Biomarkers for multiple sclerosis (MS) diagnosis and treatment

Abstract

The present disclosure provides methods of diagnosing and treating multiple sclerosis (MS) using an anti-CD3 antibody, and methods of monitoring progression of MS and / or treatment.

Description

BIOMARKERS FOR MULTIPLE SCLEROSIS (MS) DIAGNOSIS AND TREATMENTCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 744,891 filed on January 14, 2025, and U.S. Provisional Patent Application No. 63 / 793,182 filed on April 23, 2025, the contents of all of which are hereby incorporated by reference in their entireties.REFERENCE TO SEQUENCE LISTING

[0002] The Sequence Listing XML associated with this application is provided electronically in XML file format and is hereby incorporated by reference into the specification. The name of the XML file containing the Sequence Listing XML is “TIZI-043_001WO_SeqList_ST26.xml”. The XML file is 10,564 bytes in size, created on January 12, 2026 and is being submitted electronically.FIELD

[0003] The present disclosure relates to methods of diagnosing and treating multiple sclerosis (MS) using an anti-CD3 antibody, and monitoring progression of MS and / or treatment.BACKGROUND

[0004] Chronic neuroinflammation in multiple sclerosis (MS) can persist independently of relapse activity (also known as progression independent of relapses (PIRA)), revealing mechanisms of progression not addressed by current therapies. Dysregulated T-cell activity plays a central role in this process and is the main target of nasal Foralumab immunotherapy.

[0005] MS is an autoimmune disease of the central nervous system (CNS), characterized by damage of the myelin sheaths by leukocytes that leads to axonal degradation in neurons and inflammation in the CNS (e.g., neuroinflammation). MS manifests as changes in vision, movement, sensation, and thinking in subjects. Progression of MS is also associated with persistence or episodes of smoldering inflammation (or low-grade inflammation) between relapse episodes.

[0006] Relapse-remitting MS (RRMS) is characterized by subjects experiencing cycles of relapses in the form of worsening symptoms (e.g., recurrence of previously observed symptoms or emergence of new symptoms) followed by periods of remission, orimprovement of the symptoms, with each period identified by increased inflammation levels in the CNS. RRMS progression is often found to evolve into secondary progressive MS (SPMS), particularly if RRMS is left untreated. SPMS manifests as a gradual progression of symptoms with reduced episodes of relapse-remission or without these cycles. Subjects with active SPMS or non-active (na)-SPMS show slow and steady progression of the symptoms, which evolve into worsening of physical disability.

[0007] Current MS treatments have a beneficial effect on the relapsing-inflammatory component of MS but have limited efficacy on PIRA. Accordingly, there is an unmet need for developing non-invasive biomarkers and novel therapies for relapse-independent forms of MS, such as PIRA, na-SPMS, and smoldering inflammation.SUMMARY

[0008] Provided herein is a method of treating multiple sclerosis (MS) in a subject, the method comprising: (a) measuring the level of at least one neuroinflammatory biomarker in the subject, wherein the at least one neuroinflammatory biomarker comprises IL-7, CCL2, FLT3LG, VEGFa, B2M, STAT1, CXCL12, TNFSF10, INF ARI, LY86, COBAI, LAMP1, SIGLEC14, TGF-betal, CCL8, TNF, MEGF10, C1QA, CFHR1, C1QL1, or SORCS1; (b) administering an anti-CD3 antibody to the subject, (c) measuring the level of the at least one neuroinflammatory biomarker in the subject a second time; and (d) administering a second dose of the anti-CD3 antibody to the subject, if (i) the level of the at least one neuroinflammatory biomarker TGF-betal, CCL8, TNF, MEGF10, C1QA, CFHR1, and / or SORCS1 is elevated; and / or (ii) the level of the at least one neuroinflammatory biomarker IL-7, CCL2, FLT3LG, VEGFa, B2M, STAT1, CXCL12, TNFSF10, INF ARI, LY86, COBAI, C1QL1, LAMP1, and / or SIGLEC14 is reduced.

[0009] In some embodiments, if the anti-CD3 antibody is not administered, step (c) comprises monitoring the subject or administering a different therapy.

[0010] In some embodiments, the at least one neuroinflammatory biomarker is measured in the serum, blood or cerebrospinal fluid (CSF) of the subject.

[0011] In some embodiments, the biomarker measured in the serum comprises IL-7, CCL2, FLT3LG, CSF1, or VEGFa, or any combination thereof.

[0012] In some embodiments, the biomarker measured in PBMC comprises B2M, STAT1, or TGF-betal, or any combination thereof.

[0013] In some embodiments, the biomarker measured in CSF comprises CXCL12, TNFSF10, CCL8, TNF, INF ARI, LY86, COB Al, MEGF10, SORCS1, PTPRC, RGS10,NPTX2, NET01, FAP, COL8A1, CTSW, C1QA, CFHR1, C1QL1, LAMP1, or SIGLEC14, or any combination thereof.

[0014] In some embodiments, the MS is secondary progressive MS (SPMS).

[0015] In some embodiments, the SPMS is a non-active SPMS (na-SPMS).

[0016] In some embodiments, the method further comprises administering the anti-CD3 antibody one or more additional times.

[0017] In some embodiments, the method further comprises administering the anti-CD3 antibody continuously.

[0018] Provided herein is also a method of modulating the expression of at least one neuroinflammatory-associated gene in a cell, the method comprising contacting the cell with an anti-CD3 antibody.

[0019] In some embodiments, the at least one neuroinflammatory biomarker comprises IL-7, CCL2, FLT3LG, CSF1, VEGFa, B2M, STAT1, TGF-betal, CXCL12, TNFSF10, CCL8, TNF, INF ARI, LY86, COB Al, MEGF10, SORCS1, PTPRC, RGS10, NPTX2, NETO1, FAP, COL8A1, CTSW, C1QA, CFHR1, C1QL1, LAMP1, or SIGLEC14.

[0020] In some embodiments, the cell is isolated from a subject having multiple sclerosis (MS).

[0021] In some embodiments, the cell is a peripheral blood mononuclear cell (PBMC).

[0022] In some embodiments, the PBMC is aNK cell, a CD14+ monocyte, a CD16+ monocyte, a CD4+ central memory cell (Tern), a regulatory T cell (Tregs), a naive B cell, a CD8 effector memory cell (Tern), a conventional dendritic cell (eDC) and / or a central memory CD8 cell (Tcm).

[0023] Provided herein is also a method of monitoring progression of multiple sclerosis (MS) in a subject, the method comprising: (a) measuring the level of at least one neuroinflammatory biomarker in the subject to determine a baseline level of the at least one neuroinflammatory biomarker, wherein the at least one neuroinflammatory biomarker comprises IL-7, CCL2, FLT3LG, VEGFa, B2M, STAT1, CXCL12, TNFSF10, INF ARI, LY86, COBAI, LAMP1, SIGLEC14, TGF-betal, CCL8, TNF, MEGF10, C1QA, CFHR1, C1QL1, or SORCS1; (b) measuring the level of the at least one neuroinflammatory biomarker in the subject a second time; and / or (c) administering a second dose of the anti-CD3 antibody to the subject, if the level of the at least one neuroinflammatory biomarker TGF-betal, CCL8, TNF, MEGF10, C1QA, CFHR1, and / or SORCS1 is increased in step b relative to step a; and / or the level of the at least one neuroinflammatory biomarker IL-7,CCL2, FLT3LG, VEGFa, B2M, STAT1, CXCL12, TNFSF10, INF ARI, LY86, COBAI, C1QL1, LAMP1, and / or SIGLEC14 is reduced in step (b) relative to step (a).

[0024] In some embodiments, the measuring of step (b) is carried out one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, and / or twelve months after the measuring in step (a).

[0025] In some embodiments, the at least one neuroinflammatory biomarker is measured in serum, blood, or cerebrospinal fluid (CSF).

[0026] In some embodiments, the anti-CD3 antibody comprises a variable heavy chain (VH) comprising a complementarity determining region (CDR) 1 of SEQ ID NO: 1, a CDR2 of SEQ ID NO: 2 and a CDR3 of SEQ ID NO: 3; and a variable light chain region (VL) comprising a CDR1 of SEQ ID NO: 4, a CDR2 of SEQ ID NO: 5 and a CDR3 of SEQ ID NO: 6.

[0027] In some embodiments, the anti-CD3 antibody comprises a VH comprising a sequence that is at least 95% identical to the sequence of SEQ ID NO: 7.

[0028] In some embodiments, the anti-CD3 antibody comprises a VL comprising a sequence that is at least 95% identical to the sequence of SEQ ID NO: 8.

[0029] In some embodiments, the anti-CD3 antibody comprises a VH comprising the sequence of SEQ ID NO: 7.

[0030] In some embodiments, the anti-CD3 antibody comprises a VL comprising the sequence of SEQ ID NO: 8.

[0031] In some embodiments, the anti-CD3 antibody is administered intranasally.

[0032] In some embodiments, the anti-CD3 antibody is administered at a dose of 50 pg.

[0033] In some embodiments, the anti-CD3 antibody is administered at a dose of 100 pg.

[0034] In some embodiments, the dose is administered in a single nostril.

[0035] In some embodiments, dose is administered split between both nostrils.

[0036] In some embodiments, the anti-CD3 antibody is administered once a day.

[0037] In some embodiments, the anti-CD3 antibody is administered three times a week.BRIEF DESCRIPTION OF DRAWINGS

[0038] FIG. 1 is a table showing baseline characteristics of subjects in the Foralumab clinical studies described in Example 1, and their Expanded Disability Status Scale (EDSS) scores after 6 and 12 months of continuous Foralumab dosing.

[0039] FIG. 2 is a table showing incidences of treatment emergent adverse events (TEAEs).

[0040] FIG. 3 is a table showing incidences of treatment related adverse events (TRAEs).

[0041] FIG. 4 is a table showing Multiple Sclerosis Functional Composite (MSFC-4) scores from subjects in the Foralumab clinical studies from Example 1.

[0042] FIGs. 5A and 5B are tables showing Modified Fatigue Impact Scale (MFIS) scores and sub scores over 6-month (FIG. 5 A) and 12-month (FIG. 5B) continuous Foralumab dosing periods.

[0043] FIG. 6 is a table showing NeuroQoL questionnaire scores over a 6-month continuous Foralumab dosing period.

[0044] FIGs. 7A and 7B are exemplary brain PET scans showing standardized uptake value (SUV) of Subject 1 (EA1) at baseline and 3 months (FIG. 7A), and EA3, EA4, and EA6 at baseline, 3 months, and 6 months (FIG. 7B, left panel) after treatment with Foralumab. FIG. 7B (right panel) also shows mGALP z-scope maps superimposed on T2-FLAIR MRIs of the respective subjects. FIG. 7C is a series of individualized pGALP z-score maps superimposed on Tl-weighted MRI scans of subjects EA6 (left panel) and EA1 (right panel). White signal indicates radiotracer [F-18]PRB06 signal.

[0045] FIG. 8 is a table showing PET mGALP scores of subjects at baseline to 3 months (top), and baseline to last visit (bottom; average duration 7.5 months) on Foralumab treatment for global (group) or subregions (cortex, thalamus, white matter, and cerebellum).

[0046] FIGs. 9A and 9B are graphs showing average PET mGALP scores (y-axis) at baseline, 3 months, and last follow-up (x-axis) from white matter (FIG. 9A) and global (FIG.9B) in subjects on Foralumab treatment.

[0047] FIG. 10 is a table showing PET mGALP scores of subjects at baseline to 6 months on Foralumab treatment for global (group) or subregions (cortex, thalamus, white matter, and cerebellum).

[0048] FIG. 11 is a graph showing fatigue levels as measured by the Modified Fatigue Impact Scale (MFIS; y-axis) over TSPO-PET mGALP scores (x-axis) from the hippocampus of subjects treated with Foralumab treatment.

[0049] FIGs. 12A and 12B are exemplary TSPO PET scans (left) and graphs showing average mGALP scores (right) from the hippocampus (FIG. 12A) and substantia nigra (FIG.12B) from subjects at baseline and administered Foralumab at 3 months and 6 months.Subjects (n = 5) scored a total MFIS score greater than 30 or a cognitive MFIS score greater than 10.

[0050] FIGs. 13A and 13B are exemplary 3D T2 fluid-attenuated inversion recovery (FLAIR) MRI z-scans (top row), and PET scans at baseline (middle row) and after 6 or 3 months (bottom row) treatment with Foralumab. FIG. 13A shows scans from a subject (EA1) with rim lesions, and FIG. 13B shows scans from a subject (EA3) with core and rim lesions.

