibody, the RBANS score is improved to the normative mean.

[0219] In some embodiments, clinical improvement for patients with seizures before and / or after treatment is demonstrated by a decrease in the number of seizures after treatment. In some embodiments, after treatment, the number of seizures is decreased by 90% or more. In some embodiments, after treatment, the number of seizures is decreased by 80% or more. In some embodiments, after treatment, the number of seizures is decreased by 70% or more. In some embodiments, after treatment, the number of seizures is decreased by 60% or more. In some embodiments, after treatment, the number of seizures is decreased by 50% or more. In some embodiments, after treatment, the number of seizures is decreased by 40% or more. In some embodiments, after treatment, the number of seizures is decreased by 30% or more. In some embodiments, after treatment, the number of seizures is decreased by 20% or more. In some embodiments, after treatment, the number of seizures is decreased by 10% or more. In some embodiments, after treatment, the number of seizures is decreased by 5% or more. In some embodiments, clinical improvement for patients with seizures before and / or after treatment is demonstrated by a decrease in the frequency of seizures after treatment.

[0220] In some embodiments, clinical improvement for dyskinesia symptoms before and / or after treatment is evaluated using Abnormal Involuntary Movement Scale (AIMS), the Unified Parkinson's Disease Rating Scale (UPDRS) part IV, the Obeso Dyskinesia Rating Scale, the Rush Dyskinesia Rating Scale, the Clinical Dyskinesia Rating Scale (CDRS), the Lang-Fahn Activities of Daily Living Dyskinesia Scale, the Parkinson Disease Dyskinesia Scale (PDYS-26), and the Unified Dyskinesia Rating Scale (UDysRS). In some embodiments, after treatment, the dyskinesia symptoms are improved from severe to moderate. In some embodiments, after treatment, the dyskinesia symptoms are improved from severe to mild. In some embodiments, after treatment, the dyskinesia symptoms are improved from severe to minimal. In some embodiments, after treatment, the dyskinesia symptoms are improved from severe to none. In some embodiments, after treatment, the dyskinesia symptoms are improved from moderate to mild. In some embodiments, after treatment, the dyskinesia symptoms are improved from moderate to minimal. In some embodiments, after treatment, the dyskinesia symptoms are improved from moderate to none. In some embodiments, after treatment, the dyskinesia symptoms are improved from mild to minimal. In some embodiments, after treatment, the dyskinesia symptoms are improved from mild to none. In some embodiments, after treatment, the dyskinesia symptoms are improved from minimal to none.

[0221] In some embodiments, clinical improvement for memory loss before and / or after treatment is evaluated using tests such as Mini -cognition tests and Mini Mental State Exam (MMSE) after treatment. In some embodiments, after treatment, MMSE reflects normal cognitive function. In some embodiments, after treatment, MMSE is 29 or higher. In some embodiments, after treatment, MMSE is 28 or higher. In some embodiments, after treatment, MMSE is 27 or higher. In some embodiments, after treatment, MMSE is 26 or higher. In some embodiments, after treatment, MMSE is 25 or higher. In some embodiments, after treatment, MMSE is 24 or higher. In some embodiments, after treatment, MMSE is 23 or higher. In some embodiments, after treatment, MMSE is 22 or higher. In some embodiments, after treatment, MMSE is 21 or higher. In some embodiments, after treatment, MMSE is 20 or higher. In some embodiments, after treatment, MMSE is 19 or higher. In some embodiments, an individual receiving treatment will score 1, 2, 3, 4, 5 ,6, 7, 8, 9, 10, 11, 12 points or higher compared to a pretreatment assessment.

[0222] In some embodiments, clinical improvement for memory loss and cognition before and / or after treatment is evaluated using the Wechsler Adult Intelligence Scale (WAIS-IV). In some embodiments, after treatment, WAIS-IV total score is improved by 90% or more. In some embodiments, after treatment, WAIS-IV total score is improved by 80% or more. In some embodiments, after treatment, WAIS-IV total score is improved by 70% or more. In some embodiments, after treatment, WAIS-IV total score is improved by 60% or more. In some embodiments, after treatment, WAIS-IV total score is improved by 50% or more. In some embodiments, after treatment, WAIS-IV total score is improved by 40% or more. In some embodiments, after treatment, WAIS-IV total score is improved by 30% or more. In some embodiments, after treatment, WAIS-IV total score is improved by 20% or more. In some embodiments, after treatment, WAIS-IV total score is improved by 10% or more. In some embodiments, after treatment, WAIS-IV total score is improved by 5% or more. In some embodiments, after treatment, WAIS-IV total score is improved by 1, 2, 3, 4, 5 ,6, 7, 8, 9, 10, 11,12 points or higher compared to a pretreatment assessment.

[0223] In some embodiments, clinical improvement for memory loss and cognition before and / or after treatment is evaluated using the Rey Auditory Verbal Learning Test (AVLT). In some embodiments, after treatment, AVLT total score is improved by 90% or more. In some embodiments, after treatment, AVLT total score is improved by 80% or more. In some embodiments, after treatment, AVLT total score is improved by 70% or more. In some embodiments, after treatment, AVLT total score is improved by 60% or more. In some embodiments, after treatment, AVLT total score is improved by 50% or more. In some embodiments, after treatment, AVLT total score is improved by 40% or more. In someembodiments, after treatment, AVLT total score is improved by 30% or more. In some embodiments, after treatment, AVLT total score is improved by 20% or more. In some embodiments, after treatment, AVLT total score is improved by 10% or more. In some embodiments, after treatment, AVLT total score is improved by 5% or more. In some embodiments, after treatment, AVLT total score is improvedby 1, 2, 3, 4, 5 ,6, 7, 8, 9, 10, 11, 12 points or higher compared to a pretreatment assessment.

[0224] In some embodiments, clinical improvement for memory loss and cognition before and / or after treatment is evaluated using the Boston Naming Test (BNT). In some embodiments, after treatment, BNT total score is improved by 90% or more. In some embodiments, after treatment, BNT total score is improved by 80% or more. In some embodiments, after treatment, BNT total score is improved by 70% or more. In some embodiments, after treatment, BNT total score is improved by 60% or more. In some embodiments, after treatment, BNT total score is improved by 50% or more. In some embodiments, after treatment, BNT total score is improved by 40% or more. In some embodiments, after treatment, BNT total score is improved by 30% or more. In some embodiments, after treatment, BNT total score is improved by 20% or more. In some embodiments, after treatment, BNT total score is improved by 10% or more. In some embodiments, after treatment, BNT total score is improved by 5% or more. In some embodiments, after treatment, BNT total score is improvedby 1, 2, 3, 4, 5 ,6, 7, 8, 9, 10, 11, 12 points or higher compared to a pretreatment assessment.

[0225] In some embodiments, clinical improvement for memory loss and cognition before and / or after treatment is evaluated using the Brief Cognitive Assessment Tool (BCAT). In some embodiments, after treatment, BCAT total score is improved by 90% or more. In some embodiments, after treatment, BCAT total score is improved by 80% or more. In some embodiments, after treatment, BCAT total score is improved by 70% or more. In some embodiments, after treatment, BCAT total score is improved by 60% or more. In some embodiments, after treatment, BCAT total score is improved by 50% or more. In some embodiments, after treatment, BCAT total score is improved by 40% or more. In some embodiments, after treatment, BCAT total score is improved by 30% or more. In some embodiments, after treatment, BCAT total score is improved by 20% or more. In some embodiments, after treatment, BCAT total score is improved by 10% or more. In some embodiments, after treatment, BCAT total score is improved by 5% or more. In some embodiments, after treatment, BCAT total score is improvedby 1, 2, 3, 4, 5 ,6, 7, 8, 9, 10, 11, 12 points or higher compared to a pretreatment assessment. In some embodiments, after treatment, BCAT total score is improved to 34 or higher. In some embodiments, after treatment, BCAT total score is improved to 44 or higher.

[0226] In some embodiments, clinical improvement for schizophrenia before and / or after treatment is evaluated using the Positive and Negative Symptom Scale (PANSS) total score, the positive symptom sub -scale score of the PANSS, the negative symptom sub -scale score of the PANSS, the general psychopathology sub-scale of the PANSS, the Brief Psychiatric Rating Scale (BPRS) total score derived from the PANSS, the BPRS psychosis derived from the PANSS, or any combination thereof. In some embodiments, after treatment, PANSS total score is reduced by 90% or more. In some embodiments, after treatment, PANSS total score is reduced by 80% or more. In some embodiments, after treatment, PANSS total score is reduced by 70% or more. In some embodiments, after treatment, PANSS total score is reduced by 60% or more. In some embodiments, after treatment, PANSS total score is reduced by 50% or more. In some embodiments, after treatment, PANSS total score is reduced by 40% or more. In some embodiments, after treatment, PANSS total score is reduced by 30% or more. In some embodiments, after treatment, PANSS total score is reduced by 20% or more. In some embodiments, after treatment, PANSS total score is reduced by 10% or more. In some embodiments, after treatment, PANSS total score is reduced by 5% or more. In some embodiments, after treatment, PANSS Positive subscale score is reduced by 90% or more. In some embodiments, after treatment, PANSS Positive subscale score is reduced by 80% or more. In some embodiments, after treatment, PANSS Positive subscale score is reduced by 70% or more. In some embodiments, after treatment, PANSS Positive subscale score is reduced by 60% or more. In some embodiments, after treatment, PANSS Positive subscale score is reduced by 50% or more. In some embodiments, after treatment, PANSS Positive subscale score is reduced by 40% or more. In some embodiments, after treatment, PANSS Positive subscale score is reduced by 30% or more. In some embodiments, after treatment, PANSS Positive subscale score is reduced by 20% or more. In some embodiments, after treatment, PANSS Positive subscale score is reduced by 10% or more. In some embodiments, after treatment, PANSS Positive subscale score is reduced by 5% or more. In some embodiments, after treatment, PANSS Negative subscale score is reduced by 90% or more. In some embodiments, after treatment, PANSS Negative subscale score is reduced by 80% or more. In some embodiments, after treatment, PANSS Negative subscale score is reduced by 70% or more. In some embodiments, after treatment, PANSS Negative subscale score is reduced by 60% or more. In some embodiments, after treatment, PANSS Negative subscale score is reduced by 50% or more. In some embodiments, after treatment, PANSS Negative subscale score is reduced by 40% or more. In some embodiments, after treatment, PANSS Negative subscale score is reduced by 30% or more. In some embodiments, after treatment, PANSS Negative subscale score is reduced by 20% or more. In some embodiments, after treatment, PANSS Negative subscale score is reduced by10% ormore. In some embodiments, after treatment, PANSSNegative subscale score is reduced by 5% or more.

[0227] In some embodiments, clinical improvement for psychiatric symptoms before and / or after treatment is evaluated using the Brief Psychiatric Rating Scale (BPRS). In some embodiments, after treatment, BPRS total score is reduced by 90% or more. In some embodiments, after treatment, BPRS total score is reduced by 80% or more. In some embodiments, after treatment, BPRS total score is reduced by 70% or more. In some embodiments, after treatment, BPRS total score is reduced by 60% or more. In some embodiments, after treatment, BPRS total score is reduced by 50% or more. In some embodiments, after treatment, BPRS total score is reduced by 40% or more. In some embodiments, after treatment, BPRS total score is reduced by 30% or more. In some embodiments, after treatment, BPRS total score is reduced by 20% or more. In some embodiments, after treatment, BPRS total score is reduced by 10% or more. In some embodiments, after treatment, BPRS total score is reduced by 5% or more.

[0228] In some embodiments, clinical improvement for depression before and / or after treatment is evaluated using the Montgomery -Asberg Depression Rating Scale (MADRS). In some embodiments, after treatment, MADRS total score is reduced by 90% or more. In some embodiments, after treatment, MADRS total score is reduced by 80% or more. In some embodiments, after treatment, MADRS total score is reduced by 70% or more. In some embodiments, after treatment, MADRS total score is reduced by 60% or more. In some embodiments, after treatment, MADRS total score is reduced by 50% or more. In some embodiments, after treatment, MADRS total score is reduced by 40% or more. In some embodiments, after treatment, MADRS total score is reduced by 30% or more. In some embodiments, after treatment, MADRS total score is reduced by 20% or more. In some embodiments, after treatment, MADRS total score is reduced by 10% or more. In some embodiments, after treatment, MADRS total score is reduced by 5% or more. In some embodiments, after treatment, MADRS total score is reduced by 1, 2, 3, 4, 5, 6 points or more.

[0229] In some embodiments, clinical improvement for depression before and / or after treatment is evaluated using the Beck Depression Inventory (BDI). In some embodiments, after treatment, BDI total score is reduced by 90% or more. In some embodiments, after treatment, BDI total score is reduced by 80% or more. In some embodiments, after treatment, BDI total score is reduced by 70% or more. In some embodiments, after treatment, BDI total score is reduced by 60% or more. In some embodiments, after treatment, BDI total score is reduced by 50% or more. In some embodiments, after treatment, BDI total score is reduced by 40% or more. In some embodiments, after treatment, BDI total score is reduced by 30% or more. In someembodiments, after treatment, BDI total score is reduced by 20% or more. In some embodiments, after treatment, BDI total score is reduced by 10% or more. In some embodiments, after treatment, BDI total score is reduced by 5% or more. In some embodiments, after treatment, BDI total score is reduced by 1, 2, 3, 4, 5 ,6, 7, 8, 9, 10, 11, 12 points or more. In some embodiments, after treatment, BDI total score is reduced below 30.

