Compositions and methods for treating multiple system atrophy (MSA)

Abstract

The present invention relates to methods of treating early multiple system atrophy (MSA) or MSA-C using an anti-alpha synuclein antibody, such as alemtuzumab.

Description

Technical Field

[0001] This invention relates to the clinical use of antibodies that bind to human α-synuclein for the treatment of synucleinosis or precursor synucleinosis.

[0002] References to sequence lists

[0003] This application includes one or more sequence lists disclosed in a computer-readable medium (filename: "1294-WO-PCT Seq list ST26.xml", created on February 21, 2025, and 58 KB in size), which is incorporated herein by reference in its entirety. Background Technology

[0004] Synucleinopathies are neuronal inclusions characterized by pathological α-synuclein aggregates called Lewy bodies. Synucleinopathies include Parkinson's disease (PD) (including idiopathic and hereditary forms of Parkinson's disease) and diffuse Lewy body (DLB) diseases (also known as Lewy body dementia (DLB), Lewy body variant of Alzheimer's disease (LBV), combined Alzheimer's and Parkinson's disease (CAPD), isolated autonomic failure (PAF), and multiple system atrophy (MSA; e.g., oligopontine atrophy, striatal substantia nigra, and Shy-Drager syndrome)).

[0005] Alpha synuclein is commonly associated with synapses and is thought to play a role in regulating synaptic vesicle release, thereby affecting neural communication, plasticity, learning, and memory. Synuminopathy states have been extensively demonstrated to be associated with alpha synuclein aggregates; however, the exact pathological types of alpha synuclein remain unknown. Various types of misfolded / aggregated / secreted synuclein, ranging from oligomers to fibrils, and different post-translational modifications have been associated with toxicity, but there is no consensus on which is most important (or whether there is even a single type of toxicity).

[0006] The antibodies disclosed in WO 2017 / 009312 bind to a variety of α-synuclein proteins, including all known major types formed through selective splicing or post-translational modifications (such as truncation), as well as oligomeric and fibrillary forms. Such antibodies are considered useful for the treatment and / or diagnosis of diseases involving α-synuclein proteins, such as synucleinopathy and / or conditions involving the abnormal accumulation or deposition of α-synuclein proteins in the central nervous system. Methods for producing the antibodies disclosed in WO 2017 / 009312, as well as various functional and structural features of these antibodies, are also disclosed in the same application. WO 2023 / 041524 discloses certain dosage regimens for administering the antibodies disclosed in WO 2017 / 009312. Summary of the Invention

[0007] The purpose of this invention is to provide a method for using anti-α-synuclein antibodies in clinical practice to treat synucleinosis or precursor synucleinosis.

[0008] The inventors of this invention have identified a method for treating human MSA using an anti-α-synuclein antibody. Experimental section (Example 8 and...) Figure 12-20 The data presented in the study showed a consistent trend that the specific anti-α synuclein antibody GM37var2 could slow the clinical progression of the disease in MSA patients.

[0009] In one aspect, the present invention provides a monoclonal anti-α-synuclein antibody for treating synucleinopathy or precursor synucleinopathy, wherein the use comprises intravenous administration of the anti-α-synuclein antibody to a human subject suffering from or at risk of developing synucleinopathy, at a dose greater than 700 mg and less than 7000 mg, for example between 900 mg and 5000 mg, or for example between 1000 mg and 4500 mg, and wherein the monoclonal anti-α-synuclein antibody is a full-length antibody that binds to epitopes within amino acids 112-117 (SEQ ID NO: 9 (ILEDMP)) of human α-synuclein (SEQ ID NO: 10).

[0010] In one aspect, the present invention provides a monoclonal anti-α-synuclein antibody for the treatment of multiple system atrophy (MSA), wherein the use comprises intravenous administration of the anti-α-synuclein antibody to a human subject suffering from or at risk of developing MSA, at a dose greater than 700 mg and less than 7000 mg, for example between 900 mg and 5000 mg, or for example between 1000 mg and 4500 mg, and wherein the monoclonal anti-α-synuclein antibody is a full-length antibody that binds to an epitope within amino acids 112-117 (SEQ ID NO: 9 (ILEDMP)) of human α-synuclein (SEQ ID NO: 10).

[0011] In another aspect, the present invention provides a method for treating synucleinosis or precursor synucleinosis, the method comprising intravenously administering a monoclonal anti-α-synuclein antibody to a human subject in need, wherein the human subject has synucleinosis or is at risk of developing synucleinosis, at a dose greater than 700 mg and less than 7000 mg, for example between 900 mg and 5000 mg, or for example between 1000 mg and 4500 mg, wherein the monoclonal anti-α-synuclein antibody is a full-length antibody that binds to an epitope within amino acids 112-117 (SEQ ID NO: 9 (ILEDMP)) of human α-synuclein (SEQ ID NO: 10).

[0012] In another aspect, the present invention provides a method for treating MSA, the method comprising intravenously administering a monoclonal anti-α-synuclein antibody to a human subject in need, wherein the human subject has MSA or is at risk of developing MSA, the dose being greater than 700 mg and less than 7000 mg, for example between 900 mg and 5000 mg, or for example between 1000 mg and 4500 mg, wherein the monoclonal anti-α-synuclein antibody is a full-length antibody that binds to an epitope within amino acids 112-117 (SEQ ID NO: 9 (ILEDMP)) of human α-synuclein (SEQ ID NO: 10).

[0013] In another aspect, the present invention provides the use of a monoclonal anti-α-synuclein antibody in the manufacture of a medicament for treating synucleinosis or precursor synucleinosis, wherein the use comprises intravenous administration of the anti-α-synuclein antibody to a human subject suffering from or at risk of developing synucleinosis at a dose greater than 700 mg and less than 7000 mg, for example between 900 mg and 5000 mg, or for example between 1000 mg and 4500 mg, and wherein the monoclonal anti-α-synuclein antibody is a full-length antibody that binds to an epitope within amino acids 112-117 (SEQ ID NO: 9 (ILEDMP)) of human α-synuclein (SEQ ID NO: 10).

[0014] In another aspect, the present invention provides the use of a monoclonal anti-α-synuclein antibody in the manufacture of a medicament for treating synucleinopathy or precursor synucleinopathy, wherein said use comprises intravenous administration of said anti-α-synuclein antibody to a human subject suffering from or at risk of developing MSA, at a dose greater than 700 mg and less than 7000 mg, for example between 900 mg and 5000 mg, or for example between 1000 mg and 4500 mg, and wherein said monoclonal anti-α-synuclein antibody is a full-length antibody that binds to an epitope within amino acids 112-117 (SEQ ID NO: 9 (ILEDMP)) of human α-synuclein (SEQ ID NO: 10).

[0015] In one embodiment of these aspects, the present invention provides suitable clinical use for treating synucleinic diseases such as Parkinson's disease (PD) (including idiopathic and hereditary forms of Parkinson's disease), Gaucher disease (GD), diffuse Lewy body disease (DLBD), Lewy body dementia (DLB), Lewy body variant (LBV) of Alzheimer's disease, combined Alzheimer's disease and Parkinson's disease, isolated autonomic dysfunction or multiple system atrophy (MSA) (e.g., suspected MSA, possible MSA, type C MSA, type P MSA, clinically confirmed MSA or clinically possible MSA).

[0016] In another embodiment of these aspects, the present invention provides suitable clinical use for treating precursor synucleinopathy in human subjects at risk of developing synucleinopathy, said human subjects being identifiable by exhibiting one or more clinical markers of precursor synucleinopathy, such as REM sleep behavior disorder (RBD) (e.g., isolated RBD (iRBD)), olfactory dysfunction (e.g., hyposmia), abnormal cognitive performance on neuropsychological tests, fine motor dysfunction or abnormal motor function assessed by objective tests, color vision abnormalities, autonomic dysfunction (e.g., constipation, urinary symptoms, erectile dysfunction, orthostatic hypotension), reduced dopaminergic binding in the nigrostriatum and striatum (DAT-SPECT abnormalities), seborrheic dermatitis, or genotypes associated with an increased risk of phenotypic transformation, such as glucocerebrosidase (encoded by the GBA gene) mutations.

[0017] In certain embodiments, the present invention provides suitable clinical use of the monoclonal antibody GM37 and its variants (GM37 variant 1, GM37 variant 2 and GM37 variant 3); these antibodies, their manufacturing methods and characteristics are disclosed in WO 2017 / 009312.

[0018] In specific embodiments of these aspects, the monoclonal anti-α-synuclein antibody according to the invention is administered every 3-5 weeks, for example, about every 4 weeks or once a month, for example, every 28-30 days.

[0019] In specific embodiments of these aspects, the monoclonal anti-α-synuclein antibody according to the invention is administered at doses of about 750 mg, about 1050 mg, about 1400 mg, about 1750 mg, about 2100 mg, about 2450 mg, about 2800 mg, about 3150 mg, about 3500 mg, about 3850 mg, about 4200 mg, about 4550 mg, about 4900 mg, about 5250 mg, about 5600 mg, about 5950 mg, about 6300 mg, or about 6650 mg. In another specific embodiment, the monoclonal anti-α-synuclein antibody according to the invention is administered at doses of 1050 mg, 2100 mg, or 4200 mg.

[0020] In one aspect, the anti-α-synuclein antibody is administered in a liquid pharmaceutical composition comprising a full-length IgG1 monoclonal anti-α-synuclein antibody at a concentration of 20-230 mg / mL, for example, 25-225 mg / mL, wherein the antibody comprises: a. Heavy chain CDR1 having the amino acid sequence of SEQ ID NO:1; b. Heavy chain CDR2 having the amino acid sequence of SEQ ID NO:34; c. Heavy chain CDR3 having the amino acid sequence of SEQ ID NO:3; d. The light chain CDR1 having the amino acid sequence of SEQ ID NO:4; e. The light chain CDR2 having the amino acid sequence of SEQ ID NO:5; and f. Light chain CDR3 having the amino acid sequence of SEQ ID NO:6; The composition further comprises a buffer, a pharmaceutically acceptable tensile agent, and a pharmaceutically acceptable surfactant, and the pH of the composition is between 4.5 and 7.5, for example, 5.0 to 7.0, for example, 5.5 to 6.5, for example, 6.0.

[0021] Other features and advantages of the invention applicable to these aspects and embodiments will become apparent from the following detailed description, experimental section and claims of the invention. Attached Figure Description

[0022] Figure 1 The predicted relationship between dose and CSF exposure and free α-synuclein percentage was shown.

[0023] Figure 2This illustrates the principle of a competitive ELISA assay. After pre-incubation with increased concentrations of α-synuclein (aSN) monomers or fibrils, free IgG binds to the coated aSN monomers and is detected using an antibody labeled with anti-human IgG (H+L)HRP (left). The captured IgG level is inversely proportional to the concentration of aSN monomers or fibrils, plotted as relative luminescent units, and the IC50 value is calculated using a four-parameter nonlinear fitting (right).

[0024] Figure 3 Representative binding curves of GM37 variant 2 with monomers (R2 = 0.9895) and fibrils aSN (R2 = 0.994) are shown.

[0025] Figure 4 shows the median (including quartile) plasma concentration (ng / mL) of GM37 variant 2 over time after a single dose of GM37v2 at each dose level in healthy subjects (a) and patients (b).

[0026] Figure 5 The relationship between dose-normalized GM37 variant 2 plasma concentration and time (logarithmic scale) at each dose level is shown.

[0027] Figure 6 shows the relationship between plasma concentrations of free α-synuclein and time after a single dose of GM37v2 at each dose level in healthy subjects (a) and patients (b).

[0028] Figure 7 shows the relationship between free / total α-synuclein plasma concentrations and time after a single dose of GM37v2 at each dose level in healthy subjects (a) and patients (b).

[0029] Figure 8 The relationship between free / total α-synuclein plasma concentration and plasma concentration of each GM37 variant 2 was shown.

[0030] Figure 9 This study presents a competitive ELISA for measuring the binding of four antibodies—GM37 wild-type (GM37 wt), GM37 variant 1 (GM37 var 1), GM37 variant 2 (GM37 var 2), and GM37 variant 3 (GM37 var 3)—to human α-synuclein. Plates coated with α-synuclein were used to detect the amount of antibody remaining after pre-incubation with increasing concentrations of α-synuclein (0–1000 nM) in solutions of each antibody (0.3 µg / mL). All four antibodies showed similar binding to α-synuclein.

[0031] Figure 10The effects of anti-α-synuclein antibodies on phosphorylated α-synuclein levels in primary mouse neurons treated with pathological α-synuclein fibrils were compared. Primary neurons were treated with seeds (10 ng) in the presence or absence of the four antibodies GM37, GM37 var 1, GM37 var 2, and GM37 var 3 (2 µg) used according to the invention. Neurons were fixed and stained after 3 weeks, and α-synuclein phosphoserine 129 positive spots were analyzed by Cellomics ARRAYSCAN™. ​​Cells treated with seeds alone or with seeds plus an isotype control antibody (B12) showed significantly increased levels of phosphorylation. Cells treated with GM37wt and the three variants were able to inhibit α-synuclein phosphorylation, all showing the same level of phosphorylation as cells that did not receive seeds. Data are presented as mean ± SD, determined based on 7 images per well in 5 wells. N = 2.

[0032] Figure 11 The study described in Example 3 (N = 15) shows the CSF concentration of free / total α-synuclein % in Parkinson's disease (PD) patients on days 3 and 21, administered with GM37v2.

[0033] Figure 12 The clinical efficacy of GM37v2 administration every 4 weeks in the treatment of MSA was demonstrated. When treatment efficacy was measured using the UMSARS total score, a 19% slowdown in clinical progression was observed in MSA patients treated with GM37var2 compared to placebo.

[0034] Figure 13 This study demonstrates the clinical efficacy of GM37v2 in treating MSA. When treatment efficacy was measured using the UMSARS Part I score, a 22% slowdown in clinical progression was observed in MSA patients treated with GM37v2 compared to placebo.

[0035] Figure 14 The clinical efficacy of GM37v2 administration every 4 weeks in the treatment of MSA was demonstrated. When treatment efficacy was measured using the UMSARS Part II score, a 17% slowdown in clinical progression was observed in MSA patients treated with GM37var2 compared to placebo.

[0036] Figure 15 The clinical efficacy of GM37v2 administration every 4 weeks in the treatment of MSA was demonstrated. When treatment efficacy was measured using a modified UMSARS score, a 27% slowdown in clinical progression was observed in MSA patients treated with GM37v2 compared to placebo.

[0037] Figure 16a and 16bThe clinical efficacy of GM37v2 administration every 4 weeks in the treatment of MSA was demonstrated. When treatment efficacy was measured using a modified UMSARS score, a 50% slowing of clinical progression was observed in MSA-C patients treated with GM37var2 compared to placebo.

[0038] Figure 17a and 17b The clinical efficacy of GM37v2 administration every 4 weeks in the treatment of MSA was demonstrated. When treatment efficacy was measured using a modified UMSARS score, a 42% slowdown in clinical progression was observed in early-stage MSA patients treated with GM37var2 compared to placebo.

[0039] Figure 18a and 18b This study demonstrates the clinical efficacy of GM37v2 administration every 4 weeks in the treatment of MSA. When treatment efficacy was measured using the UMSARS Part IV – Overall Disability Score or the Clinical Global Impression – Disease Severity Score, treatment improvement was observed in MSA patients treated with GM37v2 compared to placebo.

[0040] Figures 19a-19c This study demonstrates the clinical efficacy of GM37v2 administration every 4 weeks in the treatment of MSA. MRI volume analysis showed that, compared with placebo, MSA patients treated with GM37var2 experienced less regional volume reduction in the pons and cerebellar white matter at week 48.

[0041] Figure 20 The clinical efficacy of GM37v2 administration every 4 weeks in the treatment of MSA was demonstrated. Compared with placebo, a greater trend of reduction in neurofilament light chain load in the CSF was observed in MSA patients treated with GM37var2.

[0042] definition

[0043] The term "full-length antibody" refers to a full-length (intact) antibody or a substantially full-length antibody form. Specifically, it refers to antibodies with a heavy chain containing an Fc region. Naturally occurring antibodies typically consist of tetramers, which generally consist of at least two heavy (H) chains and at least two light (L) chains. Each heavy chain consists of a heavy chain variable domain (abbreviated as VH) and a heavy chain constant domain, which typically consists of three domains (CH1, CH2, and CH3). The heavy chains can be, for example, selected from IgG isotypes (IgG1, IgG2, IgG3, and IgG4 isotypes). Each light chain consists of a light chain variable domain (abbreviated as VL) and a light chain constant domain (CL). The light chains include κ and λ chains. The VH and VL regions can be further subdivided into hypervariable regions called "complementarity-determining regions," interspersed with more conserved sequence regions called "framework regions" (FRs). Each VH and VL consists of three CDR domains and four FR domains arranged in the following order from the amino terminus to the carboxyl terminus: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4 (or the J region). The heavy and light chain variable domains contain binding domains that interact with the antigen. In some embodiments, the full-length antibody includes antibody variants classified as “product-related substances” according to ICH Q6B. Product-related substances are defined as “molecular variants of the desired product formed during manufacturing and / or storage that are active and do not adversely affect the safety and efficacy of the pharmaceutical product. These variants have properties equivalent to the desired product and are not considered impurities.” Such molecular variants of the antibodies according to the invention are intended to include, for example, N-terminal modifications, such as N-terminal pyroglutamate (pyroGlu), such as truncation, or such as incomplete removal of light or heavy chain signal peptides, asparagine (Asn) deamidation, aspartic acid (Asp) isomerization, succinimide formation, succinimide hydrolysis, oxidation, cysteine-related modifications such as free cysteine ​​(Cys) residues, such as selective disulfide bond linkage (scrambling), such as trisulfide bond, such as thioether formation, or such as cysteine ​​racemization, glycosylation, glycation, C-terminal modifications (e.g., removal of C-terminal Lys, such as simultaneous removal of C-terminal Lys and Gly, or such as C-terminal amidation).

[0044] The term "epitaph" refers to an antigenic determinant that specifically binds to an antibody. Epitopes are typically composed of surface groups of molecules such as amino acids or sugar side chains, and usually possess specific three-dimensional structural features and specific charge characteristics. The difference between conformational epitopes and linear epitopes is that binding to the former, but not the latter, is often lost in the presence of denaturing solvents. Epitopes can contain amino acid residues directly involved in binding, as well as other amino acid residues not directly involved in binding, such as amino acid residues that are effectively blocked by specific antigen-binding peptides (in other words, the amino acid residues are within the influence range of the specific antigen-binding peptide). The term "112-117 epitope" or "epitope within amino acid 112-117" refers to a human α-synuclein region containing at least four of the six amino acid residues of human α-synuclein, such as all six amino acid residues of human α-synuclein. This epitope does not include any residues of human α-synuclein from 1 to 111 (including any residues of 106-111) nor any residues of human α-synuclein from 118 to 140 (including residues of 118-120). As used herein, the antibody according to the invention, referred to as binding to "epitopes within amino acids 112-117", is capable of specifically binding human α-synuclein by binding at least four of the six amino acid residues of the 112-117 epitopes, for example by binding the six amino acid residues of the 112-117 epitopes, without binding any residues of human α-synuclein from 1 to 111 (including any residues of 106-111) or any residues of human α-synuclein from 118 to 140 (including residues 118-120).

[0045] As used herein, the term "human antibody" (which may be abbreviated as "humAb" or "HuMab") is intended to include antibodies having variable and constant domains derived from human immunoglobulin sequences. Human antibodies used according to the invention may include amino acid residues not encoded by human immunoglobulin sequences (e.g., mutations introduced in vitro by random or site-specific mutagenesis or during gene rearrangement or in vivo by somatic mutations).

[0046] The term "humanized" refers to molecules typically prepared using recombinant techniques that have an antigen-binding site derived from an immunoglobulin from a non-human species and a residual immunoglobulin structure based on the structure and / or sequence of a human immunoglobulin. The antigen-binding site may comprise a completely non-human antibody variable domain fused to a human constant domain or a complementarity-determining region (CDR) of such variable domains containing only appropriate human frame regions grafted to human variable domains. The frame residues of such humanized molecules may be wild-type (e.g., fully human) or they may be modified to include one or more amino acid substitutions not found in human antibodies whose sequences already serve as the basis for humanization. Another approach focuses not only on providing human-derived constant domains but also on modifying variable domains to engineer them as closely as possible to their human form. It is known that both heavy and light chain variable domains contain three complementarity-determining regions (CDRs) that change in response to the antigen in question and determine binding capacity, flanked by four frame regions (FRs) that are relatively conserved in a given species and presumably provide the scaffold for the CDRs. When preparing nonhuman antibodies relative to a specific antigen, the variable domain can be "modified" or "humanized" by grafting a CDR derived from the nonhuman antibody onto the FR present in the human antibody to be modified.

[0047] In the context of this invention, "treatment" is intended to refer to the clinically relevant management and care of a patient for the purpose of alleviating, blocking, partially blocking, removing, delaying, or slowing the progression of one or more clinical manifestations of a disease. For the purposes of this invention, "treatment" further means a method for obtaining a beneficial or desired clinical outcome, wherein "beneficial or desired clinical outcome" includes, but is not limited to, symptom relief, reduction of symptom severity or disease severity, stable (i.e., no worsening) disease or symptom state, delay or slowing of disease or symptom state progression, improvement or reduction of disease or symptom state, or remission of disease or symptom (partially or completely). In a particular embodiment, "treatment" or "treatment effect" comprises delaying or slowing the disease progression in a patient with a synucleinosis, in a particular embodiment, such synucleinosis being MSA, which may be selected from one or more MSA subtypes, such as clinically confirmed MSA, clinically probable MSA, suspected MSA, possible MSA, type C MSA, or type P MSA. In another embodiment, "treatment" means delaying the onset of disease in a patient with a precursor synucleinosis. Treatment can be measured by quantifying clinical efficacy or treatment effectiveness by measuring the slowing or delaying of disease progression, such as by longitudinal changes in the total score of the Unified Multiple System Atrophy Rating Scale (UMSARS) Parts I and II (UMSARS TS), or the modified UMSARS Part I (mUMSARS), or the abbreviated UMSARS (aUMSARS) from baseline to the end of treatment (EoT) (i.e., at the end of a treatment period of 24 weeks, 48 ​​weeks, 72 weeks, 96 weeks, or longer). Treatment can also be measured by quantifying clinical efficacy or treatment effectiveness by measuring the slowing or delaying of disease progression, such as by longitudinal changes in the scores of UMSARS Part I, the modified UMSARS Part I (mUMSARS), and / or UMSARS Part II from baseline to EoT. This disease progression can also be assessed as changes in the scores of the UMSARS TS, UMSARS Part I, mUMSARS, and / or UMSARS Part II from baseline to EoT. Disease progression can also be assessed as longitudinal changes in the EoT from baseline in abbreviated UMSARS (aUMSARS) or changes in brain volume relative to baseline (e.g., measured by volume MRI (vMRI)) or changes in neurofilament light chain (NfL) blood concentration relative to baseline.Treatment can also be measured by quantifying clinical efficacy or treatment effectiveness by measuring the slowing or delaying of disease progression, as assessed by longitudinal changes relative to baseline using one or more of the following parameters: Schwab and England Activities of Daily Living (SE-ADL) scores; Clinical Global Impression-Disease Severity (CGI-S) scores relative to baseline; Patient Global Impression-Disease Severity (PGI-S) scores relative to baseline; Observer-Reported Global Impression-Disease Severity (OGI-S) scores relative to baseline; Composite Autonomic Symptoms Selection Change (COMPASS Selection Change) scores relative to baseline; UMSARS Part IV scores relative to baseline; changes in speech, swallowing, falls, and walking relative to baseline, as assessed by UMSARS Part I item scores; changes in fall frequency, cause, and consequences relative to baseline, as assessed by a fall diary period; EuroQol Changes in 5-dimensional, 5-level (EQ-5D-5L) scores relative to baseline; changes in brain volume relative to baseline, such as those measured by volumetric MRI (vMRI); changes in tissue integrity relative to baseline, such as those measured by diffusion tensor imaging (DTI) MRI; changes in neurofilament light chain (NfL) blood concentration relative to baseline; changes in heart rate, blood pressure, and orthostatic symptoms relative to baseline, as assessed in UMSARS Part III; changes in gait parameters or fall frequency relative to baseline, such as those assessed by devices capable of tracking relevant gait parameters and / or recording falls based on digital wearable sensors; changes in cerebral blood flow relative to baseline, such as those measured by arterial spin labeling (ASL) MRI; changes in t-tau and NfL CSF concentrations relative to baseline; or changes in the pathological species of α-synuclein in CSF relative to baseline. Patients awaiting treatment can be identified or diagnosed using any recognized method or standard in the relevant field.

[0048] As used in this article, the term "kd" (sec -1 (or 1 / s) refers to the dissociation rate constant of a specific antibody-antigen interaction. This value is also known as the koff value.

[0049] As used in this article, the term "ka" (M -1 x sec -1 (or 1 / Msec) refers to the association rate constant of a specific antibody-antigen interaction.

[0050] As used herein, the term "KD" (M) refers to the dissociation equilibrium constant of a specific antibody-antigen interaction and is obtained by dividing kd by ka. KD can be determined by the method described in Example 6A or other methods known in the art.

[0051] As used in this article, the term "KA" (M -1 (or 1 / M) refers to the association equilibrium constant of a specific antibody-antigen interaction and is obtained by dividing ka by kd.

[0052] As used herein, the term "IC50" refers to the antibody concentration at which 50% maximum inhibition is achieved. The exact IC50 value (usually expressed in nM) depends on the specific assay and therefore cannot be directly compared between different assays.

[0053] As used in this article, the term "Emax" refers to the maximum effect of an antibody at high antibody concentrations, i.e., when all α-synuclein proteins are bound to the antibody.

[0054] As used herein, the term "affinity" refers to the cumulative strength of an antibody-antigen complex. This article encompasses both types of affinity in the individual non-covalent binding interaction between an IgG molecule and its antigen.

[0055] As used herein, the term “Cmax” refers to the maximum concentration of the antibody measured in the plasma of a subject after infusion of the antibody.

[0056] As used in this article, the term "tmax" refers to the time required to reach Cmax after antibody infusion.

[0057] The phrase "used according to the invention" as used throughout this disclosure is intended to apply to all uses and methods, including use in treating synucleinosis or precursor synucleinosis, methods of treating synucleinosis or precursor synucleinosis, and use of monoclonal anti-α synuclein antibodies in the manufacture of medicaments for treating synucleinosis or precursor synucleinosis. Such use may include administering monoclonal anti-α synuclein antibodies (e.g., GM37v2) to a patient in need using appropriate dosages, dosing regimens, and / or appropriate pharmaceutical formulations. The invention also provides such formulations or compositions.

[0058] The terms “preparation” and “composition” are used interchangeably throughout this application.

[0059] The term "stable composition" refers to a composition that can be stored for a specific period of time (at least 6 months or longer) under specific conditions (here, the normal storage conditions for antibody formulations, such as storage at about 5°C), wherein the proteins in the composition substantially retain their physical stability and / or chemical stability and / or biological activity. Various analytical techniques for measuring protein stability are available and are well known in the art, some of which are also described in the experimental section of this document. Stability can be measured at selected temperatures within selected time periods. In some embodiments, the formulation is stable at about 40°C for at least about 1, 2, 3, 4, 5, 6, 7, 14, 21, 28 days or longer. In some embodiments, the formulation is stable at about 40°C ± 3°C for at least about 1, 2, 3, 4, 5, 6, 7, 8 weeks or longer. In some embodiments, the formulation is stable at about 25°C for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 months or longer. In some embodiments, the formulation is stable at about 5°C ± 3°C for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 months or longer. In some embodiments, the preparation is stable at about -20°C ± 3°C for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48 months or longer. Furthermore, the preparation is preferably stable after freezing (e.g., to -20°C, -40°C, or -70°C) and after thawing (e.g., after 1, 2, 3, 4, or 5 freeze-thaw cycles). Stability can be assessed qualitatively and / or quantitatively in a variety of ways, including evaluating aggregate formation (e.g., using size exclusion chromatography, by measuring turbidity and / or by visual inspection); assessing charge heterogeneity using cation exchange chromatography, imaging capillary isoelectric focusing (icIEF), or capillary zone electrophoresis; N-terminal or C-terminal sequence analysis; mass spectrometry; SDS-PAGE analysis to compare reduced antibodies with intact antibodies; peptide mapping (e.g., trypsin or LYS-C) analysis; evaluating antibody bioactivity or antigen-binding function; etc.Instability may involve any one or more of the following: aggregation, deamidation (e.g., Asn deamidation), oxidation (e.g., Met oxidation), isomerization (e.g., Asp isomerization), shearing / hydrolysis / fragmentation (e.g., hinge region fragmentation), succinimide formation, unpaired cysteine, N-terminal extension, C-terminal processing, differential glycosylation, etc.

[0060] "Low viscosity composition" is intended to describe a liquid pharmaceutical composition with a viscosity of at least about 20 cP, for example less than 15 cP, for example less than 14 cP, for example less than 13 cP, for example less than 12 cP, for example less than 11 cP, for example less than 10 cP, for example less than 9 cP, for example less than 8 cP, for example less than 7 cP, for example less than 6 cP, for example less than 5 cP.

[0061] In this application, "buffer" refers to a buffer solution that resists pH changes through the action of its acid-base conjugate components. The buffer solution or buffering agent of the present invention (which may be used interchangeably) preferably maintains the pH of the composition in the range of about 4.5 to about 7.5, for example, about 5.5 to about 6.5, such as 5.7 to 6.4, 5.8 to 6.3, or 5.9 to 6.2. In one embodiment, the pH of the buffer solution is 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, or 7.0. Histidine buffers (such as L-histidine) are examples of buffers that control the pH within this range. Examples of buffers are acetate, citrate, tartrate, histidine (such as L-histidine), glutamate, phosphate, Tris, glycine, bicarbonate, succinate, sulfate, and nitrate buffers, or mixtures thereof. In some embodiments, the buffer is selected from sodium phosphate, histidine (such as L-histidine), citric acid, sodium citrate, sodium acetate, or mixtures thereof. In a particular embodiment, the buffer is a histidine buffer (such as L-histidine) or a mixture of histidine buffers.

[0062] In this application, "surfactant" refers to a surface-active reagent, preferably a nonionic surfactant. Examples of surfactants described herein include polysorbates (e.g., polysorbate 20 and polysorbate 80); poloxamer (e.g., poloxamer 188); Triton; Triton X-100; sodium dodecyl sulfate (SDS); sodium lauryl sulfate; sodium octyl glycoside; lauryl, myristyl, linoleoyl, or stearyl sulfobetaine; lauryl, myristyl, linoleoyl, or stearyl sarcosine; linoleoyl, myristyl, or hexadecyl betaine; lauroamide propyl, cocamidopropyl, linoleamide propyl, myristamide propyl, palmitopropyl, or isostearamide propyl betaine (e.g., lauroamide propyl); myristamide propyl, palmitopropyl, or isostearamide propyl dimethylamine; sodium methylcocoyl taurate or disodium methyloleyl taurate; polyethylene glycol, polypropylene glycol, and copolymers of ethylene and propylene glycol. In one particular embodiment, the pharmaceutically acceptable surfactant is polysorbate 80, also known as Tween 80.

[0063] In this application, "tense agent" refers to an excipient that enables the formation of isotonic liquid pharmaceutical compositions. Isotonicity means that the formulation of interest has an osmotic pressure substantially the same as that of human blood. The osmotic pressure of isotonic formulations is typically about 250 to 350 mOsm. Examples of tensile agents include mannitol, sorbitol, lactose, dextrose, trehalose, sodium chloride, potassium chloride, glycerol, and glycerol. In a particular embodiment, the tensile agent is a suitable salt, such as NaCl.

[0064] In the context of this invention, "filler" refers to an excipient that provides additional stability to a liquid pharmaceutical composition. Examples of fillers include these main classes of excipients: sugars and polyols (such as sucrose, trehalose, glucose, lactose, sorbitol, mannitol, and glycerol); amino acids (such as arginine, aspartic acid, glutamic acid, lysine, glycine, glutamic acid, histidine, methionine, or alanine); and polymers and proteins (such as gelatin, PVP, PLGA, PEG, dextran, cyclodextrins and their derivatives, starch derivatives, HSA, or BSA). In one particular embodiment, the filler is sucrose.

[0065] The term "histidine buffer" or "histidine" is intended to cover histidine buffers and mixtures thereof, such as histidine, L-histidine, L-histidine hydrochloride, L-histidine monohydrochloride, L-histidine monohydrate, and L-histidine hydrochloride monohydrate, or mixtures thereof. In one particular embodiment, the histidine buffer is a mixture of L-histidine and L-histidine monohydrochloride.

[0066] As used in this article, the term “about” means ±10% of a specified value. Detailed Implementation

[0067] This invention relates to the appropriate clinical use of monoclonal antibodies against human α-synuclein for the treatment of synucleinosis or precursor synucleinosis.

[0068] The inventors of this invention have identified a method for treating human MSA using an anti-α-synuclein antibody. Experimental section (Example 8 and...) Figure 12-20 The data presented in the study showed a consistent trend that the specific anti-alpha synuclein antibody GM37var2 (elenetumab) slowed the clinical progression of MSA in patients. Further results showed that, when treatment efficacy was measured using the mUMSARS score, participants with early-stage MSA treated with GM37v2 (elenetumab) experienced a slowdown in both functional and motor decline, as measured by the total UMSARS score and sub-scores, with a reduction of up to 27%.

[0069] Furthermore, subgroup analyses showed even greater treatment efficacy in MSA patients diagnosed with MSA-C and / or early-stage MSA, as identified by their low baseline UMSARS total score (e.g., UMSARS baseline TS below 40).

[0070] The observed treatment efficacy, when measured on the UMSARS scale, was also confirmed by efficacy trends on other clinically relevant measures of overall disease severity and function. MRI analysis of pontine and cerebellar white matter volume showed a reduction in white matter volume loss in the group exposed to GM37var2 (elenetatumab).