[0051] FIG. 14A is a series of exemplary mGALP z-score maps for Subject 1 (EA1) superimposed on T2-FLAIR MRI scans during treatment with Foralumab (constant treatment), after going on intermittent treatment (Int Rx), and subsequently after going off treatment (No Rx). FIGs. 14B and 14C are graphs of the quantified mGALP scores in white matter, cortex, and globally (FIG. 14B), and in the thalamus and cerebellum (FIG. 14C) at baseline, 3 months, 9 months, 20 months, and 30 months.

[0052] FIG. 15 is a series of graphs showing quantification of cytokine and inflammatory markers (IL-7, CCL2, CSF1, VEGFa, and CCL3) in sera from subjects at baseline (Tl), and after three months (T3) and six months (T6) of treatment with Foralumab.

[0053] FIG. 16A is a graph showing the change in the number of oligoclonal bands in the cerebrospinal fluid (CSF) of subjects at baseline and six months after treatment with Foralumab. FIG. 16B is a series of graphs showing quantification of cytokine and inflammatory markers (CXCL12, TNFSF10, CCL8, and TNF) in CSF from subjects at baseline (Tl), and after treatment with Foralumab for six months (T2).

[0054] FIG. 17 is a table showing distribution of leukocytes in peripheral blood mononuclear cell (PBMC) samples from subjects at baseline, and 3 months and 6 months after Foralumab treatment.

[0055] FIG. 18 is a heatmap of gene expression levels of PBMCs from subjects at baseline, and after treatment with Foralumab for 3 months and 6 months. Expression values are scaled.

[0056] FIG. 19 is a graph showing pathway analysis of differentially expressed genes in PBMCs from baseline versus 6-month Foralumab-treated subjects by cell type.

[0057] FIGs. 20A-20C are graphs showing median expression levels of B2M, TGFB1, and STAT1 in PMBCs from subjects at baseline, and after treatment with Foralumab for 3 months and 6 months. Values on significance bars are FDR adjusted p-values of the differential expression.DETAILED DESCRIPTION

[0058] Provided here are methods for monitoring the progression independent of relapses (PIRA) in multiple sclerosis (MS) using an anti-CD3 antibody. For instance, the presentdisclosure provides biomarkers for diagnosing and / or detecting relapse-independent forms of MS, such as PIRA, non-active secondary progressive MS (na-SPMS), and smoldering inflammation, as well as relapse-remitting forms of MS, e.g., RRMS. Also provided are methods of treating MS by measuring one or more biomarkers and administering an anti-CD3 antibody to a subject.Foralumab

[0059] In some aspects, the anti-CD3 antibody of the present disclosure is Foralumab. In some aspects, the anti-CD3 antibody of the present disclosure comprises an antigen-binding fragment of Foralumab.

[0060] Foralumab comprises a heavy chain complementarity determining region 1 (CDRH1) comprising the amino acid sequence GYGMH (SEQ ID NO: 1), a heavy chain complementarity determining region 2 (CDRH2) comprising the amino acid sequence VIWYDGSKKYYVDSVKG (SEQ ID NO: 2), a heavy chain complementarity determining region 3 (CDRH3) comprising the amino acid sequence QMGYWHFDL (SEQ ID NO: 3), a light chain complementarity determining region 1 (CDRL1) comprising the amino acid sequence RASQSVSSYLA (SEQ ID NO: 4), a light chain complementarity determining region 2 (CDRL2) comprising the amino acid sequence DASNRAT (SEQ ID NO: 5), and a light chain complementarity determining region 3 (CDRL3) comprising the amino acid sequence QQRSNWPPLT (SEQ ID NO: 6).

[0061] Foralumab comprises a variable heavy chain comprising the amino acid sequence QVQLVESGGGVVQPGRSLRLSCAASGFKFSGYGMHWVRQAPGKGLEWVAVIWYD GSKKYYVDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQMGYWHFDLW GRGTLVTVSS (SEQ ID NO: 7) and a variable light chain comprising the amino acid sequence EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGI PARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPLTFGGGTKVEIK (SEQ ID NO: 8).

[0062] Foralumab comprises a heavy chain comprising the amino acid sequence:QVQLVESGGGVVQPGRSLRLSCAASGFKFSGYGMHWVRQAPGKGLEWVAVIWYD GSKKYYVDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARQMGYWHFDLW GRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDK THTCPPCPAPEAEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAI<TI<PREEQYNSTYRVVSVLTVLHQDWLNGI<EYI<CI<VSNI<ALPAPIEI< TISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO: 9) and a light chain comprising the amino acid sequence EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGI PARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPLTFGGGTKVEIKRTVAAPSV FIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 10).

[0063] Foralumab may also be referred to herein as NI-0401, or 28F11-AE.

[0064] In the methods of the present disclosure, Foralumab may be further formulated for administration to a subject. Foralumab may be formulated in any suitable excipient. In some embodiments, the Foralumab formulation can be a liquid. In some embodiments, the liquid formulation is aqueous.

[0065] The Foralumab formulation may include one or more salts (a buffering salt), one or more polyols and one or more excipients. The Foralumab formulations may also contain buffering agents, or preservatives. As used in this application, the terms "buffer" or "buffer system" is meant a compound that, usually in combination with at least one other compound, provides a buffering system in solution that exhibits buffering capacity, that is, the capacity to neutralize, within limits, either acids or bases (alkali) with relatively little or no change in the original pH.

[0066] In some aspects, the Foralumab formulation provided herein is a nasal formulation.

[0067] In some embodiments the Foralumab formulation for nasal delivery comprises 0.25 mg / ml Foralumab, 3.4 mg / ml sodium acetate, 0.20 mg / ml polysorbate 80 and 7.31 mg / ml sodium chloride. In other embodiments the Foralumab formulation for nasal delivery comprises 0.5 mg / ml Foralumab, 3.4 mg / ml sodium acetate, 0.20 mg / ml polysorbate 80 and 7.31 mg / ml sodium chloride.

[0068] In some embodiments, the osmolality of the Foralumab formulation is about SOO- SO (e.g., about 825-925) mOsm / kg.Doses and Administration

[0069] In some embodiments, the nasal Foralumab formulation is an aerosol formulation. In some embodiments, the nasal Foralumab formulation provides for aerosol of the antibody at a dosage in the range of about 10 pg to 100 pg per administration. In some embodiments,the administration is administered once a day. In some embodiments, the nasal Foralumab formulation provides for aerosol of the antibody at a dosage of 25 pg to 50 pg per administration. In some embodiments, the nasal Foralumab formulation provides for aerosol of the antibody at a dosage of 50 pg to 100 pg per administration. In some embodiments, the nasal Foralumab is administered at a dosage of 50 pg. In some embodiments, the nasal Foralumab is administered at a dosage of 100 pg. In some embodiments, the administration is administered to one nostril or, alternatively, split between both nostrils. In some embodiments, the administration is administered to one nostril. In some embodiments, the administration is administered split between both nostrils.

[0070] In some embodiments, the average droplet size of the delivered Foralumab formulation is between 10 pm and 250 pm. For example, the droplet size may be between 10 pm and 100 pm, or between 25 pm and 250 pm.

[0071] In some embodiments, the nasal Foralumab formulation is suitable for storage at about 2 °C to about 4 °C. In some embodiments, the nasal Foralumab formulation is stored in a sealed vial or other suitable container. In some embodiments, the nasal Foralumab formulation is stored in a sealed vial or other suitable container at about 2 °C to about 4 °C.

[0072] In some aspects of the methods of the present disclosure, Foralumab can be administered (e.g. intranasally) to the subject at a dosage of about 50 pg of Foralumab. In some aspects, Foralumab can be administered (e.g. intranasally) to the subject at a dosage about 100 pg of Foralumab. In some aspects, Foralumab may be administered at a dosage of about 50 pg initially and increased to a dosage of about 100 pg later. In some embodiments, the Foralumab is administered intranasally to the subject at a dose of 50 pg. In some embodiments, the Foralumab is administered intranasally to the subject at a dose of 50 pg in a single nostril. In some embodiments, the Foralumab is administered intranasally to the subject at a dose of 50 pg split between both nostrils. In some embodiments, the Foralumab is administered intranasally to the subject at a dose of 100 pg. In some embodiments, the Foralumab is administered intranasally to the subject at a dose of 100 pg in a single nostril. In some embodiments, the Foralumab is administered intranasally to the subject at a dose of 100 pg split between both nostrils.

[0073] In some aspects, Foralumab is administered (e.g. intranasally) to the subject about three times a week. In some aspects, Foralumab is administered (e.g. intranasally) to the subject on day 1, day 3 and day 5 of a week. In some aspects, Foralumab is administered (e.g. intranasally) to the subject on day 1, day 3 and day 5 of the first week, on day 1, day 3 and day 5 of the second week and on day 1, day 3 and day 5 of the third week.

[0074] In some aspects, Foralumab is administered (e.g. intranasally) to the subject in cycles, wherein each cycle comprises about 3 weeks, wherein Foralumab is administered (e.g. intranasally) to the subject three times per week in the first two weeks of the cycle and is not administered to the subject in the third week of the cycle. Foralumab can be administered (e.g. intranasally) for at least about one, at least about two, at least about three, at least about four, at least about five, at least about six, at least about seven, at least about eight, at least about nine, or at least about 10 cycles.

[0075] Foralumab may also be administered continuously, i.e., not in cycles. In some aspects, Foralumab is administered to the subject three times a week for as long as indicated.Multiple Sclerosis (MS)

[0076] The present disclosure relates to methods for treating multiple sclerosis (MS) using an anti-CD3 antibody. The present disclosure also provides biomarkers for diagnosing MS, in particular SPMS. The present disclosure also provides methods of detecting relapseindependent forms of MS, such as PIRA, non-active secondary progressive MS (na-SPMS), and smoldering inflammation, using an anti-CD3 antibody. The present disclosure also provides biomarkers for identifying a subject having MS suited for being administered an anti-CD3 antibody and for monitoring disease progression and treatment response.Diagnosis of MS

[0077] Although RRMS and SPMS are distinguished by several criteria, including 1) reduced occurrence of relapse-remission cycles and 2) inflammation-independent neurodegeneration, SPMS is diagnosed only in subjects who have been diagnosed with RRMS, and exhibit reduced relapse episodes with gradual progression of the disorder.

[0078] Methods of assessing and monitoring MS include but are not limited to neurologic assessments including Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite (MSFC-4), Modified Fatigue Impact Scale (MFIS), California Verbal Learning Test (CVLT-II), and NeuroQoL, positron emission tomography (PET) scans, and / or magnetic resonance imaging (MRI) scans.

[0079] In some embodiments, MS severity is assessed using EDSS. EDSS is a neurological scale, ranging from 0 (no disability) to 10 (death due to MS or MS-related complications), to measure the level of disability of a subject having MS. The EDSS score of a subject is determined by assessing the following functional systems: pyramidal (motor function), cerebellar, brainstem, sensory, bowel and bladder, visual, cerebral / mental, and other.

[0080] In some embodiments, MS severity is assessed using MSFC-4. MSFC-4 is a composite assessment to assess physical and cognitive functionality of subjects. The MSFC-4 score of a subject is determined based on the time it takes for the subject to complete the Timed 25-Foot Walk, the 9-Hole Peg Test, the Paced Auditory Serial Addition Test or the Symbol Digit Modalities Test, and the Low-Contrast Letter Acuity test.

[0081] In some embodiments, MS severity is assessed using MFIS. MFIS is a selfassessment conducted by a subject to determine the effects of fatigue on quality of life.

[0082] In some embodiments, MS severity is assessed using CVLT-II. CVLT-II is a neuropsychological assessment to evaluate verbal learning and memory by having a subject memorize and recall a list of words over five rounds.

[0083] In some embodiments, MS severity is assessed using NeuroQoL. NeuroQoL determines overall quality of life by self-assessing physical, mental, and social effects experienced by subjects with neurological conditions, such as MS, by answering a series of questions.

[0084] In some embodiments, MS severity is assessed using PET scans. PET scans can be used to determine levels of inflammation in the CNS (e.g., in brain; e.g., in a subregion of the brain). For instance, the levels of inflammation can be determined by administrating an inflammation marker (e.g., translocator protein (TSPO)) linked to a radiolabel (e.g., [F-l 8]) to a subject, and detect and quantify the levels of radiolabel signal in the CNS. In some embodiments, PET scans can be used for identifying lesions (e.g., rim lesions, core lesions, or any combination thereof).

[0085] In some embodiments, MS severity is assessed using MRI scans. MRI scans can image whole brain and spinal cord to detect any lesions using, for instance, 3D magnetization-prepared rapid gradient-echo (MPRAGE), 3D T2-weighted, 3D T2 fluid-attenuated inversion recovery (FLAIR), sagittal T1 spin-echo, T2 spin-echo, short tau inversion recovery (STIR), or post-contrast sagittal and axial T1 spin-echo sequences, or any combination thereof.