[0230] In some embodiments, clinical improvement for quality of life before and / or after treatment is evaluated using EQ-ED-5 index scoring. In some embodiments, after treatment, EQ- ED-5 total score is improved by 90% or more. In some embodiments, after treatment, EQ-ED-5 total score is improved by 80% or more. In some embodiments, after treatment, EQ-ED-5 total score is improved by 70% or more. In some embodiments, after treatment, EQ-ED-5 total score is improved by 60% or more. In some embodiments, after treatment, EQ-ED-5 total score is improved by 50% or more. In some embodiments, after treatment, EQ-ED-5 total score is improved by 40% or more. In some embodiments, after treatment, EQ-ED-5 total score is improved by 30% or more. In some embodiments, after treatment, EQ-ED-5 total score is improved by 20% or more. In some embodiments, after treatment, EQ-ED-5 total score is improved by 10% or more. In some embodiments, after treatment, EQ-ED-5 total score is improved by 5% or more. In some embodiments, EQ-ED-5 total score after administration of the therapeutic anti-NMDAR antibody is improved by about 0.01, 0.05, or 0.1 points or more.

[0231] In some embodiments, clinical improvement for quality of life before and / or after treatment is evaluated using the 36-Item Short Form Health Survey (SF-36). In some embodiments, after treatment, SF-36 total score is improved by 90% or more. In some embodiments, after treatment, SF-36 total score is improved by 80% or more. In some embodiments, after treatment, SF-36 total score is improved by 70% or more. In some embodiments, after treatment, SF-36 total score is improved by 60% or more. In some embodiments, after treatment, SF-36 total score is improved by 50% or more. In some embodiments, after treatment, SF-36 total score is improved by 40% or more. In some embodiments, after treatment, SF-36 total score is improved by 30% or more. In some embodiments, after treatment, SF-36 total score is improved by 20% or more. In some embodiments, after treatment, SF-36 total score is improved by 10% or more. In some embodiments, after treatment, SF-36 total score is improved by 5% or more. In some embodiments, SF-36 total score after administration of the therapeutic anti-NMDAR antibody is improved by 1, 2, 3, 4, 5 ,6, 7, 8, 9, 10, 11, 12 points or more.

[0232] With respect to anti-NMDAR encephalitis, treatment includes, but is not limited to administering to the individual a therapeutic anti-NMDAR antibody or an anti-NMDAR binding fragment thereof that prevents binding of the pathologic anti-NMDAR autoantibody to anNMDA receptor of the individual, based upon detecting the presence of the pathologic anti- NMDAR antibody. In some embodiments, the therapeutic anti -NMD AR antibody comprises a one-armed anti-human NR1 antibody. In some embodiments, the therapeutic anti-NMDAR antibody reduces internalization of the NMD AR in the presence of the pathogenic anti-NMDAR antibody. In some embodiments, the therapeutic anti-NMDAR antibody reduces internalization of the NMD AR in the presence of the pathogenic anti-NMDAR antibody, wherein the pathogenic anti-NMDAR antibody comprises 102 Ab. In some embodiments, the therapeutic anti-NMDAR antibody reduces internalization of the NMD AR by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% in the presence of the pathogenic anti-NMDAR antibody, wherein the pathogenic anti-NMDAR antibody comprises 102 Ab. In some embodiments, the one-armed anti-human NMD AR antibody comprises ART5803 .

[0233] In some embodiments, the therapeutic anti-NMDAR antibody comprises a heavy chain variable region (VH) comprising a heavy chain complementary determining region 1 (HCDR1) comprising an amino acid sequence of SEQ ID NO: 13, a heavy chain complementary determining region 2 (HCDR2) comprising an amino acid sequence of SEQ ID NO: 14, and a heavy chain complementary determining region 3 (HCDR3) comprising an amino acid sequence of SEQ ID NO: 15; and a light chain variable region (VL) comprising a light chain complementary determining region 1 (LCDR1) comprising an amino acid sequence of SEQ ID NO: 16, a light chain complementary determining region 2 (LCDR2) comprising an amino acid sequence of SEQ ID NO: 17, and a light chain complementary determining region 3 (LCDR3) comprising an amino acid sequence of SEQ ID NO: 18.

[0234] In some embodiments, the therapeutic anti-NMDAR antibody comprises a heavy chain immunoglobulin variable region comprising an amino acid sequence with at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity or sequence similarity to SEQ ID NO: 11.

[0235] In some embodiments, the therapeutic anti-NMDAR antibody comprises a heavy chain immunoglobulin variable region comprising an amino acid sequence of SEQ ID NO: 11 .

[0236] In some embodiments, the therapeutic anti-NMDAR antibody comprises a heavy chain immunoglobulin variable region comprising an amino acid sequence with one or more insertions, deletions, and / or substitutions relative to SEQ ID NO: 11.

[0237] In some embodiments, the therapeutic anti-NMDAR antibody comprises a heavy chain immunoglobulin variable region comprising an amino acid sequence with at least 1, at least 2, at least 3, atleast 4, atleast 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, atleast 20, at least 25, at least 30, at least 35, at least 40, or at least 45 insertions, deletions, and / or substitutions relative to SEQ ID NO: 11 .

[0238] In some embodiments, the therapeutic anti-NMDAR antibody comprises a heavy chain immunoglobulin variable region comprising an amino acid sequence with at most 1, at most 2, at most 3, at most 4, at most 5, at most 6, at most 7, at most 8, at most 9, at most 10, at most 11, at most 12, at most 13, at most 14, at most 15, at most 16, at most 17, at most 18, at most 19, at most 20, at most 25, at most 30, at most 35, at most 40, or at most 45 amino acid insertions, deletions, and / or substitutions relative to SEQ ID NO: 11.

[0239] In some embodiments, the therapeutic anti-NMDAR antibody comprises a heavy chain immunoglobulin variable region comprising an amino acid sequence comprising 1 , 2, 3 , 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, or 45 amino acid insertions, deletions, and / or substitutions relative to SEQ ID NO: 11.

[0240] The one or more insertions, deletions, and / or substitutions can be at the N-terminus, the C-terminus, within the amino acid sequence, or a combination thereof. The one or more insertions can be contiguous, non -contiguous, or a combination thereof.

[0241] In some embodiments, the therapeutic anti-NMDAR antibody comprises a light chain immunoglobulin variable region comprising an amino acid sequence with at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity or sequence similarity to SEQ ID NO: 12.

[0242] In some embodiments, the therapeutic anti-NMDAR antibody comprises a light chain immunoglobulin variable region comprising an amino acid sequence of SEQ ID NO: 12.

[0243] In some embodiments, the therapeutic anti-NMDAR antibody comprises a light chain immunoglobulin variable region comprising an amino acid sequence with one or more insertions, deletions, and / or substitutions relative to SEQ ID NO: 12.

[0244] In some embodiments, the therapeutic anti-NMDAR antibody comprises a light chain immunoglobulin variable region comprising an amino acid sequence with at least 1 , at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, atleast 13, at least 14, atleast 15, at least 16, at least 17, at least 18, at least 19, at least 20, or at least 22 insertions, deletions, and / or substitutions relative to SEQ ID NO: 12.

[0245] In some embodiments, the therapeutic anti-NMDAR antibody comprises a light chain immunoglobulin variable region comprising an amino acid sequence with at most 1 , at most 2, at most 3, at most 4, at most 5, at most 6, at most 7, at most 8, at most 9, at most 10, at most 11, at most 12, at most 13, at most 14, at most 15, at most 16, at most 17, at most 18, at most 19, atmost 20, or at most 22 amino acid insertions, deletions, and / or substitutions relative to SEQ ID NO: 12.

[0246] In some embodiments, the therapeutic anti-NMDAR antibody comprises a light chain immunoglobulin variable region comprising an amino acid sequence comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, or 22 amino acid insertions, deletions, and / or substitutions relative to SEQ ID NO: 12.

[0247] The one or more insertions, deletions, and / or substitutions can be at the N-terminus, the C-terminus, within the amino acid sequence, or a combination thereof. The one or more insertions can be contiguous, non -contiguous, or a combination thereof.

[0248] In some embodiments, the therapeutic anti-NMDAR antibody comprises a heavy chain variable region (VH) comprising a heavy chain complementary determining region 1 (HCDR1) comprising an amino acid sequence of SEQ ID NO: 23, a heavy chain complementary determining region 2 (HCDR2) comprising an amino acid sequence of SEQ ID NO: 24, and a heavy chain complementary determining region 3 (HCDR3) comprising an amino acid sequence of SEQ ID NO: 25; and a light chain variable region (VL) comprising a light chain complementary determining region 1 (LCDR1) comprising an amino acid sequence of SEQ ID NO: 26, a light chain complementary determining region 2 (LCDR2) comprising an amino acid sequence EDN, and a light chain complementary determining region 3 (LCDR3) comprising an amino acid sequence of SEQ ID NO: 28.

[0249] In some embodiments, the therapeutic anti-NMDAR antibody comprises a heavy chain immunoglobulin variable region comprising an amino acid sequence with at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity or sequence similarity to SEQ ID NO: 21.

[0250] In some embodiments, the therapeutic anti-NMDAR antibody comprises a heavy chain immunoglobulin variable region comprising an amino acid sequence of SEQ ID NO: 21.

[0251] In some embodiments, the therapeutic anti-NMDAR antibody comprises a heavy chain immunoglobulin variable region comprising an amino acid sequence with one or more insertions, deletions, and / or substitutions relative to SEQ ID NO: 21.

[0252] In some embodiments, the therapeutic anti-NMDAR antibody comprises a heavy chain immunoglobulin variable region comprising an amino acid sequence with at least 1, at least 2, at least 3, atleast 4, atleast 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, or at least 13 insertions, deletions, and / or substitutions relative to SEQ ID NO: 21 .

[0253] In some embodiments, the therapeutic anti-NMDAR antibody comprises a heavy chain immunoglobulin variable region comprising an amino acid sequence with at most 1, atmost 2, at most 3, at most 4, at most 5, at most 6, at most 7, at most 8, at most 9, at most 10, at most 11, at most 12, or at most 13 amino acid insertions, deletions, and / or substitutions relative to SEQ ID NO: 21.

[0254] In some embodiments, the therapeutic anti-NMDAR antibody comprises a heavy chain immunoglobulin variable region comprising an amino acid sequence comprising 1 , 2, 3 , 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 amino acid insertions, deletions, and / or substitutions relative to SEQ ID NO: 21.

[0255] The one or more insertions, deletions, and / or substitutions can be at the N-terminus, the C-terminus, within the amino acid sequence, or a combination thereof. The one or more insertions can be contiguous, non -contiguous, or a combination thereof.

[0256] In some embodiments, the therapeutic anti-NMDAR antibody comprises a light chain immunoglobulin variable region comprising an amino acid sequence with at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity or sequence similarity to SEQ ID NO: 22.

[0257] In some embodiments, the therapeutic anti-NMDAR antibody comprises a light chain immunoglobulin variable region comprising an amino acid sequence of SEQ ID NO: 22.

[0258] In some embodiments, the therapeutic anti-NMDAR antibody comprises a light chain immunoglobulin variable region comprising an amino acid sequence with one or more insertions, deletions, and / or substitutions relative to SEQ ID NO: 22.

[0259] In some embodiments, the therapeutic anti-NMDAR antibody comprises a light chain immunoglobulin variable region comprising an amino acid sequence with at least 1 , at least 2, at least 3, at least 4, at least s, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, or at least 12 insertions, deletions, and / or substitutions relative to SEQ ID NO: 22.

[0260] In some embodiments, the therapeutic anti-NMDAR antibody comprises a light chain immunoglobulin variable region comprising an amino acid sequence with at most 1 , at most 2, at most 3, at most 4, at most 5, at most 6, at most 7, at most 8, at most 9, at most 10, at most 11, or at most 12 amino acid insertions, deletions, and / or substitutions relative to SEQ ID NO: 22.

[0261] In some embodiments, the therapeutic anti-NMDAR antibody comprises a light chain immunoglobulin variable region comprising an amino acid sequence comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , or 12 amino acid insertions, deletions, and / or substitutions relative to SEQ ID NO: 22.

[0262] The one or more insertions, deletions, and / or substitutions can be at the N-terminus, the C-terminus, within the amino acid sequence, or a combination thereof. The one or more insertions can be contiguous, non -contiguous, or a combination thereof.