[0071] Overall, the data presented in this article provide evidence of the clinical benefit of treating MSA patients with GM37var2 (elenaetamuab), and surprisingly, the treatment effect was most significant in MSA patients with early-stage MSA and / or those diagnosed with MSA-C.

[0072] In one aspect, the present invention provides a monoclonal anti-α-synuclein antibody for treating synucleinopathy or precursor synucleinopathy, wherein the use comprises intravenous administration of the anti-α-synuclein antibody to a human subject suffering from or at risk of developing synucleinopathy, at a dose greater than 700 mg and less than 7000 mg, for example between 900 mg and 5000 mg, for example between 1000 mg and 4500 mg, or for example between 2000 mg and 4300 mg, and wherein the monoclonal anti-α-synuclein antibody is a full-length antibody that binds to epitopes within amino acids 112-117 (SEQ ID NO: 9 (ILEDMP)) of human α-synuclein (SEQ ID NO: 10).

[0073] In one aspect, the present invention provides a monoclonal anti-α-synuclein antibody for the treatment of MSA, wherein the use includes administering the anti-α-synuclein antibody to a human subject suffering from MSA.

[0074] In one aspect, the present invention provides a monoclonal anti-α-synuclein antibody for the treatment of MSA, wherein the use comprises intravenous administration of the anti-α-synuclein antibody to a human subject suffering from or at risk of developing MSA, at a dose greater than 700 mg and less than 7000 mg, for example between 900 mg and 5000 mg, for example between 1000 mg and 4500 mg, or for example between 2000 mg and 4300 mg, and wherein the monoclonal anti-α-synuclein antibody is a full-length antibody that binds to an epitope within amino acids 112-117 (SEQ ID NO: 9 (ILEDMP)) of human α-synuclein (SEQ ID NO: 10).

[0075] In another aspect, the present invention provides a method for treating synucleinosis or precursor synucleinosis, the method comprising intravenously administering a monoclonal anti-α-synuclein antibody to a human subject in need, wherein the human subject has synucleinosis or is at risk of developing synucleinosis, the dose being greater than 700 mg and less than 7000 mg, for example between 900 mg and 5000 mg, for example between 1000 mg and 4500 mg, or for example between 2000 mg and 4300 mg, and wherein the monoclonal anti-α-synuclein antibody is a full-length antibody that binds to an epitope within amino acids 112-117 (SEQ ID NO: 9 (ILEDMP)) of human α-synuclein (SEQ ID NO: 10).

[0076] In another aspect, the present invention provides a method for treating MSA, the method comprising administering a monoclonal anti-α-synuclein antibody to a human subject in need, wherein the human subject suffers from MSA.

[0077] In another aspect, the present invention provides a method for treating MSA, the method comprising intravenously administering a monoclonal anti-α-synuclein antibody to a human subject in need, wherein the human subject has MSA or is at risk of developing MSA, the administered dose being greater than 700 mg and less than 7000 mg, for example between 900 mg and 5000 mg, for example between 1000 mg and 4500 mg, or for example between 2000 mg and 4300 mg, and wherein the monoclonal anti-α-synuclein antibody is a full-length antibody that binds to an epitope within amino acids 112-117 (SEQ ID NO: 9 (ILEDMP)) of human α-synuclein (SEQ ID NO: 10).

[0078] In another aspect, the present invention provides the use of a monoclonal anti-α-synuclein antibody in the manufacture of a medicament for treating synucleinosis or precursor synucleinosis, wherein said use comprises intravenous administration of said anti-α-synuclein antibody to a human subject suffering from or at risk of developing synucleinosis at a dose greater than 700 mg and less than 7000 mg, for example between 900 mg and 5000 mg, for example between 1000 mg and 4500 mg, or for example between 2000 mg and 4300 mg, and wherein said monoclonal anti-α-synuclein antibody is a full-length antibody that binds to an epitope within amino acids 112-117 (SEQ ID NO: 9 (ILEDMP)) of human α-synuclein (SEQ ID NO: 10).

[0079] In another aspect, the present invention provides the use of a monoclonal anti-α-synuclein antibody in the manufacture of a medicament for the treatment of MSA, wherein said use includes administering the anti-α-synuclein antibody to a human subject suffering from MSA.

[0080] In another aspect, the present invention provides the use of a monoclonal anti-α-synuclein antibody in the manufacture of a medicament for the treatment of MSA, wherein the use comprises intravenous administration of the anti-α-synuclein antibody to a human subject suffering from or at risk of developing MSA, at a dose greater than 700 mg and less than 7000 mg, for example between 900 mg and 5000 mg, for example between 1000 mg and 4500 mg, or for example between 2000 mg and 4300 mg, and wherein the monoclonal anti-α-synuclein antibody is a full-length antibody that binds to an epitope within amino acids 112-117 (SEQ ID NO: 9 (ILEDMP)) of human α-synuclein (SEQ ID NO: 10).

[0081] In some embodiments, the estimated KD value for the binding of monoclonal anti-α-synuclein antibody to oligomeric α-synuclein is about 0.1-1.0 nM, for example 0.2-0.8 nM, for example 0.4-0.6 nM, for example about 0.5 nM.

[0082] In some embodiments, the KD value of the monoclonal anti-α-synuclein antibody binding to the monomeric form of α-synuclein is about 30-40 nM, for example 32-38 nM, for example 34-37 nM, for example about 36 nM, and the estimated KD value binding to the oligomeric form of α-synuclein is about 0.1-1.0 nM, for example 0.2-0.8 nM, for example 0.4-0.6 nM, for example about 0.5 nM. In one embodiment, the ratio between monomeric and oligomeric binding values ​​is enhanced by about 60-70 times relative to the oligomeric form compared to the monomeric form, for example 62-68 times, for example 64-66 times, for example 65 times. This enhancement of binding between the two forms is further explained in the Experimental Section and referred to as “affinity gain”. This enhancement of binding between the two forms will be referred to as affinity gain in this disclosure. In some embodiments, the human T½ for monoclonal anti-α-synuclein antibodies is about 25-35 days, for example about 4 weeks, for example about 27-33 days, for example about 28 days, for example about 28-32 days, for example 30 days, for example 28-30 days.

[0083] In an embodiment, the monoclonal anti-α-synuclein antibody according to the present invention comprises: a. Heavy chain CDR1 having the amino acid sequence of SEQ ID NO:1; b. Heavy chain CDR2 having the amino acid sequence of SEQ ID NO:2; c. Heavy chain CDR3 having the amino acid sequence of SEQ ID NO:3; d. The light chain CDR1 having the amino acid sequence of SEQ ID NO:4; e. The light chain CDR2 having the amino acid sequence of SEQ ID NO:5; and f. Light chain CDR3 having the amino acid sequence of SEQ ID NO:6.

[0084] In a particular embodiment, the monoclonal anti-α-synuclein antibody for use according to the present invention comprises a heavy chain consisting of a variable domain of SEQ ID NO:7 and a light chain consisting of a variable domain of SEQ ID NO:8.

[0085] In an embodiment, the monoclonal anti-α-synuclein antibody according to the present invention comprises: a. Heavy chain CDR1 having the amino acid sequence of SEQ ID NO:1; b. Heavy chain CDR2 having the amino acid sequence of SEQ ID NO:33; c. Heavy chain CDR3 having the amino acid sequence of SEQ ID NO:3; d. The light chain CDR1 having the amino acid sequence of SEQ ID NO:4; e. The light chain CDR2 having the amino acid sequence of SEQ ID NO:5; and f. Light chain CDR3 having the amino acid sequence of SEQ ID NO:6.

[0086] In a particular embodiment, the monoclonal anti-α-synuclein antibody according to the present invention comprises a heavy chain consisting of a variable domain of SEQ ID NO:30 and a light chain consisting of a variable domain of SEQ ID NO:8.

[0087] In an embodiment, the monoclonal anti-α-synuclein antibody according to the present invention comprises: a. Heavy chain CDR1 having the amino acid sequence of SEQ ID NO:1; b. Heavy chain CDR2 having the amino acid sequence of SEQ ID NO:34; c. Heavy chain CDR3 having the amino acid sequence of SEQ ID NO:3; d. The light chain CDR1 having the amino acid sequence of SEQ ID NO:4; e. The light chain CDR2 having the amino acid sequence of SEQ ID NO:5; and f. Light chain CDR3 having the amino acid sequence of SEQ ID NO:6.

[0088] In a particular embodiment, the monoclonal anti-α-synuclein antibody for use according to the present invention comprises a heavy chain variable domain consisting of SEQ ID NO:31 and a light chain variable domain consisting of SEQ ID NO:8.

[0089] In an embodiment, the monoclonal anti-α-synuclein antibody according to the present invention comprises: a. Heavy chain CDR1 having the amino acid sequence of SEQ ID NO:1; b. Heavy chain CDR2 having the amino acid sequence of SEQ ID NO:35; c. Heavy chain CDR3 having the amino acid sequence of SEQ ID NO:3; d. The light chain CDR1 having the amino acid sequence of SEQ ID NO:4; e. The light chain CDR2 having the amino acid sequence of SEQ ID NO:5; and f. Light chain CDR3 having the amino acid sequence of SEQ ID NO:6.

[0090] In a particular embodiment, the monoclonal anti-α-synuclein antibody for use according to the present invention comprises a heavy chain consisting of a variable domain of SEQ ID NO:32 and a light chain consisting of a variable domain of SEQ ID NO:8.

[0091] In certain embodiments, the monoclonal anti-α-synuclein antibody according to the invention is a full-length human antibody. In such embodiments, the monoclonal anti-α-synuclein antibody may, for example, be a human IgG1 antibody.

[0092] In a particular embodiment, the monoclonal anti-α-synuclein antibody for use according to the present invention comprises a human IgG1 heavy chain constant region and / or a human κ light chain constant region.

[0093] In a particular embodiment, the monoclonal anti-α-synuclein antibody for use according to the present invention comprises a constant heavy chain domain as defined in SEQ ID NO:18 and / or a constant κ light chain domain as defined in SEQ ID NO:17.

[0094] In certain embodiments, the monoclonal anti-α-synuclein antibody used according to the present invention is antibody GM37 or a variant thereof, namely GM37 variant 1, GM37 variant 2, or GM37 variant 3. In a preferred embodiment, the antibody is GM37v2 (elenetantheline bromide). In a preferred embodiment, the antibody is elenetantheline bromide.

[0095] In one embodiment, the monoclonal anti-α-synuclein antibody according to the invention is administered at a dose greater than 700 mg and less than 7000 mg, for example between 900 mg and 5000 mg, for example between 1000 mg and 4500 mg, or for example between 2000 mg and 4300 mg. In a particular embodiment, the monoclonal anti-α-synuclein antibody is administered at intervals of 3-5 weeks, or the antibody is administered to human subjects in another regimen that provides substantially the same area under the curve (AUC) of antibody exposure, or substantially the same estimated target binding of oligomeric α-synuclein in patient CSF.

[0096] In some embodiments, the monoclonal anti-α-synuclein antibody according to the invention is administered every 6 weeks, every 5 weeks, every 4 weeks, every 3 weeks, every 2 weeks, or weekly. In some embodiments, the monoclonal anti-α-synuclein antibody according to the invention is administered every 20 days, every 21 days, every 22 days, every 23 days, every 24 days, every 25 days, every 26 days, every 27 days, every 28 days, every 29 days, every 30 days, every 31 days, every 32 days, every 33 days, every 34 days, every 35 days, every 36 days, every 37 days, every 38 days, every 39 days, or every 40 days.

[0097] In a particular embodiment, the monoclonal anti-α-synuclein antibody according to the invention is administered every 3-5 weeks, for example every 4 weeks or once a month, for example every 25-31 days, for example every 28-30 days.

[0098] In certain embodiments, the monoclonal anti-α-synuclein antibody according to the invention is administered at doses of about 75 mg, about 225 mg, about 750 mg, about 2250 mg, about 4500 mg, or about 9000 mg.

[0099] In a particular embodiment, the monoclonal anti-α-synuclein antibody according to the invention is administered at a dose of 4000 mg to 7000 mg, for example between 4000 mg and 6500 mg, or between 4200 mg and 6300 mg, for example 4200 mg or 6300 mg.

[0100] In a particular embodiment, the monoclonal anti-α-synuclein antibody according to the invention is administered at a dose of about 750 mg, about 1050 mg, about 1400 mg, about 1750 mg, about 2100 mg, about 2450 mg, about 2800 mg, about 3150 mg, about 3500 mg, about 3850 mg, about 4200 mg, about 4550 mg, about 4900 mg, about 5250 mg, about 5600 mg, about 5950 mg, about 6300 mg, or about 6650 mg. In another particular embodiment, the monoclonal anti-α-synuclein antibody according to the invention is administered at a dose of about 1050 mg, about 2100 mg, about 4200 mg, or about 6300 mg.

[0101] In a particular embodiment, the monoclonal anti-α-synuclein antibody according to the invention is administered intravenously at the dose described above over 30 minutes ± 10 minutes, for example, 20 minutes, 25 minutes, 30 minutes, 35 minutes or 40 minutes.

[0102] In a particular embodiment, the monoclonal anti-α-synuclein antibody according to the invention is administered intravenously at the dose described above over 15 minutes ± 5 minutes, for example, 10 minutes, 15 minutes, or 20 minutes.

[0103] In a particular embodiment, the monoclonal anti-α-synuclein antibody according to the invention is administered intravenously at the dose described above at a rate of about 30 mg / min to about 150 mg / min, for example about 35 mg / min, about 70 mg / min or about 140 mg / min.

[0104] In a particular embodiment, the monoclonal anti-α-synuclein antibody according to the invention is administered intravenously at the dose described above at a rate of about 25 mg / min to about 300 mg / min, for example 60 mg / min to about 300 mg / min, for example about 70 mg / min, about 140 mg / min or about 280 mg / min.

[0105] In the embodiments, the amount and frequency of application of the monoclonal anti-α-synuclein antibody according to the invention are sufficient to achieve an estimated average steady-state CSF concentration of the antibody of at least 0.5 nM, for example at least 1 nM, for example at least 2 nM, for example at least 3 nM, for example at least 4 nM, for example at least 5 nM, for example at least 6 nM, for example at least 7 nM, for example at least 8 nM, for example at least 9 nM, for example at least 10 nM, for example at least 11 nM, for example at least 12 nM, for example at least 13 nM, for example at least 14 nM, or for example at least 15 nM.

[0106] In another embodiment, the amount and frequency of application of the monoclonal anti-α-synuclein antibody according to the invention are sufficient to achieve an estimated target binding of at least 50%, for example, at least 55%, for example, at least 60%, for example, at least 75%, for example, at least 77%, for example, at least 80%, for example, at least 82%, for example, at least 85%, for example, at least 87%, for example, at least 90%, for example, at least 92%, for example, at least 95%, for example, at least 97%, or for example, at least 99%.

[0107] In another embodiment, the monoclonal anti-α-synuclein antibody according to the invention is used in the treatment of synucleinopathies. Such synucleinopathies may be selected from the group comprising: Parkinson's disease (PD) (including idiopathic and hereditary forms of Parkinson's disease), Gaucher disease (GD), diffuse Lewy body disease (DLBD), Lewy body dementia (DLB), Lewy body variant (LBV) of Alzheimer's disease, combined Alzheimer's disease and Parkinson's disease, isolated autonomic dysfunction, and multiple system atrophy (MSA). This treatment may consist of slowing or delaying the progression of the synucleinopathy (e.g., MSA progression), or delaying the onset of the disease if the patient has a precursor synucleinopathy.

[0108] In a particular embodiment, the synucleinopathy to be treated is Parkinson's disease (PD).

[0109] In yet another specific embodiment, the synucleinopathy to be treated is Lewy body dementia (DLB).

[0110] In yet another specific embodiment, the synucleinopathy to be treated is multiple system atrophy (MSA). In such an embodiment, the human subject with MSA has multiple system atrophy-Parkinsonian type (MSA-P) or multiple system atrophy-cerebellar type (MSA-C) subtypes or is diagnosed as suspected or probable MSA (such suspected or probable MSA may also be multiple system atrophy-Parkinsonian type (MSA-P) or multiple system atrophy-cerebellar type (MSA-C) subtypes), or is diagnosed as clinically confirmed MSA or clinically probable MSA, which may also be multiple system atrophy-Parkinsonian type (MSA-P) or multiple system atrophy-cerebellar type (MSA-C) subtypes.

[0111] In yet another embodiment, the MSA diagnosis is based on the presence of one or more suitable MSA biomarkers identified in the human subject. Such biomarkers may be selected from the group comprising: physiological biomarkers, biological biomarkers, genetic biomarkers, molecular biomarkers, tissue biomarkers, radiological biomarkers, imaging biomarkers, behavioral biomarkers, or digital biomarkers. In a further such embodiment, human subjects with MSA or diagnosed with suspected or probable multiple system atrophy (MSA) or other MSA subtypes can be identified by validated clinical assessment and / or diagnostic methods known in the art. In yet another such embodiment, human subjects with MSA or diagnosed with suspected or probable multiple system atrophy (MSA) or other MSA subtypes can be identified by the presence of motor and / or autonomic (orthostatic or urinary) MSA symptoms within the past 5 years (e.g., within the past 4 years, or for example, within the past 3 years, or for example, within the past 2 years, or for example, within the past year, or for example, within the past 6 months).

[0112] In yet another such embodiment, human subjects with MSA or diagnosed with suspected or probable multiple system atrophy (MSA) or other MSA subtypes can be identified by a UMSARS Part I score ≤ 16 (item 11 regarding sexual function omitted). In yet another such embodiment, human subjects with MSA or diagnosed with suspected or probable multiple system atrophy (MSA) or other MSA subtypes can be identified by cognitive performance as assessed by the Montreal Cognitive Assessment (MoCA) (score ≥ 22).

[0113] In yet another such embodiment, the human subject with MSA has MSA-C. In yet another such embodiment, the human subject with MSA has MSA-P. In yet another such embodiment, the human subject with MSA has suspected or probable MSA-C. In yet another such embodiment, the human subject with MSA has suspected or probable MSA-P. In yet another such embodiment, the human subject with MSA has clinically confirmed or clinically probable MSA. In yet another such embodiment, the human subject with MSA has clinically confirmed or clinically probable MSA-P. In yet another such embodiment, the human subject with MSA has clinically confirmed or clinically probable MSA-C.

[0114] In yet another such embodiment, the human subject with MSA has MSA in an early stage of the disease. In yet another such embodiment, the human subject with MSA has MSA in an early stage of the disease. In yet another such embodiment, the human subject with MSA has MSA in a disease stage in which the patient has not yet suffered significant damage from the disease, such as having a UMSARS TS score below 40 (e.g., 10-39, 15-39, 20-39, 25-39, 30-39, 35-39, 10-35, 15-35, 20-35, 25-35, 30-35, 10-30, 15-30, 20-30, 25-30, 10-25, 15-25, 20-25, 10-20, 15-20, or 10-15). In yet another such embodiment, the human subject with MSA has early-stage MSA. In yet another such embodiment, the UMSARS TS of human subjects with MSA is < 40, for example, less than 39, less than 38, less than 37, less than 36, less than 35, less than 34, less than 33, less than 32, less than 31, less than 30, 10-39, 15-39, 20-39, 25-39, 30-39, 35-39, 10-35, 15-35, 20-35, 25-35, 30-35, 10-30, 15-30, 20-30, 25-30, 10-25, 15-25, 20-25, 10-20, 15-20, or 10-15. In yet another such embodiment, human subjects with MSA had UMSARS TS < 40 at the start of anti-α-synuclein antibody treatment, for example, less than 39, less than 38, less than 37, less than 36, less than 35, less than 34, less than 33, less than 32, less than 31, less than 30, 10-39, 15-39, 20-39, 25-39, 30-39, 35-39, 10-35, 15-35, 20-35, 25-35, 30-35, 10-30, 15-30, 20-30, 25-30, 10-25, 15-25, 20-25, 10-20, 15-20, or 10-15.

[0115] In yet another such embodiment, human subjects with MSA have MSA-C and their UMSARS TS <40, for example, less than 39, less than 38, less than 37, less than 36, less than 35, less than 34, less than 33, less than 32, less than 31, less than 30, 10-39, 15-39, 20-39, 25-39, 30-39, 35-39, 10-35, 15-35, 20-35, 25-35, 30-35, 10-30, 15-30, 20-30, 25-30, 10-25, 15-25, 20-25, 10-20, 15-20, or 10-15. In yet another such embodiment, human subjects with MSA have MSA-C and their UMSARS TS at the start of anti-α-synuclein antibody treatment is <40, for example, less than 39, less than 38, less than 37, less than 36, less than 35, less than 34, less than 33, less than 32, less than 31, less than 30, 10-39, 15-39, 20-39, 25-39, 30-39, 35-39, 10-35, 15-35, 20-35, 25-35, 30-35, 10-30, 15-30, 20-30, 25-30, 10-25, 15-25, 20-25, 10-20, 15-20, or 10-15.

[0116] In another embodiment, the monoclonal anti-α-synuclein antibody according to the invention is used in the treatment of human subjects at risk of developing synucleinopathy with precursor synucleinopathy, said human subjects being identifiable by exhibiting one or more clinical markers of precursor synucleinopathy selected from the group consisting of: REM sleep behavior disorder (RBD) (e.g., isolated RBD (iRBD)), olfactory dysfunction (e.g., hyposmia), abnormal cognitive performance on neuropsychological tests, fine motor dysfunction or abnormal motor function as assessed by objective tests, color vision abnormalities, autonomic dysfunction (e.g., constipation, urinary symptoms, erectile dysfunction, orthostatic hypotension), reduced dopaminergic binding in the nigrostriatum and striatum (DAT-SPECT abnormalities), and genotypes associated with an increased risk of phenotypic transformation, such as mutations in glucocerebrosidase (encoded by the GBA gene). In such an embodiment, human subjects at risk of developing synucleinopathy can be identified by exhibiting an RBD such as an isolated RBD (iRBD) and at least one other clinical marker of precursor synucleinopathy (such as a DAT-SPECT scan with hyposmia and / or abnormality). In yet another such embodiment, human subjects at risk of developing synucleinopathy can be identified by exhibiting an RBD (e.g., an isolated RBD (iRBD)) and a DAT-SPECT scan with hyposmia and abnormality.

[0117] In one aspect, a monoclonal anti-α-synuclein antibody (e.g., GM37v2) is formulated in one of the specific liquid pharmaceutical compositions provided in this application.

[0118] On the other hand, a kit comprising a monoclonal anti-α-synuclein antibody according to the invention for use is provided.

[0119] In yet another embodiment, the monoclonal anti-α-synuclein antibody according to the invention is expressed in CHO cells or obtained by expression in CHO cells.

[0120] In one aspect, the monoclonal anti-α-synuclein antibody according to the invention is used to treat abnormal aggregation of α-synuclein in human subjects, wherein the human subjects have been identified as having abnormal aggregation of α-synuclein in the CNS.

[0121] In some embodiments, treatment with the monoclonal anti-α-synuclein antibody according to the invention may last for weeks, months, a year, or even years. In other embodiments, treatment may be part of a combination therapy, wherein the monoclonal antibody according to the invention is combined with or administered as an adjunct to one or more other pharmaceutical preparations. Such additional pharmaceutical preparations may be part of standard care used in a particular synucleinosis. In MSA, such standard care may include one or more of the following: medications that relieve Parkinson's-like signs and symptoms, such as levodopa and / or carbidopa, or medications known to be used to treat autonomic symptoms (e.g., urinary symptoms or neurogenic orthostatic hypotension), such medications may be selected from pyridostigmine, midodrine, or dralidopa.

[0122] Specific doses and dosing regimens

[0123] Dosage and dosing regimens can be expressed as a fixed dose, such as a specific mg amount of the monoclonal antibody used according to the invention (i.e., independent of the weight of the human subject to be treated). Such doses are described in embodiments and aspects of the invention, including Table 1 below. In some embodiments, the dose or dosing regimen may also be expressed in mg / kg (i.e., a dose varying based on the weight of the human subject to be treated). Conversion between a fixed dose and a weight-based dose (e.g., mg / kg) will be within the skill range of a trained physician. The result of the conversion will depend on the weight of the human subject to be treated with the intended dose or dosing regimen.

[0124] In one embodiment, the monoclonal anti-α-synuclein antibody according to the invention is administered at doses from 1000 mg to 4500 mg at intervals of 3-5 weeks, or the antibody is administered to human subjects in another regimen that provides estimated target binding of oligomeric α-synuclein in substantially the same patient CSF. In a particular embodiment, the antibody is administered to human subjects in a regimen that provides estimated target binding of oligomeric α-synuclein in patient CSF substantially the same as that provided by administration of 4200 mg GM37v2 approximately every 4 weeks.

[0125] In some embodiments, the monoclonal anti-α-synuclein antibody according to the invention is administered every 4 weeks. In some embodiments, the monoclonal anti-α-synuclein antibody according to the invention is administered monthly. In some embodiments, the monoclonal anti-α-synuclein antibody according to the invention is administered every 27 days, every 28 days, every 29 days, every 30 days, or every 31 days.

[0126] In a particular embodiment, the monoclonal anti-α-synuclein antibody according to the invention is administered every 3-5 weeks, for example every 4 weeks or once a month, for example every 28-30 days.

[0127] In a particular embodiment, the monoclonal anti-α-synuclein antibody according to the invention is administered at a dose of 1,000 mg to 4,500 mg, for example 2,000 mg to 4,500 mg, or 3,500 mg to 4,500 mg, for example 4,200 mg.

[0128] In a specific embodiment, the monoclonal anti-α-synuclein antibody according to the invention is administered at doses of about 1050 mg, about 1400 mg, about 1750 mg, about 2100 mg, about 2450 mg, about 2800 mg, about 3150 mg, about 3500 mg, about 3850 mg, and about 4200 mg. In another specific embodiment, the monoclonal anti-α-synuclein antibody according to the invention is administered at doses of 1050 mg, 2100 mg, or 4200 mg.

[0129] In one embodiment, the monoclonal anti-α-synuclein antibody according to the invention is administered at a dose of 13 mg / kg to 71 mg / kg, or, for example, 14 mg / kg to 64 mg / kg, or, for example, 15 mg / kg to 60 mg / kg, or, for example, 15 mg / kg, or, for example, 30 mg / kg, or, for example, 60 mg / kg, at intervals of 3-5 weeks, or the antibody is administered to human subjects in another regimen that provides estimated target binding of oligomeric α-synuclein in substantially the same patient CSF. In a particular embodiment, the antibody is administered to human subjects in a regimen that provides estimated target binding of oligomeric α-synuclein in patient CSF substantially the same as that provided by administration of 60 mg / kg GM37v2 approximately every 4 weeks.

[0130] In certain embodiments, the monoclonal anti-α-synuclein antibody according to the invention is administered at a dose of about 1 mg / kg, about 3 mg / kg, about 11 mg / kg, about 32 mg / kg, about 64 mg / kg, or about 129 mg / kg.

[0131] In a particular embodiment, the monoclonal anti-α-synuclein antibody according to the invention is administered at a dose of 14 mg / kg to 64 mg / kg, for example 15 mg / kg to 60 mg / kg, for example 30 mg / kg to 60 mg / kg, for example 60 mg / kg.

[0132] In a specific embodiment, the monoclonal anti-α-synuclein antibody according to the invention is administered at doses of about 11 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 55 mg / kg, about 60 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg, about 90 mg / kg, or about 95 mg / kg. In another specific embodiment, the monoclonal anti-α-synuclein antibody according to the invention is administered at doses of 15 mg / kg, 30 mg / kg, or 60 mg / kg.

[0133] In certain embodiments, the patients to be treated weigh between 50 and 110 kg, such as 50 kg, 55 kg, 60 kg, 65 kg, 70 kg, 75 kg, 80 kg, 85 kg, 90 kg, 95 kg, 100 kg, 105 kg, or 110 kg. In the clinical study disclosed in Example 3, the average weight of the human subjects included was approximately 70 kg.

[0134] In some embodiments, the dosage and dosing regimen of the present invention may also be expressed as the amount and frequency of administration of a monoclonal antibody (e.g., GM37v2) that provides sufficient estimated mean steady-state concentration of CSF, sufficient AUC exposure, or sufficient estimated target binding to oligomeric α-synuclein in CSF to achieve clinical efficacy.

[0135] The table below specifies the conversion between relevant dose forms for illustrative human subjects weighing 70 kg.

[0136] Table 1: Conversion between dose and dose form, and estimates of target binding in CSF and mean steady-state concentration in CSF, with an IV dosing interval of approximately 28 days.

[0137] For each dose, the estimated average Css of the CSF and the target binding of aggregated / oligomeric α-synuclein in the CSF can be calculated as described in Example 1.

[0138] The following table provides an example dosing regimen:

[0139] For the purposes of this disclosure, it is assumed that the CSF concentration of the antibody used according to the present invention is equal to the ISF concentration of the antibody.

[0140] In one embodiment, GM37v2 is administered intravenously to achieve the desired therapeutic concentration in the CSF and / or ISF of a human subject. In another embodiment, the antibody reaches a concentration sufficient to enter the brain and produce a therapeutic effect, for example, by binding to aggregated α-synuclein and triggering microglia-dependent and / or microglia-independent clearance / inactivation, and / or reducing α-synuclein aggregation, and / or preventing prion-like intracellular diffusion of α-synuclein.

[0141] In another embodiment, the desired therapeutic concentration of GM37v2 in CSF and / or ISF may be equal to at least 10%-100%, such as 20%-90%, such as 30%-80%, such as 40%-70%, such as 50%-60%, such as at least 10%, such as at least 20%, such as at least 30%, such as at least 40%, such as at least 50%, such as at least 60%, such as at least 70%, such as at least 80%, such as at least 85%, such as at least 90%, such as at least 95% of the reduced α-synuclein in the subject's ISF and / or CSF.

[0142] In one embodiment, the dosing regimen achieves a GM37v2 concentration higher than the estimated IC50 in the subject's ISF and / or CSF.

[0143] In one embodiment, the dosing regimen achieves a GM37v2 concentration that is higher than the estimated IC50 and lower than the estimated IC95 of oligomeric α-synuclein in the subject's ISF and / or CSF.

[0144] In one embodiment, the dosing regimen achieves a GM37v2 concentration higher than the estimated IC85 and lower than the estimated IC95 of oligomeric α-synuclein in the subject's ISF and / or CSF.

[0145] In one embodiment, the dosing regimen achieves a GM37v2 concentration higher than the estimated IC85 of oligomeric α-synuclein in the subject's ISF and / or CSF.

[0146] In one embodiment, the dosing regimen achieves a GM37v2 concentration higher than the estimated IC90 of oligomeric α-synuclein in the subject's ISF and / or CSF.

[0147] In one embodiment, the dosing regimen achieves a GM37v2 concentration higher than the estimated IC95 of oligomeric α-synuclein in the subject's ISF and / or CSF.

[0148] In another embodiment, the dosing regimen achieves a GM37v2 concentration that provides and maintains (after one or more doses) a reduction of more than 50% in the amount of α-synuclein accumulated in the subject's ISF and / or CSF.

[0149] In another embodiment, the dosing regimen achieves a GM37v2 concentration that provides and maintains (after one or more doses) a reduction of more than 80% in the amount of α-synuclein accumulated in the subject's ISF and / or CSF.

[0150] In another embodiment, the dosing regimen achieves a GM37v2 concentration that provides and maintains (after one or more doses) a reduction of more than 90% in the amount of α-synuclein accumulated in the subject's ISF and / or CSF.

[0151] In another embodiment, the dosing regimen achieves a GM37v2 concentration that provides and maintains (after one or more doses) a reduction of more than 95% of the estimated α-synuclein accumulated in the subject's ISF and / or CSF.

[0152] The dosage regimen is relevant and applicable to all types of synucleinosis and precursor synucleinosis. Specifically, the dosing regimen is relevant for the treatment of MSA, such as MSA-C, MSA-P, early MSA-P and / or early MSA-C, MSA in patients with less disease impairment, and MSA patients with low UMSARS TS scores at the time of the first dose, such as below 40 (e.g., below 39, below 38, below 37, below 36, below 35, below 34, below 33, below 32, below 31, below 30, 10-39, 15-39, 20-39, 25-39, 30-39, 35-39, 10-35, 15-35, 20-35, 25-35, 30-35, 10-30, 15-30, 20-30, 25-30, 10-25, 15-25, 20-25, 10-20, 15-20 or 10-15). The dosing regimen is ultimately determined based on the estimated mean steady-state concentration of CSF required to achieve desired target binding of oligomeric α-synuclein in the CSF / brain. While it is unclear how much aggregated α-synuclein must be removed from the CSF / ISF to alter and / or slow disease progression, no significant differences in CSF α-synuclein load have been found between different types of synucleinopathy. For example, Tateno et al. showed comparable levels of α-synuclein in CSF among patients with Lewy body dementia (DLB), Parkinson's disease (PD), and multiple system atrophy (MSA) (Tateno et al., Alzheimer Dis Assoc Disord [Alzheimer Disease and Related Diseases] 2012;26:213-216), suggesting that the dosing regimen can be predicted to be universally applicable to synucleinopathy and therefore not limited to specific indications such as PD, DLB, or MSA.

[0153] Furthermore, the dosage regimen is also relevant for patients with precursor synucleinopathy, as these patients have been shown to exhibit signs of altered α-synuclein processing; for example, Mollenhauer et al. demonstrated that participants with low-grade precursor synucleinopathy had the lowest mean CSF α-synuclein levels, while those with iRBD levels were between those of healthy controls and Parkinson's disease patients (Mollenhauer et al. Mov Disord. [Motor Disorders] Sep 2019; 34(9):1354-1364). These findings suggest that patients with clinical features of precursor synucleinopathy already have reduced CSF α-synuclein levels, consistent with the important pathology already present in these precursor stages.

[0154] The antibody according to the present invention is for use.