[0086] Currently available methods of monitoring progression of MS, as well as distinguishing between the subtypes of MS (e.g., RRMS versus SPMS) have limitations as described above. Accordingly, provided herein are novel biomarkers for diagnosing SPMS and / or RRMS. Provided herein are also novel biomarkers for distinguishing SPMS And RRMS. Also provided herein are novel biomarkers for monitoring progression of MS. In some embodiments, the MS is RRMS. In some embodiments, the MS is SPMS. In some embodiments, the SPMS is active SPMS or na-SPMS.

[0087] The present disclosure provides methods of diagnosing MS in a subject. In some embodiments, the method comprises measuring at least one neuroinflammatory biomarker in the subject. In some embodiments, the at least one neuroinflammatory biomarker is measured in serum, blood, and / or cerebrospinal fluid (CSF).

[0088] Biomarkers

[0089] Provided herein are biomarkers for the diagnosis, treatment and assessment of progression of MS.

[0090] In some embodiments, the biomarker measured in serum comprises one, two, three, four, or more of Interleukin 7 (IL-7), Chemokine (C-C motif) ligand 2 (CCL2), Fms-related tyrosine kinase 3 ligand (FLT3LG), Colony-stimulating factor 1 (CSF1), or Vascular endothelial growth factor A (VEGFa). In some embodiments, the biomarker measured in serum is IL-7. In some embodiments, the biomarker measured in serum is CLL2. In some embodiments, the biomarker measured in serum is FLT3LG. In some embodiments, the biomarker measured in serum is CSF1. In some embodiments, the biomarker measured in serum is VEGFa. IL-7, CCL2, CSF1, and VEGFa are cytokines involved with inflammation. IL-7 stimulates development of lymphocytes (e.g., T cells and B cells) and maintains the homeostasis between healthy and apoptotic lymphocytes. CCL2 recruits lymphocytes to sites of injury or disease, e.g., inflammation. FLGT3LG activates proliferation of hematopoietic stem cells and increases development of lymphocytes. CSF1 stimulates differentiation and proliferation of hematopoietic stem cells into monocytes and macrophages. VEGFa stimulates formation and growth of new blood vessels (angiogenesis) and stimulates permeability of blood vessels to enable cell infiltration to sites of injury or disease, e.g., inflammation.

[0091] In some embodiments, the biomarker measured in PBMC comprises one, two, or all three of Beta-2 -microglobulin (B2M), Signal transducer and activator of transcription (STAT1), or Transforming growth factor-beta 1 (TGF-betal). In some embodiments, the biomarker measured in PBMC is B2M. In some embodiments, the biomarker measured in PBMC is STAT1. In some embodiments, the biomarker measured in PBMC is TGF-beta. B2M is a component of major histocompatibility complex (MHC) class I molecules and aids in the antigen presentation pathway to T cells for proper immune response. STAT1 is a transcription factor that mediates immune response signaling by cytokines to modulate cell differentiation, activation, and death. TGF-betal is a cytokine that acts both as an immune suppressor in inflammation by deactivating stimulated or active immune cells, and a pro-inflammatory signal by recruiting immune cells to sites of injury or disease, e.g., inflammation, and promoting tissue restructuring.

[0092] In some embodiments, the biomarker measured in CSF comprises one, two, three, four, five, six, or more of C-X-C motif chemokine ligand 12 (CXCL12), Tumor necrosis factor super family member 10 (TNFSF10), Chemokine (C-C motif) ligand 8 (CCL8), Tumor necrosis factor (TNF), Interferon-alpha / beta receptor subunit 1 (INF ARI), Lymphocyte antigen 86 (LY86), Collagen alpha-l(XI) chain protein (COBAI), Multiple EGF-like-domains 10 (MEGF10), Sortilin-related VPS10 domain-containing receptor 1 (SORCS1), Protein Tyrosine Phosphatase Receptor Type C (PTPRC), Regulator of G protein signaling 10 (RGS10), Neuronal pentraxin 2 (NPTX2), Neuropilin and tolloid-like 1 (NETO1), Fibroblast activation protein (FAP), Collagen type VIII alpha 1 chain (COL8A1), Cathepsin W (CTSW), Complement Clq subcomponent subunit A (C1QA), Complement factor Id-related protein 1 (CFHR1), Complement Clq-like 1 (C1QL1), Lysosomal-associated membrane protein 1 (LAMP1), and Sialic acid-binding immunoglobulin-like lectin 14 (SIGLEC14). In some embodiments, the biomarker measured in CSF is CXCL12. In some embodiments, the biomarker measured in CSF isTNFSFlO. In some embodiments, the biomarker measured in CSF is CCL8. In some embodiments, the biomarker measured in CSF is TNF. In some embodiments, the biomarker measured in CSF is INF ARI. In some embodiments, the biomarker measured in CSF is LY86. In some embodiments, the biomarker measured in CSF is COBAL In some embodiments, the biomarker measured in CSF is MEGF10. In some embodiments, the biomarker measured in CSF is C1QA. In some embodiments, the biomarker measured in CSF is CFHR1. In some embodiments, the biomarker measured in CSF is C1QL1. In some embodiments, the biomarker measured in CSF is SORCS1. In some embodiments, the biomarker measured in CSF is PTPRC. In some embodiments, the biomarker measured in CSF is RGS10. In some embodiments, the biomarker measured in CSF is NPTX2. In some embodiments, the biomarker measured in CSF is NETO1. In some embodiments, the biomarker measured in CSF is FAP. In some embodiments, the biomarker measured in CSF is COL8A1. In some embodiments, the biomarker measured in CSF is CTSW. In some embodiments, the biomarker measured in CSF is a complement system protein. CXCL12 is a chemokine that recruits immune cells and guides blood vessel formation. TNFSF10 is a cytokine that promotes apoptosis of target cells, e.g., cells triggering an inflammatory response, in response to an injury or disease. CCL8 is a chemokine involved in recruiting lymphocytes in response to inflammation and activating them. INF ARI is part of receptors that bind to interferon proteins to aid in the response toantiviral responses and cell growth and differentiation. LY86 acts synergistically with other proteins to regulate innate immune responses to bacterial lipopolysaccharides (LPS) and the production of cytokines as a response to LPS. C0BA1 is a structural component found in connective tissues. MEGF10 is a membrane protein implicated in clearance of dead cells, as well as amyloid-beta plaque removal in neurons. SORCS1 is a transmembrane protein that regulates recruitment and positioning of neuron synaptic receptors for proper neuronal communication. PTPRC is an enzyme involved in the activation and differentiation of T cells and B cells. RGS10 is a protein involved in suppressing inflammatory responses by reducing the activity of pro-inflammatory factors. NPTX2 and NET01 are proteins associated with increased neuroplasticity and axonal health. FAP is an enzyme involved in extracellular matrix restructuring to promote wound healing and tissue repair. C0L8A1 is a short-chain collagen that is associated in adhesion of cells and blood vessel growth. CTSW is a kinase primarily expressed by natural killer (NK) cells and T cells involved in their cytolytic activity. C1QA is a component of the complement system subcomponent Clq, which is necessary for the innate immune system’s complement system pathway, and is also involved in synapse pruning. CFHR1 is a protein involved in regulating the complement system response. C1QL1 is a protein involved in synapse formation, refinement, and maintenance. LAMP1 is a protein associated with lysosomes and endosomes for proper function in autophagy and immune responses. SIGLEC14 is a receptor protein that is expressed in immune cells for identifying bacteria-associated sialic acid and inducing immune response, e.g., inflammation.

[0093] In some embodiments, the biomarker measured is a human biomarker.

[0094] In some embodiments, the method comprises measuring at least one (i.e., one or more) neuroinflammatory biomarkers. For instance, in some embodiments, the method comprises measuring one neuroinflammatory biomarker, two neuroinflammatory biomarkers, three neuroinflammatory biomarkers, etc. In some embodiments, the method comprises measuring one neuroinflammatory biomarker. In some embodiments, the method comprises measuring two neuroinflammatory biomarkers. In some embodiments, the method comprises measuring three neuroinflammatory biomarkers. In some embodiments, the method comprises measuring four neuroinflammatory biomarkers. In some embodiments, the method comprises measuring five neuroinflammatory biomarkers. In some embodiments, the method comprises measuring six neuroinflammatory biomarkers. In some embodiments, the method comprises measuring seven neuroinflammatory biomarkers.

[0095] In some embodiments, the method further comprises determining a baseline level of the at least one neuroinflammatory biomarker. The baseline level is an initial amount of the at least one neuroinflammatory biomarker detected in a subject, e.g., prior to administering a therapeutic agent, e.g., an anti-CD3 antibody, or as a first measurement when monitoring the subject. In some embodiments, the method comprises determining an additional level of the at least one neuroinflammatory biomarker. In some embodiments, the baseline level and the additional level of the at least one neuroinflammatory biomarker are compared. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is elevated or reduced compared to the baseline level of the at least one neuroinflammatory biomarker.

[0096] For instance, in some embodiments, the additional level of the at least one neuroinflammatory biomarker (e.g., a biomarker measured in serum, PBMC, and / or CSF) is elevated by about 0.5-fold, about 1.0-fold, about 1.5-fold, about 2.0-fold, about 2.5-fold, about 3.0-fold, about 3.5-fold, about 4.0-fold, about 4.5-fold, about 5.0-fold, about 5.5-fold, about 6.0-fold, about 6.5-fold, about 7.0-fold, about 7.5-fold, or about 8.0-fold compared to baseline. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is elevated by about 0.5-fold. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is elevated by about 1.0-fold. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is elevated by about 1.5-fold. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is elevated by about 2.0-fold. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is elevated by about 2.5-fold. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is elevated by about 3.0-fold. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is elevated by about 3.5-fold. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is elevated by about 4.0-fold. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is elevated by about 4.5-fold. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is elevated by about 5.0-fold. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is elevated by about 5.5-fold. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is elevated by about 6.0-fold. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is elevated by about 6.5-fold. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is elevated by about 7.0-fold. In some embodiments,the additional level of the at least one neuroinflammatory biomarker is elevated by about 7.5-fold. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is elevated by about 8.0-fold.

[0097] In some embodiments, the additional level of the at least one neuroinflammatory biomarker (e.g., a biomarker measured in serum, PBMC, and / or CSF) is elevated by about 5%, about 10%, about 15%, about 30%, about 50%, about 75%, about 100%, about 150%, about 200%, about 250%, about 300%, about 350%, about 400%, about 450%, about 500%, about 550%, about 600%, about 650%, about 700%, about 750%, or about 800% compared to baseline. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is elevated by about 5%. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is elevated by about 10%. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is elevated by about 15%. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is elevated by about 30%. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is elevated by about 50%. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is elevated by about 75%. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is elevated by about 100%. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is elevated by about 150%. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is elevated by about 200%. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is elevated by about 250%. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is elevated by about 300%. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is elevated by about 350%. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is elevated by about 400%. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is elevated by about 450%. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is elevated by about 500%. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is elevated by about 550%. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is elevated by about 600%. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is elevated by about 650%. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is elevated by about 700%. In some embodiments, the additional level of the at least oneneuroinflammatory biomarker is elevated by about 750%. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is elevated by about 800%.

[0098] In some embodiments, the additional level of the at least one neuroinflammatory biomarker is reduced compared to baseline. In some embodiments, the additional level of the biomarker measured in PBMC is reduced. In some embodiments, the additional level of the biomarker measured in CSF is reduced. For instance, in some embodiments, the additional level of the at least one neuroinflammatory biomarker (e.g., a biomarker measured in PBMC and / or CSF) is reduced by about 0.5-fold, about 1.0-fold, about 1.5-fold, about 2.0-fold, about 2.5-fold, about 3.0-fold, about 3.5-fold, about 4.0-fold, about 4.5-fold, about 5.0-fold, about 5.5-fold, about 6.0-fold, about 6.5-fold, about 7.0-fold, about 7.5-fold, or about 8.0-fold compared to baseline. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is reduced by about 0.5-fold. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is reduced by about 1.0-fold. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is reduced by about 1.5-fold. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is reduced by about 2.0-fold. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is reduced by about 2.5-fold. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is reduced by about 3.0-fold. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is reduced by about 3.5-fold. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is reduced by about 4.0-fold. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is reduced by about 4.5-fold. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is reduced by about 5.0-fold. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is reduced by about 5.5-fold. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is reduced by about 6.0-fold. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is reduced by about 6.5-fold. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is reduced by about 7.0-fold. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is reduced by about 7.5-fold. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is reduced by about 8.0-fold.