[0263] In some embodiments, the therapeutic anti-NMDAR antibody comprises a heavy chain variable region (VH) comprising a heavy chain complementary determining region 1 (HCDR1) comprising an amino acid sequence of SEQ ID NO: 33, a heavy chain complementary determining region 2 (HCDR2) comprising an amino acid sequence of SEQ ID NO: 34, and a heavy chain complementary determining region 3 (HCDR3) comprising an amino acid sequence of SEQ ID NO: 35; and a light chain variable region (VL) comprising a light chain complementary determining region 1 (LCDR1) comprising an amino acid sequence of SEQ ID NO: 36, a light chain complementary determining region 2 (LCDR2) comprising an amino acid sequence of SEQ ID NO: 37, and a light chain complementary determining region 3 (LCDR3) comprising an amino acid sequence of SEQ ID NO: 38.

[0264] In some embodiments, the therapeutic anti-NMDAR antibody comprises a heavy chain immunoglobulin variable region comprising an amino acid sequence with at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity or sequence similarity to SEQ ID NO: 31.

[0265] In some embodiments, the therapeutic anti-NMDAR antibody comprises a heavy chain immunoglobulin variable region comprising an amino acid sequence of SEQ ID NO: 31.

[0266] In some embodiments, the therapeutic anti-NMDAR antibody comprises a heavy chain immunoglobulin variable region comprising an amino acid sequence with one or more insertions, deletions, and / or substitutions relative to SEQ ID NO: 31.

[0267] In some embodiments, the therapeutic anti-NMDAR antibody comprises a heavy chain immunoglobulin variable region comprising an amino acid sequence with at least 1, at least 2, at least 3, atleast 4, atleast 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, or at least 13 insertions, deletions, and / or substitutions relative to SEQ ID NO: 31.

[0268] In some embodiments, the therapeutic anti-NMDAR antibody comprises a heavy chain immunoglobulin variable region comprising an amino acid sequence with at most 1, at most 2, at most 3, at most 4, at most 5, at most 6, at most 7, at most 8, at most 9, at most 10, at most 11, at most 12, or atmost 13 amino acid insertions, deletions, and / or substitutions relative to SEQ ID NO: 31.

[0269] In some embodiments, the therapeutic anti-NMDAR antibody comprises a heavy chain immunoglobulin variable region comprising an amino acid sequence comprising 1 , 2, 3 , 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 amino acid insertions, deletions, and / or substitutions relative to SEQ ID NO: 31.

[0270] The one or more insertions, deletions, and / or substitutions can be at the N-terminus, the C-terminus, within the amino acid sequence, or a combination thereof. The one or more insertions can be contiguous, non -contiguous, or a combination thereof.

[0271] In some embodiments, the therapeutic anti-NMDAR antibody comprises a light chain immunoglobulin variable region comprising an amino acid sequence with at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity or sequence similarity to SEQ ID NO: 32.

[0272] In some embodiments, the therapeutic anti-NMDAR antibody comprises a light chain immunoglobulin variable region comprising an amino acid sequence of SEQ ID NO: 32.

[0273] In some embodiments, the therapeutic anti-NMDAR antibody comprises a light chain immunoglobulin variable region comprising an amino acid sequence with one or more insertions, deletions, and / or substitutions relative to SEQ ID NO: 32.

[0274] In some embodiments, the therapeutic anti-NMDAR antibody comprises a light chain immunoglobulin variable region comprising an amino acid sequence with at least 1 , at least 2, at least 3, at least 4, at least s, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, or at least 12 insertions, deletions, and / or substitutions relative to SEQ ID NO: 32.

[0275] In some embodiments, the therapeutic anti-NMDAR antibody comprises a light chain immunoglobulin variable region comprising an amino acid sequence with at most 1 , at most 2, at most 3, at most 4, at most 5, at most 6, at most 7, at most 8, at most 9, at most 10, at most 11, or at most 12 amino acid insertions, deletions, and / or substitutions relative to SEQ ID NO: 32.

[0276] In some embodiments, the therapeutic anti-NMDAR antibody comprises a light chain immunoglobulin variable region comprising an amino acid sequence comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , or 12 amino acid insertions, deletions, and / or substitutions relative to SEQ ID NO: 32.

[0277] The one or more insertions, deletions, and / or substitutions can be at the N-terminus, the C-terminus, within the amino acid sequence, or a combination thereof. The one or more insertions can be contiguous, non -contiguous, or a combination thereof.

[0278] In some embodiments, the therapeutic anti-NMDAR antibody comprises a heavy chain variable region (VH) comprising a heavy chain complementary determining region 1 (HCDR1) comprising an amino acid sequence of SEQ ID NO: 43, a heavy chain complementary determining region 2 (HCDR2) comprising an amino acid sequence of SEQ ID NO: 44, and a heavy chain complementary determining region 3 (HCDR3) comprising an amino acid sequence of SEQ ID NO: 45; and a light chain variable region (VL) comprising a light chain complementary determining region 1 (LCDR1) comprising an amino acid sequence of SEQ IDNO: 46, a light chain complementary determining region 2 (LCDR2) comprising an amino acid sequence of SEQ ID NO: 47, and a light chain complementary determining region 3 (LCDR3) comprising an amino acid sequence of SEQ ID NO: 48.

[0279] In some embodiments, the therapeutic anti-NMDAR antibody comprises a heavy chain immunoglobulin variable region comprising an amino acid sequence with at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity or sequence similarity to SEQ ID NO: 41.

[0280] In some embodiments, the therapeutic anti-NMDAR antibody comprises a heavy chain immunoglobulin variable region comprising an amino acid sequence of SEQ ID NO: 41.

[0281] In some embodiments, the therapeutic anti-NMDAR antibody comprises a heavy chain immunoglobulin variable region comprising an amino acid sequence with one or more insertions, deletions, and / or substitutions relative to SEQ ID NO: 41.

[0282] In some embodiments, the therapeutic anti-NMDAR antibody comprises a heavy chain immunoglobulin variable region comprising an amino acid sequence with at least 1, at least 2, at least 3, atleast 4, atleast 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, or at least 13 insertions, deletions, and / or substitutions relative to SEQ ID NO: 41.

[0283] In some embodiments, the therapeutic anti-NMDAR antibody comprises a heavy chain immunoglobulin variable region comprising an amino acid sequence with at most 1, at most 2, at most 3, at most 4, at most 5, at most 6, at most 7, at most 8, at most 9, at most 10, at most 11, at most 12, or atmost 13 amino acid insertions, deletions, and / or substitutions relative to SEQ ID NO: 41.

[0284] In some embodiments, the therapeutic anti-NMDAR antibody comprises a heavy chain immunoglobulin variable region comprising an amino acid sequence comprising 1 , 2, 3 , 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 amino acid insertions, deletions, and / or substitutions relative to SEQ ID NO: 41.

[0285] The one or more insertions, deletions, and / or substitutions can be at the N-terminus, the C-terminus, within the amino acid sequence, or a combination thereof. The one or more insertions can be contiguous, non -contiguous, or a combination thereof.

[0286] In some embodiments, the therapeutic anti-NMDAR antibody comprises a light chain immunoglobulin variable region comprising an amino acid sequence with at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity or sequence similarity to SEQ ID NO: 42.

[0287] In some embodiments, the therapeutic anti-NMDAR antibody comprises a light chain immunoglobulin variable region comprising an amino acid sequence of SEQ ID NO: 42.

[0288] In some embodiments, the therapeutic anti-NMDAR antibody comprises a light chain immunoglobulin variable region comprising an amino acid sequence with one or more insertions, deletions, and / or substitutions relative to SEQ ID NO: 42.

[0289] In some embodiments, the therapeutic anti-NMDAR antibody comprises a light chain immunoglobulin variable region comprising an amino acid sequence with at least 1 , at least 2, at least 3, at least 4, at least s, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, or at least 12 insertions, deletions, and / or substitutions relative to SEQ ID NO: 42.

[0290] In some embodiments, the therapeutic anti-NMDAR antibody comprises a light chain immunoglobulin variable region comprising an amino acid sequence with at most 1 , at most 2, at most 3, at most 4, at most 5, at most 6, at most 7, at most 8, at most 9, at most 10, at most 11, or at most 12 amino acid insertions, deletions, and / or substitutions relative to SEQ ID NO: 42.

[0291] In some embodiments, the therapeutic anti-NMDAR antibody comprises a light chain immunoglobulin variable region comprising an amino acid sequence comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , or 12 amino acid insertions, deletions, and / or substitutions relative to SEQ ID NO: 42.

[0292] The one or more insertions, deletions, and / or substitutions can be at the N-terminus, the C-terminus, within the amino acid sequence, or a combination thereof. The one or more insertions can be contiguous, non -contiguous, or a combination thereof.

[0293] In some embodiments, the therapeutic anti-NMDAR antibody comprises a heavy chain variable region (VH) comprising a heavy chain complementary determining region 1 (HCDR1) comprising an amino acid sequence of SEQ ID NO: 53, a heavy chain complementary determining region 2 (HCDR2) comprising an amino acid sequence of SEQ ID NO: 54, and a heavy chain complementary determining region 3 (HCDR3) comprising an amino acid sequence of SEQ ID NO: 55; and a light chain variable region (VL) comprising a light chain complementary determining region 1 (LCDR1) comprising an amino acid sequence of SEQ ID NO: 56, a light chain complementary determining region 2 (LCDR2) comprising an amino acid sequence of SEQ ID NO: 57, and a light chain complementary determining region 3 (LCDR3) comprising an amino acid sequence of SEQ ID NO: 58.

[0294] In some embodiments, the therapeutic anti-NMDAR antibody comprises a heavy chain immunoglobulin variable region comprising an amino acid sequence with at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity or sequence similarity to SEQ ID NO: 51.

[0295] In some embodiments, the therapeutic anti-NMDAR antibody comprises a heavy chain immunoglobulin variable region comprising an amino acid sequence of SEQ ID NO: 51.

[0296] In some embodiments, the therapeutic anti-NMDAR antibody comprises a heavy chain immunoglobulin variable region comprising an amino acid sequence with one or more insertions, deletions, and / or substitutions relative to SEQ ID NO: 51.

[0297] In some embodiments, the therapeutic anti-NMDAR antibody comprises a heavy chain immunoglobulin variable region comprising an amino acid sequence at least 1 , at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, or at least 13 insertions, deletions, and / or substitutions relative to SEQ ID NO: 51.

[0298] In some embodiments, the therapeutic anti-NMDAR antibody comprises a heavy chain immunoglobulin variable region comprising an amino acid sequence with at most 1, at most 2, at most 3, at most 4, at most 5, at most 6, at most 7, at most 8, at most 9, at most 10, at most 11, at most 12, or atmost 13 amino acid insertions, deletions, and / or substitutions relative to SEQ ID NO: 51.

[0299] In some embodiments, the therapeutic anti-NMDAR antibody comprises a heavy chain immunoglobulin variable region comprising an amino acid sequence comprising 1 , 2, 3 , 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 amino acid insertions, deletions, and / or substitutions relative to SEQ ID NO: 51.

[0300] The one or more insertions, deletions, and / or substitutions can be at the N-terminus, the C-terminus, within the amino acid sequence, or a combination thereof. The one or more insertions can be contiguous, non -contiguous, or a combination thereof.

[0301] In some embodiments, the therapeutic anti-NMDAR antibody comprises a light chain immunoglobulin variable region comprising an amino acid sequence with at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity or sequence similarity to SEQ ID NO: 52.

[0302] In some embodiments, the therapeutic anti-NMDAR antibody comprises a light chain immunoglobulin variable region comprising an amino acid sequence of SEQ ID NO: 52.

[0303] In some embodiments, the therapeutic anti-NMDAR antibody comprises a light chain immunoglobulin variable region comprising an amino acid sequence with one or more insertions, deletions, and / or substitutions relative to SEQ ID NO: 52.

[0304] In some embodiments, the therapeutic anti-NMDAR antibody comprises a light chain immunoglobulin variable region comprising an amino acid sequence with at least 1 , at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, or at least 12 insertions, deletions, and / or substitutions relative to SEQ ID NO: 52.

[0305] In some embodiments, the therapeutic anti-NMDAR antibody comprises a light chain immunoglobulin variable region comprising an amino acid sequence with at most 1 , at most 2, at most 3, at most 4, at most 5, at most 6, at most 7, at most 8, at most 9, at most 10, at most 11, or at most 12 amino acid insertions, deletions, and / or substitutions relative to SEQ ID NO: 52.

[0306] In some embodiments, the therapeutic anti-NMDAR antibody comprises a light chain immunoglobulin variable region comprising an amino acid sequence comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , or 12 amino acid insertions, deletions, and / or substitutions relative to SEQ ID NO: 52.

[0307] The one or more insertions, deletions, and / or substitutions can be at the N-terminus, the C-terminus, within the amino acid sequence, or a combination thereof. The one or more insertions can be contiguous, non -contiguous, or a combination thereof.