[0155] The antibodies used according to the present invention bind to epitopes within epitopes 112-117. In one embodiment, the present invention relates to monoclonal antibody GM37, its variants (e.g., GM37 variant 1, GM37 variant 2, and GM37 variant 3), or GM285, for the treatment of synucleinosis or precursor synucleinosis.

[0156] Antibodies against GM37, GM37 variant 1, GM37 variant 2, and GM37 variant 3 bind to an epitope within amino acids 112-117 (SEQ ID NO:9 (ILEDMP)) of human α-synuclein (SEQ ID NO:10). Specifically, antibodies against GM37, GM37 variant 1, GM37 variant 2, and GM37 variant 3 bind to all six amino acids within this epitope.

[0157] The GM285 antibody binds to the epitopes of amino acids 112-115 (ILED; SEQ ID NO:19) of human α-synuclein (SEQ ID NO:10).

[0158] "Anti-α synuclein antibody" or "α synuclein antibody" (used interchangeably) is an antibody that binds to α synuclein or α synuclein fragments. The antibodies of this invention specifically bind to the amino acid sequence of α synuclein corresponding to SEQ ID NO 9 and / or 19.

[0159] The term "antibody GM37" is intended to include an antibody comprising the heavy chain CDR1-3 shown in SEQ ID No:1, 2, and 3 and the light chain CDR1-3 shown in SEQ ID No:4, 5, and 6. In one embodiment, antibody GM37 may comprise the heavy chain variable domain of SEQ ID NO:7 and / or the light chain variable domain of SEQ ID NO:8. For example, antibody GM37 may be an IgG antibody comprising a heavy chain consisting of the variable domain of SEQ ID NO:7 and the constant domain of SEQ ID NO:18, and a light chain consisting of the variable domain of SEQ ID NO:8 and the constant κ domain of SEQ ID NO:17.

[0160] The term "antibody GM37 variant 1" is intended to include an antibody comprising the heavy chain CDR1-3 shown in SEQ ID No: 1, 33, and 3 and the light chain CDR1-3 shown in SEQ ID No: 4, 5, and 6. In one embodiment, antibody GM37 variant 1 may comprise the heavy chain variable domain of SEQ ID NO: 30 and / or the light chain variable domain of SEQ ID NO: 8. For example, antibody GM37 variant 1 may be an IgG1 antibody comprising a heavy chain consisting of the variable domain of SEQ ID NO: 30 and the constant domain of SEQ ID NO: 18, and a light chain consisting of the variable domain of SEQ ID NO: 8 and the constant κ domain of SEQ ID NO: 17.

[0161] The terms “GM37 variant 2” or “GM37v2” or “GM37var2” (used interchangeably) are intended to include antibodies comprising the heavy chain CDR1-3 shown in SEQ ID No:1, 34 and 3 and the light chain CDR1-3 shown in SEQ ID No:4, 5 and 6. In one embodiment, antibody GM37 variant 2 comprises the heavy chain variable domain of SEQ ID NO:31 and the light chain variable domain of SEQ ID NO:8.

[0162] For example, antibody GM37 variant 2 can be an IgG1 antibody containing the heavy chain CDR1-3 shown in SEQ ID No:1, 34 and 3 and the light chain CDR1-3 shown in SEQ ID No:4, 5 and 6.

[0163] For example, antibody GM37 variant 2 can be a human IgG1 antibody containing the heavy chain CDR1-3 shown in SEQ ID No: 1, 34 and 3 and the light chain CDR1-3 shown in SEQ ID No: 4, 5 and 6.

[0164] For example, antibody GM37 variant 2 can be an IgG1 antibody containing the heavy chain variable domain of SEQ ID NO:31 and the light chain variable domain of SEQ ID NO:8.

[0165] For example, antibody GM37 variant 2 can be a human IgG1 antibody containing the heavy chain variable domain of SEQ ID NO:31 and the light chain variable domain of SEQ ID NO:8.

[0166] For example, antibody GM37 variant 2 can be an IgG1 antibody containing the heavy chain variable domain of SEQ ID NO:31 and the heavy chain constant domain of SEQ ID NO:18, as well as the light chain variable domain of SEQ ID NO:8 and the κ light chain constant domain of SEQ ID NO:17.

[0167] For example, antibody GM37 variant 2 can be a human IgG1 antibody containing the heavy chain variable domain of SEQ ID NO:31 and the heavy chain constant domain of SEQ ID NO:18, as well as the light chain variable domain of SEQ ID NO:8 and the κ light chain constant domain of SEQ ID NO:17.

[0168] In a preferred embodiment, antibody GM37 variant 2 is eleneta monoclonal antibody.

[0169] The term "antibody GM37 variant 3" is intended to include antibodies comprising the heavy chain CDR1-3 shown in SEQ ID No: 1, 35, and 3, and the light chain CDR1-3 shown in SEQ ID No: 4, 5, and 6. In one embodiment, antibody GM37 variant 3 may comprise the heavy chain variable domain of SEQ ID NO: 32 and / or the light chain variable domain of SEQ ID NO: 8. For example, antibody GM37 variant 3 may be an IgG1 antibody comprising a heavy chain consisting of the variable domain of SEQ ID NO: 32 and the constant domain of SEQ ID NO: 18, and a light chain consisting of the variable domain of SEQ ID NO: 8 and the constant κ domain of SEQ ID NO: 17.

[0170] The term "antibody GM285" is intended to include an antibody comprising the heavy chain CDR1-3 shown in SEQ ID No:20, 21, and 22 and the light chain CDR1-3 shown in SEQ ID No:23, 24, and 25. In one embodiment, antibody GM285 may comprise the heavy chain variable domain of SEQ ID NO:26 and / or the light chain variable domain of SEQ ID NO:27. For example, antibody GM285 may be an IgG1 antibody comprising a heavy chain consisting of the variable domain of SEQ ID NO:26 and the constant domain of SEQ ID NO:28, and a light chain consisting of the variable domain of SEQ ID NO:27 and the constant κ domain of SEQ ID NO:29.

[0171] In preferred embodiments, the full-length GM37, GM37 variant 1, GM37 variant 2, GM37 variant 3, or GM285 antibody is in the form of an IgG isotype, most preferably in the form of IgG1, and even more preferably in the form of human or humanized IgG1. The most preferred form is the human GM37v2 IgG1.

[0172] The table below shows the specific amino acid sequences of the anti-α-synuclein antibody used in this article:

[0173] The specific amino acid sequence used in this article: GFTFSSYAMT (SEQ ID NO:1) AIRSN GDRTD YADSVKG (SEQ ID NO:2) AIRSS GDRTD YADSVKG (SEQ ID NO:33) AIRSQ GDRTD YADSVKG (SEQ ID NO:34) AIRSH GDRTD YADSVKG (SEQ ID NO:35) AKNWAPFDS (SEQ ID NO:3) ASQSVSSSYLA (SEQ ID NO:4) GASSRAT (SEQ ID NO:5) QQYGSSPWT (SEQ ID NO:6)

[0174] AASGFTFSRFTMT (SEQ ID NO:20)

[0175] AISGSGGGTS YADSVKG (SEQ ID NO:21)

[0176] AKNWAPFDY (SEQ ID NO:22)

[0177] RASQSVSRSYLA (SEQ ID NO:23)

[0178] GASSRAT (SEQ ID NO:24)

[0179] QQYGSSPWT (SEQ ID NO:25)

[0180] The complete sequence list is given below:

[0181] The antibodies used according to the present invention can be obtained from any suitable source and, in some embodiments, can be generated in different cell lines, such as human cell lines, mammalian non-human cell lines, or insect cell lines, for example, CHO cell lines, HEK cell lines, BHK-21 cell lines, mouse cell lines (e.g., myeloma cell lines), fibrosarcoma cell lines, PER.C6 cell lines, HKB-11 cell lines, CAP cell lines, or HuH-7 human cell lines.

[0182] In one embodiment, the antibody used according to the invention is a human antibody. Human monoclonal antibodies against α-synuclein can be generated using transgenic or transchromosomal mice carrying a portion of the human immune system rather than the mouse system. Such transgenic and transchromosomal mice include mice that may be referred to as HuMAb mice and KM mice, respectively.

[0183] In one embodiment, the antibody used according to the invention (exemplified by GM37, its variants GM37 var 1-3, and GM285) is capable of binding to and neutralizing the toxicity of a toxic α-synuclein fragment consisting of residues 1-119 / 122 of α-synuclein (e.g., by binding extracellularly to the α-synuclein fragment, thereby preventing its uptake by the cell). In another embodiment, the antibody used according to the invention is capable of binding to epitopes within amino acids 112-117 of α-synuclein and to toxic α-synuclein species in the human brain. In yet another embodiment, the antibody used according to the invention has the function of clearing extracellular α-synuclein and normalizing impaired synaptic transmission induced by α-synuclein in vivo. In yet another embodiment, the antibody used according to the invention is also capable of improving the appearance of related motor phenotypes in a rat model of Parkinson's disease. All these properties are described in detail in WO 2017 / 009312.

[0184] Drug formulation and route of administration

[0185] The pharmaceutical compositions used according to the present invention may contain diluents, fillers, salts, buffers, detergents (e.g., nonionic detergents such as Tween-20 or Tween-80), stabilizers (e.g., sugars or protein-free amino acids), preservatives, tissue fixatives, solubilizers, and / or other materials suitable for inclusion in the pharmaceutical composition.

[0186] In addition, the pharmaceutical composition or formulation may also contain other carriers, or non-toxic, non-therapeutic, non-immunogenic stabilizers, etc. The composition may also contain large, slowly metabolized macromolecules, such as proteins, polysaccharides (like chitosan), polylactic acid, polyglycolic acid and copolymers (e.g., latex-functionalized cross-linked agarose, agarose, cellulose, etc.), polymeric amino acids, amino acid copolymers, and lipid aggregates (e.g., oil droplets or liposomes).

[0187] Pharmaceutically acceptable carriers include any and all suitable solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, antioxidants, and absorption delay agents, as well as analogs that are physiologically compatible with the antibodies used according to the invention. Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the invention include water, saline, phosphate-buffered saline, ethanol, dextran, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils (such as olive oil, corn oil, peanut oil, cottonseed oil, and sesame oil), carboxymethyl cellulose colloidal solutions, tragacanth gum, and organic esters (such as ethyl oleate) and / or various buffers. Other carriers are well known in the pharmaceutical field and may also be used in the present invention.

[0188] Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders used for the temporary preparation of sterile solutions.

[0189] The pharmaceutical compositions of the present invention may further comprise pharmaceutically acceptable antioxidants, such as (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and (3) metal chelating agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0190] The pharmaceutical compositions of the present invention may also contain isotonic agents, such as sugars, polyols (such as mannitol, sorbitol, glycerol) or sodium chloride.

[0191] The pharmaceutical compositions of the present invention may also contain one or more adjuvants suitable for the selected route of administration, such as preservatives, wetting agents, emulsifiers, dispersants, or buffers, which may enhance the shelf life or efficacy of the pharmaceutical composition.

[0192] The antibodies of this invention can be prepared together with carriers that protect the antibodies from rapid release, such as controlled-release formulations, including implants, transdermal patches, and microencapsulated delivery systems. Such carriers may include gelatin, glyceryl monostearate, glyceryl distearate, biodegradable biocompatible polymers (such as ethylene vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyorthoesters, and polylactic acid) (alone or with waxes), or other materials well known in the art. Methods for preparing such formulations are generally known to those skilled in the art.

[0193] Infusion pharmaceutical compositions typically must be sterile and stable under the conditions of production and storage. The compositions can be formulated as solutions, microemulsions, liposomes, or other ordered structures suitable for high drug concentrations. The carrier can be an aqueous or non-aqueous solvent or dispersion medium containing, for example, water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils (such as olive oil), and organic esters (such as ethyl oleate).

[0194] Sterile solutions for infusion can be prepared by incorporating the required amount of active antibody with one or a combination of the components listed above into a suitable solvent, followed by sterile microfiltration. Typically, dispersions are prepared by incorporating the active antibody into a sterile carrier containing a base dispersion medium and other desired components, such as those listed above. In cases where sterile powder is used to prepare sterile solutions, examples of preparation methods include vacuum drying and freeze-drying (lyophilization), which yield a powder containing the active ingredient plus any other desired components from a previously sterile filtered solution.

[0195] For ease of administration and dosage consistency, the composition can be formulated in unit dosage form. As used herein, unit dosage form refers to a single unit suitable for use as a treatment subject; each unit contains a predetermined amount of active antibody that binds to the desired pharmaceutical excipient to produce the desired therapeutic effect.

[0196] In a particular embodiment, the pharmaceutical composition is administered via intravenous infusion.

[0197] Specific liquid drug compositions

[0198] In one aspect, the antibody according to the invention is formulated as a liquid pharmaceutical composition and administered by intravenous infusion.

[0199] In one aspect, the present invention provides the use of a liquid pharmaceutical composition comprising a full-length IgG1 monoclonal anti-α-synuclein antibody at a concentration of about 20-230 mg / mL, for example, 25-225 mg / mL, wherein said antibody comprises: a. Heavy chain CDR1 having the amino acid sequence of SEQ ID NO:1; b. Heavy chain CDR2 having the amino acid sequence of SEQ ID NO:34; c. Heavy chain CDR3 having the amino acid sequence of SEQ ID NO:3; d. The light chain CDR1 having the amino acid sequence of SEQ ID NO:4; e. The light chain CDR2 having the amino acid sequence of SEQ ID NO:5; and f. Light chain CDR3 having the amino acid sequence of SEQ ID NO:6; The composition further comprises a buffer, a pharmaceutically acceptable tensile agent, and a pharmaceutically acceptable surfactant, and the pH of the composition is between 4.5 and 7.5, for example, 5.0 to 7.0, for example, 5.5 to 6.5, for example, 6.0.

[0200] In a preferred embodiment, the liquid pharmaceutical composition according to the invention is a stable liquid pharmaceutical composition. In a preferred embodiment, the liquid pharmaceutical composition is a low-viscosity liquid pharmaceutical composition. In a preferred embodiment, the liquid pharmaceutical composition is both stable and low-viscosity. In a preferred embodiment, the liquid pharmaceutical composition is suitable for clinical use and is safe for patients requiring administration / dispensing the liquid pharmaceutical composition.

[0201] In some embodiments, the monoclonal anti-α-synuclein antibody of the liquid pharmaceutical composition further comprises a heavy chain variable domain consisting of SEQ ID NO:31 and a light chain variable domain consisting of SEQ ID NO:8. In more specific embodiments, the monoclonal anti-α-synuclein antibody also comprises a constant heavy chain domain as defined in SEQ ID NO:18 and a κ light chain constant domain as defined in SEQ ID NO:17.

[0202] In some embodiments, the liquid pharmaceutical composition comprises a monoclonal anti-α-synuclein antibody at a concentration greater than 20 mg / mL, and in some embodiments, the antibody concentration is less than 230 mg / mL. In further embodiments, the concentration of monoclonal anti-α-synuclein antibody in the pharmaceutical composition is 20-225 mg / mL, 20-220 mg / mL, 20-215 mg / mL, 20-210 mg / mL, 20-205 mg / mL, 20-200 mg / mL, 20-195 mg / mL, 20-190 mg / mL, 20-185 mg / mL, 20-180 mg / mL, 20-175 mg / mL, 20-170 mg / mL, 20-165 mg / mL, 20-160 mg / mL, 20-155 mg / mL, 20-150 mg / mL, 20-145 mg / mL, 20-140 mg / mL, 20-135 mg / mL, 20-130 mg / mL, 20-125 mg / mL, 20-120 mg / mL, 20-115 mg / mL. mg / mL, 20-110 mg / mL, 20-105 mg / mL, 20-100 mg / mL, 20-95mg / mL, 20-90 mg / mL, 20-85 mg / mL, 20-80 mg / mL, 20-75 mg / mL, 20-70 mg / mL, 20-65 mg / mL, 20-60 mg / mL, 20-55 mg / mL, 20-50 mg / mL, 20-45 mg / mL, 20-40 mg / mL, 20-35 mg / mL, 20-30 mg / mL, 20-25 mg / mL, 25-230 mg / mL, 30-230 mg / mL, 35-230 mg / mL, 40-230 mg / mL, 45-230 mg / mL, 50-230 mg / mL, 55-230 mg / mL, 60-230 mg / mL, 65-230 mg / mL, 70-230 mg / mL, 75-230 mg / mL, 80-230 mg / mL, 85-230 mg / mL, 90-230 mg / mL, 95-230 mg / mL, 100-230mg / mL, 105-230 mg / mL, 110-230 mg / mL, 115-230 mg / mL, 120-230 mg / mL, 125-230 mg / mL, 130-230 mg / mL, 135-230 mg / mL, 140-230 mg / mL, 145-230 mg / mL, 150-230 mg / mL, 155-230mg / mL, 160-230 mg / mL, 165-230mg / mL, 170-230 mg / mL, 175-230 mg / mL, 180-230 mg / mL, 185-230 mg / mL, 190-230 mg / mL, 195-230 mg / mL, 200-230 mg / mL, 205-230 mg / mL, 210-230mg / mL, 215-230 mg / mL, 220-230 mg / mL, 225-230 mg / mL, 25-225 mg / mL, 30-220 mg / mL, 35-215 mg / mL, 40-210 mg / mL, 45-205 mg / mL, 50-200 mg / mL, 55-195 mg / mL, 60-190 mg / mL, 65-185 mg / mL, 70-180 mg / mL, 75-175 mg / mL, 80-170 mg / mL, 85-165 mg / mL, 90-160 mg / mL, 95-155 mg / mL, 100-150 mg / mL, 105-145 mg / mL, 110-140 mg / mL, 115-135 mg / mL, or 120-130 mg / mL; including each value between these numbers. In a particular embodiment, the liquid pharmaceutical composition comprises a monoclonal anti-α-synuclein antibody at a concentration of about 50 mg / mL. In another particular embodiment, the monoclonal anti-α-synuclein antibody in the liquid pharmaceutical composition has a concentration of about 53 mg / mL. In some embodiments, the concentration of the monoclonal anti-α-synuclein antibody in the liquid pharmaceutical composition is within + / - 30% of the value, for example + / - 25%, for example + / - 20%, for example + / - 15%, for example + / - 10% of the value, for example + / - 8%, for example + / - 6%, for example + / - 5%, for example + / - 4%, for example + / - 3%, for example + / - 2.5%, for example + / - 2%, for example + / - 1.5%, for example + / - 1%, for example + / - 0.75%, for example + / - 0.5%, for example + / - 0.25%, for example + / - 0.1%, for example + / - 0.05%, for example + / - 0.025%, for example + / - 0.01%, for example + / - 0.0075%, for example + / - 0.005%, for example + / - 0.0025%, for example + / - 0.001%, or for example + / - 0.0005%.

[0203] In some embodiments of the invention, the buffer is a single buffer or a mixture of buffers. In another embodiment, the buffer is selected from acetate, citrate, tartrate, histidine, glutamate, phosphate, Tris, glycine, bicarbonate, succinate, sulfate, or nitrate buffers, or mixtures thereof. In further embodiments, the buffer is selected from sodium phosphate, histidine (such as L-histidine), citric acid, sodium citrate, sodium acetate, or mixtures thereof. In specific embodiments, the buffer is a histidine buffer (such as L-histidine) or a mixture of histidine buffers. The histidine buffer may be selected from histidine buffers and mixtures thereof, such as histidine, L-histidine, L-histidine hydrochloride, L-histidine monohydrochloride, L-histidine monohydrate, and L-histidine hydrochloride monohydrate, or mixtures thereof. In a preferred embodiment, the histidine buffer is a mixture of L-histidine and L-histidine monohydrochloride. In some preferred embodiments of the liquid pharmaceutical composition, the buffer is present at a concentration of 10-60 mM, for example 15-55 mM, for example 20-50 mM, for example 20-45 mM, for example 20-40 mM, for example 25-40 mM, for example 10-40 mM, for example 15-35 mM, for example 20-30 mM, or for example 25 mM. In some embodiments, the concentration of the buffer in the liquid pharmaceutical composition is within + / -30% of the value, for example + / -25%, + / -20%, + / -15%, + / -10% of the value, + / -8%, + / -6%, + / -5%, + / -4%, + / -3%, + / -2.5%, + / -2%, + / -1.5%, + / -1%, + / -0.75%, + / -0.5%, + / -0.25%, + / -0.1%, + / -0.05%, + / -0.025%, + / -0.01%, + / -0.0075%, + / -0.005%, + / -0.0025%, + / -0.001%, or + / -0.0005%.

[0204] In embodiments, the pH of the liquid pharmaceutical composition according to the invention is in the range of about 4.5 to about 7.5, for example, 4.5 to about 6.5, for example, 5.0 to 6.5, for example, about 5.5 to about 6.5, for example, 5.7 to 6.4, 5.8 to 6.3, or 5.9 to 6.2. In one embodiment, the pH of the liquid pharmaceutical composition is 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, or 7.0. Histidine buffer (e.g., L-histidine) is an example of a buffer that can be included in the liquid pharmaceutical composition, which controls the pH within this range. In a preferred embodiment, the pH of the liquid pharmaceutical composition is 6.0. In some embodiments, the pH of the liquid pharmaceutical composition is within + / -30% of the stated value, for example + / -25%, + / -20%, + / -15%, + / -10%, + / -8%, + / -6%, + / -5%, + / -4%, + / -3%, + / -2.5%, + / -2%, + / -1.5%, + / -1%, + / -0.75%, + / -0.5%, + / -0.25%, + / -0.1%, + / -0.05%, + / -0.025%, + / -0.01%, + / -0.0075%, + / -0.005%, + / -0.0025%, + / -0.001%, or + / -0.0005%.

[0205] In the embodiments, the surfactant used in the liquid pharmaceutical composition according to the present invention is a nonionic surfactant. In a further embodiment, the surfactant is selected from the group consisting of: polysorbates (e.g., polysorbate 20 and polysorbate 80); poloxamer (e.g., poloxamer 188); Triton; Triton X-100; sodium dodecyl sulfate (SDS); sodium lauryl sulfate; sodium octyl glycoside; lauryl, myristyl, linoleoyl, or stearyl sulfobetaine; lauryl, myristyl, linoleoyl, or stearyl sarcosine; linoleoyl, myristyl, or hexadecyl betaine; lauroamide propyl, cocamidopropyl, linoleamide propyl, myristamide propyl, palmitopropyl, or isostearamide propyl betaine (e.g., lauroamide propyl); myristamide propyl, palmitopropyl, or isostearamide propyl dimethylamine; sodium methylcocoyl taurate or disodium methyloleyl taurate; polyethylene glycol, polypropylene glycol, and copolymers of ethylene and propylene glycol. In one particular embodiment, the pharmaceutically acceptable surfactant in the liquid pharmaceutical composition is polysorbate 80, also known as Tween 80. In some preferred embodiments of the liquid pharmaceutical composition, the surfactant is present in an amount of 0.001% to 0.10% (w / v), for example 0.005% to 0.08% (w / v), for example 0.008% to 0.06% (w / v), for example 0.01% to 0.05% (w / v), for example 0.015% to 0.05% (w / v), for example 0.01% to 0.05% (w / v), for example 0.01% to 0.03% (w / v), or for example 0.02% (w / v). In some embodiments, the concentration of the surfactant in the liquid pharmaceutical composition is within + / - 30% of the value, for example + / - 25%, + / - 20%, + / - 15%, + / - 10%, + / - 8%, + / - 6%, + / - 5%, + / - 4%, + / - 3%, + / - 2.5%, + / - 2%, + / - 1.5%, + / - 1%, + / - 0.75%, + / - 0.5%, + / - 0.25%, + / - 0.1%, + / - 0.05%, + / - 0.025%, + / - 0.01%, + / - 0.0075%, + / - 0.005%, + / - 0.0025%, + / - 0.001%, or + / - 0.0005%.

[0206] In embodiments, the tensile agent for the liquid pharmaceutical composition according to the invention is selected from mannitol, sorbitol, lactose, dextrose, trehalose, sodium chloride, potassium chloride, glycerol, and glycerol. In one particular embodiment, the tensile agent is a suitable salt, such as NaCl. In another particular embodiment, the tensile agent for the liquid pharmaceutical composition is sodium chloride (NaCl). In some preferred embodiments of the liquid pharmaceutical composition, the tensile agent is present at a concentration of 10-150 mM, for example 20-140 mM, for example 30-130 mM, for example 40-120 mM, for example 50-110 mM, for example 60-110 mM, for example 70-110 mM, for example 80-110 mM, for example 90-110 mM, or for example about 100 mM. In some embodiments, the concentration of the tensile agent in the liquid pharmaceutical composition is within + / - 30% of the value, for example + / - 25%, + / - 20%, + / - 15%, + / - 10%, + / - 8%, + / - 6%, + / - 5%, + / - 4%, + / - 3%, + / - 2.5%, + / - 2%, + / - 1.5%, + / - 1%, + / - 0.75%, + / - 0.5%, + / - 0.25%, + / - 0.1%, + / - 0.05%, + / - 0.025%, + / - 0.01%, + / - 0.0075%, + / - 0.005%, + / - 0.0025%, + / - 0.001%, or + / - 0.0005%.

[0207] In embodiments, the liquid pharmaceutical composition according to the invention further comprises a filler selected from: sugars and polyols (such as sucrose, trehalose, glucose, lactose, sorbitol, mannitol, and glycerol); amino acids (such as arginine, aspartic acid, glutamic acid, lysine, glycine, glutamate, histidine, methionine, or alanine); or polymers and proteins (such as gelatin, PVP, PLGA, PEG, dextran, cyclodextrin and its derivatives, starch derivatives, HSA, or BSA). In one particular embodiment, the filler is selected from arginine, glutamate, sucrose, glycine, or sorbitol. In one particular embodiment, the filler is sucrose. In some preferred embodiments of the liquid pharmaceutical composition, the filler is present at a concentration of 20-200 mM, for example 25-180 mM, for example 30-170 mM, for example 35-160 mM, for example 40-150 mM, for example 45-140 mM, for example 50-130 mM, for example 60-130 mM, for example 65-120 mM, for example 70-120 mM, for example 75-120 mM, for example 80-110 mM, for example 85-110 mM, for example 90-110 mM, for example 95-110 mM, for example 95-105 mM, or for example 100 mM. In some embodiments, the concentration of the filler in the liquid pharmaceutical composition is within + / - 30% of the value, for example + / - 25%, for example + / - 20%, for example + / - 15%, for example + / - 10% of the value, for example + / - 8%, for example + / - 6%, for example + / - 5%, for example + / - 4%, for example + / - 3%, for example + / - 2.5%, for example + / - 2%, for example + / - 1.5%, for example + / - 1%, for example + / - 0.75%, for example + / - 0.5%, for example + / - 0.25%, for example + / - 0.1%, for example + / - 0.05%, for example + / - 0.025%, for example + / - 0.01%, for example + / - 0.0075%, for example + / - 0.005%, for example + / - 0.0025%, for example + / - 0.001%, or for example + / - 0.0005%.

[0208] In an embodiment, the liquid pharmaceutical composition according to the invention comprises a monoclonal anti-α-synuclein antibody GM37v2, histidine buffer, and sodium chloride (NaCl) at a pH of 4.5-7.5.

[0209] In an embodiment, the liquid pharmaceutical composition according to the invention comprises 20-230 mg / mL monoclonal anti-α-synuclein antibody GM37v2, 10-60 mM histidine buffer, and 10-150 mM sodium chloride (NaCl), with a pH of 4.5-7.5.

[0210] In an embodiment, the liquid pharmaceutical composition according to the invention comprises 40-60 mg / mL monoclonal anti-α-synuclein antibody GM37v2, 20-30 mM histidine buffer, and 90-110 mM sodium chloride (NaCl), with a pH of 5.5-6.5.

[0211] In an example, the liquid pharmaceutical composition according to the invention comprises 53 mg / mL monoclonal anti-α-synuclein antibody GM37v2, 25 mM histidine buffer, and 100 mM sodium chloride (NaCl) at pH 6.0.

[0212] In an embodiment, the liquid pharmaceutical composition according to the invention comprises 53 mg / mL monoclonal anti-α-synuclein antibody GM37v2, 25 mM histidine buffer, and 100 mM sodium chloride (NaCl) at pH 6.0 or within + / - 30% of said value, for example + / - 25%, for example + / - 20%, for example + / - 15%, for example + / - 10%, for example + / - 5%, for example + / - 1%, for example + / - 0.5%, for example + / - 0.25%, or for example + / - 0.1%.

[0213] In an embodiment, the liquid pharmaceutical composition according to the invention comprises a monoclonal anti-α-synuclein antibody GM37v2, histidine buffer, and polysorbate 80 (tween 80) at a pH of 4.5-7.5.

[0214] In the embodiments, the liquid pharmaceutical composition according to the invention comprises 20-230 mg / mL monoclonal anti-α-synuclein antibody GM37v2, 10-60 mM histidine buffer, and polysorbate 80 (tween 80) in amounts between 0.001% and 0.10% (w / v), with a pH of 4.5-7.5.

[0215] In the embodiments, the liquid pharmaceutical composition according to the invention comprises 40-60 mg / mL monoclonal anti-α-synuclein antibody GM37v2, 20-30 mM histidine buffer, and polysorbate 80 (tween 80) in amounts between 0.01% and 0.03% (w / v), with a pH of 5.5-6.5.

[0216] In an example, the liquid pharmaceutical composition according to the invention comprises 53 mg / mL monoclonal anti-α-synuclein antibody GM37v2, 25 mM histidine buffer, and polysorbate 80 (tween 80) in an amount of 0.02% (w / v) at pH 6.0.

[0217] In an embodiment, the liquid pharmaceutical composition according to the invention comprises 53 mg / mL monoclonal anti-α-synuclein antibody GM37v2, 25 mM histidine buffer, and polysorbate 80 (tween 80) in an amount of 0.02% (w / v), pH 6.0, or within + / - 30% of said value, for example + / - 25%, + / - 20%, + / - 15%, + / - 10%, + / - 5%, + / - 1%, + / - 0.5%, + / - 0.25%, or + / - 0.1%.

[0218] In an embodiment, the liquid pharmaceutical composition according to the invention comprises a monoclonal anti-α-synuclein antibody GM37v2, histidine buffer, sodium chloride (NaCl), and polysorbate 80 (tween 80), with a pH of 4.5-7.5.

[0219] In the embodiments, the liquid pharmaceutical composition according to the invention comprises 20-230 mg / mL monoclonal anti-α-synuclein antibody GM37v2, 10-60 mM histidine buffer, 10-150 mM sodium chloride (NaCl), and polysorbate 80 (tween 80) in amounts between 0.001% and 0.10% (w / v), with a pH of 4.5-7.5.

[0220] In the embodiments, the liquid pharmaceutical composition according to the invention comprises 40-60 mg / mL monoclonal anti-α-synuclein antibody GM37v2, 20-30 mM histidine buffer, 90-110 mM sodium chloride (NaCl), and polysorbate 80 (tween 80) in amounts between 0.01% and 0.03% (w / v), with a pH of 5.5-6.5.

[0221] In an embodiment, the liquid pharmaceutical composition according to the invention comprises 53 mg / mL monoclonal anti-α-synuclein antibody GM37v2, 25 mM histidine buffer, 100 mM sodium chloride (NaCl), and polysorbate 80 (tween 80) in an amount of 0.02% (w / v) and a pH of 6.0.

[0222] In an embodiment, the liquid pharmaceutical composition according to the invention comprises 53 mg / mL monoclonal anti-α-synuclein antibody GM37v2, 25 mM histidine buffer, 100 mM sodium chloride (NaCl), and polysorbate 80 (tween 80) in an amount of 0.02% (w / v), pH 6.0, or within + / - 30% of said value, for example + / - 25%, for example + / - 20%, for example + / - 15%, for example + / - 10%, for example + / - 5%, for example + / - 1%, for example + / - 0.5%, for example + / - 0.25%, or for example + / - 0.1%.

[0223] In an embodiment, the liquid pharmaceutical composition according to the invention comprises a monoclonal anti-α-synuclein antibody GM37v2, histidine buffer, sodium chloride (NaCl), and sucrose, at a pH of 4.5-7.5.

[0224] In the embodiments, the liquid pharmaceutical composition according to the present invention comprises 20-230 mg / mL monoclonal anti-α-synuclein antibody GM37v2, 10-60 mM histidine buffer, 10-150 mM sodium chloride (NaCl) and 20-200 mM sucrose, with a pH of 4.5-7.5.

[0225] In an embodiment, the liquid pharmaceutical composition according to the invention comprises 40-60 mg / mL monoclonal anti-α-synuclein antibody GM37v2, 20-30 mM histidine buffer, 90-110 mM sodium chloride (NaCl), and 90-110 mM sucrose, with a pH of 5.5-6.5.

[0226] In an embodiment, the liquid pharmaceutical composition according to the invention comprises 53 mg / mL monoclonal anti-α-synuclein antibody GM37v2, 25 mM histidine buffer, 100 mM sodium chloride (NaCl), and 100 mM sucrose, at a pH of 6.0.

[0227] In an embodiment, the liquid pharmaceutical composition according to the invention comprises 53 mg / mL monoclonal anti-α-synuclein antibody GM37v2, 25 mM histidine buffer, 100 mM sodium chloride (NaCl), and 100 mM sucrose, at a pH of 6.0 or within + / - 30% of said value, for example + / - 25%, + / - 20%, + / - 15%, + / - 10%, + / - 5%, + / - 1%, + / - 0.5%, + / - 0.25%, or + / - 0.1%.

[0228] In an embodiment, the liquid pharmaceutical composition according to the invention comprises a monoclonal anti-α-synuclein antibody GM37v2, histidine buffer, sucrose, and polysorbate 80 (tween 80), with a pH of 4.5-7.5.

[0229] In the embodiments, the liquid pharmaceutical composition according to the invention comprises 20-230 mg / mL monoclonal anti-α-synuclein antibody GM37v2, 10-60 mM histidine buffer, 20-200 mM sucrose, and polysorbate 80 (tween 80) in amounts between 0.001% and 0.10% (w / v), with a pH of 4.5-7.5.