[0099] In some embodiments, the additional level of the at least one neuroinflammatory biomarker (e.g., a biomarker measured in PBMC and / or CSF) is reduced by about 5%, about10%, about 15%, about 30%, about 50%, about 75%, about 100%, about 150%, about 200%, about 250%, about 300%, about 350%, about 400%, about 450%, about 500%, about 550%, about 600%, about 650%, about 700%, about 750%, or about 800% relative to baseline. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is reduced by about 5%. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is reduced by about 10%. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is reduced by about 15%. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is reduced by about 30%. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is reduced by about 50%. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is reduced by about 75%. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is reduced by about 100%. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is reduced by about 150%. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is reduced by about 200%. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is reduced by about 250%. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is reduced by about 300%. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is reduced by about 350%. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is reduced by about 400%. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is reduced by about 450%. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is reduced by about 500%. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is reduced by about 550%. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is reduced by about 600%. In some embodiments, the base additional line level of the at least one neuroinflammatory biomarker is reduced by about 650%. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is reduced by about 700%. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is reduced by about 750%. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is reduced by about 800%.Treatment and monitoring progression of MS[000100] In some embodiments, the present disclosure provides methods of treating MS in a subject. In some embodiments, the present disclosure also provides methods of identifying a subject having MS suited for being administered an anti-CD3 antibody. In some embodiments, the method comprises (a) measuring the level of at least one neuroinflammatory biomarker in the subject, wherein the at least one neuroinflammatory biomarker comprises IL-7, CCL2, FLT3LG, VEGFa, B2M, STAT1, CXCL12, TNFSF10, INF ARI, LY86, COBAI, LAMP1, SIGLEC14, TGF-betal, CCL8, TNF, MEGF10, C1QA, CFHR1, C1QL1, or SORCS1; (b) administering an anti-CD3 antibody to the subject, (c) measuring the level of the at least one neuroinflammatory biomarker in the subject a second time; and (d) administering a second dose of the anti-CD3 antibody to the subject, if (i) the level of the at least one neuroinflammatory biomarker TGF-betal, CCL8, TNF, MEGF10, C1QA, CFHR1, and / or SORCS1 is elevated; and / or (ii) the level of the at least one neuroinflammatory biomarker IL-7, CCL2, FLT3LG, VEGFa, B2M, STAT1, CXCL12, TNFSF10, INF ARI, LY86, COBAI, C1QL1, LAMP1, and / or SIGLEC14 is reduced. In situations where a treatment is not administered, step c may comprise monitoring the patient or administering a different therapy (e.g., standard of care).[000101] In some embodiments, a method of monitoring progression of MS comprises (a), measuring the level of at least one neuroinflammatory biomarker in the subject, wherein the at least one neuroinflammatory biomarker comprises IL-7, CCL2, FLT3LG, VEGFa, B2M, STAT1, CXCL12, TNFSF10, INF ARI, LY86, COBAI, LAMP1, SIGLEC14, TGF-betal, CCL8, TNF, MEGF10, C1QA, CFHR1, C1QL1, or SORCS1; (b). administering an anti-CD3 antibody to the subject, (c). measuring the level of the at least one neuroinflammatory biomarker in the subject a second time; and (d). determining that the MS is progressing if (i). the level of the at least one neuroinflammatory biomarker TGF-betal, CCL8, TNF, MEGF10, C1QA, CFHR1, and / or SORCS1 is elevated; and / or (ii). the level of the at least one neuroinflammatory biomarker IL-7, CCL2, FLT3LG, VEGFa, B2M, STAT1, CXCL12, TNFSF10, INF ARI, LY86, COBAI, C1QL1, LAMP1, and / or SIGLEC14 is reduced. If it is determined that the MS is progressing, an anti-CD3 antibody may be administered to the subject. Alternatively, the subject may be monitored, e.g. by repeating the measurements of the at least one neuroinflammatory biomarker.[000102] Provided herein are also uses of an anti-CD3 antibody for the manufacture of a medicament for treating MS. Also provided herein are uses of an anti-CD3 antibody for the treatment of MS. Provided herein are also compositions comprising an anti-CD3 antibody foruse in the treatment of MS. In some embodiments, the use comprises (a) measuring the level of at least one neuroinflammatory biomarker in the subject, wherein the at least one neuroinflammatory biomarker comprises IL-7, CCL2, FLT3LG, VEGFa, B2M, STAT1, CXCL12, TNFSF10, INF ARI, LY86, COBAI, LAMP1, SIGLEC14, TGF-betal, CCL8, TNF, MEGF10, C1QA, CFHR1, C1QL1, or SORCS1; (b) administering an anti-CD3 antibody to the subject, (c) measuring the level of the at least one neuroinflammatory biomarker in the subject a second time; and (d) administering a second dose of the anti-CD3 antibody to the subject, if (i) the level of the at least one neuroinflammatory biomarker TGF-betal, CCL8, TNF, MEGF10, C1QA, CFHR1, and / or SORCS1 is elevated; and / or (ii) the level of the at least one neuroinflammatory biomarker IL-7, CCL2, FLT3LG, VEGFa, B2M, STAT1, CXCL12, TNFSF10, INF ARI, LY86, COBAI, C1QL1, LAMP1, and / or SIGLEC14 is reduced.. In situations where a treatment is not administered, step (c)may comprise monitoring the patient or administering a different therapy (e.g., standard of care).[000103] Monitoring the subject comprises evaluating the progression of MS in the subject by, for instance, measuring the at least one neuroinflammatory biomarker in the subject and determining changes in the levels of the at least one neuroinflammatory biomarker.Monitoring the subject also allows evaluating the effectiveness of a treatment, e.g., an anti-CD3 antibody.[000104] Measurement of the at least one neuroinflammatory biomarker may be performed by analyzing a sample from the subject. In some embodiments, the sample is a cerebrospinal fluid (CSF) sample. In some embodiments, the sample is a serum sample. In some embodiments, the sample is a blood sample. In some embodiments, the blood sample comprises peripheral blood mononuclear cells (PBMCs). In some embodiments, the sample is analyzed for gene expression levels by measuring RNA levels or protein levels using conventional methods well known in the art, including but not limited to whole genome sequencing, RNA sequencing, single-cell RNA sequencing (scRNAseq), Olink analysis, and SIMOA analysis.[000105] In some embodiments, the step of measuring the level of at least one neuroinflammatory biomarker in the subject is performed a first time, a second time, a third time, a fourth time, a fifth time, etc. In some embodiments, the step of measuring the level of at least one neuroinflammatory biomarker in the subject is performed a first time. In some embodiments, the step of measuring the level of at least one neuroinflammatory biomarker in the subject is performed a second time. In some embodiments, the step of measuring the level of at least one neuroinflammatory biomarker in the subject is performed a third time. In someembodiments, the step of measuring the level of at least one neuroinflammatory biomarker in the subject is performed a fourth time. In some embodiments, the step of measuring the level of at least one neuroinflammatory biomarker in the subject is performed a fifth time. In some embodiments, the step of measuring the level of at least one neuroinflammatory biomarker in the subject is performed a sixth time. In some embodiments, the step of measuring the level of at least one neuroinflammatory biomarker in the subject is performed a seventh time. In some embodiments, the step of measuring the level of at least one neuroinflammatory biomarker in the subject is performed an eighth time. In some embodiments, the step of measuring the level of at least one neuroinflammatory biomarker in the subject is performed a ninth time. In some embodiments, the step of measuring the level of at least one neuroinflammatory biomarker in the subject is performed a tenth time.[000106] Determining a baseline level of the at least one neuroinflammatory is an initial measurement of the at least one neuroinflammatory biomarker in a subject. The initial measurement (i.e., the baseline level) is used to monitor the progression of MS by comparing against subsequent measurements. In some embodiments, the method further comprises determining an additional level of the at least one neuroinflammatory biomarker after administering the MS treatment. Measuring and determining an additional level of the at least one neuroinflammatory biomarker allows for determining any changes in the levels of the at least one neuroinflammatory biomarker, i.e., an increase or a decrease. Changes in the levels of the at least one neuroinflammatory biomarker may be used to determine changes in the severity of MS or effectiveness of a treatment.[000107] Provided herein are also methods of monitoring progression of multiple sclerosis (MS) in a subject, the method comprising: (a) measuring the level of at least one neuroinflammatory biomarker in the subject to determine a baseline level of the at least one neuroinflammatory biomarker, wherein the at least one neuroinflammatory biomarker comprises IL-7, CCL2, FLT3LG, VEGFa, B2M, STAT1, CXCL12, TNFSF10, INF ARI, LY86, COBAI, LAMP1, SIGLEC14, TGF-betal, CCL8, TNF, MEGF10, C1QA, CFHR1, C1QL1, or SORCS1; (b) measuring the level of the at least one neuroinflammatory biomarker in the subject a second time; and (c) administering an anti-CD3 antibody to the subject, if the level of TGF-betal, CCL8, TNF, MEGF10, C1QA, CFHR1, and / or SORCS1 is increased in step (b) relative to step (a); and / or the level of IL-7, CCL2, FLT3LG, VEGFa, B2M, STAT1, CXCL12, TNFSF10, INF ARI, LY86, COBAI, C1QL1, LAMP1, and / or SIGLEC14 is reduced in step (b) relative to step (a). In some embodiments, the measuring of step (b) is carried out one month, two months, three months, four months, five months, sixmonths, seven months, eight months, nine months, ten months, eleven months, and / or twelve months after the measuring in step (a).[000108] Additional measurements of the neuroinflammatory biomarkers may be carried out to determine the progression of MS. Alternatively, the additional measurements provide a readout of whether the treatment is effective. In some embodiments, the at least one neuroinflammatory biomarker is measured after administering a treatment. In some embodiments, the at least one neuroinflammatory biomarker is measured after administering a treatment to determine the effectiveness of the treatment.[000109] In some embodiments, the measuring of the at least one neuroinflammatory biomarker is carried out one or more times. In some embodiments, the measuring of the at least one neuroinflammatory biomarker is carried out one month after administering the treatment. In some embodiments, the measuring of the at least one neuroinflammatory biomarker is carried out two months after administering the treatment. In some embodiments, the measuring of the at least one neuroinflammatory biomarker is carried out three months after administering the treatment. In some embodiments, the measuring of the at least one neuroinflammatory biomarker is carried out four months after administering the treatment. In some embodiments, the measuring of the at least one neuroinflammatory biomarker is carried out five months after administering the treatment. In some embodiments, the measuring of the at least one neuroinflammatory biomarker is carried out six months after administering the treatment. In some embodiments, the measuring of the at least one neuroinflammatory biomarker is carried out seven months after administering the treatment. In some embodiments, the measuring of the at least one neuroinflammatory biomarker is carried out eight months after administering the treatment. In some embodiments, the measuring of the at least one neuroinflammatory biomarker is carried out nine months after administering the treatment. In some embodiments, the measuring of the at least one neuroinflammatory biomarker is carried out ten months after administering the treatment. In some embodiments, the measuring of the at least one neuroinflammatory biomarker is carried out eleven months after administering the treatment. In some embodiments, the measuring of the at least one neuroinflammatory biomarker is carried out twelve months after administering the treatment.[000110] Following measurement of the at least one neuroinflammatory biomarker after administering the treatment, one or more additional levels of the at least one neuroinflammatory biomarker may be determined (e.g., measuring the level of at least one neuroinflammatory biomarker a first time, a second time, etc.). Additional levels of the at least one neuroinflammatory biomarker may then be compared to the baseline level of the atleast one neuroinflammatory biomarker to determine any changes (i.e., whether the level is elevated or reduced compared to the baseline level). In some embodiments, the additional level of the at least one neuroinflammatory biomarker is elevated compared to the baseline level of the at least one neuroinflammatory biomarker. In some embodiments, the additional level of the at least one neuroinflammatory biomarker is reduced compared to the baseline level of the at least one neuroinflammatory biomarker. In some embodiments, the baseline level of the at least one neuroinflammatory biomarker is comparable to the additional level of the at least one neuroinflammatory biomarker.[000111] In some embodiments, the measurement from the first time is compared to a subsequent measurement. In some embodiments, the measurement from the first time and the measurement from the second time are compared. In some embodiments, the measurement from the first time and the measurement from the third time are compared. In some embodiments, the measurement from the first time and the measurement from the fourth time are compared. In some embodiments, the measurement from the first time and the measurement from the fifth time are compared. In some embodiments, the measurement from the first time and the measurement from the sixth time are compared.[000112] In some embodiments, the MS treatment is an anti-CD3 antibody.[000113] In some embodiments, the MS treatment is administered if the baseline level of the at least one neuroinflammatory biomarker is elevated (e.g., elevated by about 0.5-fold, about 1.0-fold, about 1.5-fold, about 2.0-fold, about 2.5-fold, about 3.0-fold, about 3.5-fold, about 4.0-fold, about 4.5-fold, about 5.0-fold, about 5.5-fold, about 6.0-fold, about 6.5-fold, about 7.0-fold, about 7.5-fold, or about 8.0-fold) compared to a previous measurement. In some MS treatment is administered if the baseline level of the at least one neuroinflammatory biomarker is reduced (e.g., reduced by about 0.5-fold, about 1.0-fold, about 1.5-fold, about 2.0-fold, about 2.5-fold, about 3.0-fold, about 3.5-fold, about 4.0-fold, about 4.5-fold, about 5.0-fold, about 5.5-fold, about 6.0-fold, about 6.5-fold, about 7.0-fold, about 7.5-fold, or about 8.0-fold) compared to a previous measurement.[000114] As described above, the present disclosure provides novel biomarkers for identifying and / or diagnosing MS in a subject. In some embodiments, the biomarkers can be used to determine the effectiveness of a therapeutic agent for treating MS in a subject. For example, in some embodiments, the therapeutic agent may be an anti-CD3 antibody described herein.[000115] In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker from baseline level. In some embodiments, the MS treatmentis an anti-CD3 antibody. In some embodiments, the MS treatment is not an anti-CD3 antibody. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker. In some embodiments, the increase of the at least one neuroinflammatory biomarker is relative to the baseline level. In some embodiments, the at least one neuroinflammatory biomarker is measured in a sample. In some embodiments, the sample is serum, PBMC, or CSF. In some embodiments, administering the MS treatment increases the biomarker levels in serum. In some embodiments, administering the MS treatment increases the biomarker levels in PBMC. In some embodiments, administering the MS treatment increases the biomarker levels in CSF. For instance, in some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker (e.g., a biomarker measured in serum, PBMC, and / or CSF) levels by about O.l-fold, about 0.2-fold, about 0.3-fold, about 0.4-fold, about 0.5-fold, about 0.6-fold, about 0.7-fold, about 0.8-fold, about 0.9-fold, about l.O-fold, about 1.1-fold, about 1.2-fold, about 1.3-fold, about 1.4-fold, about 1.5-fold, about 1.6-fold, about 1.7-fold, about 1.8-fold, about 1.9-fold, or about 2.0-fold compared to a baseline level. In some embodiments, administering the anti-CD3 antibody increases the at least one neuroinflammatory biomarker levels by about O.l-fold. In some embodiments, administering MS treatment increases the at least one neuroinflammatory biomarker levels by about 0.2-fold. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 0.3-fold. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 0.4-fold. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 0.5-fold. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 0.6-fold. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 0.7-fold. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 0.8-fold. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 0.9-fold. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about l.O-fold. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 1.1-fold. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 1.2-fold. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 1.3-fold. In someembodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 1.4-fold. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 1.5-fold. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 1.6-fold. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 1.7-fold. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 1.8-fold. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 1.9-fold. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 2.0-fold.[000116] In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels (e.g., a biomarker measured in serum, PBMC, and / or CSF) by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 150%, about 200%, about 250%, about 300%, about 350%, about 400%, about 450%, about 500%, about 550%, about 600%, about 650%, about 700%, about 750%, or about 800% compared to a baseline level. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 1%. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 2%. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 3%. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 4%. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 5%. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 6%. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 7%. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 8%. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 9%. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 10%.In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 15%. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 20%. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 25%. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 30%. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 35%. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 40%. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 45%. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 50%. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 55%. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 60%. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 65%. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 70%. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 75%. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 80%. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 85%. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 90%. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 95%. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 100%. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 150%. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 200%. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 250%. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 300%. In some embodiments, administering the MS treatment increases the at least oneneuroinflammatory biomarker levels by about 350%. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 400%. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 450%. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 500%. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 550%. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 600%. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 650%. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 700%. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 750%. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels by about 800%.[000117] In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels after 1 month. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels after 1.5 months. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels after 2 months. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels after 2.5 months. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels after 3 months. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels after 3.5 months. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels after 4 months. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels after 4.5 months. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels after 5 months. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels after 5.5 months. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels after 6 months. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels after 6.5 months. In some embodiments, administering the MS treatment increases the at least oneneuroinflammatory biomarker levels after 7 months. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels after 7.5 months. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels after 8 months. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels after 8.5 months. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels after 9 months. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels after 9.5 months. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels after 10 months. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels after 10.5 months. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels after 11 months. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels after 11.5 months. In some embodiments, administering the MS treatment increases the at least one neuroinflammatory biomarker levels after 12 months.[000118] In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker. In some embodiments, the MS treatment is an anti-CD3 antibody. In some embodiments, the MS treatment is not an anti-CD3 antibody. In some embodiment, the MS treatment decreases the at least one neuroinflammatory biomarker. In some embodiments, the decrease of the at least one neuroinflammatory biomarker is relative to the baseline level. In some embodiments, the at least one neuroinflammatory biomarker is measured in a sample from the subject. In some embodiments, the sample is PBMC or CSF. In some embodiments, administering the MS treatment decreases the biomarker levels in PBMC. In some embodiments, administering the MS treatment decreases the biomarker levels in CSF. For instance, in some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker (e.g., a biomarker in PBMC and / or CSF) levels by about 0.1-fold, about 0.2-fold, about 0.3-fold, about 0.4-fold, about 0.5-fold, about 0.6-fold, about 0.7-fold, about 0.8-fold, about 0.9-fold, about 1.0-fold, about 1.1-fold, about 1.2-fold, about 1.3-fold, about 1.4-fold, about 1.5-fold, about 1.6-fold, about 1.7-fold, about 1.8-fold, about 1.9-fold, or about 2.0-fold compared to a baseline level. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels by about 0.1-fold. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels by about 0.2-fold. In some embodiments,administering the MS treatment decreases the at least one neuroinflammatory biomarker levels by about 0.3-fold. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels by about 0.4-fold. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels by about 0.5-fold. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels by about 0.6-fold. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels by about 0.7-fold. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels by about 0.8-fold. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels by about 0.9-fold. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels by about l.O-fold. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels by about 1.1-fold. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels by about 1.2-fold. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels by about 1.3-fold. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels by about 1.4-fold. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels by about 1.5-fold. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels by about 1.6-fold. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels by about 1.7-fold. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels by about 1.8-fold. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels by about 1.9-fold. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels by about 2.0-fold.[000119] In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels (e.g., a biomarker measured in serum, PBMC, and / or CSF) by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 150%, about 200%, about 250%, about 300%, about 350%, about 400%, about 450%, about 500%, about 550%, about600%, about 650%, about 700%, about 750%, or about 800% compared to a baseline level. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels by about 1%. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels by about 2%. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels by about 3%. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels by about 4%. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels by about 5%. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels by about 6%. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels by about 7%. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels by about 8%. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels by about 9%. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels by about 10%. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels by about 15%. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels by about 20%. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels by about 25%. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels by about 30%. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels by about 35%. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels by about 40%. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels by about 45%. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels by about 50%. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels by about 55%. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels by about 60%. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels by about 65%. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels by about 70%.In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels by about 75%. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels by about 80%. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels by about 85%. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels by about 90%. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels by about 95%. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels by about 100%.[000120] In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels after 1 month. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels after 1.5 months. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels after 2 months. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels after 2.5 months. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels after 3 months. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels after 3.5 months. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels after 4 months. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels after 4.5 months. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels after 5 months. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels after 5.5 months. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels after 6 months. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels after 6.5 months. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels after 7 months. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels after 7.5 months. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels after 8 months. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels after 8.5 months. In some embodiments, administering the MS treatment decreases the at least oneneuroinflammatory biomarker levels after 9 months. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels after 9.5 months. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels after 10 months. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels after 10.5 months. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels after 11 months. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels after 11.5 months. In some embodiments, administering the MS treatment decreases the at least one neuroinflammatory biomarker levels after 12 months.[000121] In some embodiments, administering the MS treatment decreases levels of IL-7, CCL2, and / or VEGFa in serum relative to baseline. In some embodiments, administering the MS treatment decreases biomarker levels of CXCL12 and / or TNFSF10 in serum relative to baseline. In some embodiments, administering the MS treatment decreases biomarker levels of B2M and / or STAT1 in PBMC relative to baseline.[000122] In some embodiments, administering the MS treatment increases biomarker levels of CCL8 and / or TNF in CSF relative to baseline. In some embodiments, the MS treatment increases biomarker levels of TGFB1 in PBMC relative to baseline.[000123] Also provided herein are methods to modulate the expression of at least one neuroinflammatory-associated gene in a cell. In some embodiments, the method comprises contacting the cell with an MS treatment. In some embodiments, the at least one neuroinflammatory-associated gene is a biomarker of MS disclosed herein. In some embodiments, the biomarker is measured in a sample. In some embodiments, the sample is serum, PBMC, or CSF. For instance, in some embodiments, the biomarker is measured in serum, CSF, and / or PBMC. In some embodiments, the at least one neuroinflammatory-associated gene comprises L-7, CCL2, FLT3LG, CSF1, VEGFa, B2M, STAT1, TGF-betal, CXCL12, TNFSF10, CCL8, TNF, INF ARI, LY86, COBAI, MEGF10, SORCS1, PTPRC, RGS10, NPTX2, NETO1, FAP, COL8A1, CTSW, C1QA, CFHR1, C1QL1, LAMP1, or SIGLEC14.[000124] In some embodiments, the cell is a PBMC. In some embodiments, the PBMC is a NK cell, a CD 14+ monocyte, a CD 16+ monocyte, a CD4+ central memory cell (Tern), a regulatory T cell (Tregs), a naive B cell, a CD8 effector memory cell (Tern), a conventional dendritic cell (eDC) and / or a central memory CD8 cell (Tcm).[000125] In some embodiments, the cell is an ex vivo cell. In some embodiments, the cell is an isolated cell. In some embodiments, the cell is not a germ cell. In some embodiments, the cell is a somatic cell.[000126] Combination Therapies[000127] In addition to the anti-CD3 antibodies described herein, a subject may also be administered one or more addition therapy for MS. Other known therapies for the treatment of MS include anti-CD20 antibodies and / or corticosteroids. The anti-CD20 antibody administered to a subject for treating MS may include, but is not limited to, Ocrevus, Rituxan, Kesimpta, and / or Truxima. The present disclosure provides methods of treating MS in a subject that was previously treated with an anti-CD20 antibody and / or a corticosteroid. In some embodiments, the subject was treated with the anti-CD20 antibody at least 90 days (e.g., at least 90 days, at least 91 days, at least 92 days, at least 93 days, etc.) before being administered with the anti-CD3 antibody. In some embodiments, the subject was treated with the corticosteroid at least 30 days e.g., at least 30 days, at least 31 days, at least 32 days, at least 33 days, etc.) before being administered with the anti-CD3 antibody.[000128] Non-limiting examples of MS treatments that can be used in the methods and uses of the present disclosure are put forth in Table 1.Table 1 : MS Medications[000129] Any of the MS treatments described in Table 1 may be combined with an anti-CD3 antibody such as Foralumab in the treatment of MS. A person of skill will appreciate that the MS treatments will be administered according to their prescribing information (summarized in Table 1).Kits[000130] In certain embodiments, provided herein are kits for identifying a subject having multiple sclerosis (MS). In some embodiments, provided herein are also kits for monitoring the progression of MS in a subject. In some embodiments, the kit comprises regents necessary for RNA sequencing of the genes IL-7, CCL2, FLT3LG, CSF1, VEGFa, B2M, STAT1, TGF-betal, CXCL12, TNFSF10, CCL8, TNF, INF ARI, LY86, COBAI, MEGF10,S0RCS1, PTPRC, RGS10, NPTX2, NETO1, FAP, COL8A1, CTSW, C1QA, CFHR1, C1QL1, LAMP1, or SIGLEC14, or any combination of subgroup thereof.[000131] The kits may comprise primers for the gene signature set,, optionally a housekeeping gene panel for TREx and NanoString assays, primers for housekeeping genes for qPCR assays and a control probe. A person skilled in the art can reasonably determine an appropriate housekeeping gene panel for the kit. Furthermore, a person skilled in the art can reasonably determine an appropriate assay in addition to those described herein.