[0308] In some embodiments, the therapeutic anti-NMDAR antibody comprises a heavy chain variable region (VH) comprising a heavy chain complementary determining region 1 (HCDR1) comprising an amino acid sequence of SEQ ID NO: 63, a heavy chain complementary determining region 2 (HCDR2) comprising an amino acid sequence of SEQ ID NO: 64, and a heavy chain complementary determining region 3 (HCDR3) comprising an amino acid sequence of SEQ ID NO: 65; and a light chain variable region (VL) comprising a light chain complementary determining region 1 (LCDR1) comprising an amino acid sequence of SEQ ID NO: 66, a light chain complementary determining region 2 (LCDR2) comprising an amino acid sequence of SEQ ID NO: 67, and a light chain complementary determining region 3 (LCDR3) comprising an amino acid sequence of SEQ ID NO: 68.

[0309] In some embodiments, the therapeutic anti-NMDAR antibody comprises a heavy chain immunoglobulin variable region comprising an amino acid sequence with at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity or sequence similarity to SEQ ID NO: 61.

[0310] In some embodiments, the therapeutic anti-NMDAR antibody comprises a heavy chain immunoglobulin variable region comprising an amino acid sequence of SEQ ID NO: 61.

[0311] In some embodiments, the therapeutic anti-NMDAR antibody comprises a heavy chain immunoglobulin variable region comprising an amino acid sequence with one or more insertions, deletions, and / or substitutions relative to SEQ ID NO: 61.

[0312] In some embodiments, the therapeutic anti-NMDAR antibody comprises a heavy chain immunoglobulin variable region comprising an amino acid sequence with at least 1, at least 2, at least 3, atleast 4, atleast 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, or at least 13 insertions, deletions, and / or substitutions relative to SEQ ID NO: 61.

[0313] In some embodiments, the therapeutic anti-NMDAR antibody comprises a heavy chain immunoglobulin variable region comprising an amino acid sequence with at most 1, at most 2, at most 3, at most 4, at most 5, at most 6, at most 7, at most 8, at most 9, at most 10, at most 11, at most 12, or atmost 13 amino acid insertions, deletions, and / or substitutions relative to SEQ ID NO: 61.

[0314] In some embodiments, the therapeutic anti-NMDAR antibody comprises a heavy chain immunoglobulin variable region comprising an amino acid sequence comprising 1 , 2, 3 , 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 amino acid insertions, deletions, and / or substitutions relative to SEQ ID NO: 61.

[0315] The one or more insertions, deletions, and / or substitutions can be at the N-terminus, the C-terminus, within the amino acid sequence, or a combination thereof. The one or more insertions can be contiguous, non -contiguous, or a combination thereof.

[0316] In some embodiments, the therapeutic anti-NMDAR antibody comprises a light chain immunoglobulin variable region comprising an amino acid sequence with at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity or sequence similarity to SEQ ID NO: 62.

[0317] In some embodiments, the therapeutic anti-NMDAR antibody comprises a light chain immunoglobulin variable region comprising an amino acid sequence of SEQ ID NO: 62.

[0318] In some embodiments, the therapeutic anti-NMDAR antibody comprises a light chain immunoglobulin variable region comprising an amino acid sequence with one or more insertions, deletions, and / or substitutions relative to SEQ ID NO: 62.

[0319] In some embodiments, the therapeutic anti-NMDAR antibody comprises a light chain immunoglobulin variable region comprising an amino acid sequence with at least 1 , at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, or at least 12 insertions, deletions, and / or substitutions relative to SEQ ID NO: 62.

[0320] In some embodiments, the therapeutic anti-NMDAR antibody comprises a light chain immunoglobulin variable region comprising an amino acid sequence with at most 1 , at most 2, at most 3, at most 4, at most 5, at most 6, at most 7, at most 8, at most 9, at most 10, at most 11, or at most 12 amino acid insertions, deletions, and / or substitutions relative to SEQ ID NO: 62.

[0321] In some embodiments, the therapeutic anti-NMDAR antibody comprises a light chain immunoglobulin variable region comprising an amino acid sequence comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , or 12 amino acid insertions, deletions, and / or substitutions relative to SEQ ID NO: 62.

[0322] The one or more insertions, deletions, and / or substitutions can be at the N-terminus, the C-terminus, within the amino acid sequence, or a combination thereof. The one or more insertions can be contiguous, non -contiguous, or a combination thereof.

[0323] In some embodiments, the method of detecting a pathologic anti -NMD AR autoantibody in a biological sample of an individual further comprises quantifying a level of the anti -NMD AR autoantibody in the biological sample.

[0324] In some embodiments, the level of the pathologic anti-NMDAR autoantibody in the biological sample of the individual is at a concentration of at most about 500 np, at most about 400 ng / ml, at most about 300 ng / ml, at most about 200 ng / ml, at most about 100 ng / ml, at most about 90 ng / ml, at most about 80 ng / ml, at most about 70 ng / ml, at most about 60 ng / ml, at most about 50 ng / ml, at most about 40 ng / ml, at most about 30 ng / ml, at most about 20 ng / ml, at most about 10 ng / ml, at most about 5 ng / ml, at most about 2 ng / ml, or at most about 1 ng / ml or more.

[0325] In some embodiments, the level of the pathologic anti-NMDAR autoantibody in the biological sample of the individual is at a concentration of atleast about 500 ng / ml, at least about 400 ng / ml, at least about 300 ng / ml, at least about 200 ng / ml, at least about 100 ng / ml, at least about 90 ng / ml, at least about 80 ng / ml, at least about 70 ng / ml, at least about 60 ng / ml, at least about 50 ng / ml, at least about 40 ng / ml, at least about 30 ng / ml, at least about 20 ng / ml, at least about 10 ng / ml, at least about 5 ng / ml, at least about 2 ng / ml, or at least about 1 ng / ml.

[0326] In some embodiments, the level of the pathologic anti-NMDAR autoantibody in the biological sample of the individual is at a concentration of about 500 ng / ml or less, about 400 ng / ml, about 300 ng / ml, about 200 ng / ml, about 100 ng / ml, about 90 ng / ml, about 80 ng / ml, about 70 ng / ml, about 60 ng / ml, about 50 ng / ml, about 40 ng / ml, about30 ng / ml, about20 ng / ml, about 10 ng / ml, about 5 ng / ml, about 2 ng / ml, or about 1 ng / ml.

[0327] In some embodiments, the level of the pathologic anti-NMDAR autoantibody in the biological sample of the individual is at a concentration ranging from 1 to 500 ng / ml, 2 to 500 ng / ml, 5 to 500 ng / ml, 10 to 500 ng / ml, 20 to 500 ng / ml, 30 to 500 ng / ml, 40 to 500 ng / ml, 50 to 500 ng / ml, 60 to 500 ng / ml, 70 to 500 ng / ml, 80 to 500 ng / ml, 90 to 500 ng / ml, 100 to 500 ng / ml, 200 to 500 ng / ml, 300 to 500 ng / ml, 400 to 500 ng / ml, 1 to 400 ng / ml, 2 to 400 ng / ml, 5 to 400 ng / ml, 10 to 400 ng / ml 20 to 400 ng / ml, 30 to 400 ng / ml, 40 to 400 ng / ml, 50 to 400 ng / ml, 60 to 400 ng / ml, 70 to 400 ng / ml, 80 to 400 ng / ml, 90 to 400 ng / ml, 100 to 400 ng / ml, 200 to 400 ng / ml, 300 to 400 ng / ml, 1 to 300 ng / ml, 2 to 300 ng / ml, 5 to 300 ng / ml, 10 to 300 ng / ml, 20 to 300 ng / ml, 30 to 300 ng / ml, 40 to 300 ng / ml, 50 to 300 ng / ml, 60 to 300 ng / ml, 70 to 300 ng / ml, 80 to 300 ng / ml, 90 to 300 ng / ml, 100 to 300 ng / ml, 200 to 300 ng / ml, 1 to 200 ng / ml, 2 to 200 ng / ml, 5 to 200 ng / ml, 10 to 200 ng / ml, 20 to 200 ng / ml, 30 to 200 ng / ml, 40 to 200 ng / ml, 50 to 200 ng / ml, 60 to 200 ng / ml, 70 to 200 ng / ml, 80 to 200 ng / ml, 90 to 200 ng / ml,100 to 200 ng / ml, 1 to 100 ng / ml, 2 to 100 ng / ml, 5 to 100 ng / ml, 10 to 100 ng / ml, 20 to 100 ng / ml, 30 to 100 ng / ml, 40 to 100 ng / ml, 50 to 100 ng / ml, 60 to 100 ng / ml, 70 to 100 ng / ml, 80 to 100 ng / ml, 90 to 100 ng / ml, 1 to 90 ng / ml, 2 to 90 ng / ml, 5 to 90 ng / ml, 10 to 90 ng / ml, 20 to 90 ng / ml, 30 to 90 ng / ml, 40 to 90 ng / ml, 50 to 90 ng / ml, 60 to 90 ng / ml, 70 to 90 ng / ml, 80 to 90 ng / ml, 1 to 80 ng / ml, 2 to 80 ng / ml, 5 to 80 ng / ml, 10 to 80 ng / ml, 20 to 80 ng / ml, 30 to 80 ng / ml, 40 to 80 ng / ml, 50 to 80 ng / ml, 60 to 80 ng / ml, 70 to 80 ng / ml, 1 to 70 ng / ml, 2 to 70 ng / ml, 5 to 70 ng / ml, 10 to 70 ng / ml, 20 to 70 ng / ml, 30 to 70 ng / ml, 40 to 70 ng / ml, 50 to 70 ng / ml, 60 to 70 ng / ml, 1 to 60 ng / ml, 2 to 60 ng / ml, 5 to 60 ng / ml, 10 to 60 ng / ml, 20 to 60 ng / ml, 30 to 60 ng / ml, 40 to 60 ng / ml, 50 to 60 ng / ml, 1 to 50 ng / ml, 2 to 50 ng / ml, 5 to 50 ng / ml, 10 to 50 ng / ml, 20 to 50 ng / ml, 30 to 50 ng / ml, 40 to 50 ng / ml, 1 to 40 ng / ml, 2 to 40 ng / ml, 5 to 40 ng / ml, 10 to 40 ng / ml, 20 to 40 ng / ml, 30 to 40 ng / ml, 1 to 30 ng / ml, 2 to 30 ng / ml, 5 to 30 ng / ml, 10 to 30 ng / ml , 20 to 30 ng / ml, 1 to 20 ng / ml, 2 to 20 ng / ml, 5 to 20 ng / ml, 10 to 20 ng / ml, 1 to 10 ng / ml, 2 to 10 ng / ml, 5 to 10 ng / ml, 1 to 5 ng / ml, 2 to 5 ng / ml, or 1 to 2 ng / ml.

[0328] In some embodiments, the method of detecting a pathologic anti -NMD AR autoantibody in a biological sample of an individual further comprises generating a report that indicates the presence of or the level of the anti-NMDAR antibody in the biological sample.

[0329] In some embodiments, the report comprises the presence of or level of anti-NMDAR autoantibodies, the diagnosis of the diseases associated with anti-NMDAR autoantibodies, or treatment recommendations for therapeutic agents. In some embodiments, the report comprises the presence of or the level of anti-NMDAR autoantibodies. In some embodiments, the report comprises the diagnosis of the diseases associated with anti-NMDAR autoantibodies disclosed herein. In some embodiments, the report comprises treatment recommendations for therapeutic agents such as ART5803 . In some embodiments, the report is on physical media such as a paper, or stored and displayed on a computer, a phone, or a tablet. In some embodiments, the report is sent to a healthcare provider.

[0330] It is understood by those of skill in the art that not all individuals will respond equally or at all to a treatment that is administered, nevertheless these individuals are considered to be treated.Pharmaceutically acceptable excipients, carriers, and diluents

[0331] In certain embodiments the anti-NMDAR antibodies of the current disclosure are included in a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients, carriers, and diluents. Pharmaceutically acceptable excipients, carriers and diluents can be included to increase shelf-life, stability, or the administrability of the antibody. Suchcompounds include salts, pH buffers, detergents, anti -coagulants, and preservatives. In certain embodiments, the antibodies of the current disclosure are administered suspended in a sterile solution. In certain embodiments, the solution is an aqueous solution. In certain embodiments, the solution comprises about 0.9%NaCl. In certain embodiments, the solution comprises about 5.0% dextrose. In certain embodiments, the solution further comprises one or more of: buffers, for example, acetate, citrate, histidine, succinate, phosphate, bicarbonate, sodium acetate, and hydroxymethylaminomethane (Tris); surfactants, for example, polysorbate 80, polysorbate 20, and poloxamer 188; polyol / disaccharide / polysaccharides, for example, glucose, dextrose, mannose, mannitol, sorbitol, sucrose, trehalose, and dextran 40; amino acid, for example, glycine or arginine; antioxidants, for example, ascorbic acid, methionine; or chelating agents, for example, EDTA orEGTA. In some embodiments, the pharmaceutical composition comprises a buffer of sodium acetate, polysorbate 80, and an amino acid L-arginine. In some embodiments, the pharmaceutical composition comprises about 1 mMto about 20 mM, 5 mM to about 25 mM, about 10 mMto about 30 mM, about 15 mMto about 35mM, or about 20 mMto about 40 mM of a buffer of sodium acetate. In some embodiments, the pharmaceutical composition comprises about 0.001% to about 0.02%, 0.005% to about 0.025%, about 0.01% to about 0.03%, about 0.015% to about 0.035%, or about 0.02% to about 0.04 of a surfactant of polysorbate 80. In some embodiments, the pharmaceutical composition comprises about 90 mM to about 140 mM, about 100 mMto about 150 mM, about 110 mM to about 160 mM, about 120 mM to about 170 mM, about 130 mM to about 180 mM, or about 140 mM to about 190 mM of an amino acid L- arginine. In some embodiments, the pharmaceutical composition comprises about 20mM of a buffer of sodium acetate, about 0.02% of a surfactant of polysorbate 80, and about 140 mM of an amino acid L-arginine.