[0230] In the embodiments, the liquid pharmaceutical composition according to the invention comprises 40-60 mg / mL monoclonal anti-α-synuclein antibody GM37v2, 20-30 mM histidine buffer, 90-110 mM sucrose, and polysorbate 80 (tween 80) in amounts between 0.01% and 0.03% (w / v), with a pH of 5.5-6.5.

[0231] In an example, the liquid pharmaceutical composition according to the invention comprises 53 mg / mL monoclonal anti-α-synuclein antibody GM37v2, 25 mM histidine buffer, 100 mM sucrose, and polysorbate 80 (tween 80) in an amount of 0.02% (w / v) and a pH of 6.0.

[0232] In an embodiment, the liquid pharmaceutical composition according to the invention comprises 53 mg / mL monoclonal anti-α-synuclein antibody GM37v2, 25 mM histidine buffer, 100 mM sucrose, and polysorbate 80 (tween 80) in an amount of 0.02% (w / v), pH 6.0, or within + / - 30% of said value, for example + / - 25%, + / - 20%, + / - 15%, + / - 10%, + / - 5%, + / - 1%, + / - 0.5%, + / - 0.25%, or + / - 0.1%.

[0233] In an embodiment, the liquid pharmaceutical composition according to the invention comprises a monoclonal anti-α-synuclein antibody GM37v2, histidine buffer, sodium chloride (NaCl), sucrose, and polysorbate 80 (tween 80), with a pH of 4.5-7.5.

[0234] In the embodiments, the liquid pharmaceutical composition according to the invention comprises 20-230 mg / mL monoclonal anti-α-synuclein antibody GM37v2, 10-60 mM histidine buffer, 10-150 mM sodium chloride (NaCl), 20-200 mM sucrose, and polysorbate 80 (tween 80) in amounts between 0.001% and 0.10% (w / v), with a pH of 4.5-7.5.

[0235] In an embodiment, the liquid pharmaceutical composition according to the invention comprises 40-60 mg / mL monoclonal anti-α-synuclein antibody GM37v2, 20-30 mM histidine buffer, 90-110 mM sodium chloride (NaCl), 90-110 mM sucrose, and polysorbate 80 (tween 80) in amounts between 0.01% and 0.03% (w / v), with a pH of 5.5-6.5.

[0236] In an embodiment, the liquid pharmaceutical composition according to the invention comprises 53 mg / mL monoclonal anti-α-synuclein antibody GM37v2, 25 mM histidine buffer, 100 mM sodium chloride (NaCl), 100 mM sucrose, and polysorbate 80 (tween 80) in an amount of 0.02% (w / v) and a pH of 6.0.

[0237] In an embodiment, the liquid pharmaceutical composition according to the invention comprises 53 mg / mL monoclonal anti-α-synuclein antibody GM37v2, 25 mM histidine buffer, 100 mM sodium chloride (NaCl), 100 mM sucrose, and polysorbate 80 (tween 80) in an amount of 0.02% (w / v), pH 6.0, or within + / - 30% of said value, for example + / - 25%, + / - 20%, + / - 15%, + / - 10%, + / - 5%, + / - 1%, + / - 0.5%, + / - 0.25%, or + / - 0.1%.

[0238] In some embodiments, the liquid pharmaceutical composition according to the invention is presented in 20 mL vials, each vial containing about 1000-1060 mg of GM37v2, for example about 1060 mg.

[0239] Synucleoproteinopathy and precursor synucleoproteinopathy

[0240] Synucleinopathies are neuronal inclusions characterized by pathological α-synuclein aggregates called Lewy bodies. Synucleinopathies include Parkinson's disease (PD) (including idiopathic and hereditary forms of Parkinson's disease) and diffuse Lewy body (DLB) diseases (also known as Lewy body dementia (DLB), Lewy body variant of Alzheimer's disease (LBV), combined Alzheimer's and Parkinson's disease (CAPD), isolated autonomic failure (PAF), and multiple system atrophy (MSA; e.g., oligopontine atrophy, striatal substantia nigra, and Shy-Drager syndrome)). In one aspect, the present invention provides suitable dosage regimens for treating synucleinosis, such as Parkinson's disease (PD) (including idiopathic and hereditary forms of Parkinson's disease), Gaucher disease (GD), diffuse Lewy body disease (DLBD), Lewy body dementia (DLB), Lewy body variant (LBV) of Alzheimer's disease, combined Alzheimer's disease and Parkinson's disease, isolated autonomic dysfunction, and multiple system atrophy (MSA). In a preferred embodiment, the synucleinosis is PD. In another preferred embodiment, the synucleinosis is DLB. In yet another preferred embodiment, the synucleinosis is MSA.

[0241] In yet another preferred embodiment, the human subject with MSA has MSA-C. In yet another embodiment, the human subject with MSA has MSA-P. In yet another preferred embodiment, the human subject with MSA has suspected or probable MSA-C. In yet another embodiment, the human subject with MSA has suspected or probable MSA-P.

[0242] In yet another preferred embodiment, the human subject with MSA has MSA at an early stage of the disease. In yet another such embodiment, the human subject with MSA has MSA at an early stage of the disease. In yet another such embodiment, the human subject with MSA has early-stage MSA. In yet another such embodiment, the UMSARS TS of human subjects with MSA is < 40, for example, less than 39, less than 38, less than 37, less than 36, less than 35, less than 34, less than 33, less than 32, less than 31, less than 30, 10-39, 15-39, 20-39, 25-39, 30-39, 35-39, 10-35, 15-35, 20-35, 25-35, 30-35, 10-30, 15-30, 20-30, 25-30, 10-25, 15-25, 20-25, 10-20, 15-20, or 10-15. In yet another such embodiment, human subjects with MSA had UMSARS TS < 40 at the start of anti-α-synuclein antibody treatment, for example, less than 39, less than 38, less than 37, less than 36, less than 35, less than 34, less than 33, less than 32, less than 31, less than 30, 10-39, 15-39, 20-39, 25-39, 30-39, 35-39, 10-35, 15-35, 20-35, 25-35, 30-35, 10-30, 15-30, 20-30, 25-30, 10-25, 15-25, 20-25, 10-20, 15-20, or 10-15. In yet another such embodiment, human subjects with MSA had UMSARS TS < 40 at the time of first administration of an anti-α-synuclein antibody (e.g., GM37v2 (eleneta)), for example, less than 39, less than 38, less than 37, less than 36, less than 35, less than 34, less than 33, less than 32, less than 31, less than 30, 10-39, 15-39, 20-39, 25-39, 30-39, 35-39, 10-35, 15-35, 20-35, 25-35, 30-35, 10-30, 15-30, 20-30, 25-30, 10-25, 15-25, 20-25, 10-20, 15-20, or 10-15.

[0243] In yet another preferred embodiment, the human subject with MSA has MSA-C and their UMSARS TS <40, for example, less than 39, less than 38, less than 37, less than 36, less than 35, less than 34, less than 33, less than 32, less than 31, less than 30, 10-39, 15-39, 20-39, 25-39, 30-39, 35-39, 10-35, 15-35, 20-35, 25-35, 30-35, 10-30, 15-30, 20-30, 25-30, 10-25, 15-25, 20-25, 10-20, 15-20, or 10-15. In yet another such embodiment, human subjects with MSA have MSA-C and their UMSARS TS at the start of anti-α-synuclein antibody treatment is <40, for example, less than 39, less than 38, less than 37, less than 36, less than 35, less than 34, less than 33, less than 32, less than 31, less than 30, 10-39, 15-39, 20-39, 25-39, 30-39, 35-39, 10-35, 15-35, 20-35, 25-35, 30-35, 10-30, 15-30, 20-30, 25-30, 10-25, 15-25, 20-25, 10-20, 15-20, or 10-15. In yet another such embodiment, a human subject with MSA has MSA-C and whose UMSARS TS at the start of treatment with an anti-α synuclein antibody (e.g., GM37v2 (elenetamab)) is < 40, for example, < 39, < 38, < 37, < 36, < 35, < 34, < 33, < 32, < 31, < 30, 10-39, 15-39, 20-39, 25-39, 30-39, 35-39, 10-35, 15-35, 20-35, 25-35, 30-35, 10-30, 15-30, 20-30, 25-30, 10-25, 15-25, 20-25, 10-20, 15-20, or 10-15. In yet another such embodiment, human subjects with MSA who also have MSA-C and whose UMSARS TS at the time of first administration of an anti-α-synuclein antibody (e.g., GM37v2 (eleneta)) is < 40, for example, less than 39, less than 38, less than 37, less than 36, less than 35, less than 34, less than 33, less than 32, less than 31, less than 30, 10-39, 15-39, 20-39, 25-39, 30-39, 35-39, 10-35, 15-35, 20-35, 25-35, 30-35, 10-30, 15-30, 20-30, 25-30, 10-25, 15-25, 20-25, 10-20, 15-20, or 10-15.

[0244] In another aspect, the present invention provides appropriate dosing regimens for treating precursor synucleinopathy in human subjects at risk of developing synucleinopathy, identified by exhibiting one or more clinical markers of precursor synucleinopathy. Such clinical markers of precursor synucleinopathy may be selected from REM sleep behavior disorders (RBD) (e.g., isolated RBD (iRBD)), olfactory dysfunction (e.g., hyposmia), abnormal cognitive performance on neuropsychological tests, fine motor dysfunction or abnormal motor function assessed by objective tests, color vision abnormalities, autonomic dysfunction (e.g., constipation, urinary symptoms, erectile dysfunction, orthostatic hypotension), reduced dopaminergic binding in the nigrostriatum and striatum (DAT-SPECT abnormalities), seborrheic dermatitis, and genotypes associated with an increased risk of phenotypic transformation, such as mutations in glucocerebrosidase (encoded by the GBA gene).

[0245] In some embodiments of these aspects, human subjects are identified as having signs of synucleinopathy or precursor synucleinopathy in the form of abnormal accumulation or deposition of α-synuclein in the central nervous system. In some embodiments, human subjects are identified by in vivo imaging of α-synuclein (e.g., in the brain) using methods including: positron emission tomography (PET), single-photon emission tomography (SPECT), near-infrared (NIR) optical imaging, magnetic resonance imaging (MRI), dopamine transporter (DAT) imaging, or substantia nigra ultrasound.

[0246] In some embodiments, human subjects are identified as having signs of synucleinosis or precursor synucleinosis by measuring α-synuclein levels in blood, plasma, or cerebrospinal fluid (CSF) samples obtained from subjects and comparing the measured α-synuclein levels in the subjects with reference standards, wherein the difference or similarity between the α-synuclein levels in the blood, plasma, or CSF samples and reference standards is correlated with the α-synuclein levels in the subject's brain. The level of α-synuclein can be assessed by methods known in the art, including, for example, analysis of α-synuclein by one or more techniques selected from: Western blotting, immunoprecipitation, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), fluorescence activated cell sorting (FACS), two-dimensional gel electrophoresis, mass spectrometry (MS), matrix-assisted laser desorption / ionization-time-of-flight MS (MALDI-TOF), surface-enhanced laser desorption / ionization-time-of-flight MS (SELDI-TOF), high-performance liquid chromatography (HPLC), rapid protein liquid chromatography (FPLC), multidimensional liquid chromatography (LC), then tandem mass spectrometry (MS / MS), and laser density determination.

[0247] In some embodiments, human subjects are identified as having symptoms of synucleinosis or precursor synucleinosis using methods and standards recognized in the art.

[0248] Recently, Wenning et al. published new diagnostic criteria for MSA, "The Movement Disorder Society Criteria for the Diagnosis of Multiple System Atrophy," which is hereby incorporated by reference (Wenning et al., Movement Disorders, 2022, Vol. 37, No. 6, pp. 1131-1148). These new criteria describe "study criteria for suspected precursor MSA," which can be used to identify patients with precursor synucleinopathy:

[0249] Parkinson's disease (PD)

[0250] Parkinson's disease (PD) is a synuclein disorder. There are no definitive diagnostic criteria for PD; however, various symptoms and diagnostic tests can be used in combination to support a PD diagnosis. Accurate diagnosis of Parkinson's (especially in its early stages) is challenging, but skilled practitioners can arrive at a reasonable conclusion that a human subject has PD using clinical assessment tools. In some embodiments, a PD diagnosis can be based on the presence of at least two of the four major symptoms of PD: a) Tremor or shaking b) Bradykinesia, also known as slowed movement. c) Stiffness or rigidity in the arms, legs, or torso d) Difficulty maintaining balance and the possibility of falling, also known as postural instability.

[0251] Imaging techniques such as MRI, brain ultrasound, PET scans, and / or specific single-photon emission computed tomography (SPECT) scans (DaTscan) used to analyze dopamine transport can also be used to support the diagnosis of PD.

[0252] Lewy body dementia (DLB)

[0253] Lewy body dementia (DLB) is a synucleinopathy involving progressive dementia that leads to a decline in thinking, reasoning, and independent functioning. DLB is often difficult to diagnose because its early symptoms can resemble Alzheimer's disease or other mental illnesses. There are no definitive diagnostic criteria, but some core clinical signs of DLB ​​include dementia, motor problems / Parkinson's disease, cognitive fluctuations, visual hallucinations, and REM sleep behavior disorder. Some supportive clinical signs include extreme sensitivity to antipsychotic medications, falls or fainting, severe problems with involuntary functions (maintaining blood pressure, incontinence, constipation, loss of smell), and personality and mood changes (depression, apathy, anxiety).

[0254] A diagnosis of Lewy body dementia requires a progressive decline in cognitive abilities and at least two of the following: a) Fluctuating alertness and cognitive function b) Recurring visual hallucinations c) Symptoms of Parkinson's disease d) REM sleep behavior disorder Autonomic dysfunction involves unstable blood pressure and heart rate, poor thermoregulation, sweating, and related signs and symptoms, further supporting the diagnosis of Lewy body dementia, as well as sensitivity to antipsychotic drugs.

[0255] Physical and neurological examinations, along with various tests, help differentiate DLB from other diseases and support its diagnosis. Specific tests of this kind can include positron emission tomography (PET) or single-photon emission computed tomography (SPECT) showing reduced dopamine transporter (DAT) uptake in the basal ganglia (brain region); abnormalities... 123 Iodine-MIBG myocardial scintigraphy shows reduced cardiac neural communication; or sleep studies confirm REM sleep behavior disorder without loss of muscle tone.

[0256] Multiple system atrophy (MSA)

[0257] Multiple system atrophy (MSA) is the most progressive synucleinopathies, a group of conditions characterized by abnormal deposition of α-synuclein in the central and peripheral autonomic nervous systems. In the context of this invention, the term MSA refers to all types of MSA, such as multiple system atrophy-Parkinsonian type (MSA-P) or multiple system atrophy-cerebellar type (MSA-C). MSA is sometimes referred to as olivary pontocerebellar atrophy, progressive autonomic failure with multiple system atrophy, striatal nigrostriatum degeneration, or Shy-Drager syndrome. This invention also provides dosing regimens for treating MSA at all stages of disease progression, including the prodromal, early, middle, and late stages, and all stages in between.

[0258] Diagnosing multiple system atrophy (MSA) can be challenging because some of the signs and symptoms of MSA, such as muscle stiffness and gait instability, can also occur in other conditions, such as Parkinson's disease. Appropriate clinical examination, including a variety of autonomic tests and imaging studies, can help determine whether the diagnosis is probable or suspicious MSA. Examples of clinical methods that can be used to support the diagnosis of MSA in patients with suspected MSA include structural and functional brain imaging, cardiac sympathetic imaging, cardiovascular autonomic testing, olfactory testing, sleep studies, urological evaluation and dysphagia assessment, cognitive assessment, skin biopsy, retinal biomarkers, blood and / or cerebrospinal fluid biomarkers, and genetic testing. For example, the so-called Gilman criteria can facilitate the diagnosis of suspicious or probable MSA (Gilman et al., Neurology. [Neurology] 2008 Aug 26; 71(9): 670-676).

[0259] In some embodiments, the human subject to be treated may have a potential MSA, which can be identified by the following: a) Autonomic dysfunction involving urinary incontinence or a drop in blood pressure of at least 30 mmHg systolic or 15 mmHg diastolic within 3 minutes of standing; and b) Parkinson's disease with poor levodopa response (bradykinesia with rigidity, tremor, or postural instability); or c) Cerebellar syndrome (gait ataxia with cerebellar dysarthria, limb ataxia or cerebellar oculomotor dysfunction).

[0260] In some embodiments, the human subject to be treated has suspected MSA, which can be identified by the following: a) Parkinson's disease (bradykinesia with rigidity, tremor, or postural instability); or b) Cerebellar syndrome (gait ataxia with cerebellar dysarthria, limb ataxia, or cerebellar oculomotor dysfunction); and c) At least one feature indicating autonomic dysfunction (in addition, unexplained urinary urgency or incomplete bladder emptying in men, erectile dysfunction, or significant orthostatic hypotension not meeting the levels required for possible MSA); and d) At least one of the following characteristics: For suspected MSA-P or MSA-C: i. Babinski sign with hyperreflexia ii. Wheezing For suspected MSA-P: iii. Rapidly progressive Parkinson's disease iv. Poor response to levodopa v. Postural instability within 3 years of motor onset vi. Gait ataxia, cerebellar dysarthria, limb ataxia, or cerebellar oculomotor dysfunction vii. Dysphagia occurring within 5 years of motor onset viii. MRI atrophy of the putamen, middle cerebellar peduncle, pons, or cerebellum. ix. Decreased metabolism of fluorodeoxyglucose positron emission tomography (FDG-PET) in the putamen, brainstem, or cerebellum. For questionable MSA-C: x. Parkinson's disease (bradykinesia and rigidity) xi. MRI atrophy of the putamen, middle cerebellar peduncle, or pons xii. Decreased FDG-PET metabolism in the shell and core xiii. Presynaptic dopaminergic denervation of the subsynaptic striatum on single-photon emission computed tomography (SPECT) or PET.

[0261] Currently, a definitive diagnosis of MSA can only be confirmed after an autopsy through the following examinations: a) Abundant and widespread alpha-synuclein-positive glial cytoplasmic inclusions in the brain; and / or b) Neurodegenerative changes in the striatum, substantia nigra, or olivary pontine-cerebellar regions.

[0262] In a preferred embodiment, the human subjects with MSA also have MSA-C.

[0263] In a preferred embodiment, human subjects with MSA also had UMSARS TS < 40 at the time of first administration of an anti-α-synuclein antibody (e.g., GM37v2 (eleneta)), for example, less than 39, less than 38, less than 37, less than 36, less than 35, less than 34, less than 33, less than 32, less than 31, less than 30, 10-39, 15-39, 20-39, 25-39, 30-39, 35-39, 10-35, 15-35, 20-35, 25-35, 30-35, 10-30, 15-30, 20-30, 25-30, 10-25, 15-25, 20-25, 10-20, 15-20, or 10-15.

[0264] In a preferred embodiment, human subjects with MSA also had UMSARS TS < 40 at the start of treatment with anti-α synuclein antibody (e.g., GM37v2 (eleneta)), for example, less than 39, less than 38, less than 37, less than 36, less than 35, less than 34, less than 33, less than 32, less than 31, less than 30, 10-39, 15-39, 20-39, 25-39, 30-39, 35-39, 10-35, 15-35, 20-35, 25-35, 30-35, 10-30, 15-30, 20-30, 25-30, 10-25, 15-25, 20-25, 10-20, 15-20, or 10-15.

[0265] In a preferred embodiment, the human subject with MSA also has MSA-C and has UMSARS TS < 40 at the time of the first administration of an anti-α-synuclein antibody (e.g., GM37v2 (eleneta)), for example, less than 39, less than 38, less than 37, less than 36, less than 35, less than 34, less than 33, less than 32, less than 31, less than 30, 10-39, 15-39, 20-39, 25-39, 30-39, 35-39, 10-35, 15-35, 20-35, 25-35, 30-35, 10-30, 15-30, 20-30, 25-30, 10-25, 15-25, 20-25, 10-20, 15-20, or 10-15.

[0266] In a preferred embodiment, the human subject with MSA also has MSA-C and their UMSARS TS at the start of anti-α synuclein antibody (e.g., GM37v2 (eleneta)) treatment is < 40, for example, less than 39, less than 38, less than 37, less than 36, less than 35, less than 34, less than 33, less than 32, less than 31, less than 30, 10-39, 15-39, 20-39, 25-39, 30-39, 35-39, 10-35, 15-35, 20-35, 25-35, 30-35, 10-30, 15-30, 20-30, 25-30, 10-25, 15-25, 20-25, 10-20, 15-20, or 10-15.

[0267] Recently, Wenning et al. published a new diagnostic standard for MSA, "The Movement Disorder Society Criteria for the Diagnosis of Multiple System Atrophy" (Wenning et al., Movement Disorders, 2022, Vol. 37, No. 6, pp. 1131-1148).

[0268] These criteria include both clinically confirmed MSA and clinically probable MSA:

[0269] The defining characteristic of MSA-C is predominantly cerebellar symptoms. These cerebellar dysfunction symptoms typically manifest as gait ataxia, limb ataxia, ataxic dysarthria, and / or oculomotor abnormalities, such as dysmetria, saccade intrusion, and / or visual dysmetria.

[0270] MSA-P is characterized by major Parkinson's disease features. These features include bradykinesia, rigidity, irregular tremor, postural tremor, and / or abnormal postures (trunk flexion, Pisa syndrome, and disproportionate neck flexion).

[0271] Early-stage MSA refers to patients with less damage at this stage of the disease. In the context of this invention, such MSA patients will have low scores on any of the UMSARS scales (e.g., mUMSARS, aUMSARS, UMSARS TS, UMSARS Part I, or UMSARS Part II). In a preferred embodiment, early MSA means that the patient's UMSARS TS at the start of treatment is below 40, for example below 39, below 38, below 37, below 36, below 35, below 34, below 33, below 32, below 31, below 30, 10-39, 15-39, 20-39, 25-39, 30-39, 35-39, 10-35, 15-35, 20-35, 25-35, 30-35, 10-30, 15-30, 20-30, 25-30, 10-25, 15-25, 20-25, 10-20, 15-20, or 10-15.

[0272] REM sleep behavior disorder (RBD)

[0273] Rapid eye movement (REM) sleep behavior disorder (RBD) is considered an early manifestation of synucleinopathy. REM sleep behavior disorder (RBD) is characterized by the "actions" of dreams and is diagnosed via video polysomnography (vPSG), which shows dystonia typically associated with REM sleep. REM sleep behavior disorder (RBD), such as clinically isolated RBD (iRBD) (formerly sometimes called idiopathic RBD), is the most reliable clinical marker of precursor synucleinopathy, a group of neurodegenerative disorders including Parkinson's disease (PD), Lewy body dementia (DLB), and multiple system atrophy (MSA). The vast majority of individuals with REM sleep behavior disorder (RBD) (e.g., iRBD) are diagnosed with synucleinopathy within 20 years of the onset of iRBD, for example, within 3, 5, 8, or 16 years. Therefore, the REM sleep behavior disorder (RBD) population can serve as an ideal group for administering the antibody according to the present invention to alter the synuclein-specific neurodegenerative progression, i.e., to obtain disease-modifying therapy that delays or prevents the phenotype from converting to dominant synucleinopathy.

[0274] RBD diagnosis can be based on certain consensus criteria, such as those established by the International Classification of Sleep Disorders (ICSD-3), the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V), or the American Academy of Sleep Medicine (AASM) Sleep and Related Events Scoring Manual. A confirmatory RBD diagnosis may require confirmation via vPSG analysis. Further support for the RBD diagnosis can be provided by assessments using various imaging techniques also used to identify synucleinopathy, such as positron emission tomography (PET), single-photon emission computed tomography (SPECT), near-infrared (NIR) optical imaging, magnetic resonance imaging (MRI), dopamine transporter (DAT) imaging, or substantia nigra ultrasound.

[0275] Unified Multisystem Atrophy Rating Scale (UMSARS)

[0276] The UMSARS scale is a well-known comprehensive scale reported by clinicians and patients / caregivers for assessing disease progression in patients with MSA. The UMSARS scale can be used in clinical settings to assess MSA patients to monitor disease progression and / or quantify treatment response.

[0277] UMSARS consists of four parts: Part I assesses the patient's and caregiver's historical information on symptoms and activities of daily living reported over the past two weeks (12 items), with a rating range from 0 = unaffected to 4 = unable to perform activities (Note: each item uses a different anchoring descriptor related to the problem being addressed).

[0278] Part II consists of a clinical examination of key MSA motor signs and symptoms (14 items), with a scoring range from 0 = normal to 4 = significant / severe impairment (Note: each item uses a different anchoring descriptor related to the problem being addressed).

[0279] Part III includes an autonomic nervous system examination (4 items), separate measurements of systolic and diastolic blood pressure, heart rate, and orthostatic symptoms (yes / no).

[0280] Part IV assesses overall disability (1 item), with a rating range from 1 = fully independent to 5 = fully dependent and unable to care for oneself / bedridden.

[0281] The UMSARS total score (UMSARS TS) is obtained by summing the items from Part I and Part II. Part I scores range from 0 to 48, and Part II scores range from 0 to 56. Higher scores indicate greater damage. Experienced neurologists can use UMSARS after short-term training.

[0282] The modified UMSARS (mUMSARS) score, in the context of this invention, consists of UMSARS Part 1, where response option scores 0 and 1 will be compressed into a single category in the analysis.

[0283] The simplified UMSARS (aUMSARS) score can be derived from a subset of items from Parts I and II of UMSARS, which have been shown to be patient-centric and sensitive to the progression of MSA. The simplified UMSARS can be developed to be patient-centric (patient-relevant) and sensitive to changes in patients diagnosed with suspected MSA, probable MSA, clinically confirmed MSA, or clinically probable MSA. The simplified UMSARS score is based on a subset of items from Parts I and II of the original UMSARS scale. For example, items included in the aUMSARS score can be identified by: 1) identifying items sensitive to changes based on slope and / or patient-centric / focused items based on their relevance to the QoL scale; and 2) combining them into a simplified version of UMSARS; i.e., excluding items with low patient-centricity / focus and low ability to detect changes over time. For example, data used to develop aUMSARS can be taken from the European MSA Study Group's Natural History Study and the MSA-Ras trial. When modeling the progression of a variable over time using a linear mixture model, the sensitivity to change of a uniform MSA rating scale item can be assessed by calculating the sensitivity ratio to change using the average progression slope divided by the standard deviation of the slope. Patient-centricity can be assessed based on the correlation between uniform MSA rating scale items and quality of life measurements.

[0284] The following are examples of this type of aUMSARS, which includes the following 19 Part I and Part II UMSARS items:

[0285] Specific embodiments

[0286] The following embodiments further describe the present invention in detail.

[0287] In one embodiment, the present invention provides a monoclonal α-synuclein antibody for treating synucleinopathy or precursor synucleinopathy, wherein the use comprises intravenous administration of the monoclonal α-synuclein antibody to a human subject suffering from or at risk of developing synucleinopathy, at a dose greater than 700 mg and less than 7000 mg, for example between 900 mg and 5000 mg, or for example between 1000 mg and 4500 mg, and wherein the monoclonal α-synuclein antibody is a full-length antibody that binds to epitopes in amino acids 112-117 (SEQ ID NO: 9 (ILEDMP)) of human α-synuclein (SEQ ID NO: 10).

[0288] In one embodiment, the present invention provides a monoclonal α-synuclein antibody for treating synucleinopathy, wherein the use comprises intravenous administration of the monoclonal α-synuclein antibody to a human subject suffering from or at risk of developing synucleinopathy, at a dose greater than 700 mg and less than 7000 mg, for example between 900 mg and 5000 mg, or for example between 1000 mg and 4500 mg, and wherein the monoclonal α-synuclein antibody is a full-length antibody that binds to an epitope within amino acids 112-117 (SEQ ID NO: 9 (ILEDMP)) of human α-synuclein (SEQ ID NO: 10).

[0289] In one embodiment, the present invention provides a monoclonal α-synuclein antibody for treating precursor synucleinopathy, wherein the use comprises intravenous administration of the monoclonal α-synuclein antibody to a human subject suffering from or at risk of developing synucleinopathy, at a dose greater than 700 mg and less than 7000 mg, for example between 900 mg and 5000 mg, or for example between 1000 mg and 4500 mg, and wherein the monoclonal α-synuclein antibody is a full-length antibody that binds to epitopes in amino acids 112-117 (SEQ ID NO: 9 (ILEDMP)) of human α-synuclein (SEQ ID NO: 10).

[0290] In one embodiment, the present invention provides a monoclonal α-synuclein antibody for the treatment of MSA, wherein the use comprises intravenous administration of the monoclonal α-synuclein antibody to a human subject suffering from MSA at a dose greater than 700 mg and less than 7000 mg, for example between 900 mg and 5000 mg, for example between 4000 mg and 7000 mg, or for example between 1000 mg and 4500 mg, and wherein the monoclonal α-synuclein antibody is a full-length antibody that binds to an epitope within amino acids 112-117 (SEQ ID NO: 9 (ILEDMP)) of human α-synuclein (SEQ ID NO: 10).

[0291] In one embodiment, the present invention provides a monoclonal α-synuclein antibody for the treatment of MSA, wherein the use comprises intravenous administration of the monoclonal α-synuclein antibody to a human subject suffering from MSA at a dose greater than 700 mg and less than 7000 mg, for example between 900 mg and 5000 mg, for example between 4000 mg and 7000 mg, or for example between 1000 mg and 4500 mg, and wherein the monoclonal α-synuclein antibody is a full-length antibody that binds to an epitope within amino acids 112-117 (SEQ ID NO: 9 (ILEDMP)) of human α-synuclein (SEQ ID NO: 10).

[0292] In one embodiment, the present invention provides a monoclonal α-synuclein antibody for the treatment of early-stage MSA, wherein the use comprises intravenous administration of the monoclonal α-synuclein antibody to a human subject with MSA in an early clinical phase at a dose greater than 700 mg and less than 7000 mg, for example between 900 mg and 5000 mg, for example between 4000 mg and 7000 mg, or for example between 1000 mg and 4500 mg, and wherein the monoclonal α-synuclein antibody is a full-length antibody that binds to an epitope within amino acids 112-117 (SEQ ID NO: 9 (ILEDMP)) of human α-synuclein (SEQ ID NO: 10).

[0293] In some embodiments, the estimated KD value for the binding of monoclonal anti-α-synuclein antibody to oligomeric α-synuclein is about 0.5 nM.

[0294] In another embodiment, the KD value of the monoclonal α-synuclein antibody binding to the monomeric form of α-synuclein is approximately 36 nM.

[0295] In another embodiment, the KD value of the monoclonal α-synuclein antibody binding to the monomeric form of α-synuclein is about 36 nM, and the estimated KD value binding to the oligomeric form of α-synuclein is about 0.5 nM.

[0296] In one embodiment, the ratio between monomer binding and oligomer binding values ​​is enhanced by approximately 65 times relative to the oligomer form compared to the monomer form.

[0297] In another embodiment, the human T½ of the monoclonal α-synuclein antibody is about 25-35 days, for example about 4 weeks, for example about 27-33 days, for example 28-32 days, for example 28-30 days, for example 28 days, for example 29 days, for example 30 days.

[0298] In another embodiment, the monoclonal α-synuclein antibody has a KD value of approximately 36 nM when binding to the monomeric form of α-synuclein and an estimated KD value of 0.5 nM when binding to the oligomeric form of α-synuclein, thereby enhancing the ratio between monomeric and oligomeric binding by approximately 65-fold.

[0299] In another embodiment, the monoclonal α-synuclein antibody has a KD value of approximately 36 nM when binding to the monomeric form of α-synuclein and an estimated KD value of 0.5 nM when binding to the oligomeric form of α-synuclein, thereby enhancing the ratio between monomeric and oligomeric binding by approximately 65-fold, and the antibody has a T½ of approximately 28-30 days, for example, 29 days.

[0300] In another embodiment, the monoclonal α-synuclein antibody comprises: a. Heavy chain CDR1 having the amino acid sequence of SEQ ID NO:1; b. Heavy chain CDR2 having the amino acid sequence of SEQ ID NO:2; c. Heavy chain CDR3 having the amino acid sequence of SEQ ID NO:3; d. The light chain CDR1 having the amino acid sequence of SEQ ID NO:4; e. The light chain CDR2 having the amino acid sequence of SEQ ID NO:5; and f. Light chain CDR3 having the amino acid sequence of SEQ ID NO:6.

[0301] In another embodiment, the monoclonal α-synuclein antibody comprises a heavy chain consisting of the variable domain of SEQ ID NO:7 and a light chain consisting of the variable domain of SEQ ID NO:8.

[0302] In another embodiment, the monoclonal α-synuclein antibody comprises: a. Heavy chain CDR1 having the amino acid sequence of SEQ ID NO:1; b. Heavy chain CDR2 having the amino acid sequence of SEQ ID NO:33; c. Heavy chain CDR3 having the amino acid sequence of SEQ ID NO:3; d. The light chain CDR1 having the amino acid sequence of SEQ ID NO:4; e. The light chain CDR2 having the amino acid sequence of SEQ ID NO:5; and f. Light chain CDR3 having the amino acid sequence of SEQ ID NO:6.

[0303] In another embodiment, the monoclonal α-synuclein antibody comprises a heavy chain consisting of a variable domain of SEQ ID NO:30 and a light chain consisting of a variable domain of SEQ ID NO:8.

[0304] In another embodiment, the monoclonal α-synuclein antibody comprises: a. Heavy chain CDR1 having the amino acid sequence of SEQ ID NO:1; b. Heavy chain CDR2 having the amino acid sequence of SEQ ID NO:34; c. Heavy chain CDR3 having the amino acid sequence of SEQ ID NO:3; d. The light chain CDR1 having the amino acid sequence of SEQ ID NO:4; e. The light chain CDR2 having the amino acid sequence of SEQ ID NO:5; and f. Light chain CDR3 having the amino acid sequence of SEQ ID NO:6.

[0305] In another embodiment, the monoclonal α-synuclein antibody comprises a heavy chain variable domain consisting of SEQ ID NO:31 and a light chain variable domain consisting of SEQ ID NO:8.