[000132] In some embodiments, the kit comprises reagents necessary for detecting levels of the proteins IL-7, CCL2, FLT3LG, CSF1, VEGFa, B2M, STAT1, TGF-betal, CXCL12, TNFSF10, CCL8, TNF, INF ARI, LY86, COB Al, MEGF10, SORCS1, PTPRC, RGS10, NPTX2, NETO1, FAP, COL8A1, CTSW, C1QA, CFHR1, C1QL1, LAMP1, or SIGLEC14, or any combination of subgroup thereof. Protein levels may be determined using conventional methods well known in the art, including but not limited to enzyme-linked immunosorbent assay (ELISA), Olink analysis, SIMOA analysis, and Western blot.[000133] A kit may further comprise one or more RNA extraction reagents and / or reagents for cDNA synthesis. In other embodiments, the kit can comprise one or more containers into which the biological agents are placed and, preferably, suitably aliquoted. The kit may also contain printed instructions for use of the kit materials.[000134] The components of the kits may be packaged either in aqueous media or in lyophilized form. The kits may also comprise one or more pharmaceutically acceptable excipients, diluents, and / or carriers. Non-limiting examples of pharmaceutically acceptable excipients, diluents, and / or carriers including RNAase-free water, distilled water, buffered water, physiological saline, PBS, reaction buffers, labeling buffers, washing buffers, and hybridization buffers.[000135] The kits of the disclosure can take on a variety of forms. Typically, a kit will include reagents suitable for determining gene set expression levels (e.g., those disclosed herein) in a sample. Optionally, the kits may contain one or more control samples. In addition, the kits, in some cases, may include written information providing a reference (e.g., predetermined values), wherein a comparison between the gene expression levels in the subject and the reference (predetermined values) is indicative of a clinical status.EXAMPLESExample 1: Nasal Foralumab Treatment of PIRA Induces Regulatory Immunity, Dampens Microglial Activation and Stabilizes Clinical Progression in Non-active Secondary Progressive Multiple Sclerosis (MS)[000136] An open-label clinical study for using nasal anti-CD3 antibody Foralumab in subjects with non-active secondary progressive MS (naSPMS) was conducted.[000137] Ten patients with naSPMS that continued to progress on B cell therapy were treated with Foralumab for a minimum of six months. Safety monitoring included otolaryngology evaluation and neurologic assessments including Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite (MSFC-4), Modified Fatigue Impact Scale (MFIS), California Verbal Learning Test (CVLT-II), and Low-Contrast Visual Acuity (LCVA). Magnetic resonance imaging (MRI) and microglial translocator protein (TSPO)-positron emission tomography (PET) imaging with [F-18]PBR06 were conducted. Serum and cerebrospinal fluid (CSF) proteomic biomarkers and single cell RNA sequencing of blood was performed to evaluate Foralumab-induced immunomodulation. The endpoints of the study were safety, clinical effects, microglial signal, and immune measures.[000138] Methods:[000139] Patient eligibility[000140] Patients with naSPMS and defined by the absence of relapses or new MRI lesions in the past two years were included in this study. Patients were referred by their primary neurologist, and included if they met eligibility criteria.[000141] Key inclusion criteria: 1) confirmed diagnosis of MS and MRI consistent with a diagnosis of MS; 2) age 25-70; 3) failed standard of care treatment and continued to decline clinically for at least 6 months.[000142] Key exclusion criteria: 1) corticosteroid treatment in the past 30 days; 2) treatment with Ocrevus, Rituxan, Kesimpta or Truxima in the past 90 days; 3) inability to tolerate nasally administered medications.[000143] Additionally, patients were required to be high or medium affinity TSPO-binders evaluated by DNA polymorphism testing. All patients provided informed consent. The protocol was approved by the Institutional Review Board (IRB). Investigational New Drug Application (IND) approval was obtained for use of Foralumab in naSPMS in an expanded access program. Patient 1 (EA1) initiated treatment in May 2021, and following demonstration of safety and efficacy as defined by decreased microglial TSPO-PET signal,additional INDs were approved for EA2, and then EA3-6, followed by EA7-11 (IND 161148).[000144] Foralumab administration[000145] Foralumab was administered three times a week (typically, Monday, Wednesday, and Friday) at a total dose of 50pg per day (25pg / 100pL to each nostril) for two weeks, followed by a one week drug holiday. This three-week cycle was repeated for up to six months in some patients and longer in other patients who wished to continue treatment and with the recommendation of their primary treating neurologist. The dose of 50pg was based on studies in healthy volunteers, and the dosing regimen was based on immune responses observed in animal preclinical studies.[000146] Clinical visits[000147] Clinical visits took place every three weeks with a physical examination, neurological examination and monitoring bloodwork. Multiple Sclerosis Functional Composite (MSFC-4), Modified Fatigue Impact Scale (MFIS) and California Verbal Learning Test (CVLT-II) were administered every three weeks. A short Quality of Life in Neurological Disorders (NeuroQoL) questionnaire was administered at baseline and every three months.[000148] Nasal questionnaire and nasal examination[000149] Nasal examinations with nasal endoscope by a board-certified ear, nose, and throat (ENT) physician were conducted at baseline and every three months at minimum. The Nasal Symptoms Questionnaire (NSQ) was administered every three weeks at the first visit of the cycle both prior to dosing and following dosing and once during the rest week.[000150] Anti-drug antibody assay[000151] Anti-drug antibody (ADA) assay was conducted in samples from EA1 and EA2 (baseline, three months, four to five months, nine months, 12 months and 15-17 months, as well as in EA3-6 (baseline, three months and six months). An electrochemiluminescence (ECL) immunoassay method was developed and validated for the detection (screening, confirmation, and titration) of anti -Foralumab antibodies (AD As) in human serum samples. The screening portion of the method was used to detect potentially positive anti-drug antibodies to Foralumab in human serum. The confirmation assay was used to determine if potentially positive samples were specific to Foralumab. The titration assay provided a quasi -quantitative estimate of ADA in the positive human serum samples.[000152] PET scan[000153] Participants were genotyped for a polymorphism within the TSPO gene on chromosome 22ql3.2 using a Taqman assay. Only high and medium affinity binders were included in the study.[000154] [F-18]PBR06 was produced in a PET radiochemistry facility according to standardized procedures. [F-18]PBR06 was injected as a bolus via an intravenous (IV) catheter in an upper extremity vein; images were acquired in a list acquisition mode using a high-resolution, whole-body PET / CT scanner. Summed PET SUV images based on data acquired between 60 and 90 minutes after tracer injection were co-registered to each individual patient's T1 MRI (the spin-echo or MPRAGE) scans using the PMOD 3.8 / 3.9 platform. This standardized algorithm involved co-regi strati on of the T1 -weighted series and PET images of each patient with the Automated Anatomical Template. 60-90-minute SUV images for EA1 were initially evaluated visually. Subsequently, z-score-based approaches were used for parametric image generation to evaluate regional changes in the brain.Individualized parametric 3 -dimensional z-score maps of brain parenchymal TSPO-PET were generated by voxel -by-voxel statistical comparison between each subject's normalized PET images and a HC dataset. Given that the initial SUV-based evaluation showed a global decrease in [F-18]PBR06 uptake in the brain following nasal Foralumab at three months in the index case, global normalization was not considered to be an appropriate approach to detect treatment effects of nasal Foralumab. For initial alternate analysis and as a proof of concept, normalization was performed using a white matter pseudoreference region based on PET voxels showing the lowest quartile of 60-90-minute SUVs in the index-case (GALP 2.0 or p-GALP approach) and the z-score images hence generated were used for initial visual interpretation.[000155] Subsequently, for additional unbiased analyses, normalization was performed against a modified pseudo reference region based on white matter voxels showing no significant differences between MS patients and healthy controls in historical cross-sectional cohort, similar to approaches adopted by other investigators for other PET tracers (GALP 3.0 or m-GALP approach). Global, cortical, white matter, thalamic and cerebellar regions of interest (ROIs) were defined in the atlas space and average z-scores from images generated using the above approaches (referred to as GALP2.0 (or p-GALP) and GALP 3.0 (or m-GALP) approach) were extracted in these ROIs using PMOD.29 Global ROI represented a composite region comprising of the cortical, white matter, thalamic and cerebellar ROIs.[000156] 3 T MRI acquisition and analysis[000157] All subjects underwent brain and spinal cord MRI scans on the same scanner using the same acquisition protocol. Whole-brain images were acquired at high-resolution (voxel sizes 1 mm3) with 3D magnetization-prepared rapid gradient-echo (MPRAGE), 3D T2-weighted, and 3D T2 fluid-attenuated inversion recovery (FLAIR) sequences as previously reported. Cervical and thoracic spinal imaging was obtained with sagittal T1 spinecho, T2 spin-echo, short tau inversion recovery (STIR), and post-contrast sagittal and axial T1 spin-echo sequences. Within 6 months prior to the start of Foralumab, patients underwent MRI of the brain, cervical and thoracic spine with administration of intravenous gadolinium contrast to confirm the absence of new / enlarging T2 or gadolinium-enhancing lesions prior to enrollment. Brain MRI was performed at approximately 3 months after treatment start, and complete brain, cervical and thoracic spine MRI was obtained at approximately six months. For these three- and six-month follow-up scans, gadolinium was not administered. MRI scans were evaluated by an expert for the presence of new or enlarging T2 lesions.[000158] Lumbar puncture[000159] A lumbar puncture for clinical purposes was conducted in Subjects 3 through 11 (EA3-EA11) at baseline and 6 months. Cerebrospinal fluid was evaluated for cell count, oligoclonal bands and viral testing.[000160] Statistical methods[000161] To estimate the change after treatment in the EDSS, MSFC-4, MFIS, and NeuroQoL, the change over the subsequent six- and twelve-month periods, were calculated for each outcome for subjects with complete data, and a Wilcoxon signed rank test was used to calculate the p-value for the null hypothesis of no change over time. When proportions were calculated, 95% confidence intervals were based on the exact binomial distribution.[000162] Proteomic analyses[000163] Olink analysis: A 48-Plex by Olink® using Proximity Extension Assay (PEA) technology was conducted in the serum and CSF. Changes in proteins across different timepoints were compared using a linear mixed effect model (random intercepts) adjusting for plate using the nlme library in R. All comparisons were adjusted for multiple testing using the Holm's method.[000164] SIMOA analysis: sNFL and GFAP by Quanterix™ using the SIMOA assay.[000165] Single cell RNA sequencing (scRNAseq)[000166] RNA sequencing: Peripheral blood mononuclear cells (PBMCs) from EA3-6 at baseline, three, and six months were processed for scRNAseq. PBMCs were thawed and processed into single cell suspensions using established methods. Initial cell viabilitymeasurements from all vials were greater than 90%. Cell suspensions were loaded onto a Chromium Single Cell 3' Chip and processed into Illumina-compatible libraries using the Chromium Single Cell 3' dual index kit according to the manufacturer's protocol. Sequencing was performed on a NovaSeq 6000 platform. Raw data was processed using cell ranger v6.0 and input into R / Seurat (v5.0.1) for downstream analysis.[000167] Whole genome sequencing and Demultiplexing: DNA corresponding to PBMCs from each of the four individual patients was extracted using the Qiagen DNeasy Blood & Tissue Kit. Extracted gDNA was converted into sequencing libraries using the NEBNext Ultra II FS DNA Library Prep Kit. Libraries were sequenced on a NovaSeq 6000 platform. Germline variants were called from raw sequencing data using the Sarek workflow following GATK best practice guidelines. A "cohort" GVCF file was generated for use in demultiplexing the pooled scRNAseq data.[000168] scRNAseq data analysis: Using Seurat, genes were filtered for only those which were present in three or more cells, and cells were filtered for those which had at least 200 genes and <10% of reads mapping to mitochondrial genes. Data were then normalized and scaled, before integration using the Harmony method. Genetic demultiplexing was performed using souporcell; any cells not mapping to a subject or which mapped to multiple subjects were removed. Cell type assignments were called using Azimuth utilizing a PBMC reference. Differential expression analysis was limited to genes which have 100 reads or more. Using AggregateExpression and FindMarkers functions with the DESeq2 method, comparisons were run of overall expression, and expression by cell type comparing the three- and six-month time points back to the baseline expression levels. The DEG lists were then used to perform GSEA using the MSigDB Hallmark gene set and fgsea in R.[000169] Results:[000170] Baseline characteristics of subjects are shown in FIG. 1. There was one screen failure due to nasal exam findings that precluded sufficient drug delivery.[000171] Treatment periods[000172] Patient 1 was treated over 1.8 years with breaks, then discontinued due to an unrelated medical issue that made the subject ineligible. Patients 2, 7, 8, and 9 were treated continuously for over a year and are ongoing. Patients 3-6 were treated for six months, after which patients 3, 4, and 5 had a treatment hiatus for approximately three months, then resumed and are ongoing. Patient 6 discontinued after six months due to pseudorelapses without MRI evidence of new lesions and environmental allergies. Patient 10 was treated for nine months, then discontinued after a fall at month eight resulting in a quadriceps tear.[000173] Adverse events (AEs)[000174] There were 206 treatment emergent adverse events (TEAEs) (FIG. 2) of which 34 were treatment related (TRAEs) (FIG. 3). Adverse events were reported by the patient or through an exam or laboratory finding. There was one episode of tingling and numbness in the lips and tongue which was deemed related to treatment, and this patient was treated with cetirizine prior to dosing which alleviated this symptom. After 11 cycles, cetirizine-pre-treatment was suspended, and the patient continued treatment without further incidents. Two patients discontinued treatment, one due to an orthopedic tear which was unrelated to the drug, and the other due to pseudorelapses and environmental allergies, which were unrelated to treatment. Both resumed B-cell therapy. No treatment-related severe adverse events (SAEs) were reported. Two patients were hospitalized for COVID in 2022; both had uneventful recoveries There were no deaths during the clinical study period.[000175] 3TMRI[000176] Standardized non-contrast 3T MRls of the brain and spine on the same Siemens scanner were conducted at baseline and every three months. None of the patients demonstrated any new T2 lesions over the treatment period.[000177] EDSS[000178] Because all patients completed six months of continuous dosing, we first evaluated EDSS changes at the six-month timepoint (FIG. 1). All patients stabilized, and three out of 10 improved in their EDSS scores. One of 10 improved using a more stringent definition of EDSS improvement (EDSS-5.5, improvement of 1.0; EDSS >5.5, improvement of 0.5). In four patients continuously treated for 12-months, three had improvements in EDSS, and the fourth had no change (FIG. 1).[000179] MSFC-4[000180] MSFC-4 was conducted every three weeks. MSFC-4 scores are tabulated in FIG.4. At six months of Foralumab treatment, there was no overall change in the Timed 25-Foot Walk (T25FW) or Nine Hole Peg Test (9-HPT) in the dominant and non-dominant hand. The SDMT improved by >3 points in nine out of 10 patients, likely due to practice effect.Interestingly, there was significant improvement (p = 0.049) in binocular LCLA, with four out of 9 patients having an improvement of >8 points. (FIG. 4).[000181] MFIS and NeuroQoL[000182] MFIS questionnaires were conducted every three weeks. The mean change from baseline to 6 months in the MFIS total score and subscores in FIG. 5A, demonstrating trends in score reductions. A four-point change in MFIS has been determined to be clinicallysignificant. Six out of 10 patients demonstrated a reduction in total MFIS of four points or more over the six-month period. Of the four patients with continuous dosing over a 12-month period, 100% experienced a >4 point reduction in total MFIS at 12 months compared to baseline (FIG. 5B). A short NeuroQoL questionnaire was administered every three months. There was no significant change in the subscores from baseline to six months (FIG. 6).