[0332] In some embodiments, the anti-NMDAR antibodies of the current disclosure are included in a pharmaceutical composition at a concentration of about 10 mg / mL to about 50 mg / mL, about 20 mg / mL to about 60 mg / mL, about 30 mg / mL to about 70 mg / mL, about 40 mg / mL to about 80 mg / mL, or about 50 mg / mL to about 90 mg / mL. In some embodiments, the anti-NMDAR antibodies of the current disclosure are included in a pharmaceutical composition at a concentration of about 30 mg / mL to about 50 mg / mL, about 40 mg / mL to about 60 mg / mL, or about 50 mg / mL to about 70 mg / mL. In some embodiments, the anti-NMDAR antibodies of the current disclosure are included in a pharmaceutical composition at a concentration of about 50 mg / mL.

[0333] In some embodiments, the pharmaceutical composition comprises an anti-NMDAR antibody included in a pharmaceutical composition at a concentration of about 50 mg / mL, wherein the pharmaceutical composition comprises about 20mM sodium acetate, about 0.02% polysorbate80, and about 140 mM L-arginine, wherein the pharmaceutical composition is at a pH of about 5.0 wherein the anti-NMDAR antibody comprises a heavy chain immunoglobulin variable region comprising an amino acid sequence of SEQ ID NO: 11 and a light chain immunoglobulin variable region comprising an amino acid sequence of SEQ ID NO: 12.

[0334] In certain embodiments, the antibodies of the current disclosure can be shipped / stored lyophilized and reconstituted before administration. In certain embodiments, lyophilized antibody formulations comprise a bulking agent such as, mannitol, sorbitol, sucrose, trehalose, dextran 40, or combinations thereof. The lyophilized formulation can be contained in a vial comprised of glass or other suitable non-reactive material. The antibodies when formulated, whether reconstituted or not, can be buffered at a certain pH, generally less than 7.0. In certain embodiments, the pH canbe between 4.5 and 7.0, 4.5 and 6.5, 4.5 and 6.0, 4.5 and 5.5, 4.5 and 5.0, or 5.0 and 6.0. In some embodiments, the pH of the solution is about 5.0.

[0335] Also described herein are kits comprising one or more of the antibodies described herein in a suitable container and one or more additional components selected from: instructions for use; a diluent, an excipient, a carrier, and a device for administration.

[0336] In certain embodiments, described herein is a method of preparing an anti-NMDAR receptor encephalitis treatment comprising admixing one or more pharmaceutically acceptable excipients, carriers, or diluents and an antibody of the current disclosure. In certain embodiments, described herein is a method of preparing an anti-NMDAR receptor encephalitis treatment for storage or shipping comprising lyophilizing one or more antibodies of the current disclosure.EXAMPLES

[0337] The followingillustrative examples are representative of embodiments of compositions and methods described herein and are not meant to be limiting in any way.Example 1: ART5803 shows no impact on NMDAR activity

[0338] Pathogenic autoantibodies bind to the NR1-NTD and decrease NMDAR activity through cross-linking by their two arms and subsequent receptor internalization, but do not impact NMDAR activity directly. An in vitro study was performed to confirm whether one-arm antibody ART5803 has no effect on NMDAR. The study relied on HEK293 cells expressing human NMDAR NR1 and NR2B subunits. The NMDAR-expressingHEK293 cells were evaluated for Ca2+ influx as a readout for NMDAR function.

[0339] Calcium influx was assessed by fluorescence imaging plate reader (FLIPR) assay. NMDAR expressing HEK293 cells (HEK293 cells expressing tetracycline inducible humanNMD AR GluNl / GluN2B) were purchased from Charles River. The control cell line, T-REx293, a non-NMDAR expressing cell line, was purchased from Invitrogen. Cells were passaged according to their manufacturer specifications. FLIPR Calcium 6 Assay Kit (Molecular Devices) was used to detect Ca2+ influx.

[0340] FIG. 1A found no agnostic effects on Ca2+ influx via human NMD AR after cells were incubated with ART5803, a control antibody, orMK-801 (NMD AR antagonist). Control human IgGl antibody was purchased from BioLegend. Additionally, no antagonistic effects were observed among the cells after incubation with ART5803 and the control antibody in the presence of NMDA (NMDAR agonist) (FIG. IB). Data was calculated based on the mean of three independent replicates and were analyzed by unpaired Student’s t-test. These results demonstrate that one-arm antibody ART5803 has no intrinsic agonistic or antagonistic effects on NMDARs.Example 2: ART5803 blocks NMDAR internalization and NMDAR hypofunction driven by pathogenic autoantibody

[0341] A competition ELISA was used to test the ability of one-arm antibody ART5803 to block#003-102 Ab binding to NR1-NTD. MaxiSorp 384-well ELISA plates (Thermo Fisher Scientific) were coated with 15 pL / well of human NR1 -NTD protein at a concentration of 1.0 pg / mL diluted in TBS (Fujifilm Wako Chemicals) and incubated overnight in 4.0 °C. The remaining steps were performed at room temperature. Plates were washed (BioTek) once with TBS-T (Nippon Gene Co Ltd.) and 50 pL / well of Blocking One (BO; Nacalai Tesque Inc.) was added to block wells for 1 hour. BO was removed, and plates were washed once with TBS-T. Antibodies were serially diluted in the range of 100000 ng / mL to 0. 1 ng / mL with 5.0% BO / TBS- T. Diluted antibodies or 5.0% BO / TBS-T were applied in 15 pL / well and incubated for 20 minutes. #003-102 Ab was biotinylated with Biotin Labeling Kit NH2 (Dojindo) according to manufacturer’s instructions, with the exception in the final step, conjugate was resuspendedin PBS (Gibco). Biotinylated #003-102 Ab was diluted with 5.0% BO / TBS-T, and was applied at a final concentration of 600 ng / mL at 15 pL / well, and incubated atRT for 1 hr. After plates were washed three times with TBS-T, streptavidin-HRP at 1 :8000 in 5.0% BO / TBS-T 15 pL / well was added and incubated for 30 minutes. Wells were washed three times with TBS-T. BM Chemiluminescence ELISA substrate POD was prepared and used according to manufacturer’s instructions and chemiluminescence was measured with EnVision (PerkinElmer). The 50% maximal effective concentration (EC50) of ART5803 was calculated using sigmoid-Emax nonlinear regression analysis.

[0342] The percentage of inhibition was compared between ART5803, #003-102 Ab, and a control antibody. There was a range of antibodies released including 10'5to 103ug / mL. FIG. 2found that ART5803 was able to compete with the binding of biotinylated #003 -102 Ab (0.60 pg / mL) to human NR1 with an EC50of 0.30 pg / mL.

[0343] The ability of ART5803 to block NMD AR internalization inducedby #003 -102 Ab was also tested in a cell-based flow cytometry assay as visualized by the schematic in FIG.3. NMDAR- expressingHEK293 cells were exposed to either #003-102 Ab or ART5803 for two hours. #003- 102 Ab was manufactured by LakePharma. #003-102 Ab demonstrated a robust reduction of NMD AR surface expression due to receptor internalization in a concentration dependent manner (FIG. 4A), while ART5803 did not show any reduction of NMD AR surface expression (FIG. 4B).The data suggests that NMD AR-expressing HEK293 cells are able to detect and quantify NMD AR internalization induced by pathogenic antibodies.

[0344] The study also examined the ability of ART5803 to both block and rescue NMD AR internalization caused by #003-102 Ab. The NMD AR-expressing HEK293 cells were exposed to #003-102 Ab (10 pg / mL) and co-incubated with ART5803 for two hours. ART5803 blocked the ability of #003-102 Ab to induce NMDAR internalization with an EC50 of 0.55 pg / mL (FIG. 5A). ART5803 also rescued NMDAR surface expression when #003-102 Ab was pre-incubated for 2 hours then co-incubated with ART5803 for 2 hours, with an EC50of 0.69 pg / mL (FIG. 5B). The results suggest that the blocking and rescue profiles of ART5803 against #003 -102 Ab induced NMDAR internalization were similar. Subsequent efficacy studies consequently tested the ability of ART5803 to block autoantibodies pathogenicity.

[0345] FIG. 6 tests the functional effects of ART5803 against NMDAR internalization driven by #003-102 Ab. HEK293 cells were incubated with either #003-102 Ab or a control IgGl antibody (1 .0 pg / mL each) for 15 minutes. ART5803 or the control IgGl antibody (0.1-10 pg / mL each) were then added to the cells and further incubated for 6 hours. After incubation, NMDAR Ca2+ influx was measured. Pathogenic #003 -102 Ab shows reduced Ca2+ influx in response to NMD A, which demonstrates NMDAR hypofunction. ART5803 blocks Ca2+ influx reduction driven by #003 -102 Ab treatment. The experiments demonstrate thatblocking of pathogenic #003 - 102 Ab binding to the NR1 -NTD by ART5803 prevents NMDAR internalization and hypofunction most effectively at concentrations 0.1 pg / mL and above when compared to the control antibody.Example 3: ART5803 rescued NMDAR internalization and spine shrinkage caused by pathogenic autoantibodies in mouse hippocampal neurons

[0346] NMDAR surface expression levels were examined in response to #003-102 Ab treatment (25 pg / mL). NMDAR surface expression levels decreased from a baseline of 100% to 72 ± 4% after three hours and 59 ± 4% after 14 hours (FIG. 7A). The spine size also decreased in response to #003-102 Ab treatment from a baseline of 100% to 84 ± 6% at three hours and 68 ±6% after 14 hours (FIG. 7B). ART5803 was also tested alone (25 pg / mL) to assess potential adverse effects of ART5803. The results showed no effect on NMD AR surface levels or spine size (106 ± 8% at three hours, 99 ± 7% at 14 hours for NMD AR surface expression or 116 ± 14% at three hours, 110 ± 11% at 14 hours for spine size). ART5803 (25 pg / mL) was also administered in conjunction with #003-102 Ab (25 pg / mL). When mixed, ART5803 blocked changes in NMD AR surface expression (96 ± 5% at three hours; 95 ± 6% at 14 hours) and spine size (102 ± 4% at three hours; 101 ± 8% at 14 hours) compared to baseline levels.

[0347] It was also assessed whether ART5803 treatment could rescue the effects of #003-102 Ab on NMD AR surface expression and spine size. The slice cultures were treated with #003-102 Ab (25 pg / mL) for three hours. ART5803 (25 pg / mL) was then added directly to the culture. After 3 hours, imaging was performed. (FIG. 8A) Imaging shows that the NMD AR surface expression (80 ± 4%) and spine size (87 ± 4%) both decreased from baseline levels. A rescue experiment was conducted and the data was shown in FIG. 8B. After 14 hours, the data shows that both NMDAR surface expression (from 80 ± 4% at three hours to 92 ± 5% at 14 hours ) and spine size (from 87 ± 4% at three hours to 102 ± 7% at 14 hours) was like baseline levels.Example 4: ART5803 reversed behavioral abnormalities induced by pathogenic autoantibodies (#003-102 Ab) in a marmoset model of anti-NMDAR encephalitis

[0348] An animal model of anti-NMDAR encephalitis in marmosets, a non-human primate, is used to examine in vivo efficacy of ART5803 . Adult marmosets were purchased from Shin Nippon Biomedical Laboratories, Ltd.

[0349] This study requires continuous intracerebroventricular (ICV) infusion of pathogenic #003-102 Ab into the third ventricle with a cannula via a micro-infusion pumps. Marmosets were equipped with a respirator (SN-480-7; Shinano Seisakusho) and anesthesia was induced by isoflurane (871119; Mylan Pharmaceutical). A preliminary dose was established at 10 pg / hr. Abnormal behaviors and movements were quantified using a modified version of the Abnormal Rating Scale (ARS) based on behaviors and movement dysfunctions resembling anti-NMDAR encephalitis patients.

[0350] The efficacy of ART5803 was tested in the marmoset model using #003-102 Ab to confirm that the ART5803 blocking effects observed in vitro translated to in vivo efficacy (FIG. 9A). The preliminary study confirmed that continuous ICV infusion of ART5803 alone for two weeks was well tolerated and did not induce any noticeable behavioral changes in marmosets. The study included twelve marmosets. At day 14, after continuous ICV infusion of #003-102 Ab, the marmosets exhibited robust behavioral abnormalities. There was a significant increase in ARS scores compared to the baseline before pathogenic #003-102 Ab infusion (1.8 ± 0.4 at baseline to9.6 ± 2.1 14 days post infusion) (FIG. 9B-C). ICV infusion of ART5803 (nine marmosets) or a control antibody (three marmosets) (10 pg / hr) was administered alongside the ICV infusion of #003-102 Ab for two additional weeks. After two weeks treatment with ART5803, ARS scores decreased from 9.6 ± 2.1 at day 14 to 3.6 ± 1.0 at day 28.