[0306] In another embodiment, the monoclonal α-synuclein antibody comprises: a. Heavy chain CDR1 having the amino acid sequence of SEQ ID NO:1; b. Heavy chain CDR2 having the amino acid sequence of SEQ ID NO:35; c. Heavy chain CDR3 having the amino acid sequence of SEQ ID NO:3; d. The light chain CDR1 having the amino acid sequence of SEQ ID NO:4; e. The light chain CDR2 having the amino acid sequence of SEQ ID NO:5; and f. Light chain CDR3 having the amino acid sequence of SEQ ID NO:6.

[0307] In another embodiment, the monoclonal α-synuclein antibody comprises a heavy chain consisting of a variable domain of SEQ ID NO:32 and a light chain consisting of a variable domain of SEQ ID NO:8.

[0308] In another embodiment, the monoclonal α-synuclein antibody is a full-length human antibody.

[0309] In another embodiment, the monoclonal α-synuclein antibody is a human IgG1 antibody.

[0310] In another embodiment, the monoclonal α-synuclein antibody is GM37.

[0311] In another embodiment, the monoclonal α-synuclein antibody is GM37 variant 1.

[0312] In another embodiment, the monoclonal α-synuclein antibody is GM37 variant 2.

[0313] In another embodiment, the monoclonal α-synuclein antibody is GM37 variant 3.

[0314] In another embodiment, the monoclonal α-synuclein antibody further comprises a constant heavy chain domain as defined in SEQ ID NO:18 and a constant κ light chain domain as defined in SEQ ID NO:17.

[0315] In another embodiment, the monoclonal α-synuclein antibody is administered every 4 weeks or 28 days.

[0316] In another embodiment, the monoclonal α-synuclein antibody is administered once a month.

[0317] In another embodiment, the monoclonal α-synuclein antibody is administered at a dose greater than 700 mg and less than 7000 mg, for example between 900 mg and 5000 mg, for example between 4000 mg and 7000 mg, or for example between 1000 mg and 4500 mg, at intervals of 3-5 weeks.

[0318] In another embodiment, the monoclonal α-synuclein antibody was administered at doses of 750 mg, 2250 mg, 4500 mg, or 6300 mg.

[0319] In another embodiment, the monoclonal α-synuclein antibody is administered at a dose of 1,000 mg to 4,500 mg, for example, between 2,000 mg and 4,500 mg, for example, between 4,000 mg and 7,000 mg, or between 3,500 mg and 4,500 mg.

[0320] In another embodiment, the monoclonal α-synuclein antibody was administered at doses of 750 mg, 1050 mg, 1400 mg, 1750 mg, 2100 mg, 2450 mg, 2800 mg, 3150 mg, 3500 mg, 3850 mg, 4200 mg, 4550 mg, 4900 mg, 5250 mg, 5600 mg, 5950 mg, 6300 mg, or 6650 mg.

[0321] In another embodiment, the monoclonal α-synuclein antibody was administered at doses of 1050 mg, 2100 mg, 4200 mg, or 6300 mg.

[0322] In another embodiment, the monoclonal α-synuclein antibody was administered at a dose of 4200 mg.

[0323] In another embodiment, the monoclonal α-synuclein antibody was administered at a dose of 6300 mg.

[0324] In one embodiment, the dose is a fixed dose.

[0325] In another embodiment, the monoclonal α-synuclein antibody was administered every 28-30 days at doses of 1050 mg, 2100 mg, 4200 mg, or 6300 mg.

[0326] In another embodiment, the monoclonal α-synuclein antibody is administered at a dose of 4200 mg every 4 weeks or every 28-30 days, for example every 28 days, every 29 days, or every 30 days.

[0327] In another embodiment, the monoclonal α-synuclein antibody was administered via intravenous infusion over 30 minutes ± 10 minutes.

[0328] In another embodiment, the monoclonal α-synuclein antibody was administered via intravenous infusion over 15 minutes ± 5 minutes.

[0329] In another embodiment, the monoclonal α-synuclein antibody was administered via intravenous infusion at a rate of 25 mg / min to 300 mg / min.

[0330] In another embodiment, the monoclonal α-synuclein antibody is administered via intravenous infusion at a rate of 30 mg / min to 150 mg / min, such as 35 mg / min, 70 mg / min, or 140 mg / min.

[0331] In another embodiment, the monoclonal α-synuclein antibody is administered via intravenous infusion at a rate of 60 mg / min to 300 mg / min, such as 70 mg / min, 140 mg / min, or 280 mg / min.

[0332] In another embodiment, the amount and frequency of administration of the monoclonal α-synuclein antibody are sufficient to achieve an estimated average steady-state CSF concentration of at least 0.5 nM, for example at least 1 nM, for example at least 2 nM, for example at least 3 nM, for example at least 6 nM, for example at least 12 nM, or for example 18 nM.

[0333] In another embodiment, the amount and frequency of administration of the monoclonal α-synuclein antibody are sufficient to achieve an estimated average steady-state CSF concentration of at least 3 nM for the antibody.

[0334] In another embodiment, the amount and frequency of administration of the monoclonal α-synuclein antibody are sufficient to achieve an estimated average steady-state CSF concentration of at least 6 nM for the antibody.

[0335] In another embodiment, the amount and frequency of administration of the monoclonal α-synuclein antibody are sufficient to achieve an estimated average steady-state CSF concentration of at least 12 nM for the antibody.

[0336] In another embodiment, the amount and frequency of administration of the monoclonal α-synuclein antibody are sufficient to achieve an estimated average steady-state CSF concentration of at least 18 nM for the antibody.

[0337] In another embodiment, the amount and frequency of administration of the monoclonal α-synuclein antibody are sufficient to achieve an estimated target binding of at least 50%, for example, at least 60%, for example, at least 75%, for example, at least 80%, for example, at least 85%, for example, at least 90%, for example, at least 95%, or for example, at least 99% with the oligomeric form of α-synuclein in CSF.

[0338] In another embodiment, the amount and frequency of administration of the monoclonal α-synuclein antibody are sufficient to achieve an estimated target binding of at least 85% to the oligomeric form of α-synuclein in CSF.

[0339] In another embodiment, the amount and frequency of administration of the monoclonal α-synuclein antibody are sufficient to achieve an estimated target binding of at least 90% to the oligomeric form of α-synuclein in CSF.

[0340] In another embodiment, the amount and frequency of administration of the monoclonal α-synuclein antibody are sufficient to achieve an estimated target binding of at least 95% to the oligomeric form of α-synuclein in CSF.

[0341] In another embodiment, the amount and frequency of administration of the monoclonal α-synuclein antibody are sufficient to achieve an estimated target binding of at least 97% to the oligomeric form of α-synuclein in CSF.

[0342] In another embodiment, the synucleinic disease to be treated is selected from the list consisting of: Parkinson's disease (PD) (including idiopathic and hereditary forms of Parkinson's disease), Gaucher disease (GD), diffuse Lewy body disease (DLBD), Lewy body dementia (DLB), Lewy body variant of Alzheimer's disease (LBV), combined Alzheimer's disease and Parkinson's disease, simple autonomic dysfunction and multiple system atrophy (MSA).

[0343] In another embodiment, the synucleinopathy to be treated is selected from: Parkinson's disease (PD), Lewy body dementia (DLB), or multiple system atrophy (MSA).

[0344] In another embodiment, the synucleinopathy to be treated is multiple system atrophy (MSA) or selected from the following MSA subtypes: suspected MSA, possible MSA, C-type MSA, P-type MSA, clinically confirmed MSA, or clinically possible MSA.

[0345] In another embodiment, the synucleinic disease to be treated is selected from: Parkinson's disease (PD) (including idiopathic and hereditary forms of Parkinson's disease), Gaucher disease (GD), diffuse Lewy body disease (DLBD), Lewy body dementia (DLB), Lewy body variant (LBV) of Alzheimer's disease, combined Alzheimer's disease and Parkinson's disease, isolated autonomic dysfunction and multiple system atrophy (MSA), and the treatment includes administering the monoclonal α-synuclein antibody to the patient in an amount and frequency sufficient to achieve a CSF steady-state concentration of the antibody of at least 0.5 nM, for example at least 1 nM, for example at least 2 nM, for example at least 3 nM, for example at least 6 nM, or for example at least 12 nM.

[0346] In another embodiment, the synucleinic disease to be treated is selected from: Parkinson's disease (PD) (including idiopathic and hereditary forms of Parkinson's disease), Gaucher disease (GD), diffuse Lewy body disease (DLBD), Lewy body dementia (DLB), Lewy body variant (LBV) of Alzheimer's disease, combined Alzheimer's disease and Parkinson's disease, isolated autonomic dysfunction and multiple system atrophy (MSA), and the treatment includes administering the monoclonal α-synuclein antibody to the patient in an amount and frequency sufficient to achieve a CSF steady-state concentration of the antibody of at least 3 nM, for example at least 6 nM, or for example at least 12 nM.

[0347] In another embodiment, the present invention provides a method for treating synuclein diseases selected from: Parkinson's disease (PD) (including idiopathic and hereditary forms of Parkinson's disease), Gaucher disease (GD), diffuse Lewy body disease (DLBD), Lewy body dementia (DLB), Lewy body variant (LBV) of Alzheimer's disease, combined Alzheimer's disease and Parkinson's disease, isolated autonomic dysfunction and multiple system atrophy (MSA), wherein the treatment comprises administering the monoclonal α-synuclein antibody to the patient in an amount and frequency sufficient to achieve an estimated target binding of at least 50%, for example, at least 60%, for example, at least 75%, for example, at least 80%, for example, at least 85%, for example, at least 90%, for example, at least 95%, for example, at least 97%, or for example, at least 99%.

[0348] In another embodiment, the present invention provides a method for treating synuclein diseases selected from: Parkinson's disease (PD) (including idiopathic and hereditary forms of Parkinson's disease), Gaucher disease (GD), diffuse Lewy body disease (DLBD), Lewy body dementia (DLB), Lewy body variant (LBV) of Alzheimer's disease, combined Alzheimer's disease and Parkinson's disease, isolated autonomic dysfunction and multiple system atrophy (MSA), wherein the treatment comprises administering the monoclonal α-synuclein antibody to the patient in an amount and frequency sufficient to achieve an estimated target binding of at least 85%, for example at least 90%, for example at least 95%, or for example at least 97%, to the oligomeric form of α-synuclein in CSF.

[0349] In another embodiment, the present invention provides a method for treating synucleinic diseases selected from the following: Parkinson's disease (PD) (including idiopathic and hereditary forms of Parkinson's disease), Gaucher disease (GD), diffuse Lewy body disease (DLBD), Lewy body dementia (DLB), Lewy body variant (LBV) of Alzheimer's disease, combined Alzheimer's disease and Parkinson's disease, isolated autonomic dysfunction or multiple system atrophy (MSA).

[0350] In another embodiment, the present invention provides a method for treating synucleinosis selected from Parkinson's disease (PD), Lewy body dementia (DLB), or multiple system atrophy (MSA).

[0351] In another embodiment, the present invention provides a method for treating synucleinosis, which is multiple system atrophy (MSA), for example selected from the following MSA subtypes: suspected MSA, possible MSA, C-type MSA, P-type MSA, clinically confirmed MSA, or clinically possible MSA.

[0352] In another embodiment, the present invention provides a monoclonal α-synuclein antibody for treating human subjects with multiple system atrophy (MSA) of either the multiple system atrophy-Parkinsonian type (MSA-P) or the multiple system atrophy-cerebellar type (MSA-C) subtype.

[0353] In another embodiment, the present invention provides a monoclonal α-synuclein antibody for treating human subjects with multiple system atrophy (MSA), which can be identified by the occurrence of motor and / or autonomic (orthostatic or urinary) MSA symptoms within the past 5 years (e.g., within the past 4 years, or for example, within the past 3 years, or for example, within the past 2 years, or for example, within the past 1 year).

[0354] In another embodiment, the present invention provides a monoclonal α-synuclein antibody for treating human subjects with multiple system atrophy (MSA), who can be identified by a UMSARS Part I score ≤ 16 (question 11 regarding sexual function omitted).

[0355] In another embodiment, the present invention provides a monoclonal α-synuclein antibody for treating human subjects with multiple system atrophy (MSA), identifiable by cognitive performance (score ≥ 22) as assessed by the Montreal Cognitive Assessment (MoCA).

[0356] In yet another preferred embodiment, the human subject with MSA has MSA-C. In yet another embodiment, the human subject with MSA has MSA-P. In yet another preferred embodiment, the human subject with MSA has suspected or probable MSA-C. In yet another embodiment, the human subject with MSA has suspected or probable MSA-P.

[0357] In yet another preferred embodiment, the human subject with MSA has MSA at an early stage of the disease. In yet another such embodiment, the human subject with MSA has MSA at an early stage of the disease. In yet another such embodiment, the human subject with MSA has early-stage MSA. In yet another such embodiment, the UMSARS TS of human subjects with MSA is < 40, for example, less than 39, less than 38, less than 37, less than 36, less than 35, less than 34, less than 33, less than 32, less than 31, less than 30, 10-39, 15-39, 20-39, 25-39, 30-39, 35-39, 10-35, 15-35, 20-35, 25-35, 30-35, 10-30, 15-30, 20-30, 25-30, 10-25, 15-25, 20-25, 10-20, 15-20, or 10-15. In yet another such embodiment, human subjects with MSA had UMSARS TS < 40 at the start of anti-α-synuclein antibody treatment, for example, less than 39, less than 38, less than 37, less than 36, less than 35, less than 34, less than 33, less than 32, less than 31, less than 30, 10-39, 15-39, 20-39, 25-39, 30-39, 35-39, 10-35, 15-35, 20-35, 25-35, 30-35, 10-30, 15-30, 20-30, 25-30, 10-25, 15-25, 20-25, 10-20, 15-20, or 10-15. In yet another such embodiment, human subjects with MSA had UMSARS TS < 40 at the time of their first infusion of an anti-α-synuclein antibody (e.g., GM37v2 (elenetamarab)), for example, less than 39, less than 38, less than 37, less than 36, less than 35, less than 34, less than 33, less than 32, less than 31, less than 30, 10-39, 15-39, 20-39, 25-39, 30-39, 35-39, 10-35, 15-35, 20-35, 25-35, 30-35, 10-30, 15-30, 20-30, 25-30, 10-25, 15-25, 20-25, 10-20, 15-20, or 10-15.

[0358] In yet another preferred embodiment, the human subject with MSA has MSA-C and their UMSARS TS <40, for example, less than 39, less than 38, less than 37, less than 36, less than 35, less than 34, less than 33, less than 32, less than 31, less than 30, 10-39, 15-39, 20-39, 25-39, 30-39, 35-39, 10-35, 15-35, 20-35, 25-35, 30-35, 10-30, 15-30, 20-30, 25-30, 10-25, 15-25, 20-25, 10-20, 15-20, or 10-15. In yet another such embodiment, human subjects with MSA have MSA-C and their UMSARS TS at the start of anti-α-synuclein antibody treatment is <40, for example, less than 39, less than 38, less than 37, less than 36, less than 35, less than 34, less than 33, less than 32, less than 31, less than 30, 10-39, 15-39, 20-39, 25-39, 30-39, 35-39, 10-35, 15-35, 20-35, 25-35, 30-35, 10-30, 15-30, 20-30, 25-30, 10-25, 15-25, 20-25, 10-20, 15-20, or 10-15. In yet another such embodiment, a human subject with MSA has MSA-C and whose UMSARS TS at the start of treatment with an anti-α synuclein antibody (e.g., GM37v2 (elenetamab)) is < 40, for example, < 39, < 38, < 37, < 36, < 35, < 34, < 33, < 32, < 31, < 30, 10-39, 15-39, 20-39, 25-39, 30-39, 35-39, 10-35, 15-35, 20-35, 25-35, 30-35, 10-30, 15-30, 20-30, 25-30, 10-25, 15-25, 20-25, 10-20, 15-20, or 10-15. In yet another such embodiment, a human subject with MSA has MSA-C and UMSARS TS < 40 at the time of the first infusion of an anti-α-synuclein antibody (e.g., GM37v2 (elenetamarab)), for example, less than 39, less than 38, less than 37, less than 36, less than 35, less than 34, less than 33, less than 32, less than 31, less than 30, 10-39, 15-39, 20-39, 25-39, 30-39, 35-39, 10-35, 15-35, 20-35, 25-35, 30-35, 10-30, 15-30, 20-30, 25-30, 10-25, 15-25, 20-25, 10-20, 15-20, or 10-15.

[0359] In this embodiment, treatment for synucleinosis consists of delaying or slowing disease progression.

[0360] In this embodiment, treatment for synucleinosis consists of delaying or slowing clinical progression.

[0361] In the embodiments, the delay or slowing of disease or clinical progression is quantified by the longitudinal change of any relevant Unified Multisystem Atrophy Rating Scale (UMSARS) score described herein or any relevant portion of such scales (e.g., Part I, Part II, Part III, or Part IV) relative to baseline, or any combination of such portions of UMSARS relative to baseline.

[0362] In another embodiment, the delay or slowing of disease or clinical progression is quantified by the longitudinal change of the Unified Multisystem Atrophy Rating Scale (UMSARS) Part I and / or Part II or the modified UMSARS Part I (mUMSARS) or the simplified UMSARS (aUMSARS) score relative to baseline.

[0363] In another embodiment, the delay or slowing of disease or clinical progression is quantified by the longitudinal change of the Unified Multisystem Atrophy Rating Scale (UMSARS) Part I or Part II score relative to baseline.

[0364] In another embodiment, the delay or slowing of disease or clinical progression is quantified by longitudinal changes in scores of Part I and Part II of the Unified Multisystem Atrophy Rating Scale (UMSARS) relative to baseline.

[0365] In another embodiment, the delay or slowing of disease or clinical progression is quantified by longitudinal changes in scores relative to baseline using the Unified Multisystem Atrophy Rating Scale (UMSARS) Part I, the modified UMSARS Part I (mUMSARS), and / or UMSARS Part II scores.

[0366] In another embodiment, the delay or slowing of disease or clinical progression is quantified by the longitudinal change of UMSARS TS, UMSARS Part I, mUMSARS and / or UMSARS Part II scores relative to baseline.

[0367] In another embodiment, the delay or slowing of disease or clinical progression is quantified by the longitudinal change of the abbreviated UMSARS (aUMSARS) score relative to baseline.

[0368] In another embodiment, the delay or slowing of disease or clinical progression is quantified by the longitudinal change of the modified UMSARS (mUMSARS) score relative to baseline.

[0369] In another embodiment, the delay or slowing of disease or clinical progression is quantified by the longitudinal change in the total score of the Unified Multisystem Atrophy Scale (UMSARS TS) relative to baseline.

[0370] In another embodiment, the delay or slowing of disease or clinical progression is quantified by longitudinal changes in brain volume relative to baseline, as measured by volumetric MRI (vMRI).

[0371] In another embodiment, the delay or slowing of MSA disease progression is quantified by longitudinal changes in brain volume relative to baseline, such as as measured by pontine volume MRI (vMRI).

[0372] In another embodiment, the delay or slowing of MSA disease progression is quantified by longitudinal changes in brain volume relative to baseline, such as by volumetric MRI (vMRI) of the cerebellar white matter.

[0373] In another embodiment, the delay or slowing of MSA disease progression is quantified by longitudinal changes in brain volume relative to baseline, such as by volumetric MRI (vMRI) of cerebellar gray matter.

[0374] In another embodiment, the delay or slowing of clinical progression of MSA is quantified by longitudinal changes in brain volume relative to baseline, such as as measured by pontine volume MRI (vMRI).

[0375] In another embodiment, the delay or slowing of clinical progression of MSA is quantified by longitudinal changes in brain volume relative to baseline, such as by volumetric MRI (vMRI) of the cerebellar white matter.

[0376] In another embodiment, the delay or slowing of clinical progression of MSA is quantified by longitudinal changes in brain volume relative to baseline, such as by volumetric MRI (vMRI) of cerebellar gray matter.

[0377] In another embodiment, the treatment effect of GM37v2 (elenetamab) administered every 4 weeks or monthly is a reduction in clinical progression of MSA as measured by the UMSARS total score of at least 10%, such as at least 15%, at least 20%, at least 30%, at least 35%, 10%-35%, 15%-35%, 19%-35%, 20%-35%, 25%-35%, 30%-35%, 10%-30%, 15%-30%, 19%-30%, 20%-30%, 25%-30%, 10%-25%, 15%-25%, 19%-25%, 20%-25%, 10%-20%, 15%-20%, 19%-20%, or 10%-15%. In another embodiment, the treatment effect of GM37v2 (elenetamab) administered every 4 weeks or monthly is a reduction in clinical progression of MSA as measured by the UMSARS total score of at least 19%. In another embodiment, treatment with GM37v2 (elenetamab) administered every 4 weeks or monthly resulted in a reduction in clinical progression of MSA as measured by approximately 10%-35%, 15%-35%, 19%-35%, 20%-35%, 25%-35%, 30%-35%, 10%-30%, 15%-30%, 19%-30%, 20%-30%, 25%-30%, 10%-25%, 15%-25%, 19%-25%, 20%-25%, 10%-20%, 15%-20%, 19%-20%, or 10%-15%. In another embodiment, treatment with GM37v2 (elenetamab) administered every 4 weeks or monthly resulted in a reduction in clinical progression of MSA as measured by approximately 19%.

[0378] In another embodiment, treatment with GM37v2 (elenetamab) administered every 4 weeks or monthly is a reduction in clinical progression of MSA by approximately 10%, such as at least 15%, at least 20%, at least 30%, at least 35%, 10%-35%, 15%-35%, 20%-35%, 22%-35%, 25%-35%, 30%-35%, 10%-30%, 15%-30%, 20%-30%, 22%-30%, 25%-30%, 10%-25%, 15%-25%, 20%-25%, 22%-25%, 10%-20%, 15%-20%, or 10%-15%. In another embodiment, treatment with GM37v2 (elenetamab) administered every 4 weeks or monthly is a reduction in clinical progression of MSA by approximately 22%, as measured by the UMSARS Part I score. In another embodiment, treatment with GM37v2 (elenetamab) administered every 4 weeks or monthly resulted in a reduction in clinical progression of MSA as measured by approximately 10%-35%, 15%-35%, 20%-35%, 22%-35%, 25%-35%, 30%-35%, 10%-30%, 15%-30%, 20%-30%, 22%-30%, 25%-30%, 10%-25%, 15%-25%, 20%-25%, 22%-25%, 10%-20%, 15%-20%, or 10%-15%. In another embodiment, treatment with GM37v2 (elenetamab) administered every 4 weeks or monthly resulted in a reduction in clinical progression of MSA as measured by approximately 22%.

[0379] In another embodiment, the therapeutic effect of GM37v2 (elenetatumab) administered every 4 weeks or monthly is a reduction in clinical progression of MSA by approximately 10%, as measured by the UMSARS Part II score, for example, at least 15%, at least 20%, at least 30%, at least 35%, 10%-35%, 15%-35%, 17%-35%, 20%-35%, 25%-35%, 30%-35%, 10%-30%, 15%-30%, 17%-30%, 20%-30%, 25%-30%, 10%-25%, 15%-25%, 17%-25%, 20%-25%, 10%-20%, 15%-20%, 17%-20%, or 10%-15%. In another embodiment, treatment with GM37v2 (elenetamab) administered every 4 weeks or monthly resulted in a reduction of clinical progression of MSA by at least approximately 17%, as measured by the UMSARS Part II score. In yet another embodiment, treatment with GM37v2 (elenetamab) administered every 4 weeks or monthly resulted in a reduction of clinical progression of MSA by approximately 10%-35%, 15%-35%, 17%-35%, 20%-35%, 25%-35%, 30%-35%, 10%-30%, 15%-30%, 17%-30%, 20%-30%, 25%-30%, 10%-25%, 15%-25%, 17%-25%, 20%-25%, 10%-20%, 15%-20%, 17%-20%, or 10%-15%, as measured by the UMSARS Part II score. In another embodiment, treatment with GM37v2 (elenetatumab) administered every 4 weeks or monthly resulted in a reduction of approximately 17% in clinical progression of MSA, as measured by the UMSARS Part II score.

[0380] In another embodiment, treatment with GM37v2 (elenetamab) administered every 4 weeks or monthly is a reduction in clinical progression of MSA by approximately 10%, such as at least 15%, at least 20%, at least 30%, at least 35%, 10%-35%, 15%-35%, 20%-35%, 25%-35%, 27%-35%, 30%-35%, 10%-30%, 15%-30%, 20%-30%, 25%-30%, 27%-30%, 10%-25%, 15%-25%, 20%-25%, 10%-20%, 15%-20%, or 10%-15%. In another embodiment, treatment with GM37v2 (elenetamab) administered every 4 weeks or monthly is a reduction in clinical progression of MSA by approximately 27%, as measured by a modified UMSARS score. In another embodiment, treatment with GM37v2 (elenetamab) administered every 4 weeks or monthly resulted in a reduction in clinical progression of MSA as measured by modified UMSARS scores of approximately 10%-35%, 15%-35%, 20%-35%, 25%-35%, 27%-35%, 30%-35%, 10%-30%, 15%-30%, 20%-30%, 25%-30%, 27%-30%, 10%-25%, 15%-25%, 20%-25%, 10%-20%, 15%-20%, or 10%-15%. In another embodiment, treatment with GM37v2 (elenetamab) administered every 4 weeks or monthly resulted in a reduction in clinical progression of MSA as measured by modified UMSARS scores of approximately 27%.

[0381] In another embodiment, treatment with GM37v2 (elenetatumab) administered every 4 weeks or monthly is a reduction in clinical progression of MSA-C by approximately 30%, such as at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, 30%-99%, 40%-99%, 50%-99%, 60%-99%, 70%-99%, 80%-99%, 9 ... 9%, 30%-90%, 40%-90%, 50%-90%, 60%-90%, 70%-90%, 80%-90%, 30%-80%, 40%-80%, 50%-80%, 60%-80%, 70%-80%, 30%-70%, 40%-70%, 50%-70%, 60%-70%, 30%-60%, 40%-60%, 50%-60%, 30%-50%, 40%-50%, or 30%-40%. In another embodiment, treatment with GM37v2 (elenetatumab) administered every 4 weeks or monthly resulted in a reduction of clinical progression of MSA-C by approximately 50% as measured by a modified UMSARS score. In another embodiment, treatment with GM37v2 (elenetatumab) administered every 4 weeks or monthly resulted in a reduction in MSA-C clinical progression as measured by modified UMSARS scores of approximately 30%-99%, 40%-99%, 50%-99%, 60%-99%, 70%-99%, 80%-99%, 90%-99%, 30%-90%, 40%-90%, 50%-90%, 60%-90%, 70%-90%, 80%-90%, 30%-80%, 40%-80%, 50%-80%, 60%-80%, 70%-80%, 30%-70%, 40%-70%, 50%-70%, 60%-70%, 30%-60%, 40%-60%, 50%-60%, 30%-50%, 40%-50%, or 30%-40%. In another embodiment, treatment with GM37v2 (elenetatumab) administered every 4 weeks or monthly resulted in a reduction of approximately 50% in clinical progression of MSA-C as measured by a modified UMSARS score.

[0382] In another embodiment, treatment with GM37v2 (elenetatumab) administered every 4 weeks or monthly is effective in slowing the clinical progression of MSA-C as measured by the UMSARS total score by approximately 30%, for example, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, 30%-99%, 40%-99%, 50%-99%, 60%-99%, 70%-99%, 80%-99%, 90%-99%. The percentages are 30%-90%, 40%-90%, 50%-90%, 60%-90%, 70%-90%, 80%-90%, 30%-80%, 40%-80%, 50%-80%, 60%-80%, 70%-80%, 30%-70%, 40%-70%, 50%-70%, 60%-70%, 30%-60%, 40%-60%, 50%-60%, 30%-50%, 40%-50%, or 30%-40%. In another embodiment, the treatment effect of GM37v2 (elenetamab) administered every 4 weeks or monthly is a reduction in clinical progression of MSA-C by at least 50% as measured by the UMSARS total score. In another embodiment, the treatment effect of GM37v2 (elenetamab) administered every 4 weeks or monthly is a reduction in clinical progression of MSA-C by at least 50% as measured by the UMSARS total score. In another embodiment, treatment with GM37v2 (elenetatumab) administered every 4 weeks or monthly resulted in a reduction in MSA-C clinical progression as measured by the UMSARS total score of approximately 30%-99%, 40%-99%, 50%-99%, 60%-99%, 70%-99%, 80%-99%, 90%-99%, 30%-90%, 40%-90%, 50%-90%, 60%-90%, 70%-90%, 80%-90%, 30%-80%, 40%-80%, 50%-80%, 60%-80%, 70%-80%, 30%-70%, 40%-70%, 50%-70%, 60%-70%, 30%-60%, 40%-60%, 50%-60%, 30%-50%, 40%-50%, or 30%-40%. In another embodiment, treatment with GM37v2 (elenetatumab) administered every 4 weeks or monthly resulted in a reduction of approximately 50% in clinical progression of MSA-C as measured by the UMSARS total score.

[0383] In another embodiment, treatment with GM37v2 (elenetatumab) administered every 4 weeks or monthly is effective in slowing the clinical progression of MSA-C as measured by the UMSARS Part I score by approximately 30%, for example, at least 40%, at least 50%, at least 57%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, 30%-99%, 40%-99%, 50%-99%, 57%-99%, 60%-99%, 70%-99%, 80%-99%, 90%-99%, 30%-99%, 9 ... 0%, 40%-90%, 50%-90%, 57%-90%, 60%-90%, 70%-90%, 80%-90%, 30%-80%, 40%-80%, 50%-80%, 57%-80%, 60%-80%, 70%-80%, 30%-70%, 40%-70%, 50%-70%, 57%-70%, 60%-70%, 30%-60%, 40%-60%, 50%-60%, 57%-60%, 30%-50%, 40%-50%, or 30%-40%. In another embodiment, treatment with GM37v2 (elenetatumab) administered every 4 weeks or monthly resulted in a reduction of clinical progression of MSA-C by approximately 57%, as measured by the UMSARS Part I score. In another embodiment, the treatment efficacy of GM37v2 (elenetatumab) administered every 4 weeks or monthly was as follows: a slowdown in MSA-C clinical progression measured by UMSARS Part I scores of approximately 30%-99%, 40%-99%, 50%-99%, 57%-99%, 60%-99%, 70%-99%, 80%-99%, 90%-99%, 30%-90%, 40%-90%, 50%-90%, 57%-90%, and 60%-99%. The percentages are 30%-90%, 70%-90%, 80%-90%, 30%-80%, 40%-80%, 50%-80%, 57%-80%, 60%-80%, 70%-80%, 30%-70%, 40%-70%, 50%-70%, 57%-70%, 60%-70%, 30%-60%, 40%-60%, 50%-60%, 57%-60%, 30%-50%, 40%-50%, or 30%-40%. In another embodiment, treatment with GM37v2 (elenetatumab) administered every 4 weeks or monthly resulted in a reduction of approximately 57% in clinical progression of MSA-C, as measured by the UMSARS Part I score.

[0384] In another embodiment, treatment with GM37v2 (elenetatumab) administered every 4 weeks or monthly is effective in slowing the clinical progression of MSA-C as measured by UMSARS Part II scores by approximately 30%, for example, at least 40%, at least 41%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, 30%-99%, 40%-99%, 41%-99%, 50%-99%, 60%-99%, 70%-99%, 80%-99%, 90%-99%, 30%-90%, 4 0%-90%, 41%-90%, 50%-90%, 60%-90%, 70%-90%, 80%-90%, 30%-80%, 40%-80%, 41%-80%, 50%-80%, 60%-80%, 70%-80%, 30%-70%, 40%-70%, 41%-70%, 50%-70%, 60%-70%, 30%-60%, 40%-60%, 41%-60%, 50%-60%, 30%-50%, 40%-50%, 41%-50%, or 30%-40%. In another embodiment, treatment with GM37v2 (elenetatumab) administered every 4 weeks or monthly resulted in a reduction of clinical progression of MSA-C by approximately 41% as measured by the UMSARS Part II score. In another embodiment, treatment with GM37v2 (elenetatumab) administered every 4 weeks or monthly resulted in a reduction in MSA-C clinical progression as measured by UMSARS Part II scores of approximately 30%-99%, 40%-99%, 41%-99%, 50%-99%, 60%-99%, 70%-99%, 80%-99%, 90%-99%, 30%-90%, 40%-90%, 41%-90%, 50%-90%, and 60%-99%. 0%, 70%-90%, 80%-90%, 30%-80%, 40%-80%, 41%-80%, 50%-80%, 60%-80%, 70%-80%, 30%-70%, 40%-70%, 41%-70%, 50%-70%, 60%-70%, 30%-60%, 40%-60%, 41%-60%, 50%-60%, 30%-50%, 40%-50%, 41%-50%, or 30%-40%. In another embodiment, treatment with GM37v2 (elenetatumab) administered every 4 weeks or monthly resulted in a reduction of approximately 41% in clinical progression of MSA-C as measured by UMSARS Part II scores.

[0385] In another embodiment, the therapeutic effect of GM37v2 (elenetamab) administered to MSA-C every 4 weeks or monthly is a slowdown in the reduction of pontine region volume, with a reduction of approximately 0.8%-1.5%, for example, 1.0%-1.5%, 1.2%-1.5%, 0.8%-1.2%, 1%-1.2%, or 0.8%-1.0%. In another embodiment, the therapeutic effect of GM37v2 (elenetamab) administered to MSA-C every 4 weeks or monthly is a slowdown in the reduction of pontine region volume, with a reduction of approximately 1.2%.

[0386] In another embodiment, the treatment effect of MSA-C with GM37v2 (elenetamab) administered every 4 weeks or monthly was a slowdown in the reduction of cerebellar white matter volume, with a reduction of approximately 2.5%-5%, 3%-5%, 3.5%-5%, 4%-5%, 2.5%-4%, 3%-4%, 3.5%-4%, or 2.5%-3%. In another embodiment, the treatment effect of MSA-C with GM37v2 (elenetamab) administered every 4 weeks or monthly was a slowdown in the reduction of cerebellar white matter volume, with a reduction of approximately 3.8%.