[000183] TSPO-PET[000184] Widespread increased radiotracer uptake was observed in the brain of the index case (Subject 1; EA 1) on evaluation of the baseline standardized uptake value (SUV) image. Following treatment, there was a marked reduction in [F-18]PBR06 uptake throughout the brain at three months (FIG. 7A). Similar reductions were seen in other subjects after 3 and 6 months (FIG. 7B). Individualized evaluation of abnormal z-score maps revealed widespread abnormal voxels in subjects prior to treatment that decreased with treatment (FIGs. 7B and 7C).[000185] Quantitative group analysis after three months of treatment demonstrated a reduction in average PET mGALP score in the white matter ROI (0.40 + / - 0.09 versus 0.47 + / - 0.09, -14.9%, effect size 0.875, p=0.055) and the global ROI (0.31+ / -0.23 versus 0.42 + / -0.36, -26.2%, effect size 0.78, p=0.016) (FIG. 8 and FIGs. 9A-9B). Quantitative analysis at the time of the last PET scan on treatment (average duration 7.5 months) demonstrated a reduction in white matter (0.38+ / -0.09 versus 0.47+ / -0.09, -19.1%, effect size 0.89, p=0.047, respectively, n=7) and global (0.26+ / -0.24 versus 0.42+ / -0.36, -38.1%, effect size 0.73, p=0.11, n=7) ROIs (FIG. 8 and FIGs. 9A-9B). Changes in PET mGALP score at the 6-month timepoint as compared to baseline are depicted in FIG. 10.[000186] Nasal Foralumab was associated with a major reduction of fatigue in most patients treated (FIG. 6). Thus, the relationship between MFIS scores and microglial PET signal was analyzed. The analysis was focused on the hippocampus and the substantia nigra, as functional and neuroinflammatory changes in these regions have been associated with fatigue in MS. Total MFIS scores correlated strongly with mGALP scores in the hippocampus (r=0.89, p=0.007) at baseline (FIG. 11). Among the subjects with total MFIS>30 or cognitive MFIS>10 (n=5), there was a significant reduction in PET mGALP scores in the hippocampus (FIG. 12A) and substantia nigra (FIG. 12B) following nasal Foralumab treatment (p<0.05).[000187] After observing a decrease in the global and white matter PET signal after treatment, whether the PET signal specifically associated with perilesional white matter lesions also changed with treatment was evaluated. As shown in FIGs. 13A and 13B, PETimaging showed rim (FIG. 13A) or a combination of rim and core (FIG. 13B) lesions before treatment with Foralumab. Following 6 months or 3 months of Foralumab treatment, there was a clear reduction in perilesional PET signal in individual subjects.[000188] Patient 1 (EA1), the first subject treated, had the longest microglia PET follow up, including scans performed at baseline and at 3, 9, 20 and 30 months from the time of treatment initiation. At 20 months, EA1 received intermittent treatment. At 30 months, the subject was off treatment for 8 months. Such treatment schedule allowed evaluating the microglial PET signal while on treatment, while receiving only intermittent treatment, and when the subject was off treatment for 8 months. As shown in FIGs. 14A-14C, there was a reduction of PET signal while on treatment with an increase back to baseline after stopping treatment.[000189] Blood biomarkers[000190] Cytokines and inflammatory markers in the serum were assayed using the Olink proximity extension assay platform (48-plex) at baseline (T 1 ), three months (T3) and six months (T6). Foralumab treatment resulted in a reduction in interleukin-7 (IL-7), C-C Motif Chemokine Ligand 2 (CCL2), FLT3LG, Colony stimulating factor 1 (CSF1) and Vascular Endothelial Growth Factor A (VEGFa) (p<0.05) over the six-month period (FIG. 15).FLT3LG levels in the serum were also reduced over the six-month period. Serum Neurofilament light protein (NfL) and Glial Fibrillary Acidic Protein (GFAP) SIMOA assay were measured over the same three timepoints and no changes were found in these two biomarkers.[000191] Anti-drug antibodies[000192] Anti-drug antibodies (AD As) were evaluated in serum samples from EA1 and EA2 (baseline, three months, four-five months, nine months, 12 months and 15-17 months), as well as EA3-6 (baseline, three, and six months). No AD As were found in any samples.[000193] CSF[000194] Lumbar punctures (LPs) were conducted at baseline and six months in six patients. Two patients had only one LP due to access issues. Total nucleated cell number ranged between 0-6 for all LPs. There was no significant change in the number of oligoclonal bands at 6 months compared to baseline (FIG. 16A). Olink 48-plex cytokine analysis in the CSF of foralumab-treated patients at baseline (Tl) and six months (T2) showed a trend in reduction of Stromal Cell-Derived Factor-12 (CXCL12) and Tumor Necrosis Factor Superfamily Member 10 (TNFSF10), and a trend in increase of C-C motif chemokine ligand 8 (CCL8) and Tumor Necrosis Factor (TNF) (FIG. 16B).[000195] scRNAseq[000196] scRNAseq of PBMC samples at baseline, three and six months in four subjects showed changes in overall gene expression at the three-month timepoint and sustained at six months (FIG. 17). Only those genes which have an absolute average log2 fold-change greater than 2 and a Bonferroni adjusted p-value < 0.001 in at least one cell type were included.[000197] Gene expression was significantly altered in the following cell subsets: NK cells, CD14+ monocytes, CD16+ monocytes, CD4+ central memory cells (Tern), regulatory T cells (Tregs), naive B cells, CD8 effector memory cells (Tern), conventional dendritic cells (eDCs) and central memory CD8 cells (Tcm) as shown by heatmap of differential gene expression in cell subsets with the most significant changes at three and six months compared to baseline (FIG. 18). Genes which were differentially expressed at six months also contributed to pathway differences, which varied by cell type, but included a robust decrease in interferonalpha pathways (FIG. 19). Three key differentially expressed genes were identified in these six cell subtypes, representing critical pathways involved in MS pathogenesis: Beta-2 microglobulin (B2M) which associates with MHC class I molecules was decreased at three and six months in all six cell types (FIGs. 20A-20C); Signal Transducer and Activator of Transcription 1 (STAT1) was reduced in naive B cells, CD4 Tcm and CD8 Tern, and Foxp3+ Tregs at three months, and Tregs at six months compared to baseline; and Transforming Growth Factor-beta 1 (TGFB1) was increased in CD14+ monocytes, CD16+ monocytes, naive B cells, CD4 Tcm and CD8 Tern.[000198] Discussion:[000199] In this study, 10 naSPMS patients were treated with nasal Foralumab in this expanded access program for at least six months, and one for 1.8 years. All patients stabilized in terms of their EDSS scores, and three out of four patients treated for 12 months continuously demonstrated improvement on their EDSS. Six out of ten patients demonstrated an improvement in fatigue scoring on the MFIS scale. There were no treatment-related SAEs or severe AEs. There was a significant reduction in white matter PET TSPO signal over six months, as well as a significant increase in TGF-beta expressing T cells in circulation, consistent with effects seen in previous EAE studies of anti-CD3.[000200] 9 of the 10 patients were previously treated with B cell depleting therapy and were worsening despite therapy. After starting nasal Foralumab, the EDSS score stabilized in all patients, and none worsened over the six-month period, with some patients experiencing an improvement in EDSS after longer-term treatment.[000201] A four-point reduction in the total MFIS score is clinically significant. Fatigue measured by the MFIS score improved by at least four points in 6 out of 10 patients at six months. Fatigue is found to correlate with PIRA, suggesting similar biological mechanisms. A previous study found fatigue to be correlated with the TSPO signal in the multiple brain regions including substantia nigra, and recent analyses suggest that increased microglial activation may mediate the relationship between fatigue and PIRA, and PIRA may be mediated by similar mechanisms, including CNS-centric inflammation. In the present study, a significant reduction in fatigue scores was observed following nasal Foralumab treatment among the subjects who had baseline fatigue, which was accompanied by a reduction in TSPO-PET signal in substantia nigra and hippocampus. This finding has several important implications: 1) nasal Foralumab may have a clinically significant impact on fatigue, a highly disabling symptom, in na-SPMS patients; 2) the effect of nasal Foralumab on fatigue may be mediated by its effects on microglial activation; and 3) this finding provides further longitudinal evidence for a causal relationship between microglial activation and fatigue in MS.[000202] While multiple, cross-sectional studies have shown increased TSPO-PET uptake in progressive MS as compared to relapsing MS, no PET studies have studied treatment effects in an exclusive population of na-SPMS subjects. One study evaluated the effects of natalizumab on a mixed population of relapsing remitting and secondary progressive MS and showed that there was less than 5%, albeit statistically significant reduction, in distribution volume ratio of [C-l 1]PK11195-PET in the treated population, as compared to an increase in the untreated population. In other treatment-related PET studies in RR-MS, fmgolimod and glatiramer acetate resulted in a 3-12% reduction in [C-l 1]PK11195-PET. While the various PET measurement indices across tracers, patient populations, multiple centers and differing methodologies may not be comparable, 15-38% TSPO-PET reduction in a previous study of treatment-refractory, na-SPMS patients following nasal foralumab represented a significant treatment effect.[000203] The present study provides unique human data supporting preclinical findings showing that nasal anti-CD3 decreased microglial activation in animal models of neurologic diseases including progressive MS.[000204] The longitudinal PET data in the index subject (EA1) collected over 30 months showed a progressive increase in PET signal after the subject stopped nasal Foralumab, serving as a within-subject control, and providing additional evidence that the reduction in PET signal during treatment was likely related to the effects of nasal Foralumab.[000205] Overall, the treatment was well-tolerated and there were no treatment-related SAEs or severe adverse events. The majority of TRAEs were nasal or respiratory in nature, and included nasal congestion, runny nose and abnormalities on nasal endoscopy examination. None of the patients discontinued treatment due to nasal symptoms or abnormalities. There was no increase in infections in nasal Foralumab treated patients, some treated as long as a year. In animal studies, nasal anti-CD3 treatment did not interfere with ability of the lung to clear a bacterial infection or interfere with clearance of lung infection in CO VID patients treated with nasal Foralumab.[000206] Nasal Foralumab resulted in changes in key gene expression by single cell RNA sequencing in monocytes and CD8 T cells including a reduction in beta-2 microglobulin (B2M) and an increase in the regulatory molecule TGF-betal (TGFB1) as early as three months post treatment in a variety of cell types including T cells and monocytes, leading to an immunoregulatory, tolerizing environment. These results are consistent with prior studies demonstrating an increase in TGFB1 in healthy controls and patients with COVID-19 treated with nasal Foralumab as well as murine studies with nasal anti-CD3 which resulted in TGFB1 -expressing regulatory T cells within the CNS and suppression of disease in a progressive model of MS. Thus, the induction of TGFB1 by nasal Foralumab in multiple of cell types may be a key mechanism by which it suppresses innate inflammation in the CNS of MS patients as was shown in the murine model. The results of this study show a reduction in STAT1 in CD4 and CDB T cell subsets in response to nasal Foralumab accompanied by a reduction in type I and type II interferons.[000207] In terms of serum proteomic biomarkers, a reduction in CCL2 (MCP-1), which recruits monocytes, dendritic cells and T cells to the sites of inflammation, was observed, consistent with the reduction in microglial TSPO-PET signal in the CNS of treated patients.[000208] In summary, without wishing to be bound by theory, nasal Foralumab in treatment-refractory non-active SPMS patients showed stabilization in EDSS, improvement in fatigue scores and improvement in TSPO-PET imaging. This was accompanied by an increase in TGFB1 in monocytes amongst other immunological changes starting as early as three months after treatment. These results form the basis for an ongoing phase 2a multicenter randomized double-blind study comparing nasal Foralumab to placebo(NCT06292923).Example 2: Nasal Foralumab Downregulates CSF Inflammation and Upregulates CSF Neuroprotective Proteomic Pathways[000209] The aim of this study was to investigate the relationship between [F-18]PBR06-PET and CSF proteomics in non-active secondary progressive multiple sclerosis (na-SPMS) patients with progression independent of relapse activity (PIRA) and evaluate the effects of nasal Foralumab on CSF proteomics in relation to PET changes.[000210] 10 na-SPMS patients (mean age 59.2±8.01 years, 10 females and 3 males, median EDSS 6.25, 5 high (HAB) and 5 medium (MAB) affinity binders) underwent 14 paired evaluations of [F-18]PB06-PET scans and CSF proteomics at baseline and / or followup over a 6 month period during nasal Foralumab treatment. Whole brain, cortical, white matter and cerebellar (Glial Activity Load on PET) m-GALP z-scores were correlated with un-targeted data-independent acquisition (DAI) proteomics in the CSF. 1) Pre- and post-nasal foralumab treatment paired comparisons and 2) Spearman’s correlation analysis between PET and CSF proteomics were performed. p<0.05 was considered statistically significant.[000211] m-GALP PET scores were positively correlated with CSF markers of interferon pathway activation (IFNAR1) and NF-KB pathway activation (LY86) in global, cortical and cerebellar (r=0.943, p=0.005) and white matter (r=0.738, p=0.037) regions among HABs and MABs, respectively. m-GALP PET scores in the global, cortical and cerebellar regions were inversely correlated with CSF COB Al (fibrosis pathway) and MEGF10 (neuroprotective protein, r=-0.943, p=0.005), among HABs. Foralumab treatment led to a reduction in CSF markers of inflammation and fibrosis (IFNAR1, LY86 and COBAI) and an increase in CSF markers of neuroprotection (SORCS1 and MEGF10), concomitant with a reduction in white matter PET signal.[000212] Without wishing to be limited by theory, these results demonstrate that nasal Foralumab reduces inflammatory CSF biomarkers and microglial PET signal and increases CSF markers of neuroprotection. [F-18]PBR06-PET positively correlated with CSF inflammatory proteins and negatively correlated with CSF neuroprotective proteins in na-SPMS with PIRA. These results demonstrate that microglia PET is linked to the biologic processes that drive SPMS, and that CSF proteomics can be used to measure response to therapy in SPMS.Example 3: Integrated Multiomics Profiling Reveals MS-specific Molecular Signatures Linked to Progression and Response to Nasal Foralumab Therapy[000213] The aim of this study was to identify central nervous system (CNS)-related biomarkers in the cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients linked to disease progression and to define the molecular effects of Foralumab in secondary progressive (SP) MS.[000214] Single-cell and proteomic data from peripheral blood mononuclear cell (PBMC) (n = 4) and CSF (n = 23) of MS patients on anti-CD20 therapy or untreated were integrated. Data-independent acquisition (DAI) proteomics was performed in CSF of relapsing-remitting (RR) and SP patients.[000215] CSF proteomic profiling revealed distinct molecular signatures between RR and SP patients. RR samples showed higher levels of immune activation markers (PTPRC, RGS10) and proteins associated with neuronal plasticity and axonal injury (NPTX2, NETO1). In contrast, SP samples were enriched for fibroblast-related proteins involved in tissue injury, fibrosis, and extracellular matrix (ECM) remodeling (FAP, COL8A1), along with elevated cytotoxicity markers (CTSW) and components of the complement cascade.[000216] Foralumab treatment of SP-MS subjects significantly reduced the expression of proteins linked to cytotoxic activity (LAMP1), interferon signaling (IFNAR1), tissue injury / fibrosis (COBAI), and NF-xB-dependent inflammation (SIGLEC14, LY86). Notably, increased TGFB1 expression was observed in both CSF and PBMCs, suggesting a regulatory and immunomodulatory effect of the therapy.[000217] Without wishing to be bound by theory, these results identify biomarkers to distinguish RR-MS and SP-MS patients, and proteins linked to disease progression. These results also demonstrate that nasal Foralumab ameliorates SP-MS by increasing TGFB1 and suppressing T cell cytotoxicity and inflammation.