[0351] FIG. 10A evaluated whether ART5803 delivered via intraperitoneal administration (IP) could reverse abnormal behaviors in the marmoset model. Marmosets were continuously intracerebroventricular (ICV) infused with #003-102 Ab for 21 days to maintain behavior and motor abnormalities. On day 6 after ICV infusion of #003-102 Ab, marmosets showing robust abnormalities were divided into two treatment groups. The first group comprises eight marmosets dosed with 400 mg / kg ART5803 via intraperitoneal (IP) infusion twice a week for two weeks starting on Day 7 (FIG. 10A). The second group comprises sevenmarmosets treated with a control vehicle via IP twice a week for 2 weeks starting on Day 7 (FIG. 10B). ICV administration of #003- 102 Ab for 6 days resulted in abnormal behaviors in both treatment groups, with ARS scores increasing from 2.4 ± 0.5 at baseline (Day 0) to 11 .4 ± 0.8 (Day 6) (p < 0.01) forthe ART5803 treatment group and 2.0 ± 0.7 to 12.1 ± 0.8 (p < 0.01) forthe vehicle treatment group. 7 days post- ART5803 IP injections of 400 mg / kg, the ART5803 treatment group shows a reduction in ARS scores from 11.4 ± 0.8 at Day 6 to 7.3 ± 0.8 atDay 14 (p < 0.01) (FIG. 10C). ARS scores of the ART5803 treatment group 7.3 ± 0.8 were lower compared to the vehicle treatment group 11 .4 ± 1 .4 atDay 14 (p < 0.05). The reduction in ARS scores was maintained for 14 days. The ART5803 treatment group resulted in an ARS score of 11.4 ± 0.8 atDay 6 to 7.5 ± 0.8 atDay 21 . The vehicle treatment group resulted in an ARS score of 10.6 ± 1.2 at Day 21 (p < 0.05) (FIG. 10D). IP injections of ART5803 at400 mg / kgtwice a week for two weeks demonstrate a potential peripheral route of therapeutic administration in patients.Example 5: ART5803 blocks NMDAR internalization driven by mixtures of pathogenic monoclonal autoantibodies

[0352] A cell-based flow cytometry assay wasusedto assess the efficacy of ART5803 against anti-NMDAR encephalitis patient CSF derived autoantibody induced NMDAR internalization. This study included a mixture of four monoclonal autoantibodies from three patients. The concentrations of each autoantibody in the mixture was adapted to reflect concentrations observed in a patient’s CSF. NMDAR-expressing HEK293 cells were co-incubated with the pathogenic autoantibody mixture for 18 hours. ART5803 was then added to the cells and incubated for 30 hours. ART5803 blocked NMDAR internalization induced by pathogenic polyclonal antibodies in a concentration dependent manner (FIG. 11A). The data illustrates that ART5803 can rescue almost 100% of NMDAR expression at 1.0 pg / mL. The control antibody had no effect onautoantibodies induced NMD AR internalization. Furthermore, ART5803’s blocking activity was tested against five different monoclonal autoantibody mixtures to represent five patients’ CSF conditions (FIG. 11B). The CSF condition of patients #2, #3 and #4, which contains high concentrations of #003-102 Ab, attenuated NMD AR cell surface expression by about 80%. Monoclonal autoantibody mixtures of patient #5 and #6 showed approximately a 50% reduction in NMDAR expression despite the presence of higher amounts of autoantibody compared with patients #2, #3, and #4. ART5803 blocked NMDAR internalization induced by all patient-like autoantibody mixtures, achieving nearly complete blocking at 1.0 pg / mL.Example 6: ART5803 blocks NMDAR internalization driven by anti-NMDAR encephalitis patients’ sera and CSF

[0353] A cell-based flow cytometry assay wasusedto assess the efficacy of ART5803 against anti-NMDAR encephalitis patient sera and CSF induced internalization. Seven anti-NMDA receptor encephalitis patients' serum and CSF were obtained under collaboration with Kitasato University. To protect patient identities in this report, patient serum and CSF were given new IDs # 1 -7, with matchingIDs indicative of samples drawn from the same patient. Healthy human pooled serum was purchased from Cosmo Bio Co. Ltd, and healthy human pooled CSF were purchased from BioIVT Lie.

[0354] A new recombinant pathogenic antibody was developed, 502Ab, with a strong affinity to the NMDAR and in vitro pathogenicity. Reference anti-NMDAR pathogenic antibody 502 Ab was prepared by Astellas Pharma Inc. (Tokyo, Japan). The synthesis methods and amino acid sequences for both ART5803 and 502 Ab are published in WO2021241616A1. The antibodies were expressed in ExpiCHO-S cells (Thermo Fisher Scientific) and then purified by affinity chromatography. Size exclusion chromatography was used for further purification.

[0355] 502Ab was used as a standard pathogenic antibody for quantitation. Seraand CSF from seven patients was evaluated for NMDAR binding by a cell-based flow cytometry assay using NMDAR-expressingHEK293 cells to obtain pseudo-concentration equivalents to 502Ab binding activity. Pseudo-concentrations of anti-NMDAR autoantibodies was determined for six patients serum, and all patients CSF based on 502Ab binding to NMDAR. Autoantibody concentrations range from 0.24 - 2.2 pg / mL (502Ab equivalent) in serum and 0.0078 - 0.15 pg / mL (502Ab equivalent) in CSF, showed significant correlation (R2=0.847, p=0.0093, n=6) (FIG. 11C and Table 1). The pathogenicity of seven patients’ sera and CSF was evaluated by the NMDAR internalization assay in comparison to the reference antibody 502Ab. All patients’ sera showed NMDAR internalization activity ranging from 1.0 to 5.5 pg / mL equivalent to 502Ab internalization activity. Robust reduction of NMDAR surface expression was detected in 3 CSFsamples. These 3 CSF samples induced detectable NMD AR internalization activity ranging from 0.56 to 1.4 pg / mL equivalent to 502Ab internalization activity.

[0356] ART5803 blocked NMD AR internalization induced by sera and CSF from patients in a concentration-dependent manner. The effective concentration of ART5803 for patient serum- induced NMD AR internalization blocking was determined to be 3.0-10 pg / mL. The concentration of ART5803 required to completely block the NMDAR internalization caused by CSF from patients #2 and #3 was 1.3 pg / mL and 0.63 pg / mL, respectively. Although the NMDAR internalization caused by CSF from Patient 1 was not completely blocked, ART5803 at 2.5 pg / mLwas able to maintain the NMDAR surface expression level at 74%, which is roughly double the level from 42% reduced by strong Patient 1 CSF (FIG. 12A-B and Table 2).Table 2Example 7: Cynomolgus monkey population PK (PopPKj modelins with human scaling and simulation demonstrated ART5803 IV dosing feasibility in patients

[0357] Cynomolgus monkeys were tested with a single 30-minute intravenous (IV) infusion of ART5803 at 100 mg / kg and 1000 mg / kg. The study resulted in dose proportional maximum concentration (Cmax) and area under the curve (AUC) exposure both in the serum and CSF (FIG. 12C). The time to maximal concentration ranged from 5 to 30 minutes in the serum (Cmax 2400 ± 340 pg / mL at 100 mg / kg and 21000 ± 4300 pg / mL at 1000 mg / kg) and 24 and 168 hours in the CSF (Cmax 3.0 ± 2.4 pg / mL at 100 mg / kg and 15 ± 8.0 pg / mL at 1000 mg / kg). The mean half - lives were 237 hours and 220 hours in the serum, and 208 hours and 339 hours in the CSF at a dose of 100 mg / kg and 1000 mg / kg, respectively. The concentration observed in the CSF was lower than that measured in the serum at all comparable timepoints. The exposure of ART5803 in the CSF as compared to serum, measured by Cmax and AUC (0-1008h), was 0.13% and 0.26% at a dose of 100 mg / kg and 0.072% and 0.19% at a dose of 1000 mg / kg, respectively. The data and human simulation demonstrates that about 0.6 - 2.5 pg / mL of ART5803 in the CSF would be the target concentration necessary to treat anti-NMDAR encephalitis patients, which translates to approximately 40 - 100 mg / kg IV weekly dosing of ART5803 patients (FIG. 12D).Example 8: Efficacy of one-arm antibody ART5803 in patients with anti-NMDAR encephalitis

[0358] The marmoset model was given via intracerebroventricular (IC V) infusion of #003-102 Ab. #003-102 Ab induced robust behavior and motor abnormalities. Hypo-NMDAR function related behavior and motor dysfunctions induced by #003 -102 Ab were completely blocked andrestored by concurrent administration of one-arm antibody ART5803. The study demonstrates that ART5803 lacks any pathogenic activity on NMDAR in both cellular and neuronal models. ART5803 did not induce NMDAR internalization. It did not exhibit agonist or antagonist effects in NMDAR-expressing HEK293 cells. ART5803 was administered alone via either continuous ICV (10 ug / hr) or IP injection (up to 800 mg / kg twice a week) in marmosets for two weeks and it did not induce any observable behavioral or motor abnormalities.

[0359] The study also evaluated the blocking activity of ART5803 against the pathogenic effects of #003-102 Ab. Treatment with #003-102 Ab induced NMDAR internalization in mouse hippocampal neurons resulted in NMDAR internalization and reduction in spine size whereas treatment with ART5803 did not result in NMDAR internalization or spine size reduction.

[0360] The study also found that ART5803 blocked NMDAR internalization induced by autoantibodies mixtures, sera and cerebrospinal fluid (CSF) from anti-NMDAR encephalitis patients. The data suggests that ANRE pathogenicity (NMDAR internalization) is driven by autoantibodies binding to selective epitopes of the NR1 -NTD. The blocking ability of ART5803 against all tested samples suggests its ability to compete with autoantibodies by either direct competition on the same epitope or by blocking the binding by steric hindrance due to the bulky nature of one-arm antibody ART5803 (100 kDa).

[0361] At a concentration of 1 pg / mL, ART5803 was able to fully block NMDAR internalization caused by #003-102 Ab and other monoclonal antibody mixtures mimicking patient’s CSF conditions. Three CSF samples were collected from each patient with inducedrobust NMDAR internalization activities (Table 1) The concentrations of ART5803 required to completely block the NMDAR internalization induced by CSF from patients 2 and 3 were 0.63 pg / mL and 1.3 pg / mL, respectively. For patient 1, 2.5 pg / mL of ART5803 was able to block it partially and maintained NMDAR surface expression at 74% of baseline. For patients 4-7, robust NMDAR internalization was not detected in their CSF samples likely due to either lower concentrations or weaker NMDAR internalization activities of autoantibodies compared to those found in patients 1 -3 (Table 1). The effective ART5803 concentrations against CSF samples of patients 4-7 is expected to be lower than those of patients 1 - 3, potentially less than 0.63 pg / mL.