[0387] In another embodiment, the therapeutic effect of MSA-C with GM37v2 (elenetamab) administered every 4 weeks or monthly is a slowdown in the reduction of cerebellar gray matter volume, with a reduction of approximately 0.2%-0.6%, such as 0.3%-0.6%, 0.4%-0.6%, 0.5%-0.6%, 0.3%-0.5%, 0.4%-0.5%, or 0.3%-0.4%. In another embodiment, the therapeutic effect of MSA-C with GM37v2 (elenetamab) administered every 4 weeks or monthly is a slowdown in the reduction of cerebellar gray matter volume, with a reduction of approximately 0.4%.

[0388] In another embodiment, the therapeutic effect of GM37v2 (elenetamab) administered to MSA-C every 4 weeks or monthly is a slowdown in the reduction of pontine region volume, with a reduction of at least about 0.8%-1.5%, such as 1.0%-1.5%, 1.2%-1.5%, 0.8%-1.2%, 1%-1.2%, or 0.8%-1.0%. In another embodiment, the therapeutic effect of GM37v2 (elenetamab) administered to MSA-C every 4 weeks or monthly is a slowdown in the reduction of pontine region volume, with a reduction of at least about 1.2%.

[0389] In another embodiment, the therapeutic effect of GM37v2 (elenetamab) administered to MSA-C every 4 weeks or monthly is a slowdown in the reduction of cerebellar white matter volume, with a reduction of at least approximately 2.5%-5%, 3%-5%, 3.5%-5%, 4%-5%, 2.5%-4%, 3%-4%, 3.5%-4%, or 2.5%-3%. In another embodiment, the therapeutic effect of GM37v2 (elenetamab) administered to MSA-C every 4 weeks or monthly is a slowdown in the reduction of cerebellar white matter volume, with a reduction of at least approximately 3.8%.

[0390] In another embodiment, the therapeutic effect of MSA-C with GM37v2 (elenetamarab) administered every 4 weeks or monthly is a slowdown in the reduction of cerebellar gray matter volume, with a reduction of at least about 0.2%-0.6%, such as 0.3%-0.6%, 0.4%-0.6%, 0.5%-0.6%, 0.3%-0.5%, 0.4%-0.5%, or 0.3%-0.4%. In another embodiment, the therapeutic effect of MSA-C with GM37v2 (elenetamarab) administered every 4 weeks or monthly is a slowdown in the reduction of cerebellar gray matter volume, with a reduction of at least about 0.4%.

[0391] In another embodiment, treatment with GM37v2 (elenetamarab) administered every 4 weeks or monthly was effective in slowing the clinical progression of early MSA by at least approximately 30%, such as at least 40%, at least 42%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, 30%-99%, 40%-99%, 42%-99%, 50%-99%, 60%-99%, 70%-99%, 80%-99%, 90%-99%, 30%-90%, 40 The percentages of GM37v2 (elenetatumab) administered every 4 weeks or monthly were 90%, 42%, 50%, 60%, 70%, 90%, 80%, 30%, 80%, 40%, 42%, 50%, 60%, 70%, 30%, 70%, 40%, 42%, 50%, 70%, 60%, 30%, 60%, 42%, 50%, 50%, 60%, 30%, 60%, 40%, 42%, 60%, 50%, 50%, 30%, 50%, 40%, 50%, 42%, or 30%-40%. In another embodiment, treatment with GM37v2 (elenetatumab) every 4 weeks or monthly resulted in a reduction of clinical progression of early MSA by at least approximately 42%, as measured by a modified UMSARS score. In another embodiment, treatment with GM37v2 (elenetatumab) administered every 4 weeks or monthly resulted in a reduction in clinical progression of early MSA as measured by modified UMSARS scores of approximately 30%-99%, 40%-99%, 42%-99%, 50%-99%, 60%-99%, 70%-99%, 80%-99%, 90%-99%, 30%-90%, 40%-90%, 42%-90%, 50%-90%, and 60%-90%. %, 70%-90%, 80%-90%, 30%-80%, 40%-80%, 42%-80%, 50%-80%, 60%-80%, 70%-80%, 30%-70%, 40%-70%, 42%-70%, 50%-70%, 60%-70%, 30%-60%, 40%-60%, 42%-60%, 50%-60%, 30%-50%, 40%-50%, 42%-50%, or 30%-40%. In another embodiment, treatment with GM37v2 (elenetatumab) administered every 4 weeks or monthly resulted in a reduction of approximately 42% in clinical progression of early MSA as measured by a modified UMSARS score.

[0392] In another embodiment, treatment with GM37v2 (elenetatumab) administered every 4 weeks resulted in a reduction in clinical progression of early MSA by at least approximately 30%, as measured by the UMSARS total score, for example, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, 30%-99%, 37%-99%, 40%-99%, 50%-99%, 60%-99%, 70%-99%, 80%-99%, 90%-99%, 30%-90%, 37%-90%, 40%- 90%, 50%-90%, 60%-90%, 70%-90%, 80%-90%, 30%-80%, 37%-80%, 40%-80%, 50%-80%, 60%-80%, 70%-80%, 30%-70%, 37%-80%, 40%-70%, 50%-70%, 60%-70%, 30%-60%, 37%-60%, 40%-60%, 50%-60%, 30%-50%, 37%-50%, 40%-50%, 37%-40%, or 30%-40%. In another embodiment, treatment with GM37v2 (elenetatumab) administered every 4 weeks or monthly resulted in a reduction of at least approximately 37% in clinical progression of early-stage MSA, as measured by the UMSARS total score. In another embodiment, treatment with GM37v2 (elenetatumab) administered every 4 weeks or monthly resulted in a reduction in clinical progression of early MSA by approximately 30%-99%, 37%-99%, 40%-99%, 50%-99%, 60%-99%, 70%-99%, 80%-99%, 90%-99%, 30%-90%, 37%-90%, 40%-90%, 50%-90%, 60%-90%, and 70% as measured by the UMSARS total score. -90%, 80%-90%, 30%-80%, 37%-80%, 40%-80%, 50%-80%, 60%-80%, 70%-80%, 30%-70%, 37%-80%, 40%-70%, 50%-70%, 60%-70%, 30%-60%, 37%-60%, 40%-60%, 50%-60%, 30%-50%, 37%-50%, 40%-50%, 37%-40%, or 30%-40%. In another embodiment, treatment with GM37v2 (elenetatumab) administered every 4 weeks resulted in a reduction of approximately 37% in clinical progression of early-stage MSA, as measured by the UMSARS total score.

[0393] In another embodiment, treatment with GM37v2 (elenetatumab) administered every 4 weeks or monthly is effective in slowing the clinical progression of early MSA by at least approximately 30%, as measured by UMSARS Part I scores, for example, at least 40%, at least 42%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, 30%-99%, 40%-99%, 42%-99%, 50%-99%, 60%-99%, 70%-99%, 80%-99%, 90%-99%, 30%-90%, 4 0%-90%, 42%-90%, 50%-90%, 60%-90%, 70%-90%, 80%-90%, 30%-80%, 40%-80%, 42%-80%, 50%-80%, 60%-80%, 70%-80%, 30%-70%, 40%-70%, 42%-70%, 50%-70%, 60%-70%, 30%-60%, 40%-60%, 42%-60%, 50%-60%, 30%-50%, 40%-50%, 42%-50%, or 30%-40%. In another embodiment, treatment with GM37v2 (elenetatumab) administered every 4 weeks or monthly resulted in a reduction of clinical progression of early MSA by at least approximately 42%, as measured by the UMSARS Part I score. In another embodiment, treatment with GM37v2 (elenetatumab) administered every 4 weeks or monthly resulted in a reduction in clinical progression of early MSA as measured by UMSARS Part I scores of approximately 30%-99%, 40%-99%, 42%-99%, 50%-99%, 60%-99%, 70%-99%, 80%-99%, 90%-99%, 30%-90%, 40%-90%, 42%-90%, 50%-90%, and 60%-99%. 0%, 70%-90%, 80%-90%, 30%-80%, 40%-80%, 42%-80%, 50%-80%, 60%-80%, 70%-80%, 30%-70%, 40%-70%, 42%-70%, 50%-70%, 60%-70%, 30%-60%, 40%-60%, 42%-60%, 50%-60%, 30%-50%, 40%-50%, 42%-50%, or 30%-40%. In another embodiment, treatment with GM37v2 (elenetatumab) administered every 4 weeks or monthly resulted in a reduction of approximately 42% in clinical progression of early MSA, as measured by the UMSARS Part I score.

[0394] In another embodiment, treatment with GM37v2 (elenetatumab) administered every 4 weeks or monthly is effective in slowing the clinical progression of early MSA by at least approximately 10%, as measured by the UMSARS Part II score, for example, at least 15%, at least 20%, at least 30%, at least 35%, at least 40%, at least 50%, 10%-50%, 15%-50%, 20%-50%, 25%-50%, 30%-50%, 35%-50%, 40%-50%, 45%-50%, 10%-45%, 15%-45%, and 20%-45%. The treatment efficacy of GM37v2 (elenetatumab) administered every 4 weeks or monthly was at least a 30% slowdown in clinical progression of early MSA, as measured by UMSARS Part II scores. In another embodiment, treatment with GM37v2 (elenetatumab) administered every 4 weeks or monthly resulted in a reduction in clinical progression of early MSA by approximately 10%-50%, 15%-50%, 20%-50%, 25%-50%, 30%-50%, 35%-50%, 40%-50%, 45%-50%, 10%-45%, 15%-45%, 20%-45%, 25%-45%, 30%-45%, and 35%-45% respectively. 5%, 40%-45%, 10%-40%, 15%-40%, 20%-40%, 25%-40%, 30%-40%, 35%-40%, 10%-35%, 15%-35%, 20%-35%, 25%-35%, 30%-35%, 10%-30%, 15%-30%, 20%-30%, 25%-30%, 10%-25%, 15%-25%, 20%-25%, 10%-20%, 15%-20%, or 10%-15%. In another embodiment, treatment with GM37v2 (elenetatumab) administered every 4 weeks or monthly resulted in a reduction of approximately 30% in clinical progression of early MSA, as measured by UMSARS Part II scores.

[0395] In another embodiment, the treatment effect of early MSA with GM37v2 (elenetamab) administered every 4 weeks or monthly was a slowdown in the reduction of pontine region volume, with a reduction of approximately 1.8%-3.0%, 2%-2.8%, 2.2%-2.6%, or 2.3%-2.5%. In yet another embodiment, the treatment effect of early MSA with GM37v2 (elenetamab) administered every 4 weeks or monthly was a slowdown in the reduction of pontine region volume, with a reduction of approximately 2.4%.

[0396] In another embodiment, the treatment effect of early MSA with GM37v2 (elenetamab) administered every 4 weeks or monthly was a slowdown in the reduction of cerebellar white matter volume, with a reduction of approximately 3%-5%, 3.5%-4.5%, 4%-5%, or 4%-4.5%. In yet another embodiment, the treatment effect of early MSA with GM37v2 (elenetamab) administered every 4 weeks or monthly was a slowdown in the reduction of cerebellar white matter volume, with a reduction of approximately 4.2%.

[0397] In another embodiment, the therapeutic effect of early MSA treatment with GM37v2 (elenetamab) administered every 4 weeks or monthly is a slowdown in the reduction of cerebellar gray matter volume, with a reduction of approximately 0.2%-0.6%, such as 0.3%-0.6%, 0.4%-0.6%, 0.5%-0.6%, 0.3%-0.5%, 0.4%-0.5%, or 0.3%-0.4%. In another embodiment, the therapeutic effect of early MSA treatment with GM37v2 (elenetamab) administered every 4 weeks or monthly is a slowdown in the reduction of cerebellar gray matter volume, with a reduction of approximately 0.4%.

[0398] In another embodiment, the treatment effect of early MSA with GM37v2 (elenetamab) administered every 4 weeks or monthly was a slowdown in the reduction of pontine region volume, with a reduction of at least about 2.4%. In another embodiment, the treatment effect of early MSA with GM37v2 (elenetamab) administered every 4 weeks or monthly was a slowdown in the reduction of pontine region volume, with a reduction of about 1.8%-3.0%, 2%-2.8%, 2.2%-2.6%, or 2.3%-2.5%.

[0399] In another embodiment, the treatment effect of early MSA with GM37v2 (elenetamab) administered every 4 weeks or monthly was a slowdown in the reduction of cerebellar white matter volume, with a reduction of at least approximately 4.2%. In another embodiment, the treatment effect of early MSA with GM37v2 (elenetamab) administered every 4 weeks or monthly was a slowdown in the reduction of cerebellar white matter volume, with a reduction of approximately 3%-5%, 3.5%-4.5%, 4%-5%, or 4%-4.5%.

[0400] In another embodiment, the therapeutic effect of early MSA treatment with GM37v2 (elenetamarab) administered every 4 weeks or monthly is a slowdown in the reduction of cerebellar gray matter volume, with a reduction of at least about 0.4%. In another embodiment, the therapeutic effect of early MSA treatment with GM37v2 (elenetamarab) administered every 4 weeks or monthly is a slowdown in the reduction of cerebellar gray matter volume, with a reduction of at least about 0.2%-0.6%, such as 0.3%-0.6%, 0.4%-0.6%, 0.5%-0.6%, 0.3%-0.5%, 0.4%-0.5%, or 0.3%-0.4%.

[0401] In another embodiment, the therapeutic effect of GM37v2 (elenetatumab) administered to MSA every 4 weeks or monthly is damage reduction, as measured by UMSARS Part IV - Overall Disability Score.

[0402] In another embodiment, the effect of early MSA treatment with GM37v2 (elenetatumab) administered every 4 weeks or monthly is damage reduction, as measured by UMSARS Part IV - Overall Disability Score.

[0403] In another embodiment, the therapeutic effect of GM37v2 (elenetatumab) administered to MSA-C every 4 weeks or monthly is a reduction in damage, as measured by UMSARS Part IV - Overall Disability Score.

[0404] In another embodiment, the therapeutic effect of GM37v2 (elenetamab) administered to MSA every 4 weeks or monthly is a reduction in damage, as measured by the UMSARS Part IV - Overall Disability Score, with a reduction in damage of approximately 0.1-0.3, 0.2-0.3, or 0.1-0.2 points. In another embodiment, the therapeutic effect of GM37v2 (elenetamab) administered to MSA every 4 weeks or monthly is a reduction in damage, as measured by the UMSARS Part IV - Overall Disability Score, with a reduction in damage of approximately 0.2 points.

[0405] In another embodiment, the therapeutic effect of early MSA with GM37v2 (elenetamab) administered every 4 weeks or monthly was a reduction in damage, as measured by the UMSARS Part IV – Overall Disability Score, with a reduction in damage of approximately 0.6–1.0, 0.7–1.0, 0.8–1.0, 0.6–0.9, 0.7–0.9, 0.6–0.8, or 0.7–0.8 points. In another embodiment, the therapeutic effect of early MSA with GM37v2 (elenetamab) administered every 4 weeks or monthly was a reduction in damage, as measured by the UMSARS Part IV – Overall Disability Score, with a reduction in damage of approximately 0.8 points.

[0406] In another embodiment, the therapeutic effect of early MSA treatment with GM37v2 (elenetamab) administered every 4 weeks or monthly is a reduction in damage, as measured by the UMSARS Part IV – Overall Disability Score, with a reduction in damage of at least about 0.8 points. In another embodiment, the therapeutic effect of early MSA treatment with GM37v2 (elenetamab) administered every 4 weeks or monthly is a reduction in damage, as measured by the UMSARS Part IV – Overall Disability Score, with a reduction in damage of about 0.6–1.0, 0.7–1.0, 0.8–1.0, 0.6–0.9, 0.7–0.9, 0.6–0.8, or 0.7–0.8 points.

[0407] In another embodiment, the therapeutic effect of GM37v2 (elenetamab) administered every 4 weeks or monthly for MSA is a reduction in damage, as measured by the Clinical Global Impression-Disease Severity Score. In another embodiment, the therapeutic effect of GM37v2 (elenetamab) administered every 4 weeks or monthly for early MSA is a reduction in damage, as measured by the Clinical Global Impression-Disease Severity Score.

[0408] In another embodiment, the therapeutic effect of MSA-C with GM37v2 (elenetatumab) administered every 4 weeks or monthly is damage reduction, as measured by the Clinical Global Impression-Disease Severity Score.

[0409] In another embodiment, the therapeutic effect of GM37v2 (elenetumab) administered to MSA every 4 weeks or monthly is a reduction in damage, as measured by the Clinical Global Impression-Disease Severity Score, with a reduction in damage of at least about 0.2 points. In another embodiment, the therapeutic effect of GM37v2 (elenetumab) administered to MSA every 4 weeks or monthly is a reduction in damage, as measured by the Clinical Global Impression-Disease Severity Score, with a reduction in damage of about 0.1–0.3, 0.2–0.3, or 0.1–0.2 points. In another embodiment, the therapeutic effect of GM37v2 (elenetumab) administered to MSA every 4 weeks or monthly is a reduction in damage, as measured by the Clinical Global Impression-Disease Severity Score, with a reduction in damage of about 0.2 points.

[0410] In another embodiment, the therapeutic effect of early MSA with GM37v2 (elenetumab) administered every 4 weeks or monthly is a reduction in damage, as measured by the Clinical Global Impression-Disease Severity Score, with a reduction in damage of at least about 0.5 points. In another embodiment, the therapeutic effect of early MSA with GM37v2 (elenetumab) administered every 4 weeks or monthly is a reduction in damage, as measured by the Clinical Global Impression-Disease Severity Score, with a reduction in damage of about 0.3–0.7, 0.3–0.6, 0.3–0.5, 0.4–0.7, 0.4–0.6, 0.5–0.7, or 0.5–0.6 points. In another embodiment, the therapeutic effect of early MSA with GM37v2 (elenetumab) administered every 4 weeks or monthly is a reduction in damage, as measured by the Clinical Global Impression-Disease Severity Score, with a reduction in damage of about 0.5 points.

[0411] In another embodiment, the therapeutic effect of GM37v2 (elenetumab) administered to MSA every 4 weeks or monthly is a slowdown in the reduction of pontine region volume, with a reduction of at least about 1.9%. In another embodiment, the therapeutic effect of GM37v2 (elenetumab) administered to MSA every 4 weeks or monthly is a slowdown in the reduction of pontine region volume, with a reduction of about 1%-3%, 1.5%-3%, 1.9%-3%, 2%-3%, 1%-2.5%, 1%-2%, 1.5%-2%, 1%-1.9%, or 1.9%-2.5%. In another embodiment, the therapeutic effect of GM37v2 (elenetumab) administered to MSA every 4 weeks or monthly is a slowdown in the reduction of pontine region volume, with a reduction of about 1.9%.

[0412] In another embodiment, the therapeutic effect of GM37v2 (elenetumab) administered to MSA every 4 weeks or monthly is a slowdown in the reduction of cerebellar white matter volume, with a reduction of at least approximately 3.3%. In another embodiment, the therapeutic effect of GM37v2 (elenetumab) administered to MSA every 4 weeks or monthly is a slowdown in the reduction of cerebellar white matter volume, with a reduction of approximately 2%-5%, 2.5%-5%, 3%-5%, 3.3%-5%, 2%-4%, 2.5%-4%, 3%-4%, 3.3%-4%, 2%-3.5%, 2.5%-3.5%, 3%-3.5%, 2%-3.3%, 2.5%-3.3%, or 3%-3.3%. In another embodiment, the therapeutic effect of GM37v2 (elenetumab) administered to MSA every 4 weeks or monthly is a slowdown in the reduction of cerebellar white matter volume, with a reduction of approximately 3.3%.

[0413] In another embodiment, the therapeutic effect of GM37v2 (elenetumab) administered to MSA every 4 weeks or monthly is a slowdown in the reduction of cerebellar gray matter volume, with a reduction of at least about 1.5%. In another embodiment, the therapeutic effect of GM37v2 (elenetumab) administered to MSA every 4 weeks or monthly is a slowdown in the reduction of cerebellar gray matter volume, with a reduction of about 1%-3%, 1%-2.5%, 1%-2%, 1%-1.5%, 1.5%-3%, 1.5%-2.5%, or 1.5%-2%. In another embodiment, the therapeutic effect of GM37v2 (elenetumab) administered to MSA every 4 weeks or monthly is a slowdown in the reduction of cerebellar gray matter volume, with a reduction of about 1.5%.

[0414] In another embodiment, treatment with GM37v2 (elenetumab) administered to MSA every 4 weeks or monthly resulted in a greater reduction in the neurofilament light chain load of CSF. In another embodiment, treatment with GM37v2 (elenetumab) administered to MSA every 4 weeks or monthly resulted in a reduction in the neurofilament light chain load of CSF of at least about 16.3%. In another embodiment, treatment with GM37v2 (elenetumab) administered to MSA every 4 weeks or monthly resulted in a reduction in the neurofilament light chain load of CSF of about 10%-25%, 10%-20%, 10%-16.3%, 10%-15%, 15%-25%, 15%-20%, 15%-16.3%, 16.3%-25%, or 16.3%-20%. In another embodiment, treatment with GM37v2 (elenetatumab) administered to MSA every 4 weeks or monthly resulted in a reduction of approximately 16.3% in the neurofilament light chain load of CSF.

[0415] In another embodiment, the therapeutic effect of early MSA treatment with GM37v2 (elenetumab) administered every 4 weeks or monthly is a reduction in CSF neurofilament light chain load of at least about 14.4%. In another embodiment, the therapeutic effect of early MSA treatment with GM37v2 (elenetumab) administered every 4 weeks or monthly is a reduction in CSF neurofilament light chain load of about 5%-25%, 10%-25%, 14.4%-25%, 15%-25%, 20%-25%, 5%-20%, 10%-20%, 14.4%-20%, 15%-20%, 5%-15%, 10%-15%, or 5%-10%. In another embodiment, the therapeutic effect of early MSA treatment with GM37v2 (elenetumab) administered every 4 weeks or monthly is a reduction in CSF neurofilament light chain load of about 14.4%.

[0416] In another embodiment, the therapeutic effect of GM37v2 (elenetumab) administered to MSA every 4 weeks or monthly is a reduction in damage, as measured by the UMSARS Part I single item "speech". In another embodiment, the therapeutic effect of GM37v2 (elenetumab) administered to MSA every 4 weeks or monthly is a reduction in damage, as measured by the UMSARS Part I single item "speech", with a reduction in damage of at least about 0.4 points. In another embodiment, the therapeutic effect of GM37v2 (elenetumab) administered to MSA every 4 weeks or monthly is a reduction in damage, as measured by the UMSARS Part I single item "speech", with a reduction in damage of about 0.2–0.6, 0.3–0.6, 0.4–0.6, 0.5–0.6, 0.2–0.5, 0.3–0.5, 0.4–0.5, 0.2–0.4, 0.3–0.4, or 0.2–0.3 points. In another embodiment, the therapeutic effect of GM37v2 (elenetatumab) administered to MSA every 4 weeks or monthly was a reduction in damage, measured as approximately 0.4 points using the single item “speech” in Part I of UMSARS.

[0417] In another embodiment, the therapeutic effect of GM37v2 (elenetatumab) administered to MSA-C every 4 weeks or monthly is damage reduction, as measured by the single item “speech” in Part I of UMSARS.

[0418] In another embodiment, the therapeutic effect of early MSA treatment with GM37v2 (elenetatumab) administered every 4 weeks or monthly is damage reduction, as measured by the single item “speech” in Part I of UMSARS.

[0419] In another embodiment, the therapeutic effect of early MSA with GM37v2 (elenetumab) administered every 4 weeks or monthly is a reduction in damage, as measured by the UMSARS Part I single item "speech," with a reduction in damage of at least about 0.8 points. In another embodiment, the therapeutic effect of early MSA with GM37v2 (elenetumab) administered every 4 weeks or monthly is a reduction in damage, as measured by the UMSARS Part I single item "speech," with a reduction in damage of about 0.6–1.0, 0.7–1.0, 0.8–1.0, 0.6–0.9, 0.7–0.9, 0.6–0.8, or 0.7–0.8 points. In another embodiment, the therapeutic effect of early MSA with GM37v2 (elenetumab) administered every 4 weeks or monthly is a reduction in damage, as measured by the UMSARS Part I single item "speech," with a reduction in damage of about 0.8 points.

[0420] In another embodiment, the therapeutic effect of GM37v2 (elenetamarab) administered to MSA every 4 weeks or monthly is a reduction in damage, as measured by the UMSARS Part I single item "Cutting Food / Using Cutlery". In another embodiment, the therapeutic effect of GM37v2 (elenetamarab) administered to MSA every 4 weeks or monthly is a reduction in damage, as measured by the UMSARS Part I single item "Cutting Food / Using Cutlery", with a reduction in damage of at least about 0.3 points. In another embodiment, the therapeutic effect of GM37v2 (elenetamarab) administered to MSA every 4 weeks or monthly is a reduction in damage, as measured by the UMSARS Part I single item "Cutting Food / Using Cutlery", with a reduction in damage of about 0.2-0.4, 0.3-0.4, or 0.2-0.3 points. In another embodiment, the effect of treatment with GM37v2 (elenetatumab) administered to MSA every 4 weeks or monthly was a reduction in damage, as measured by the single item “Cutting food / Using utensils” in Part I of UMSARS, with a reduction in damage of approximately 0.3 points.

[0421] In another embodiment, the therapeutic effect of GM37v2 (elenetatumab) administered to MSA-C every 4 weeks or monthly was a reduction in damage, as measured by the single item “Cutting food / Using utensils” in Part I of UMSARS.

[0422] In another embodiment, the therapeutic effect of early MSA treatment with GM37v2 (elenetatumab) administered every 4 weeks or monthly was a reduction in damage, as measured by the single item “Cutting food / Using utensils” in Part I of UMSARS.

[0423] In another embodiment, the therapeutic effect of early MSA with GM37v2 (elenetamarab) administered every 4 weeks or monthly was a reduction in damage, as measured by the UMSARS Part I single item "Cutting Food / Using Cutlery," with a reduction in damage of at least about 0.7 points. In another embodiment, the therapeutic effect of early MSA with GM37v2 (elenetamarab) administered every 4 weeks or monthly was a reduction in damage, as measured by the UMSARS Part I single item "Cutting Food / Using Cutlery," with a reduction in damage of about 0.5–0.9, 0.6–0.9, 0.7–0.9, 0.5–0.8, 0.6–0.8, 0.7–0.8, 0.5–0.7, or 0.6–0.7 points. In another embodiment, the effect of early MSA treatment with GM37v2 (elenetatumab) administered every 4 weeks or monthly was a reduction in damage, as measured by the single item “Cutting food / Using utensils” in Part I of UMSARS, with a reduction in damage of approximately 0.7 points.

[0424] In another embodiment, the therapeutic effect of GM37v2 (elenetumab) administered to MSA every 4 weeks or monthly is a reduction in damage, as measured by the UMSARS Part I single item "Health". In another embodiment, the therapeutic effect of GM37v2 (elenetumab) administered to MSA every 4 weeks or monthly is a reduction in damage, as measured by the UMSARS Part I single item "Health", with a reduction in damage of at least about 0.2 points. In another embodiment, the therapeutic effect of GM37v2 (elenetumab) administered to MSA every 4 weeks or monthly is a reduction in damage, as measured by the UMSARS Part I single item "Health", with a reduction in damage of about 0.1-0.3, 0.2-0.3, or 0.1-0.2 points. In another embodiment, the therapeutic effect of GM37v2 (elenetatumab) administered to MSA every 4 weeks or monthly was a reduction in damage, measured as approximately 0.2 points in damage reduction using the single item “Health” in Part I of UMSARS.

[0425] In another embodiment, the therapeutic effect of GM37v2 (elenetatumab) administered to MSA-C every 4 weeks or monthly is damage reduction, as measured by the single item “Health” in Part I of UMSARS.

[0426] In another embodiment, the therapeutic effect of GM37v2 (elenetamab) administered every 4 weeks or monthly in early MSA was a reduction in damage, as measured by the UMSARS Part I single item "Health". In another embodiment, the therapeutic effect of GM37v2 (elenetamab) administered every 4 weeks or monthly in early MSA was a reduction in damage, as measured by the UMSARS Part I single item "Health", with a reduction in damage of at least about 0.6 points. In another embodiment, the therapeutic effect of GM37v2 (elenetumab) administered every 4 weeks or monthly in early MSA was a reduction in damage, as measured by the UMSARS Part I individual item "Health," with a damage reduction of approximately 0.4–0.8, 0.5–0.8, 0.6–0.8, 0.7–0.8, 0.4–0.7, 0.5–0.7, 0.6–0.7, 0.4–0.6, 0.5–0.6, or 0.4–0.5 points. In another embodiment, the therapeutic effect of GM37v2 (elenetumab) administered every 4 weeks or monthly in early MSA was a reduction in damage, as measured by the UMSARS Part I individual item "Health," with a damage reduction of approximately 0.6 points.

[0427] In another embodiment, the therapeutic effect of GM37v2 (elenetatumab) administered to MSA every 4 weeks or monthly is damage reduction, as measured by the single item “walking” in Part I of UMSARS.

[0428] In another embodiment, the therapeutic effect of GM37v2 (elenetumab) administered to MSA every 4 weeks or monthly is a reduction in damage, as measured by the UMSARS Part I single item "walking," with a reduction in damage of at least about 0.2 points. In another embodiment, the therapeutic effect of GM37v2 (elenetumab) administered to MSA every 4 weeks or monthly is a reduction in damage, as measured by the UMSARS Part I single item "walking," with a reduction in damage of about 0.1–0.3, 0.2–0.3, or 0.1–0.2 points. In another embodiment, the therapeutic effect of GM37v2 (elenetumab) administered to MSA every 4 weeks or monthly is a reduction in damage, as measured by the UMSARS Part I single item "walking," with a reduction in damage of about 0.2 points.

[0429] In another embodiment, the therapeutic effect of GM37v2 (elenetatumab) administered to MSA-C every 4 weeks or monthly is damage reduction, as measured by the single item “walking” in Part I of UMSARS.

[0430] In another embodiment, the therapeutic effect of early MSA treatment with GM37v2 (elenetatumab) administered every 4 weeks or monthly was a reduction in damage, as measured by the single item “walking” in Part I of UMSARS.

[0431] In another embodiment, the therapeutic effect of early MSA with GM37v2 (elenetumab) administered every 4 weeks or monthly was a reduction in damage, as measured by the UMSARS Part I single item "walking," with a reduction in damage of at least about 0.4 points. In another embodiment, the therapeutic effect of early MSA with GM37v2 (elenetumab) administered every 4 weeks or monthly was a reduction in damage, as measured by the UMSARS Part I single item "walking," with a reduction in damage of about 0.2–0.6, 0.3–0.6, 0.4–0.6, 0.5–0.6, 0.2–0.5, 0.3–0.5, 0.4–0.5, 0.2–0.4, 0.3–0.4, or 0.2–0.3 points. In another embodiment, the treatment effect of early MSA with GM37v2 (elenetatumab) administered every 4 weeks or monthly was damage reduction, as measured by the single item “walking” in UMSARS Part I, with a damage reduction of approximately 0.4 points.

[0432] In another embodiment, the therapeutic effect of GM37v2 (elenetatumab) administered to MSA every 4 weeks or monthly is a reduction in damage, as measured by the single item “from sitting to standing” in Part II of UMSARS.

[0433] In another embodiment, the therapeutic effect of GM37v2 (elenetumab) administered to MSA every 4 weeks or monthly is a reduction in damage, as measured by the UMSARS Part II single item "From Sitting to Standing," with a reduction in damage of at least about 0.3 points. In another embodiment, the therapeutic effect of GM37v2 (elenetumab) administered to MSA every 4 weeks or monthly is a reduction in damage, as measured by the UMSARS Part II single item "From Sitting to Standing," with a reduction in damage of about 0.2–0.4, 0.3–0.4, or 0.2–0.3 points. In another embodiment, the therapeutic effect of GM37v2 (elenetumab) administered to MSA every 4 weeks or monthly is a reduction in damage, as measured by the UMSARS Part II single item "From Sitting to Standing," with a reduction in damage of about 0.3 points.

[0434] In another embodiment, the therapeutic effect of GM37v2 (elenetatumab) administered to MSA-C every 4 weeks or monthly is damage reduction, as measured by the single item “from sitting to standing” in Part II of UMSARS.

[0435] In another embodiment, the therapeutic effect of early MSA treatment with GM37v2 (elenetatumab) administered every 4 weeks or monthly was a reduction in damage, as measured by the single item “from sitting to standing” in Part II of UMSARS.

[0436] In another embodiment, the effect of early MSA treatment with GM37v2 (elenetumab) administered every 4 weeks or monthly was a reduction in damage, as measured by the UMSARS Part II single item "From Sitting to Standing," with a reduction in damage of at least about 1.2 points. In another embodiment, the effect of early MSA treatment with GM37v2 (elenetumab) administered every 4 weeks or monthly was a reduction in damage, as measured by the UMSARS Part II single item "From Sitting to Standing," with a reduction in damage of about 1.0–1.4, 1.1–1.4, 1.2–1.4, 1.3–1.4, 1.0–1.3, 1.1–1.3, 1.2–1.3, 1.0–1.2, 1.1–1.2, or 1.0–1.1 points. In another embodiment, the effect of early MSA treatment with GM37v2 (elenetatumab) administered every 4 weeks or monthly was a reduction in damage, as measured by the single item “from sitting to standing” in Part II of UMSARS, with a reduction in damage of approximately 1.2 points.

[0437] In another embodiment, treatment for synucleinosis consists of delaying or slowing disease progression by at least 5%, for example at least 10%, for example at least 15%, for example at least 20%, for example at least 25%, for example at least 30%, for example at least 35%, for example at least 40%, for example at least 45%, for example at least 50%, for example at least 55%, for example at least 60%, for example at least 65%, for example at least 70%, for example at least 75%, for example at least 80%, for example at least 85%, or for example at least 90%.