Claims

CLAIMSWhat is claimed:

1. A method of treating multiple sclerosis (MS) in a subject, the method comprising:a. measuring the baseline level of at least one neuroinflammatory biomarker in the subject, wherein the at least one neuroinflammatory biomarker comprises IL-7, CCL2, FLT3LG, VEGFa, B2M, STAT1, CXCL12, TNFSF10, INF ARI, LY86, COBAI, LAMP1, SIGLEC14, TGF-betal, CCL8, TNF, MEGF10, C1QA, CFHR1, C1QL1, or SORCS1;b. administering an anti-CD3 antibody to the subject,c. measuring the level of the at least one neuroinflammatory biomarker in the subject a second time; andd. administering a second dose of the anti-CD3 antibody to the subject, ifi. the level of TGF-betal, CCL8, TNF, MEGF10, C1QA, CFHR1, and / or SORCS1 is elevated relative to the baseline level; and / orii. the level of IL-7, CCL2, FLT3LG, VEGFa, B2M, STAT1, CXCL12, TNFSF10, INF ARI, LY86, C0BA1, C1QL1, LAMP1, and / or SIGLEC14 is reduced relative to the baseline level.

2. The method of claim 1, wherein if the anti-CD3 antibody is not administered, step (c) comprises monitoring the subject or administering a different therapy.

3. The method of claim 1 or 2, wherein the at least one neuroinflammatory biomarker is measured in the serum, blood or cerebrospinal fluid (CSF) of the subject.

4. The method of claim 3, wherein the at least one neuroinflammatory biomarker measured in the serum comprises IL-7, CCL2, FLT3LG, CSF1, or VEGFa, or any combination thereof.

5. The method of claim 3, wherein the at least one neuroinflammatory biomarker measured in PBMC comprises B2M, STAT1, or TGF-betal, or any combination thereof.

6. The method of claim 3, wherein the at least one neuroinflammatory biomarker measured in CSF comprises CXCL12, TNFSF10, CCL8, TNF, INF ARI, LY86, COB Al, MEGF10, SORCS1, PTPRC, RGS10, NPTX2, NETO1, FAP, COL8A1, CTSW, C1QA, CFHR1, C1QL1, LAMP1, or SIGLEC14, or any combination thereof.

7. The method of any one of claims 1-6, wherein the MS is secondary progressive MS (SPMS).

8. The method of claim 7, wherein the SPMS is a non-active SPMS (na-SPMS).

9. The method of any one of claims 1-8, further comprising administering the anti-CD3 antibody one or more additional times.

10. The method of claim 9, further comprising administering the anti-CD3 antibody continuously.

11. A method of modulating the expression of at least one neuroinflammatory-associated gene in a cell, the method comprising contacting the cell with an anti-CD3 antibody.

12. The method of claim 11, wherein the at least one neuroinflammatory-associated gene comprises IL-7, CCL2, FLT3LG, CSF1, VEGFa, B2M, STAT1, TGF-betal, CXCL12, TNFSF10, CCL8, TNF, INF ARI, LY86, COBAI, MEGF10, SORCS1, PTPRC, RGS10, NPTX2, NETO1, FAP, COL8A1, CTSW, C1QA, CFHR1, C1QL1, LAMP1, or SIGLEC14.

13. The method of claim 11 or 12, wherein the cell is isolated from a subject having multiple sclerosis (MS).

14. The method of any one of claims 11-13, wherein the cell is a peripheral blood mononuclear cell (PBMC).

15. The method of claim 14, wherein the PBMC is a NK cell, a CD14+ monocyte, a CD 16+ monocyte, a CD4+ central memory cell (Tern), a regulatory T cell (Tregs), a naive B cell, a CD8 effector memory cell (Tern), a conventional dendritic cell (eDC) and / or a central memory CD8 cell (Tcm).

16. A method of monitoring progression of multiple sclerosis (MS) in a subject, the method comprising:a. measuring the level of at least one neuroinflammatory biomarker in the subject to determine a baseline level of the at least one neuroinflammatory biomarker, wherein the at least one neuroinflammatory biomarker comprises IL-7, CCL2, FLT3LG, VEGFa, B2M, STAT1, CXCL12, TNFSF10, INF ARI, LY86, COBAI, LAMP1, SIGLEC14, TGF-betal, CCL8, TNF, MEGF10, C1QA, CFHR1, C1QL1, or SORCS1;b. measuring the level of the at least one neuroinflammatory biomarker in the subject a second time; andc. administering an anti-CD3 antibody to the subject, if the level of TGF-betal, CCL8, TNF, MEGF10, C1QA, CFHR1 and / or SORCS1 is increased in step b relative to step a; and / or the level of IL-7, CCL2, FLT3LG, VEGFa, B2M, STAT1, CXCL12, TNFSF10, INF ARI, LY86, COBAI, C1QL1, LAMP1, and / or SIGLEC14 is reduced in step b relative to step a.

17. The method of claim 16, wherein the measuring of step (b) is carried out one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, and / or twelve months after the measuring in step (a).

18. The method of claim 16 or 17, wherein the at least one neuroinflammatory biomarker is measured in serum, blood, or cerebrospinal fluid (CSF).

19. The method of any one of claims 1-18, wherein the anti-CD3 antibody comprises a variable heavy chain (VH) comprising a complementarity determining region (CDR) 1 of SEQ ID NO: 1, a CDR2 of SEQ ID NO: 2 and a CDR3 of SEQ ID NO: 3; and a variable light chain region (VL) comprising a CDR1 of SEQ ID NO: 4, a CDR2 of SEQ ID NO: 5 and a CDR3 of SEQ ID NO: 6.

20. The method of any one of claims 1-19, wherein the anti-CD3 antibody comprises a VH comprising a sequence that is at least 95% identical to the sequence of SEQ ID NO: 7.

21. The method of any one of claims 1-20, wherein the anti-CD3 antibody comprises a VL comprising a sequence that is at least 95% identical to the sequence of SEQ ID NO: 8.

22. The method of any one of claims 1-21, wherein the anti-CD3 antibody comprises a VH comprising the sequence of SEQ ID NO: 7.

23. The method of any one of claims 1-22, wherein the anti-CD3 antibody comprises a VL comprising the sequence of SEQ ID NO: 8.

24. The method of any one of claims 1-23, wherein the anti-CD3 antibody is administered intranasally.

25. The method of any one of claims 1-24, wherein the anti-CD3 antibody is administered at a dose of 50 pg.

26. The method of any one of claims 1-24, wherein the anti-CD3 antibody is administered at a dose of 100 pg.

27. The method of any one of claims 1-26, wherein the dose is administered in a single nostril.

28. The method of any one of claims 1-26, wherein the dose is administered split between both nostrils.

29. The method of any one of claims 1-28, wherein the anti-CD3 antibody is administered once a day.

30. The method of any one of claims 1-29, wherein the anti-CD3 antibody is administered three times a week.

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