[0362] All publications, patent applications, issued patents, and other documents referred to in this specification are herein incorporated by reference as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions that are contained in text incorporated by reference are excluded to the extent that they contradict definitions in this disclosure.Example 9: Phase 1 Clinical Trial of ART5803A randomized, double blind Phase 1 clinical trial was performed to evaluate the safety, tolerability, pharmacokinetics and immunogenicity of an anti-NMDAR antibody provided herein in healthy volunteers.Single Ascending Dose (SAD) Arm:Healthy volunteers received a single dose of ART5803 anti- NMD AR antibody or a placebo. Antibody doses were administered at 5 dose levels: 3 mg / kg, 10 mg / kg, 30 mg / kg, 60 mg / kg, and 100 mg / kg. Safety monitoring (including physical and neurological exams, vital sign measurements, 12-lead electrocardiograms [ECGs], Columbia-Suicide Severity Rating Scale [C- SSRS], adverse events, prior / concomitant medications, and exploratory safety assessments including Mini-Mental Status Exam [MMSE], Trails Making Test Part A [TMT-A], and Trails Making Test Part B [TMT-B]) and clinical laboratory assessments were performed at predose, at select visits, and at the end of study or at early termination. Pharmacokinetic assessments were also performed and included a serum sampling and lumbar puncture cerebrospinal fluid sampling. Immunogenicity was assessed by serum anti-ART5803 antibody sampling.ART5803 was generally well-tolerated as a single infusion with no observed dose-limiting toxicity. Following a single IV infusion of ART5803, maximum observed concentration (Cmax) increased in a nearly dose-proportional manner across doses of 3 and 100 mg / kg (FIG. 13 A). Mean Cmaxranged from 67 to 1820 pg / mL between doses of 3 and 100 mg / kg. The time to maximal concentration (Tmax) ranged from 1 to 4 hours post-dose.ART5803 area under the curve (AUC) from time 0 to 168 hours post-dose (AUCo-i68h) and AUC from time 0 to 1008 hours post-dose (AUCo-ioosh) in the serum increased in a dose proportional manner between doses of 3 and 100 mg / kg following a single dose. AUCO-ioo8h was utilized for comparison purposes as all SAD dosing groups had data available through 1008 hours post-dose (Day 43). Mean ART5803 serum AUCo-i68h following a single dose ranged from 4,830 to 152,000 hr*pg / mL between doses of 3 and 100 mg / kg. Mean ART5803 serum AUCO-ioo8h following a single dose ranged from 11 ,000 to 321 ,000 hr* pg / mL between doses of 3 and 100 mg / kg.In the SAD cohort, average ART5803 concentrations (ng / mL) in the CSF at Day 3 (48 hours post-dose) were 37.8 (n=6), 113 (n=6), 522 (n=6), 1070 (n=5), and 1490 (n=6) at doses of 3, 10, 30, 60, and 100 mg / kg, respectively. Concentrations of ART5803 in the CSF were lower than theexposure observed in the serum. At Day 3, the percent concentration of ART5803 in CSF as compared to serum was 0.105%, 0.125%, 0.150%, 0.151%, and 0.133% at single doses of 3, 10, 30, 60, and 100 mg / kg, respectively.On Day 29 (672 hours post-dose), the percent concentration in CSF was 0%, 0.208%, 0.220%, 0.622%, and 0.273% at single doses of 3, 10, 30, 60, and 100 mg / kg, respectively. On Day 43 (1008 hours post-dose), the percent concentration in CSF was 0%, 0%, 0.198%, 0.651%, and 0.357% at single doses of 3, 10, 30, 60, and 100 mg / kg, respectively. This range includes data where concentrations in the CSF were below the limit of quantification (0%).Multiple Ascending Dose (MAD) Arm:Healthy volunteers received ART5803 anti- NMD AR antibody or a placebo once per week for a total of 4 weeks. Antibody doses were administered at 30 mg / kg. Safety monitoring, clinical laboratory assessments, pharmacokinetic assessments, and immunogenicity were performed at predose, at select visits, and at the end of study or at early termination. Study assessments were identical to those performed in the SAD study arm. Minimal to no accumulation in Cmaxwas observed for ART5803 at a dose of 30 mg / kg between Day 1 and Day 8 (FIG. 13B). Mean Cmaxat 30 mg / kg in the MAD cohort was 746 pg / mL on Day 1 and 940 pg / mL on Day 8. The concentration of ART5803 in the CSF on Day 3 was 508 ng / mL, similar to what was observed (522 ng / mL) in the 30 mg / kg SAD cohort. The percent concentration of ART5803 in the CSF on Day 3 post-dose was 0.149%, which was similar to the percent observed in the SAD cohort.Additional doses of ART5803 are evaluated in the MAD study arm. Healthy volunteers receive ART5803 anti- NMD AR antibody or a placebo once per week for a total of 4 weeks. Antibody doses are administered at 60 mg / kg and 100 mg / kg. Safety monitoring, clinical laboratory assessments, pharmacokinetic assessments, and immunogenicity are performed at predose, at select visits, and at the end of study or at early termination. Study assessments are identical to those performed in the SAD study arm. The percent concentration of ART5803 in the CSF on Day 3 post-dose is similar to the percent observed in the SAD cohort of the corresponding dose. ART5803 is generally well-tolerated as a once-weekly infusion with no observed dose-limiting toxicity.Inclusion Criteria:The participant is between the ages of 18 and 65 years with no clinically relevant abnormalities identified by medical history and physical examination, and a Body Mass Index (BMI) of 18 to32 kg / m2. Participants must agree to not donate blood for at least 3 months after the end-of-study (EOS) visit. The participant must be willing and able to provide written, signed informed consent after the nature of the study has been explained, and prior to any research -related procedures.Exclusion Criteria:The participant is pregnant or breastfeeding, has a condition of such severity and acuity that it warrants immediate surgical intervention, or has any clinically significant illness, such as cardiovascular, neurologic, pulmonary, hepatic, renal, metabolic, gastrointestinal, urologic, immunologic, endocrine, or psychiatric disease or disorder, or other abnormality, which may interfere with the evaluation or administration of the study drug, interpretation of participant safety or study results, or would make participation in the study an unacceptable risk including any significant acute or chronic medical condition.Example 10: Phase 2 Clinical Trial of ART5803A multicenter, randomized, dose blind Phase 2 clinical trial is performed to evaluate the safety and efficacy of an anti- NMD AR antibody provided herein in adult patients with anti-NMDA receptor encephalitis (ANRE) or anti-NMDAR antibody-associated psychiatric disease.Adult patients with ANRE or anti-NMDAR antibody-associated psychiatric disease receive a single dose, or multiple doses, of ART5803 anti- NMD AR antibody or a placebo. Antibody doses are administered at 3 dose levels between 3 to 100 mg / kg. Safety monitoring (including physical and neurological exams, vital sign measurements, 12-lead electrocardiograms [ECGs], Columbia-Suicide Severity Rating Scale [C-SSRS], adverse events, prior / concomitant medications, and exploratory safety assessments including Mini-Mental Status Exam [MMSE], Trails Making Test Part A [TMT-A], and Trails Making Test Part B [TMT-B]) and clinical laboratory assessments are performed at predose, at select visits, and at the end of study or at early termination. Pharmacokinetic assessments are also performed and included a serum sampling and lumbar puncture cerebrospinal fluid sampling. Immunogenicity is assessed by serum anti-ART5803 antibody sampling. Efficacy is evaluated by outcome measures such as Beck’s Depression Inventory for depression, SF-36 and EQ-ED-5 for quality of life, cognitive outcomes (such as WAIS-IV, Boston naming test, AVLT, BCAT), Psychiatric outcomes (such as PANSS, SANS, CGI), and neurological outcomes such as mRS, CASE, Seizure diary, RBANS and MOCA.

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A method of treating a central nervous system disease in an individual in need thereof, the method comprising administering a therapeutically effective amount of a therapeutic anti- NMDAR antibody to the individual, wherein the therapeutically effective amount is administered in an amount of about 5 mg / to about 200 mg / kg.

2. The method of claim 1 , wherein administration of the therapeutic anti-NMDAR antibody to the individual provides a cerebrospinal fluid (CSF) concentration of the therapeutic anti-NMDAR antibody in the individual in an amount of about 0.6 pg / mL to about 2.5 pg / mL.

3. A method of treating a central nervous system disease in an individual in need thereof, the method comprising administering a therapeutically effective amount of a therapeutic anti- NMDAR antibody to the individual, wherein the therapeutically effective amount provides a cerebrospinal fluid (CSF) concentration of the therapeutic anti-NMDAR antibody in an amount of about 0.6 pg / mL to about 2.5 pg / mL.

4. The method of any one of claims 1 to 3, wherein the therapeutic anti-NMDAR antibody is administered intravenously (IV).

5. The method of any one of claims 1 to 4, wherein the therapeutic anti-NMDAR antibody is administered less frequently than once a day.

6. The method of any one of claims 1 to 5, wherein the therapeutic anti-NMDAR antibody is administered once a week.

7. The method of any one of claims 1 to 6, wherein the therapeutic anti-NMDAR antibody is administered twice a week.

8. The method of any one of claims 1 to 7, wherein the therapeutic anti-NMDAR antibody is administered once every two weeks.

9. The method of any one of claims 1 to 8, wherein the therapeutic anti-NMDAR antibody is administered once every three weeks.

10. The method of any one of claims 1 to 9, wherein the therapeutic anti-NMDAR antibody is administered once every four weeks.

11. The method of any one of claims 1 to 10, wherein the therapeutically effective amount is about 5 mg / kg to about 100 mg / kg.

12. The method of any one of claims 1 to 11 , wherein the therapeutically effective amount is about 10 mg / kg to about 100 mg / kg.

13. The method of any one of claims 1 to 12, wherein the therapeutically effective amount is about 20 mg / kg to about 100 mg / kg.

14. The method of any one of claims 1 to 13, wherein the therapeutically effective amount is about 30 mg / kg to about 100 mg / kg.

15. The method of any one of claims 1 to 14, wherein the therapeutically effective amount is about 40 mg / kg to about 100 mg / kg.

16. The method of any one of claims 1 to 15, wherein the therapeutically effective amount is about 50 mg / kg to about 90 mg / kg.

17. The method of any one of claims 1 to 16, wherein the therapeutically effective amount is about 60 mg / kg to about 80 mg / kg.

18. The method of any one of claims 1 to 17, wherein the therapeutically effective amount is about 5 mg / kg.

19. The method of any one of claims 1 to 18, wherein the therapeutically effective amount is about 10 mg / kg.

20. The method of any one of claims 1 to 19, wherein the therapeutically effective amount is about 20 mg / kg.

21. The method of any one of claims 1 to 20, wherein the therapeutically effective amount is about 30 mg / kg.

22. The method of any one of claims 1 to 21 , wherein the therapeutically effective amount is about 40 mg / kg.

23. The method of any one of claims 1 to 22, wherein the therapeutically effective amount is about 50 mg / kg.

24. The method of any one of claims 1 to 23, wherein the therapeutically effective amount is about 60 mg / kg.

25. The method of any one of claims 1 to 24, wherein the therapeutically effective amount is about 70 mg / kg.

26. The method of any one of claims 1 to 25, wherein the therapeutically effective amount is about 80 mg / kg.

27. The method of any one of claims 1 to 26, wherein the therapeutically effective amount is about 90 mg / kg.

28. The method of any one of claims 1 to 27, wherein the therapeutically effective amount is about 100 mg / kg.

29. The method of any one of claims 1 to 28, wherein the concentration of the therapeutic anti-NMDAR antibody in the CSF of the individual is about 0.8 pg / mL to about 2.0 pg / mL.

30. The method of any one of claims 1 to 29, wherein the concentration of the therapeutic anti-NMDAR antibody in the CSF of the individual is about 1.0 pg / mL to about 1.8 pg / mL.

31. The method of any one of claims 1 to 30, wherein the concentration of the therapeutic anti-NMDAR antibody in the CSF of the individual is about 1.2 pg / mL to about 1.6 pg / mL.

32. The method of any one of claims 1 to 31, wherein the concentration of the therapeutic anti-NMDAR antibody in the CSF of the individual is about 0.6 pg / mL.

33. The method of any one of claims 1 to 32, wherein the concentration of the therapeutic anti-NMDAR antibody in the CSF of the individual is about 0.8 pg / mL.

34. The method of any one of claims 1 to 33, wherein the concentration of the therapeutic anti-NMDAR antibody in the CSF of the individual is about 1.0 pg / mL.

35. The method of any one of claims 1 to 34, wherein the concentration of the therapeutic anti-NMDAR antibody in the CSF of the individual is about 1.2 pg / mL.

36. The method of any one of claims 1 to 35, wherein the concentration of the therapeutic anti-NMDAR antibody in the CSF of the individual is about 1.4 pg / mL.

37. The method of any one of claims 1 to 36, wherein the concentration of the therapeutic anti-NMDAR antibody in the CSF of the individual is about 1.6 pg / mL.

38. The method of any one of claims 1 to 37, wherein the concentration of the therapeutic anti-NMDAR antibody in the CSF of the individual is about 1.8 pg / mL.

39. The method of any one of claims 1 to 38, wherein the concentration of the therapeutic anti-NMDAR antibody in the CSF of the individual is about 2.0 pg / mL.

40. The method of any one of claims 1 to 39, wherein the concentration of the therapeutic anti-NMDAR antibody in the CSF of the individual is about 2.2 pg / mL.

41. The method of any one of claims 1 to 40, wherein the concentration of the therapeutic anti-NMDAR antibody in the CSF of the individual is about 2.4 pg / mL.

42. The method of any one of claims 1 to 41 , wherein the therapeutic anti-NMDAR antibody comprises a polypeptide comprising an antigen binding domain that binds to NR1.

43. The method of claim 42, wherein the polypeptide is a monospecific polypeptide.

44. The method of claim 42, wherein the polypeptide does not comprise a second antigen binding domain.

45. The method of claim 42, wherein the antigen binding domain that binds to NR1 comprises a one-armed antibody.

46. The method of any one of claims 1 to 45, wherein the therapeutic anti -NMD AR antibody is not an NR1 antagonist.

47. The method of any one of claims 1 to 46, wherein the therapeutic anti-NMDAR antibody is not an NR1 agonist.

48. The method of any one of claims 45 to 47, wherein the one-armed antibody comprises: a heavy chain variable region (VH) comprising: a) a heavy chain complementary determining region 1 (HCDR1) comprising an amino acid sequence of SEQ ID NO: 13; b) a heavy chain complementary determining region 2 (HCDR2) comprising an amino acid sequence of SEQ ID NO: 14; and / or c) a heavy chain complementary determining region 3 (HCDR3) comprising an amino acid sequence of SEQ ID NO: 15; and a light chain variable region (VL) comprising: d) a light chain complementary determining region 1 (LCDR1) comprising an amino acid sequence of SEQ ID NO: 16; e) a light chain complementary determining region 2 (LCDR2) comprising an amino acid sequence of SEQ ID NO: 17; and / or f) a light chain complementary determining region 3 (LCDR3) comprising an amino acid sequence of SEQ ID NO: 18.