[0438] In another embodiment, treatment for synucleinosis consists of delaying disease progression by at least 25%, such as at least 30%, such as at least 35%, or such as at least 40%.

[0439] In another embodiment, therapeutic effects against synucleinosis were observed after administration of at least 10 doses (e.g., at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20) of GM37v2 (elenetatumab).

[0440] In another embodiment, the therapeutic effect against synucleinosis was observed after treatment with GM37v2 (elenetatumab) for at least 24 weeks, such as at least 48 weeks, such as at least 72 weeks, or such as at least 96 weeks.

[0441] In another embodiment, a therapeutic effect against synucleinosis was observed after treatment with GM37v2 (elenetatumab) for at least 44 weeks or at least 48 weeks.

[0442] In another embodiment, a therapeutic effect against synucleinosis was observed after administration of at least 10 doses (e.g., at least 11 or at least 12 doses) of GM37v2 (elenetatumab).

[0443] In yet another such embodiment, the human subject with MSA has MSA-C. In yet another such embodiment, the human subject with MSA has MSA-P. In yet another such embodiment, the human subject with MSA has suspected or probable MSA-C. In yet another such embodiment, the human subject with MSA has suspected or probable MSA-P.

[0444] In another embodiment, the delay in disease progression is quantified by longitudinal changes in neurofilament light chain (NfL) blood concentration relative to baseline.

[0445] In another embodiment, the delay or slowing of MSA disease progression is quantified by longitudinal changes in neurofilament light chain (NfL) blood concentration relative to baseline.

[0446] In another embodiment, the delay in disease progression was quantified by longitudinal change relative to baseline of one or more parameters selected from the following: Schwab and England Activities of Daily Living (SE-ADL) scores; changes in Clinical Global Impression-Disease Severity (CGI-S) scores relative to baseline; changes in Patient Global Impression-Disease Severity (PGI-S) scores relative to baseline; changes in Observer-Reported Global Impression-Disease Severity (OGI-S) scores relative to baseline; changes in Composite Autonomic Symptoms Selection (COMPASS Selection) scores relative to baseline; changes in UMSARS Part IV scores relative to baseline; changes in speech, swallowing, falls, and walking relative to baseline, as assessed by UMSARS Part I item scores; changes in fall frequency, cause, and consequences relative to baseline, as assessed by a fall diary period; EuroQol Changes in 5-dimensional, 5-level (EQ-5D-5L) scores relative to baseline; changes in brain volume relative to baseline, such as those measured by volumetric MRI (vMRI); changes in tissue integrity relative to baseline, such as those measured by diffusion tensor imaging (DTI) MRI; changes in neurofilament light chain (NfL) blood concentration relative to baseline; changes in heart rate, blood pressure, and orthostatic symptoms relative to baseline, as assessed in UMSARS Part III; changes in gait parameters or fall frequency relative to baseline, such as those assessed by a digital wearable sensor-based device capable of tracking relevant gait parameters and / or recording falls; changes in cerebral blood flow relative to baseline, such as those measured by arterial spin labeling (ASL) MRI; changes in t-tau and NfL CSF concentrations relative to baseline; or changes in the concentration of pathological species of α-synuclein in CSF relative to baseline.

[0447] In another embodiment, human subjects at risk of developing synucleinosis or suffering from precursor synucleinosis can be identified by exhibiting one or more clinical markers of precursor synucleinosis selected from the group consisting of: REM sleep behavior disorder (RBD) (e.g., isolated RBD (iRBD)), olfactory dysfunction (e.g., hyposmia), abnormal cognitive performance on neuropsychological tests, fine motor dysfunction or abnormal motor function as assessed by objective tests, color vision abnormalities, autonomic dysfunction (e.g., constipation, urinary symptoms, erectile dysfunction, orthostatic hypotension), reduced dopaminergic binding in the nigrostriatum and striatum (DAT-SPECT abnormality), seborrheic dermatitis, and genotypes associated with an increased risk of phenotypic transformation, such as mutations in glucocerebrosidase (encoded by the GBA gene).

[0448] In another embodiment, human subjects at risk of developing synucleinopathy or suffering from precursor synucleinopathy can be identified by exhibiting an RBD (such as an isolated RBD (iRBD)) and at least one additional clinical marker of precursor synucleinopathy (such as hyposmia and / or abnormal DAT-SPECT).

[0449] In another embodiment, treatment for precursor synucleinosis consists of delaying disease onset.

[0450] In another embodiment, treatment for precursor synucleinosis consists of delaying the onset or diagnosis of the disease by at least 5%, for example at least 10%, for example at least 15%, for example at least 20%, for example at least 25%, for example at least 30%, for example at least 35%, for example at least 40%, for example at least 45%, for example at least 50%, for example at least 55%, for example at least 60%, for example at least 65%, for example at least 70%, for example at least 75%, for example at least 80%, for example at least 85%, or for example at least 90%.

[0451] In another embodiment, treatment for precursor synucleinosis consists of delaying the onset or diagnosis of the disease by at least 6 months, for example at least 8 months, for example at least 10 months, for example at least 12 months, for example at least 14 months, for example at least 16 months, for example at least 18 months, for example at least 20 months, for example at least 22 months, for example at least 24 months, for example at least 2 years, for example at least 3 years, for example at least 4 years, for example at least 5 years.

[0452] In another embodiment, the present invention provides a method for treating precursor synucleinosis, wherein the treatment comprises administering the monoclonal α-synuclein antibody in an amount and frequency sufficient to achieve a steady-state CSF concentration of the antibody of at least 0.5 nM, for example at least 1 nM, for example at least 2 nM, for example at least 3 nM, for example at least 6 nM, or for example at least 12 nM.

[0453] In another embodiment, the present invention provides a method for treating precursor synucleinosis, wherein the treatment comprises administering the monoclonal α-synuclein antibody in an amount and frequency sufficient to achieve a steady-state CSF concentration of the antibody of at least 3 nM, for example at least 6 nM, or for example at least 12 nM.

[0454] In another embodiment, the present invention provides a method for treating precursor synucleinosis, wherein the treatment comprises administering the monoclonal α-synuclein antibody in an amount and frequency sufficient to achieve an estimated target binding of at least 50%, for example, at least 60%, for example, at least 75%, for example, at least 80%, for example, at least 85%, for example, at least 90%, for example, at least 95%, or for example, at least 99% to the oligomeric form of α-synuclein in CSF.

[0455] In another embodiment, the present invention provides a method for treating precursor synucleinosis, wherein the treatment comprises administering the monoclonal α-synuclein antibody in an amount and frequency sufficient to achieve an estimated target binding of at least 85%, for example at least 90%, or for example at least 95% to the oligomeric form of α-synuclein in CSF.

[0456] In one aspect, the present invention also provides the use of a liquid pharmaceutical composition comprising a full-length IgG1 monoclonal anti-α-synuclein antibody at a concentration of 25-225 mg / mL, wherein the antibody comprises: a. Heavy chain CDR1 having the amino acid sequence of SEQ ID NO:1; b. Heavy chain CDR2 having the amino acid sequence of SEQ ID NO:34; c. Heavy chain CDR3 having the amino acid sequence of SEQ ID NO:3; d. The light chain CDR1 having the amino acid sequence of SEQ ID NO:4; e. The light chain CDR2 having the amino acid sequence of SEQ ID NO:5; and f. Light chain CDR3 having the amino acid sequence of SEQ ID NO:6; The composition further comprises a histidine buffer, a pharmaceutically acceptable tensile agent, and a pharmaceutically acceptable surfactant, and the pH of the composition is between 5.5 and 6.5. This liquid pharmaceutical composition is suitable for administration of monoclonal α-synuclein antibodies in any treatment method for any purpose described in any aspect, embodiment, or claim of this application.

[0457] In the embodiments, the monoclonal antibody of the liquid pharmaceutical composition comprises a heavy chain variable domain consisting of SEQ ID NO:31 and a light chain variable domain consisting of SEQ ID NO:8.

[0458] In the examples, the monoclonal antibody in the liquid pharmaceutical composition is a human antibody.

[0459] In the examples, the monoclonal antibody in the liquid pharmaceutical composition is a human IgG1 antibody.

[0460] In the examples, the monoclonal antibody in the liquid pharmaceutical composition is GM37 variant 2.

[0461] In another embodiment, the monoclonal antibody of the liquid pharmaceutical composition comprises a constant heavy chain domain as defined in SEQ ID NO:18 and a constant κ light chain domain as defined in SEQ ID NO:17.

[0462] In the embodiments, the tensile agent of the liquid pharmaceutical composition is selected from mannitol, sorbitol, lactose, dextrose, trehalose, sodium chloride (NaCl), potassium chloride (KCl), glycerol, or glycerol.

[0463] In the examples, the tensile agent of the liquid pharmaceutical composition is sodium chloride (NaCl).

[0464] In the examples, the tensile agent of the liquid pharmaceutical composition is sodium chloride (NaCl) at a concentration of about 70-140 mM.

[0465] In the examples, the tensile agent of the liquid pharmaceutical composition is sodium chloride (NaCl) at a concentration of about 50-150 mM.

[0466] In the examples, the tensile agent of the liquid pharmaceutical composition is sodium chloride (NaCl) at a concentration of about 100 mM.

[0467] In the examples, the surfactant of the liquid pharmaceutical composition is selected from polysorbate 20 (Tween 20), polysorbate 80 (Tween 80), poloxamer 188, or Triton X-100.

[0468] In the examples, the surfactant of the liquid pharmaceutical composition is polysorbate 80 (Tween 80) in an amount of 0.02% to 0.05% (w / v).

[0469] In the examples, the surfactant of the liquid pharmaceutical composition is polysorbate 80 (Tween 80) in an amount of about 0.02% (w / v).

[0470] In the examples, the tensile agent of the liquid pharmaceutical composition is sodium chloride (NaCl), and the surfactant is polysorbate 80 (Tween 80).

[0471] In the examples, the concentration of histidine buffer in the liquid pharmaceutical composition was 25-40 mM.

[0472] In the examples, the concentration of histidine buffer in the liquid pharmaceutical composition is about 25 mM.

[0473] In the examples, the pH of the liquid pharmaceutical composition is 6.0.

[0474] In the examples, the concentration of the monoclonal anti-α-synuclein antibody in the liquid pharmaceutical composition is about 30-225 mg / mL.

[0475] In the examples, the concentration of the monoclonal anti-α-synuclein antibody in the liquid pharmaceutical composition is about 30-200 mg / mL.

[0476] In the examples, the concentration of the monoclonal anti-α-synuclein antibody in the liquid pharmaceutical composition is about 30-150 mg / mL.

[0477] In the examples, the concentration of the monoclonal anti-α-synuclein antibody in the liquid pharmaceutical composition is about 30-100 mg / mL.

[0478] In the examples, the concentration of the monoclonal anti-α-synuclein antibody in the liquid pharmaceutical composition is about 45-55 mg / mL.

[0479] In the examples, the concentration of the monoclonal anti-α-synuclein antibody in the liquid pharmaceutical composition is about 50 mg / mL.

[0480] In the examples, the concentration of the monoclonal anti-α-synuclein antibody in the liquid pharmaceutical composition was approximately 53 mg / mL.

[0481] In the embodiments, any of the liquid pharmaceutical compositions of the foregoing embodiments further comprises at least one filler selected from the following: sucrose, trehalose, glucose, lactose, sorbitol, mannitol, glycerol, arginine, aspartic acid, glutamic acid, glutamate, lysine, glycine, histidine, methionine, alanine, gelatin, PVP, PLGA, PEG, dextran, cyclodextrin and its derivatives, starch derivatives, HSA or BSA.

[0482] In the examples, the filler for the liquid pharmaceutical composition is arginine, glutamate, sucrose, glycine, or sorbitol, with a concentration of 100-200 mM.

[0483] In the examples, the filler for the liquid pharmaceutical composition is sucrose at a concentration of 100 mM.

[0484] In the examples, the liquid pharmaceutical composition comprises 53 mg / mL monoclonal anti-α-synuclein antibody, 25 mM histidine buffer, 100 mM sucrose, 100 mM sodium chloride (NaCl), and 0.02% polysorbate 80 (Tween 80) (w / v) at pH 6.0.

[0485] In the examples, the liquid pharmaceutical composition consisted essentially of 53 mg / mL monoclonal anti-α-synuclein antibody, 25 mM histidine buffer, 100 mM sucrose, 100 mM sodium chloride (NaCl), 0.02% polysorbate 80 (Tween 80) (w / v), and water, at a pH of 6.0.

[0486] In the examples, the liquid pharmaceutical composition comprises 53±5 mg / mL monoclonal anti-α-synuclein antibody, 1.40 mg / mL L-histidine, 3.34 mg / mL L-histidine monohydrochloride, 34.16 mg / mL sucrose, 5.83 mg / mL sodium chloride (NaCl), 0.20 mg / mL polysorbate 80 (Tween 80), and pH 6.0.

[0487] In the examples, the liquid pharmaceutical composition consisted essentially of 53±5 mg / mL monoclonal anti-α-synuclein antibody, 1.40 mg / mL L-histidine, 3.34 mg / mL L-histidine monohydrochloride, 34.16 mg / mL sucrose, 5.83 mg / mL sodium chloride (NaCl), 0.20 mg / mL polysorbate 80 (Tween 80), and water, at a pH of 6.0.

[0488] In an example, the liquid pharmaceutical composition comprises 53 mg / mL monoclonal anti-α-synuclein antibody, 25 mM histidine buffer, 100 mM sucrose, 100 mM sodium chloride (NaCl), and 0.02% polysorbate 80 (Tween 80) (w / v), or the amount of each component is within + / - 10% of the stated value, and the liquid pharmaceutical composition has a pH of 6.0 or within + / - 10% of the stated value.

[0489] In the examples, the liquid pharmaceutical composition is substantially composed of 53 mg / mL monoclonal anti-α-synuclein antibody, 25 mM histidine buffer, 100 mM sucrose, 100 mM sodium chloride (NaCl), 0.02% polysorbate 80 (Tween 80) (w / v) and water, or the amount of each component is within + / - 10% of the stated value, and the liquid pharmaceutical composition has a pH of 6.0 or within + / - 10% of the stated value.

[0490] In an example, the liquid pharmaceutical composition comprises 53 mg / mL monoclonal anti-α-synuclein antibody, 1.40 mg / mL L-histidine, 3.34 mg / mL L-histidine monohydrochloride, 34.16 mg / mL sucrose, 5.83 mg / mL sodium chloride (NaCl), 0.20 mg / mL polysorbate 80 (Tween 80), or the amount of each component is within + / - 10% of the stated value, and the liquid pharmaceutical composition has a pH of 6.0 or within + / - 10% of the stated value.

[0491] In the examples, the liquid pharmaceutical composition is substantially composed of 53 mg / mL monoclonal anti-α-synuclein antibody, 1.40 mg / mL L-histidine, 3.34 mg / mL L-histidine monohydrochloride, 34.16 mg / mL sucrose, 5.83 mg / mL sodium chloride (NaCl), 0.20 mg / mL polysorbate 80 (Tween 80), and water, or the amount of each component is within + / - 10% of the stated value, and the liquid pharmaceutical composition has a pH of 6.0 or within + / - 10% of the stated value.

[0492] In an example, the liquid pharmaceutical composition comprises 53 mg / mL monoclonal anti-α-synuclein antibody, 25 mM histidine buffer, 100 mM sucrose, 100 mM sodium chloride (NaCl), and 0.02% polysorbate 80 (Tween 80) (w / v), or the amount of each component is within + / - 5% of the stated value, and the liquid pharmaceutical composition has a pH of 6.0 or within + / - 5% of the stated value.

[0493] In the examples, the liquid pharmaceutical composition is substantially composed of 53 mg / mL monoclonal anti-α-synuclein antibody, 25 mM histidine buffer, 100 mM sucrose, 100 mM sodium chloride (NaCl), 0.02% polysorbate 80 (Tween 80) (w / v) and water, or the amount of each component is within + / - 5% of the stated value, and the liquid pharmaceutical composition has a pH of 6.0 or within + / - 5% of the stated value.

[0494] In an example, the liquid pharmaceutical composition comprises 53 mg / mL monoclonal anti-α-synuclein antibody, 1.40 mg / mL L-histidine, 3.34 mg / mL L-histidine monohydrochloride, 34.16 mg / mL sucrose, 5.83 mg / mL sodium chloride (NaCl), 0.20 mg / mL polysorbate 80 (Tween 80), or the amount of each component is within + / - 5% of the stated value, and the liquid pharmaceutical composition has a pH of 6.0 or within + / - 5% of the stated value.

[0495] In the examples, the liquid pharmaceutical composition is substantially composed of 53 mg / mL monoclonal anti-α-synuclein antibody, 1.40 mg / mL L-histidine, 3.34 mg / mL L-histidine monohydrochloride, 34.16 mg / mL sucrose, 5.83 mg / mL sodium chloride (NaCl), 0.20 mg / mL polysorbate 80 (Tween 80), and water, or the amount of each component is within + / - 5% of the stated value, and the liquid pharmaceutical composition has a pH of 6.0 or within + / - 5% of the stated value.

[0496] In an example, the liquid pharmaceutical composition comprises 53 mg / mL monoclonal anti-α-synuclein antibody, 25 mM histidine buffer, 100 mM sucrose, 100 mM sodium chloride (NaCl), and 0.02% polysorbate 80 (Tween 80) (w / v), or the amount of each component is within + / - 1% of the stated value, and the liquid pharmaceutical composition has a pH of 6.0 or within + / - 1% of the stated value.

[0497] In the examples, the liquid pharmaceutical composition is substantially composed of 53 mg / mL monoclonal anti-α-synuclein antibody, 25 mM histidine buffer, 100 mM sucrose, 100 mM sodium chloride (NaCl), 0.02% polysorbate 80 (Tween 80) (w / v) and water, or the amount of each component is within + / - 1% of the stated value, and the liquid pharmaceutical composition has a pH of 6.0 or within + / - 1% of the stated value.

[0498] In an example, the liquid pharmaceutical composition comprises 53 mg / mL monoclonal anti-α-synuclein antibody, 1.40 mg / mL L-histidine, 3.34 mg / mL L-histidine monohydrochloride, 34.16 mg / mL sucrose, 5.83 mg / mL sodium chloride (NaCl), 0.20 mg / mL polysorbate 80 (Tween 80), or the amount of each component is within + / - 1% of the stated value, and the liquid pharmaceutical composition has a pH of 6.0 or within + / - 1% of the stated value.

[0499] In the examples, the liquid pharmaceutical composition is substantially composed of 53 mg / mL monoclonal anti-α-synuclein antibody, 1.40 mg / mL L-histidine, 3.34 mg / mL L-histidine monohydrochloride, 34.16 mg / mL sucrose, 5.83 mg / mL sodium chloride (NaCl), 0.20 mg / mL polysorbate 80 (Tween 80), and water, or the amount of each component is within + / - 1% of the stated value, and the liquid pharmaceutical composition has a pH of 6.0 or within + / - 1% of the stated value.

[0500] In an example, the liquid pharmaceutical composition comprises 53 mg / mL monoclonal anti-α-synuclein antibody, 25 mM histidine buffer, 100 mM sucrose, 100 mM sodium chloride (NaCl), or the amount of each component is within + / - 20% of the stated value, and comprises 0.02% polysorbate 80 (Tween 80) (w / v), or the concentration is within + / - 30% of the stated concentration, and the liquid pharmaceutical composition has a pH of 6.0 or within + / - 20% of the stated value.

[0501] In an example, the liquid pharmaceutical composition comprises 53 mg / mL monoclonal anti-α-synuclein antibody, 25 mM histidine buffer, 100 mM sucrose, 100 mM sodium chloride (NaCl), or the amount of each component is within + / - 15% of the stated value, and comprises 0.02% polysorbate 80 (Tween 80) (w / v), or the concentration is within + / - 25% of the stated concentration, and the liquid pharmaceutical composition has a pH of 6.0 or within + / - 15% of the stated value.

[0502] In an example, the liquid pharmaceutical composition comprises 53 mg / mL monoclonal anti-α-synuclein antibody, 25 mM histidine buffer, 100 mM sucrose, 100 mM sodium chloride (NaCl), or the amount of each component is within + / - 10% of the stated value, and comprises 0.02% polysorbate 80 (Tween 80) (w / v), or the concentration is within + / - 20% of the stated concentration, and the liquid pharmaceutical composition has a pH of 6.0 or within + / - 10% of the stated value.

[0503] In the embodiments, the liquid pharmaceutical composition is a stable liquid pharmaceutical composition.

[0504] In the embodiments, the liquid pharmaceutical composition is a low-viscosity liquid pharmaceutical composition.

[0505] It will be appreciated that one or more features of any of the embodiments disclosed herein can be combined and / or rearranged within the scope of the invention to produce other embodiments that are also within the scope of the invention. All embodiments are intended to be applied to all aspects of the invention.

[0506] Specific numbered example: 1. A method for treating multiple system atrophy (MSA), wherein the method comprises intravenously administering a monoclonal anti-α-synuclein antibody to a human subject suffering from MSA at a dose between 4000 mg and 7000 mg or between 2000 mg and 4300 mg, and wherein the monoclonal anti-α-synuclein antibody binds to an epitope in amino acids 112-117 (SEQ ID NO: 9 (ILEDMP)) of human α-synuclein (SEQ ID NO: 10).

[0507] 2. The method for treating MSA according to Example 1, wherein the human subject has early-stage MSA.

[0508] 3. The method for treating MSA according to Example 1, wherein the human subject has MSA in an early stage.

[0509] 4. The method for treating MSA according to any one of Examples 1-3, wherein the total UMSARS score of the human subject is less than 40.

[0510] 5. The method for treating MSA according to any one of Examples 1-4, wherein the human subject had a total UMSARS score of less than 40 at the start of treatment.

[0511] 6. The method for treating MSA according to any one of Examples 1-4, wherein the human subject had a total UMSARS score of less than 40 at the time of the first administration of the antibody.

[0512] 7. The method for treating MSA according to Example 1, wherein the human subject has MSA-C.

[0513] 8. The method for treating MSA according to Example 1, wherein the human subject has early MSA-C.

[0514] 9. The method for treating MSA according to Example 1, wherein the human subject has MSA-C in an early stage.

[0515] 10. The method for treating MSA according to Example 1, wherein the human subject has MSA-C and a total UMSARS score of less than 40.

[0516] 11. The method for treating MSA according to Example 1, wherein the human subject has MSA-C and a total UMSARS score of less than 40 at the start of treatment.

[0517] 12. The method for treating MSA according to Example 1, wherein the human subject has MSA-C and a total UMSARS score of less than 40 at the time of the first administration of the antibody.

[0518] 13. The method for treating MSA according to any one of Examples 1-12, wherein the monoclonal antibody comprises: a. Heavy chain CDR1 having the amino acid sequence of SEQ ID NO:1; b. Heavy chain CDR2 having the amino acid sequence of SEQ ID NO:34; c. Heavy chain CDR3 having the amino acid sequence of SEQ ID NO:3; d. The light chain CDR1 having the amino acid sequence of SEQ ID NO:4; e. The light chain CDR2 having the amino acid sequence of SEQ ID NO:5; and f. Light chain CDR3 having the amino acid sequence of SEQ ID NO:6.

[0519] 14. The method for treating MSA according to any one of Examples 1-13, wherein the monoclonal antibody comprises the heavy chain variable domain of SEQ ID NO:31 and the light chain variable domain of SEQ ID NO:8.

[0520] 15. A method for treating MSA according to any one of Examples 1-13, wherein the monoclonal antibody comprises a heavy chain variable domain having the sequence of SEQ ID NO:31 and a light chain variable domain having the sequence of SEQ ID NO:8.

[0521] 16. The method for treating MSA according to any one of Examples 1-15, wherein the monoclonal antibody is a human antibody.

[0522] 17. The method for treating MSA according to any one of Examples 1-16, wherein the monoclonal antibody is a human IgG1 antibody.

[0523] 18. A method for treating MSA according to any one of Examples 1-17, wherein the monoclonal antibody is GM37 variant 2 (eleneta monoclonal antibody).

[0524] 19. The method for treating MSA according to any one of Examples 1-18, wherein the monoclonal antibody comprises the constant heavy chain domain of SEQ ID NO:18 and the constant κ light chain domain of SEQ ID NO:17.

[0525] 20. The method of treating MSA according to any one of Examples 1-19, wherein the monoclonal antibody is administered about once every 4 weeks or about once a month.

[0526] 21. The method of treating MSA according to any one of Examples 1-20, wherein the monoclonal antibody is administered at a dose of about 2100 mg or about 4200 mg.

[0527] 22. The method of treating MSA according to any one of Examples 1-21, wherein the monoclonal antibody is administered at a dose of about 2100 mg.

[0528] 23. The method of treating MSA according to any one of Examples 1-21, wherein the monoclonal antibody is administered at a dose of about 4200 mg.

[0529] 24. A method for treating MSA according to any one of Examples 1-23, wherein the treatment comprises delaying disease progression.

[0530] 25. A method for treating MSA according to any one of Examples 1-23, wherein the treatment comprises delaying clinical progression.

[0531] 26. A method for treating MSA according to any one of Examples 1-23, wherein the treatment comprises slowing disease progression.

[0532] 27. A method for treating MSA according to any one of Examples 1-23, wherein the treatment comprises slowing clinical progression.

[0533] 28. A method for treating MSA according to any one of Examples 1-27, wherein the treatment comprises delaying or slowing the disease or clinical progression by at least 5%, for example at least 10%, for example at least 15%, for example at least 20%, for example at least 25%, for example at least 30%, for example at least 35%, for example at least 40%, for example at least 45%, for example at least 50%, for example at least 55%, for example at least 60%, for example at least 65%, for example at least 70%, for example at least 75%, for example at least 80%, for example at least 85%, or for example at least 90%.

[0534] 29. The method of treating MSA according to any one of Examples 1-28, wherein the treatment effect is quantified by any relevant Unified Multiple System Atrophy Rating Scale (UMSARS) score or any relevant part of such scales, such as Part I, Part II, Part III or Part IV, or the longitudinal change of any single item of any of such scales relative to baseline, or the change of any combination of such UMSARS scales or any combination of single items of such UMSARS scales relative to baseline.

[0535] 30. A method for treating MSA according to any one of Examples 1-29, wherein the therapeutic effect is quantified by longitudinal change of the Unified Multisystem Atrophy Rating Scale (UMSARS) Part I and / or Part II or Modified UMSARS Part I (mUMSARS) or Abbreviated UMSARS (aUMSARS) score relative to baseline.

[0536] 31. The method of treating MSA according to any one of Examples 1-30, wherein the therapeutic effect is quantified by longitudinal change of the Uniform Multisystem Atrophy Scale Total Score (UMSARS TS) relative to baseline.

[0537] 32. The method for treating MSA according to any one of Examples 1-30, wherein the therapeutic effect is quantified by longitudinal change of modified UMSARS (mUMSARS) relative to baseline.

[0538] 33. The method for treating MSA according to any one of Examples 1-28, wherein the therapeutic effect is quantified by longitudinal changes in brain volume relative to baseline, such as by volumetric MRI (vMRI).

[0539] 34. The method for treating MSA according to any one of Examples 1-28, wherein the therapeutic effect is quantified by longitudinal changes in brain volume relative to baseline, such as by volumetric MRI (vMRI) of the pons.

[0540] 35. The method for treating MSA according to any one of Examples 1-28, wherein the therapeutic effect is quantified by longitudinal changes in brain volume relative to baseline, such as by volumetric MRI (vMRI) of cerebellar white matter.

[0541] 36. The method for treating MSA according to any one of Examples 1-28, wherein the therapeutic effect is quantified by longitudinal changes in brain volume relative to baseline, such as by volumetric MRI (vMRI) of cerebellar gray matter.

[0542] 37. The method of treating MSA according to any one of Examples 1-28, wherein the treatment effect is a reduction in the clinical progression of MSA by at least 19%, as measured by the UMSARS total score.

[0543] 38. The method of treating MSA according to any one of Examples 1-28, wherein the treatment effect is a reduction of at least 22% in the clinical progression of MSA as measured by the UMSARS Part I score.

[0544] 39. The method of treating MSA according to any one of Examples 1-28, wherein the treatment effect is a reduction of clinical progression of MSA by at least 17%, as measured by the UMSARS Part II score.

[0545] 40. The method of treating MSA according to any one of Examples 1-28, wherein the treatment effect is a reduction in the clinical progression of MSA by at least 27%, as measured by a modified UMSARS score.

[0546] 41. The method of treating MSA according to any one of Examples 1-28, wherein the treatment effect is a reduction of clinical progression of MSA-C by at least 50% as measured by a modified UMSARS score.

[0547] 42. The method of treating MSA according to any one of Examples 1-28, wherein the treatment effect is a reduction of clinical progression of MSA-C by at least 50% as measured by the UMSARS total score.

[0548] 43. The method of treating MSA according to any one of Examples 1-28, wherein the treatment effect is a reduction of clinical progression of MSA-C by at least 57% as measured by the UMSARS Part I score.

[0549] 44. The method of treating MSA according to any one of Examples 1-28, wherein the treatment effect is a reduction in the clinical progression of MSA-C by at least 41% as measured by the UMSARS Part II score.

[0550] 45. The method of treating MSA according to any one of Examples 1-28, wherein the therapeutic effect is a reduction in the clinical progression of early MSA by at least about 42% as measured by a modified UMSARS score.

[0551] 46. ​​The method of treating MSA according to any one of Examples 1-28, wherein the treatment effect is a reduction in the clinical progression of early MSA by at least about 37%, as measured by the UMSARS total score.

[0552] 47. The method of treating MSA according to any one of Examples 1-28, wherein the treatment effect is a reduction in the clinical progression of early MSA by at least about 42% as measured by the UMSARS Part I score.

[0553] 48. A method for treating MSA according to any one of Examples 1-28, wherein the therapeutic effect is a reduction in the clinical progression of early MSA by at least about 30%, as measured by the UMSARS Part II score.

[0554] 49. The method for treating MSA according to any one of Examples 1-28, wherein the therapeutic effect is a slowing of the reduction in pontine region volume, with the volume reduction being at least about 1.9%.

[0555] 50. The method for treating MSA according to any one of Examples 1-28, wherein the therapeutic effect is a slowing of the reduction in volume of the cerebellar white matter region, with the volume reduction being at least about 3.3%.

[0556] 51. The method for treating MSA according to any one of Examples 1-28, wherein the therapeutic effect is a slowing of the reduction in the volume of the cerebellar gray matter region, with the volume reduction being at least about 1.5%.

[0557] 52. The method for treating MSA according to any one of Examples 1-28, wherein the therapeutic effect of early MSA is a slowing of the reduction in pontine region volume, with the volume reduction being at least about 2.4%.

[0558] 53. The method for treating MSA according to any one of Examples 1-28, wherein the therapeutic effect of early MSA is a slowing of the reduction in volume of the cerebellar white matter region, with the volume reduction being at least about 4.2%.

[0559] 54. The method for treating MSA according to any one of Examples 1-28, wherein the therapeutic effect of early MSA is a slowing of the reduction in the volume of the cerebellar gray matter region, with the volume reduction being at least about 0.4%.

[0560] 55. The method for treating MSA according to any one of Examples 1-28, wherein the therapeutic effect of MSA-C is a slowing of the reduction in pontine region volume, with the volume reduction being at least about 1.2%.

[0561] 56. The method for treating MSA according to any one of Examples 1-28, wherein the therapeutic effect of MSA-C is a slowdown in the reduction of cerebellar white matter volume, with the volume reduction being at least about 3.8%.

[0562] 57. The method for treating MSA according to any one of Examples 1-28, wherein the therapeutic effect of MSA-C is a slowdown in the reduction of cerebellar gray matter volume, with the volume reduction being at least about 0.4%.

[0563] 58. The method of treating MSA according to any one of Examples 1-28, wherein the therapeutic effect is damage reduction, as measured by UMSARS Part IV - Overall Disability Score, with a reduction in damage of at least about 0.2 points.

[0564] 59. The method of treating MSA according to any one of Examples 1-28, wherein the therapeutic effect of early MSA is damage reduction, as measured by UMSARS Part IV - Overall Disability Score, with a reduction in damage of at least about 0.8 points.

[0565] 60. The method of treating MSA according to any one of Examples 1-28, wherein the therapeutic effect is damage reduction, as measured by the Clinical Global Impression-Disease Severity Score, with a reduction in damage of at least about 0.2 points.

[0566] 61. The method of treating MSA according to any one of Examples 1-28, wherein the therapeutic effect of early MSA is damage reduction, as measured by the Clinical Global Impression-Disease Severity Score, with a reduction in damage of at least about 0.5 points.

[0567] 62. The method for treating MSA according to any one of Examples 1-28, wherein the therapeutic effect is a reduction in the neurofilament light chain load of CSF by at least about 16.3%.

[0568] 63. The method for treating MSA according to any one of Examples 1-28, wherein the therapeutic effect of early MSA is a reduction in the neurofilament light chain load of CSF by at least about 14.4%.

[0569] 64. The method of treating MSA according to any one of Examples 1-28, wherein the therapeutic effect is damage reduction, as measured by the single item “speech” in Part I of UMSARS, with a reduction in damage of at least about 0.4 points.

[0570] 65. The method of treating MSA according to any one of Examples 1-28, wherein the therapeutic effect of early MSA is damage reduction, such as a reduction of at least about 0.8 points as measured by the single item “speech” in Part I of UMSARS.

[0571] 66. The method of treating MSA according to any one of Examples 1-28, wherein the therapeutic effect of MSA is damage reduction, as measured by the single item “Cutting food / Using utensils” in Part I of UMSARS, with a damage reduction of at least about 0.3 points.

[0572] 67. The method of treating MSA according to any one of Examples 1-28, wherein the therapeutic effect of early MSA is damage reduction, as measured by the single item “Cutting food / Using utensils” in Part I of UMSARS, with a damage reduction of at least about 0.7 points.