49. The method of any one of claims 45 to 47, wherein the one-armed antibody comprises: a heavy chain variable region (VH) comprising: a) a heavy chain complementary determining region 1 (HCDR1) comprising an amino acid sequence of SEQ ID NO: 23; b) a heavy chain complementary determining region 2 (HCDR2) comprising an amino acid sequence of SEQ ID NO: 24; and / or c) a heavy chain complementary determining region 3 (HCDR3) comprising an amino acid sequence of SEQ ID NO: 25; and a light chain variable region (VL) comprising: d) a light chain complementary determining region 1 (LCDR1) comprising an amino acid sequence of SEQ ID NO: 26; e) a light chain complementary determining region 2 (LCDR2) comprising an amino acid sequence of SEQ ID NO: 27; and / orf) a light chain complementary determining region 3 (LCDR3) comprising an amino acid sequence of SEQ ID NO: 28.

50. The method of any one of claims 45 to 47, wherein the one-armed antibody comprises: a heavy chain variable region (VH) comprising: a) a heavy chain complementary determining region 1 (HCDR1) comprising an amino acid sequence of SEQ ID NO: 33; b) a heavy chain complementary determining region 2 (HCDR2) comprising an amino acid sequence of SEQ ID NO: 34; and / or c) a heavy chain complementary determining region 3 (HCDR3) comprising an amino acid sequence of SEQ ID NO: 35; and a light chain variable region (VL) comprising: d) a light chain complementary determining region 1 (LCDR1) comprising an amino acid sequence of SEQ ID NO: 36; e) a light chain complementary determining region 2 (LCDR2) comprising an amino acid sequence of SEQ ID NO: 37; and / or f) a light chain complementary determining region 3 (LCDR3) comprising an amino acid sequence of SEQ ID NO: 38.

51. The method of any one of claims 45 to 47, wherein the one-armed antibody comprises: a heavy chain variable region (VH) comprising: a) a heavy chain complementary determining region 1 (HCDR1) comprising an amino acid sequence of SEQ ID NO: 43; b) a heavy chain complementary determining region 2 (HCDR2) comprising an amino acid sequence of SEQ ID NO: 44; and / or c) a heavy chain complementary determining region 3 (HCDR3) comprising an amino acid sequence of SEQ ID NO: 45; and a light chain variable region (VL) comprising: d) a light chain complementary determining region 1 (LCDR1) comprising an amino acid sequence of SEQ ID NO: 46; e) a light chain complementary determining region 2 (LCDR2) comprising an amino acid sequence of SEQ ID NO: 47; and / or f) a light chain complementary determining region 3 (LCDR3) comprising an amino acid sequence of SEQ ID NO: 48.

52. The method of any one of claims 45 to 47, wherein the one-armed antibody comprises: a heavy chain variable region (VH) comprising:a) a heavy chain complementary determining region 1 (HCDR1) comprising an amino acid sequence of SEQ ID NO: 53; b) a heavy chain complementary determining region 2 (HCDR2) comprising an amino acid sequence of SEQ ID NO: 54; and / or c) a heavy chain complementary determining region 3 (HCDR3) comprising an amino acid sequence of SEQ ID NO: 55; and a light chain variable region (VL) comprising: d) a light chain complementary determining region 1 (LCDR1) comprising an amino acid sequence of SEQ ID NO: 56; e) a light chain complementary determining region 2 (LCDR2) comprising an amino acid sequence of SEQ ID NO: 57; and / or f) a light chain complementary determining region 3 (LCDR3) comprising an amino acid sequence of SEQ ID NO: 58.

53. The method of any one of claims 45 to 47, wherein the one-armed antibody comprises: a heavy chain variable region (VH) comprising: a) a heavy chain complementary determining region 1 (HCDR1) comprising an amino acid sequence of SEQ ID NO: 63; b) a heavy chain complementary determining region 2 (HCDR2) comprising an amino acid sequence of SEQ ID NO: 64; and / or c) a heavy chain complementary determining region 3 (HCDR3) comprising an amino acid sequence of SEQ ID NO: 65; and a light chain variable region (VL) comprising: d) a light chain complementary determining region 1 (LCDR1) comprising an amino acid sequence of SEQ ID NO: 66; e) a light chain complementary determining region 2 (LCDR2) comprising an amino acid sequence of SEQ ID NO: 67; and / or f) a light chain complementary determining region 3 (LCDR3) comprising an amino acid sequence of SEQ ID NO: 68.

54. The method of any one of claims 45 to 47, wherein the one-armed antibody comprises a heavy chain immunoglobulin variable region and a light chain immunoglobulin variable region selected from: a) SEQ ID NO: 11 and SEQ ID NO: 12, b) SEQ ID NO: 21 and SEQ ID NO: 22, c) SEQ ID NO: 31 and SEQ ID NO: 32, d) SEQ ID NO: 41 and SEQ ID NO: 42,e) SEQ ID NO: 51 and SEQ ID NO: 52, or f) SEQ ID NO: 61 and SEQ ID NO: 62.

55. The method of any one of claims 45 to 47, wherein the one-armed antibody comprises a heavy chain immunoglobulin variable region comprising an amino acid sequence of SEQ ID NO: 11 and a light chain immunoglobulin variable region comprising an amino acid sequence of SEQ ID NO: 12.

56. The method of claim 53, wherein the therapeutic anti-NMDAR antibody comprises a heavy chain immunoglobulin variable region comprising an amino acid sequence having at least 90% sequence identity to the sequence of SEQ ID NO: 11 and a light chain immunoglobulin variable region comprising an amino acid sequence having at least 90% sequence identity to the sequence of SEQ ID NO: 12.

57. The method of any one of claims 1 to 56, wherein the central nervous systems disease comprises autoimmune encephalitis, dementia, psychosis, schizophrenia, bipolar disorder, seizure, epilepsy, or depression.

58. The method of any one of claims 1 to 57, wherein the central nervous systems disease comprises dementia, psychosis, schizophrenia, bipolar disorder, seizure, epilepsy, or depression.

59. The method of any one of claims 1 to 58, wherein the central nervous systems disease comprises autoimmune encephalitis.

60. The method of any one of claims 1 to 59, wherein the therapeutic anti-NMDAR antibody further comprises an Fc region.61 . The method of claim 60, wherein the Fc region comprises a LALA mutation (L234A and L235A according to EU numbering).

62. The method of claim 60, wherein the Fc region comprises a knobs-into-holes mutation.

63. The method of claim 60, wherein the Fc region comprises a LALA mutation (L234A and L235A according to EU numbering) and a knobs-into-holes mutation.

64. The method of any one of claims 1 to 63, wherein the therapeutic anti-NMDAR antibody further comprises a pharmaceutically acceptable excipient carrier or diluent comprising an aqueous solution of sodium acetate, polysorbate 80, and L-arginine.

65. The method of any one of claims 1 to 64, wherein the therapeutic anti-NMDAR antibody further comprises a pharmaceutically acceptable excipient carrier or diluent comprising an aqueous solution of sodium acetate, polysorbate 80, and L-arginine.

66. The method of claim 64 or 65, wherein the aqueous solution comprises about 10 mM to about 30mM of sodium acetate, about 0.01% to about 0.03% of polysorbate 80, and about 130 mM to about 150 mM of L-arginine.

67. The method of any one of claims 64 to 66, wherein the aqueous solution comprises about 20 mM of sodium acetate, about 0.02% of polysorbate 80, and about 140 mM of L- arginine.

68. The method of any one of claims 64 to 67, wherein the aqueous solution further comprises about 40 mg / mL to about 60 mg / mL of the therapeutic anti -NMD AR antibody.

69. The method of any one of claims 64 to 68, wherein the aqueous solution further comprises about 50 mg / mL of the therapeutic anti-NMDAR antibody.

70. A pharmaceutical composition comprising an aqueous solution of sodium acetate, polysorbate 80, and L-arginine, and a therapeutic anti-NMDAR antibody, wherein the therapeutic anti-NMDAR antibody comprises a heavy chain immunoglobulin variable region and a light chain immunoglobulin variable region selected from: a) SEQ ID NO: 11 and SEQ ID NO: 12, b) SEQ ID NO: 21 and SEQ ID NO: 22, c) SEQ ID NO: 31 and SEQ ID NO: 32, d) SEQ ID NO: 41 and SEQ ID NO: 42, e) SEQ ID NO: 51 and SEQ ID NO: 52, or f) SEQ ID NO: 61 and SEQ ID NO: 62.

71. The pharmaceutical composition of claim 70, wherein the aqueous solution comprises about 10 mM to about 30mM of sodium acetate, about 0.01% to about 0.03% of polysorbate 80, and about 130 mM to about 150 mM of L-arginine.

72. The pharmaceutical composition of any one of claims 70 or 71, wherein the aqueous solution comprises about20 mM of sodium acetate, about 0.02% of polysorbate 80, and about 140 mM of L-arginine.

73. The pharmaceutical composition of any one of claims 70 to 72, wherein the aqueous solution further comprises about 40 mg / mL to about 60 mg / mL of the therapeutic anti- NMDAR antibody.

74. The pharmaceutical composition of any one of claims 70 to 73, wherein the aqueous solution further comprises about 50 mg / mL of the therapeutic anti-NMDAR antibody.

75. The pharmaceutical composition of any one of claims 70 to 74, wherein the therapeutic anti-NMDAR antibody further comprises an Fc region76. The pharmaceutical composition of claim 75, wherein the Fc region comprises a LALA mutation (L234A and L235A according to EU numbering).

77. The pharmaceutical composition of claim 75, wherein the Fc region comprises a knobs- into-holes mutation.

78. The pharmaceutical composition of claim 75, wherein the Fc region comprises a LALA mutation (L234A and L235A according to EU numbering) and a knobs-into-holes mutation.

79. The method of any one of claims 1 to 69, wherein the therapeutic anti-NMDAR antibody is administered as a single dose.

80. The method of any one of claims 1 to 69, wherein the therapeutic anti-NMDAR antibody is administered once a week for four weeks.81 . The method of any one of claims 1 to 69, wherein administration of the therapeutic anti- NMDAR antibody reduces a severity of the central nervous system disease in the individual in need thereof based on a clinical score, wherein the clinical score is selected from the list consisting of Rankin Scale (mRS), Montreal Cognitive Assessment score (MOCA), Cognitive Assessment Scale for the Elderly (CASE), Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Abnormal Involuntary Movement Scale (AIMS), Unified Parkinson's Disease Rating Scale (UPDRS), Obeso Dyskinesia Rating Scale, Rush Dyskinesia Rating Scale, Clinical Dyskinesia Rating Scale (CDRS), Lang-Fahn Activities of Daily Living Dyskinesia Scale, Parkinson Disease Dyskinesia Scale (PDYS-26), Unified Dyskinesia Rating Scale (UDysRS), Wechsler Adult Intelligence Scale (WAIS-IV), Rey Auditory Verbal Learning Test (AVLT), Boston Naming Test (BNT), Brief Cognitive Assessment Tool (BCAT), Positive and Negative Symptom Scale (PANSS), Brief Psychiatric Rating Scale (BPRS), Montgomery -Asb erg Depression Rating Scale (MADRS), Beck Depression Inventory (BDI), EQ-ED-5 index scoring, or the 36-Item Short Form Health Survey (SF-36), and combinations thereof.

82. The method of claim 81, wherein the Rankin Scale (mRS) score after administration of the therapeutic anti-NMDAR antibody is 1, 2, 3, 4, or 5.

83. The method of claim 81, wherein the Positive and Negative Syndrome Scale (PANSS) score after administration of the therapeutic anti-NMDAR antibody is reduced by 10% or more.

84. The method of claim 81, wherein the Montgomery -Asberg Depression Rating Scale (MADRS) score after administration of the therapeutic anti-NMDAR antibody is lowered by about 1, 2, 3, 4, 5, or 6 points or more.

85. The method of claim 81, wherein the EQ-ED-5 total score after administration of the therapeutic anti-NMDAR antibody is improved by about 0.01, 0.05, or 0. 1 points or more.

86. The method of claim 81, wherein the CASE score after administration of the therapeutic anti-NMDAR antibody is improved to about 3 standard deviations (SD) below the normative mean, about 2.5 SD below the normative mean, about 2 SD below the normativemean, about 1.5 SD below the normative mean, about 1 SD below the normative mean, about 0.5 SD below the normative mean, or about the normative mean.

87. The method of claim 81, wherein the RBANS score after administration of the therapeutic anti-NMDAR antibody is improved to about 3 standard deviations (SD) below the normative mean, about 2.5 SD below the normative mean, about 2 SD below the normative mean, about 1.5 SD below the normative mean, about 1 SD below the normative mean, about 0.5 SD below the normative mean, or about the normative mean.

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