[0573] 68. The method of treating MSA according to any one of Examples 1-28, wherein the therapeutic effect is damage reduction, as measured by the single item “from sitting to standing” in Part II of UMSARS, with a damage reduction of at least about 0.3 points.

[0574] 69. The method of treating MSA according to any one of Examples 1-28, wherein the therapeutic effect of early MSA is damage reduction, such as a reduction in damage of at least about 1.2 points as measured by the single item “from sitting to standing” in Part II of UMSARS.

[0575] 70. The method for treating MSA according to any one of Examples 1-69, wherein the monoclonal antibody is elenetatumab.

[0576] A1. A monoclonal anti-α-synuclein antibody for the treatment of multiple system atrophy (MSA), wherein the use comprises intravenous administration of the monoclonal anti-α-synuclein antibody to a human subject suffering from MSA at a dose between 4000 mg and 7000 mg or between 2000 mg and 4300 mg, and wherein the monoclonal anti-α-synuclein antibody binds to an epitope in amino acids 112-117 (SEQ ID NO: 9 (ILEDMP)) of human α-synuclein (SEQ ID NO: 10).

[0577] A2. The monoclonal anti-α-synuclein antibody used according to Example A1, wherein the human subject has early MSA.

[0578] A3. The monoclonal anti-α-synuclein antibody used according to Example A1, wherein the human subject has MSA in an early stage.

[0579] A4. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A3, wherein the total UMSARS score of the human subject is less than 40.

[0580] A5. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A4, wherein the human subject had a total UMSARS score of less than 40 at the start of treatment.

[0581] A6. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A4, wherein the human subject had a total UMSARS score of less than 40 at the time of the first administration of the antibody.

[0582] A7. The monoclonal anti-α-synuclein antibody used according to Example A1, wherein the human subject has MSA-C.

[0583] A8. The monoclonal anti-α-synuclein antibody used according to Example A1, wherein the human subject has early MSA-C.

[0584] A9. The monoclonal anti-α-synuclein antibody used according to Example A1, wherein the human subject has MSA-C in an early stage.

[0585] A10. The monoclonal anti-α-synuclein antibody used according to Example A1, wherein the human subject has MSA-C and a total UMSARS score of less than 40.

[0586] A11. The monoclonal anti-α-synuclein antibody used according to Example A1, wherein the human subject has MSA-C and a total UMSARS score of less than 40 at the start of treatment.

[0587] A12. The monoclonal anti-α-synuclein antibody used according to Example A1, wherein the human subject has MSA-C and a total UMSARS score of less than 40 at the time of the first administration of the antibody.

[0588] A13. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A12, wherein the monoclonal antibody comprises: a. Heavy chain CDR1 having the amino acid sequence of SEQ ID NO:1; b. Heavy chain CDR2 having the amino acid sequence of SEQ ID NO:34; c. Heavy chain CDR3 having the amino acid sequence of SEQ ID NO:3; d. The light chain CDR1 having the amino acid sequence of SEQ ID NO:4; e. The light chain CDR2 having the amino acid sequence of SEQ ID NO:5; and f. Light chain CDR3 having the amino acid sequence of SEQ ID NO:6.

[0589] A14. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A13, wherein the monoclonal antibody comprises the heavy chain variable domain of SEQ ID NO:31 and the light chain variable domain of SEQ ID NO:8.

[0590] A15. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A13, wherein the monoclonal antibody comprises a heavy chain variable domain having the sequence of SEQ ID NO:31 and a light chain variable domain having the sequence of SEQ ID NO:8.

[0591] A16. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A15, wherein the monoclonal antibody is a human antibody.

[0592] A17. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A16, wherein the monoclonal antibody is a human IgG1 antibody.

[0593] A18. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A17, wherein the monoclonal antibody is GM37 variant 2 (eleneta monoclonal antibody).

[0594] A19. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A18, wherein the monoclonal antibody comprises the constant heavy chain domain of SEQ ID NO:18 and the constant κ light chain domain of SEQ ID NO:17.

[0595] A20. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A19, wherein the monoclonal antibody is administered approximately every 4 weeks or approximately monthly.

[0596] A21. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A20, wherein the monoclonal antibody is administered at a dose of about 2100 mg or about 4200 mg.

[0597] A22. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A21, wherein the monoclonal antibody is administered at a dose of about 2100 mg.

[0598] A23. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A21, wherein the monoclonal antibody is administered at a dose of about 4200 mg.

[0599] A24. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A23, wherein the treatment comprises delaying disease progression.

[0600] A25. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A23, wherein the treatment comprises delaying clinical progression.

[0601] A26. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A23, wherein the treatment consists of slowing disease progression.

[0602] A27. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A23, wherein the treatment consists of slowing clinical progression.

[0603] A28. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A27, wherein the treatment comprises delaying or slowing disease or clinical progression by at least 5%, for example at least 10%, for example at least 15%, for example at least 20%, for example at least 25%, for example at least 30%, for example at least 35%, for example at least 40%, for example at least 45%, for example at least 50%, for example at least 55%, for example at least 60%, for example at least 65%, for example at least 70%, for example at least 75%, for example at least 80%, for example at least 85%, or for example at least 90%.

[0604] A29. The monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A28, wherein the therapeutic effect is quantified by any relevant Unified Multiple System Atrophy Rating Scale (UMSARS) score, or any relevant part of these scales, such as Part I, Part II, Part III, or Part IV, or the longitudinal change of any single item of any of these scales relative to baseline, or the change of any combination of these UMSARS scales or any combination of single items of these UMSARS scales relative to baseline.

[0605] A30. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A29, wherein the therapeutic effect is quantified by the longitudinal change of the Unified Multisystem Atrophy Rating Scale (UMSARS) Part I and / or Part II or modified UMSARS Part I (mUMSARS) or abbreviated UMSARS (aUMSARS) score relative to baseline.

[0606] A31. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A30, wherein the therapeutic effect is quantified by longitudinal change of the Unified Multisystem Atrophy Scale Total Score (UMSARS TS) relative to baseline.

[0607] A32. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A30, wherein the therapeutic effect is quantified by the longitudinal change of modified UMSARS (mUMSARS) relative to baseline.

[0608] A33. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A28, wherein the therapeutic effect is quantified by longitudinal changes in brain volume relative to baseline, such as by volumetric MRI (vMRI).

[0609] A34. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A28, wherein the therapeutic effect is quantified by longitudinal changes in brain volume relative to baseline, such as by volumetric MRI (vMRI) of the pons.

[0610] A35. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A28, wherein the therapeutic effect is quantified by longitudinal changes in brain volume relative to baseline, such as by volumetric MRI (vMRI) of cerebellar white matter.

[0611] A36. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A28, wherein the therapeutic effect is quantified by longitudinal changes in brain volume relative to baseline, such as by volumetric MRI (vMRI) of cerebellar gray matter.

[0612] A37. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A28, wherein the therapeutic effect is a reduction in the clinical progression of MSA by at least 19% as measured by the UMSARS total score.

[0613] A38. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A28, wherein the therapeutic effect is a reduction in the clinical progression of MSA by at least 22% as measured by the UMSARS Part I score.

[0614] A39. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A28, wherein the therapeutic effect is a reduction in the clinical progression of MSA by at least 17% as measured by the UMSARS Part II score.

[0615] A40. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A28, wherein the therapeutic effect is a reduction in the clinical progression of MSA by at least 27% as measured by a modified UMSARS score.

[0616] A41. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A28, wherein the therapeutic effect is a reduction of clinical progression of MSA-C by at least 50% as measured by a modified UMSARS score.

[0617] A42. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A28, wherein the therapeutic effect is a reduction of at least 50% in the clinical progression of MSA-C as measured by the UMSARS total score.

[0618] A43. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A28, wherein the therapeutic effect is a reduction in the clinical progression of MSA-C by at least 57% as measured by the UMSARS Part I score.

[0619] A44. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A28, wherein the therapeutic effect is a reduction in the clinical progression of MSA-C by at least 41% as measured by the UMSARS Part II score.

[0620] A45. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A28, wherein the therapeutic effect is a reduction in clinical progression of early MSA by at least about 42% as measured by a modified UMSARS score.

[0621] A46. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A28, wherein the therapeutic effect is a reduction in clinical progression of early MSA by at least about 37% as measured by the UMSARS total score.

[0622] A47. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A28, wherein the therapeutic effect is a reduction in clinical progression of early MSA by at least about 42% as measured by the UMSARS Part I score.

[0623] A48. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A28, wherein the therapeutic effect is a reduction of at least about 30% in the clinical progression of early MSA as measured by UMSARS Part II score.

[0624] A49. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A28, wherein the therapeutic effect is a slowing of the reduction in pontine region volume, with the volume reduction being at least about 1.9%.

[0625] A50. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A28, wherein the therapeutic effect is a slowing of the reduction in volume of the cerebellar white matter region, with the volume reduction being at least about 3.3%.

[0626] A51. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A28, wherein the therapeutic effect is a slowing of the reduction in volume of the cerebellar gray matter region, with the volume reduction being at least about 1.5%.

[0627] A52. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A28, wherein the therapeutic effect of early MSA is a slowing of the reduction in pontine region volume, with a reduction in volume of at least about 2.4%.

[0628] A53. The monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A28, wherein the therapeutic effect of early MSA is a slowing of the reduction in volume of the cerebellar white matter region, with a reduction in volume of at least about 4.2%.

[0629] A54. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A28, wherein the therapeutic effect of early MSA is a slowing of the reduction in cerebellar gray matter volume, with the volume reduction being at least about 0.4%.

[0630] A55. The monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A28, wherein the therapeutic effect of MSA-C is a slowing of the reduction in pontine region volume, with the volume reduction being at least about 1.2%.

[0631] A56. The monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A28, wherein the therapeutic effect of MSA-C is a slowing of the reduction in volume of the cerebellar white matter region, with a reduction in volume of at least about 3.8%.

[0632] A57. The monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A28, wherein the therapeutic effect of MSA-C is a slowing of the reduction in cerebellar gray matter volume, with the volume reduction being at least about 0.4%.

[0633] A58. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A28, wherein the therapeutic effect is damage reduction, as measured by UMSARS Part IV - Overall Disability Score, with a reduction in damage of at least about 0.2 points.

[0634] A59. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A28, wherein the therapeutic effect of early MSA is damage reduction, as measured by UMSARS Part IV - Overall Disability Score, with a reduction in damage of at least about 0.8 points.

[0635] A60. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A28, wherein the therapeutic effect is damage reduction, as measured by the Clinical Global Impression-Disease Severity Score, with a reduction in damage of at least about 0.2 points.

[0636] A61. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A28, wherein the therapeutic effect of early MSA is damage reduction, as measured by the Clinical Global Impression-Disease Severity Score, with a reduction in damage of at least about 0.5 points.

[0637] A62. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A28, wherein the therapeutic effect is a reduction in the neurofilament light chain load of CSF by at least about 16.3%.

[0638] A63. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A28, wherein the therapeutic effect of early MSA is a reduction in the neurofilament light chain load of CSF by at least about 14.4%.

[0639] A64. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A28, wherein the therapeutic effect is damage reduction, as measured by the single item “speech” in Part I of UMSARS, with a reduction in damage of at least about 0.4 points.

[0640] A65. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A28, wherein the therapeutic effect of early MSA is damage reduction, as measured by the single item “speech” in Part I of UMSARS, with a reduction in damage of at least about 0.8 points.

[0641] A66. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A28, wherein the therapeutic effect of MSA is damage reduction, as measured by the single item “Cutting food / Using utensils” in Part I of UMSARS, with a damage reduction of at least about 0.3 points.

[0642] A67. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A28, wherein the therapeutic effect of early MSA is damage reduction, as measured by the single item “Cutting food / using utensils” in Part I of UMSARS, with a damage reduction of at least about 0.7 points.

[0643] A68. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A28, wherein the therapeutic effect is damage reduction, such as a reduction in damage of at least about 0.3 points as measured by the single item “From sitting to standing” in Part II of UMSARS.

[0644] A69. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A28, wherein the therapeutic effect of early MSA is damage reduction, such as a reduction in damage of at least about 1.2 points as measured by the single item “from sitting to standing” in Part II of UMSARS.

[0645] A70. A monoclonal anti-α-synuclein antibody for use according to any one of Examples A1-A69, wherein the antibody is ileneta monoclonal antibody.

[0646] B1. Use of a monoclonal anti-α-synuclein antibody in the manufacture of a medicament for the treatment of multiple system atrophy (MSA), wherein said treatment comprises intravenous administration of a monoclonal anti-α-synuclein antibody to a human subject suffering from MSA at a dose between 4000 mg and 7000 mg or between 2000 mg and 4300 mg, and wherein said monoclonal anti-α-synuclein antibody binds to an epitope in amino acids 112-117 (SEQ ID NO: 9 (ILEDMP)) of human α-synuclein (SEQ ID NO: 10).

[0647] B2. The use as described in Example B1, wherein the human subject has early-stage MSA.

[0648] B3. The use as described in Example B1, wherein the human subject suffers from MSA in an early stage.

[0649] B4. Use according to any one of Examples B1-B3, wherein the total UMSARS score of the human subject is less than 40.

[0650] B5. Use according to any one of Examples B1-B4, wherein the human subject has a total UMSARS score of less than 40 at the start of treatment.

[0651] B6. Use according to any one of Examples B1-B4, wherein the human subject had a total UMSARS score of less than 40 at the time of the first administration of the antibody.

[0652] B7. The use as described in Example B1, wherein the human subject suffers from MSA-C.

[0653] B8. The use as described in Example B1, wherein the human subject has early MSA-C.

[0654] B9. The use according to Example B1, wherein the human subject suffers from MSA-C in an early stage.

[0655] B10. The use according to Example B1, wherein the human subject has MSA-C and a total UMSARS score of less than 40.

[0656] B11. The use according to Example B1, wherein the human subject has MSA-C and a total UMSARS score of less than 40 at the start of treatment.

[0657] B12. The use as described in Example B1, wherein the human subject has MSA-C and a total UMSARS score of less than 40 at the time of the first administration of the antibody.

[0658] B13. The use according to any one of Examples B1-B12, wherein the monoclonal antibody comprises: a. Heavy chain CDR1 having the amino acid sequence of SEQ ID NO:1; b. Heavy chain CDR2 having the amino acid sequence of SEQ ID NO:34; c. Heavy chain CDR3 having the amino acid sequence of SEQ ID NO:3; d. The light chain CDR1 having the amino acid sequence of SEQ ID NO:4; e. The light chain CDR2 having the amino acid sequence of SEQ ID NO:5; and f. Light chain CDR3 having the amino acid sequence of SEQ ID NO:6.

[0659] B14. The use according to any one of Examples B1-B13, wherein the monoclonal antibody comprises the heavy chain variable domain of SEQ ID NO:31 and the light chain variable domain of SEQ ID NO:8.

[0660] B15. The use according to any one of Examples B1-B13, wherein the monoclonal antibody comprises a heavy chain variable domain having the sequence of SEQ ID NO:31 and a light chain variable domain having the sequence of SEQ ID NO:8.

[0661] B16. The use according to any one of Examples B1-B15, wherein the monoclonal antibody is a human antibody.

[0662] B17. The use according to any one of Examples B1-B16, wherein the monoclonal antibody is a human IgG1 antibody.

[0663] B18. Use according to any one of Examples B1-B17, wherein the monoclonal antibody is GM37 variant 2 (eleneta monoclonal antibody).

[0664] B19. Use according to any one of Examples B1-B18, wherein the monoclonal antibody comprises the constant heavy chain domain of SEQ ID NO:18 and the constant κ light chain domain of SEQ ID NO:17.

[0665] B20. The use according to any one of Examples B1-B19, wherein the monoclonal antibody is administered about once every 4 weeks or about once a month.

[0666] B21. The use according to any one of Examples B1-B20, wherein the monoclonal antibody is administered at a dose of about 2100 mg or about 4200 mg.

[0667] B22. The use according to any one of Examples B1-B21, wherein the monoclonal antibody is administered at a dose of about 2100 mg.

[0668] B23. The use according to any one of Examples B1-B21, wherein the monoclonal antibody is administered at a dose of about 4200 mg.

[0669] B24. The use according to any one of embodiments B1-B23, wherein the treatment comprises delaying disease progression.

[0670] B25. Use according to any one of Examples B1-B23, wherein the treatment comprises delaying clinical progression.

[0671] B26. The use according to any one of embodiments B1-B23, wherein the treatment consists of slowing the progression of the disease.

[0672] B27. Use according to any one of Examples B1-B23, wherein the treatment comprises slowing clinical progression.

[0673] B28. The use according to any one of embodiments B1-B27, wherein the treatment comprises delaying or slowing the disease or clinical progression by at least 5%, for example at least 10%, for example at least 15%, for example at least 20%, for example at least 25%, for example at least 30%, for example at least 35%, for example at least 40%, for example at least 45%, for example at least 50%, for example at least 55%, for example at least 60%, for example at least 65%, for example at least 70%, for example at least 75%, for example at least 80%, for example at least 85%, or for example at least 90%.

[0674] B29. The use according to any one of Examples B1-B28, wherein the therapeutic effect is quantified by any relevant Uniform Multiple System Atrophy Rating Scale (UMSARS) score, or any relevant part of such scales, such as Part I, Part II, Part III or Part IV, or the longitudinal change of any single item of any of such scales relative to baseline, or the change of any combination of such UMSARS scales or any combination of single items of such UMSARS scales relative to baseline.

[0675] B30. The use according to any one of Examples B1-B29, wherein the therapeutic effect is quantified by the longitudinal change of the Unified Multisystem Atrophy Rating Scale (UMSARS) Part I and / or Part II or the modified UMSARS Part I (mUMSARS) or the simplified UMSARS (aUMSARS) score relative to baseline.

[0676] B31. The use according to any one of embodiments B1-B30, wherein the therapeutic effect is quantified by the longitudinal change of the Unified Multisystem Atrophy Rating Scale Total Score (UMSARS TS) relative to baseline.

[0677] B32. The use according to any one of embodiments B1-B30, wherein the therapeutic effect is quantified by the longitudinal change of modified UMSARS (mUMSARS) relative to baseline.

[0678] B33. The use according to any one of embodiments B1-B28, wherein the therapeutic effect is quantified by longitudinal changes in brain volume relative to baseline, such as by volumetric MRI (vMRI).

[0679] B34. Use according to any one of Examples B1-B28, wherein the therapeutic effect is quantified by longitudinal changes in brain volume relative to baseline, such as by volumetric MRI (vMRI) of the pons.

[0680] B35. Use according to any one of Examples B1-B28, wherein the therapeutic effect is quantified by longitudinal changes in brain volume relative to baseline, such as by volumetric MRI (vMRI) of cerebellar white matter.

[0681] B36. Use according to any one of Examples B1-B28, wherein the therapeutic effect is quantified by longitudinal changes in brain volume relative to baseline, such as by volumetric MRI (vMRI) of cerebellar gray matter.

[0682] B37. Use according to any one of Examples B1-B28, wherein the therapeutic effect is a reduction in the clinical progression of MSA by at least 19%, as measured by the UMSARS total score.

[0683] B38. Use according to any one of Examples B1-B28, wherein the therapeutic effect is a reduction in the clinical progression of MSA by at least 22%, as measured by the UMSARS Part I score.

[0684] B39. Use according to any one of Examples B1-B28, wherein the therapeutic effect is a reduction in the clinical progression of MSA by at least 17%, as measured by the UMSARS Part II score.

[0685] B40. Use according to any one of Examples B1-B28, wherein the therapeutic effect is a reduction in the clinical progression of MSA by at least 27%, as measured by a modified UMSARS score.

[0686] B41. The use according to any one of Examples B1-B28, wherein the therapeutic effect is a reduction of clinical progression of MSA-C by at least 50% as measured by a modified UMSARS score.

[0687] B42. The use according to any one of Examples B1-B28, wherein the therapeutic effect is a reduction of clinical progression of MSA-C by at least 50% as measured by the UMSARS total score.

[0688] B43. Use according to any one of Examples B1-B28, wherein the therapeutic effect is a reduction of clinical progression of MSA-C by at least 57% as measured by the UMSARS Part I score.

[0689] B44. Use according to any one of Examples B1-B28, wherein the therapeutic effect is a reduction of clinical progression of MSA-C by at least 41% as measured by the UMSARS Part II score.

[0690] B45. Use according to any one of Examples B1-B28, wherein the therapeutic effect is a reduction in clinical progression of early MSA by at least about 42% as measured by a modified UMSARS score.

[0691] B46. Use according to any one of Examples B1-B28, wherein the therapeutic effect is a reduction in clinical progression of early MSA by at least about 37%, as measured by the UMSARS total score.

[0692] B47. Use according to any one of Examples B1-B28, wherein the therapeutic effect is a reduction in clinical progression of early MSA by at least about 42% as measured by the UMSARS Part I score.

[0693] B48. Use according to any one of Examples B1-B28, wherein the therapeutic effect is a reduction of clinical progression of early MSA by at least about 30% as measured by the UMSARS Part II score.

[0694] B49. The use according to any one of embodiments B1-B28, wherein the therapeutic effect is a slowing of the reduction in pontine region volume, with the volume reduction being at least about 1.9%.

[0695] B50. The use according to any one of Examples B1-B28, wherein the therapeutic effect is a slowing of the reduction in volume of the cerebellar white matter region, with the volume reduction being at least about 3.3%.

[0696] B51. The use according to any one of embodiments B1-B28, wherein the therapeutic effect is a slowing of the reduction in the volume of the cerebellar gray matter region, with the volume reduction being at least about 1.5%.

[0697] B52. The use according to any one of Examples B1-B28, wherein the therapeutic effect of early MSA is a slowing of the reduction in pontine region volume, with the volume reduction being at least about 2.4% less.

[0698] B53. The use according to any one of Examples B1-B28, wherein the therapeutic effect of early MSA is a slowing of the reduction in volume of the cerebellar white matter region, with the volume reduction being at least about 4.2%.

[0699] B54. The use according to any one of Examples B1-B28, wherein the therapeutic effect of early MSA is a slowing of the reduction in the volume of the cerebellar gray matter region, with the volume reduction being at least about 0.4%.

[0700] B55. The use according to any one of embodiments B1-B28, wherein the therapeutic effect of MSA-C is a slowing of the reduction in pontine region volume, with the volume reduction being at least about 1.2% less.

[0701] B56. The use according to any one of Examples B1-B28, wherein the therapeutic effect of MSA-C is a slowing of the reduction in volume of the cerebellar white matter region, with the volume reduction being at least about 3.8%.

[0702] B57. The use according to any one of embodiments B1-B28, wherein the therapeutic effect of MSA-C is a slowing of the reduction in the volume of the cerebellar gray matter region, with the volume reduction being at least about 0.4%.

[0703] B58. Use according to any one of Examples B1-B28, wherein the therapeutic effect is damage reduction, as measured by UMSARS Part IV - Overall Disability Score, with a reduction in damage of at least about 0.2 points.

[0704] B59. Use according to any one of Examples B1-B28, wherein the therapeutic effect of early MSA is damage reduction, as measured by UMSARS Part IV - Overall Disability Score, with a reduction in damage of at least about 0.8 points.

[0705] B60. Use according to any one of Examples B1-B28, wherein the therapeutic effect is damage reduction, as measured by the Clinical Global Impression-Disease Severity Score, with a reduction in damage of at least about 0.2 points.

[0706] B61. The use according to any one of Examples B1-B28, wherein the therapeutic effect of early MSA is damage reduction, as measured by the Clinical Global Impression-Disease Severity Score, with a reduction in damage of at least about 0.5 points.

[0707] B62. The use according to any one of Examples B1-B28, wherein the therapeutic effect is a reduction in the neurofilament light chain load of the CSF by at least about 16.3%.

[0708] B63. The use according to any one of Examples B1-B28, wherein the therapeutic effect of early MSA is a reduction in the neurofilament light chain load of CSF by at least about 14.4%.

[0709] B64. Use according to any one of Examples B1-B28, wherein the therapeutic effect is damage reduction, as measured by the single item “speech” in Part I of UMSARS, with a reduction in damage of at least about 0.4 points.

[0710] B65. Use according to any one of Examples B1-B28, wherein the therapeutic effect of early MSA is damage reduction, as measured by the single item “speech” in Part I of UMSARS, with a reduction in damage of at least about 0.8 points.

[0711] B66. The use according to any one of Examples B1-B28, wherein the therapeutic effect of MSA is damage reduction, as measured by the single item “Cutting food / Using utensils” in Part I of UMSARS, with a damage reduction of at least about 0.3 points.

[0712] B67. The use according to any one of Examples B1-B28, wherein the therapeutic effect of early MSA is damage reduction, as measured by the single item “Cutting food / Using utensils” in Part I of UMSARS, with a damage reduction of at least about 0.7 points.

[0713] B68. Use according to any one of Examples B1-B28, wherein the therapeutic effect is damage reduction, as measured by the single item “from seated to standing” in Part II of UMSARS, with a reduction in damage of at least about 0.3 points.

[0714] B69. Use according to any one of Examples B1-B28, wherein the therapeutic effect of early MSA is damage reduction, as measured by the single item “from seated to standing” in Part II of UMSARS, with a reduction in damage of at least about 1.2 points.

[0715] B70. Use according to any one of Examples B1-B69, wherein the monoclonal antibody is elenetatumab.

[0716] Using only conventional experiments, those skilled in the art will recognize or be able to identify many equivalents of the particular embodiments described herein. Such equivalents are intended to fall within the scope of this invention.

[0717] Experimental Section - Dosing Regimen and Clinical Use in MSA

[0718] The examples provided below are intended to aid in a more complete understanding of the invention. However, the scope of the invention is not limited to the specific embodiments disclosed in these examples, which are for illustrative purposes only, as similar results can be obtained using alternative methods.

[0719] Example 1 - Modeling a dosage regimen for an antibody according to the invention, illustrated by GM37 variant 2.

[0720] The dosing regimen for the antibody according to the invention is achieved by establishing a specific relationship between the binding of GM37v2 to monomeric α-synuclein and its binding to oligomeric α-synuclein. This specific relationship is specific to each α-synuclein antibody and is essential for establishing a clinically relevant dosing regimen that provides the desired target binding to the pathological form of α-synuclein in the patient's CSF. In vitro, the KD value of GM37v2 binding to the monomeric form of α-synuclein was measured to be 36 nM (5,400 ng / mL) (see Example 6A), and the affinity-mediated enhanced KD of GM37v2 with the oligomeric form was estimated to be about 65-fold lower (64.1 + / - 5.2) (i.e., 0.5 nM; 83 ng / mL) (see Example 2).

[0721] In addition to this fold change between monomeric and oligomeric binding, detailed PK knowledge of GM37v2 is required to determine the dosing regimen. PK characteristics were obtained through experiments disclosed in Example 3. The clearance of GM37 variant 2 was found to be approximately 0.25 L / day, e.g., 0.24 L / day, with a T½ of approximately 30 days, e.g., 29 days.

[0722] The target binding of GM37 variant 2 to α-synuclein can be calculated from the percentage of free α-synuclein in plasma or CSF (which does not bind to GM37 variant 2).

[0723] Figure 6 shows the median plasma concentration of free α-synuclein versus time in healthy subjects and patients. A significant dose-related inhibitory effect was observed. The same was observed for the percentage of free / total α-synuclein (Figure 7). Figure 8 The study also showed a good correlation between free / total α-synuclein % and plasma concentration of GM37 variant 2, with the Emax model (see below) fitting the data.

[0724] It is noteworthy that the observed IC50 value is similar to the in vitro measured KD value, which provides experimental validation of the maximum inhibition Emax model described below.

[0725] Based on simple maximum inhibition E max The model, with the percentage of free / total associated with binding to monomeric α-synuclein targets, is given by the following formula: Free / Total Monomeric α-synuclein % = E max • (CSS / (KD + CSS)) Emax is set to 100%, Css is the estimated average steady-state concentration of GM37v2, and KD is the in vitro measured binding to monomeric α-synuclein (GM37v2 is 36 nM).

[0726] To establish a relevant clinical dose of GM37v2 for the treatment of synucleinopathy (where aggregated α-synuclein is the primary target of treatment rather than the monomeric form), the model needs to be adjusted to account for the 65-fold affinity gain of GM37v2 between monomeric and oligomeric binding – as described in Example 2 and Figure 1 As shown, this affinity gain is obtained when targeting aggregates relative to monomers. For GM37v2, the affinity gain is 65-fold, therefore the model for the aggregation species of α-synuclein as the primary target should use a KD representative value that is 1 / 65 of the monomer KD of 36 nM (36 nM / 65 = 0.5 nM). In the model below, this estimated KD enhancement is expressed as "(KD - affinity gain)".

[0727] Therefore, E associated with binding to α-synuclein targets in aggregated form max The free / total percentage in the model is given by the following formula: Free / Total Aggregated α-synuclein % = E max • (CSS / (KD - Affinity Gain + CSS)) The CSS value can be calculated based on the result obtained in Example 3: For example, these parameters: dose = 4200 mg; dosing interval = 28 days; clearance = 0.25 L / day; estimated mean plasma Css = (4200 mg / 28 days) / 0.25 L / day = 600 mg / L = 600 µg / mL.

[0728] Accordingly, the average CSF Css is 0.3% of 600 µg / mL = 1.8 µg / mL, which is equal to 12 nM (because 1 µg / mL = 6.67 nM, see below).

[0729] When Emax is set to 100% and KD affinity gain is 0.5 nM, in this particular instance of GM37v2 CSF Css=12 nM, the estimated CSF target binding to oligomeric / aggregated α-synuclein is 96% according to the following calculations: Free / Total Aggregated α-synuclein % = E max • (Css / (KD-affinity gain + Css)) = 100% • (12nM / (0.5nM+12nM)) = 96%.

[0730] Based on the data summarized above and the fold difference in affinity / affinity with the target; the dosage of GM37 variant 2 was modeled based on the α-synuclein monomer versus oligomeric form found in Example 2. Figure 1The figures show that these doses, administered at a fixed dose (70 kg body weight) every 4 weeks or less, predict 85% to 95% target binding in the steady-state CSF of the α-synuclein oligomeric form: 1050 mg (15 mg / kg), 2100 mg (30 mg / kg), and 4200 mg (60 mg / kg). These figures are based on the predicted mean CSF Css (calculated as dose / dosing interval / clearance, as illustrated above) and the fraction of 0.3% CSF Css in the CSF. Binding is assumed to follow a simple sigmoid model of the Emax type, with 1 nM GM37v2 = 0.15 μg / mL (1 µg / mL = 6.67 nM).

[0731] Predictions are made based on these calculations: It is predicted that an IV infusion of 1050 mg every 4 weeks can maintain the concentration of GM37 variant 2 in CSF and interstitial fluid (ISF) at around IC85, which is the average concentration of 85% oligomeric α-synuclein bound.

[0732] It is predicted that an IV infusion of 2100 mg every 4 weeks can maintain the concentration of GM37 variant 2 in CSF and interstitial fluid (ISF) at around IC90, which is the average concentration of 90% oligomeric α-synuclein bound.

[0733] It is predicted that an IV infusion of 4200 mg every 4 weeks can maintain the concentration of GM37 variant 2 in CSF and interstitial fluid (ISF) at around IC95, which is the average concentration of oligomeric α-synuclein bound to 95%.

[0734] Example 2 - Competitive ELISA - Target-binding monomers versus oligomers illustrated by GM37 variant 2

[0735] The binding characteristics of GM37 variant 2 to monomeric and protofibrillary α-synuclein were characterized in this assay (also known as a competitive ELISA) to determine the fold difference in binding to monomeric and protofibrillary α-synuclein.

[0736] The assay principle is based on the high-density coating of monomeric α-synuclein, used to capture unbound anti-α-synuclein mAbs after pre-incubation with increased concentrations of monomeric α-synuclein or α-synuclein fibrils. Therefore, the observed IC50 values ​​of α-synuclein monomers or α-synuclein fibrils are relative measurements of the differential binding strength with two representative bioactive species of α-synuclein. The assay principle is as follows: Figure 2 As shown.

[0737] Production of preformed fibrils

[0738] The α-synuclein monomers used for prefibrillated fibrils (PFFs) were produced from eukaryotic sources and fibrillated according to the protocol published by Polinski et al. in J Parkinsons Dis. 2018; 8(2): 303-322.

[0739] In short, monomeric α-synuclein was prepared in 400 µL PBS at 4 mg / mL and stirred for 5 days at 1000 rpm in 2 mL round-bottom tubes using a hot mixer at 37°C. Protein fibrillation was validated by increased fluorescence in response to thiosulfate T and by an increase in hydrodynamic diameter measured via dynamic light scattering (DLS). The fibrils were sonicated using a QSonica R800 (amplitude 50, on for 20 seconds, off for 10 seconds, 10 minutes) to obtain a monodisperse size distribution (Z-mean) below 100 nm as measured by DLS. The PFFs were then aliquoted into 10 μL volumes and stored at -80°C until use.

[0740] On day 1, 384-well plates were coated with α-synuclein monomer (1.4 μg / ml, 50 μl / well). The plates were incubated at 4°C. All solutions and plates were placed on ice and then transferred directly to the freezer. Measurements were performed on day 2.

[0741] Serial two-fold dilutions of α-synuclein monomers and fibrils, ranging from 60 μM to 7.15 pM, were prepared in blocking buffer for low-binding polypropylene plates. The α-synuclein fibril formulation was thawed at room temperature, while the α-synuclein monomer formulation was thawed on ice. Just before use, the monomer and fibril stock solutions were gently mixed by pipetting half the total volume three times. An equal volume of mAb (40 ng / ml) was added to all wells containing the serial dilutions of α-synuclein, and the low-binding plate was incubated for 2 hours at room temperature on a vertical plate shaker (300 rpm) with gentle agitation to form antibody-antigen complexes. Two wells with blocking buffer served as blanks, and two wells with mAb + blocking buffer served as positive controls. One hour before the completion of the above pre-incubation, the α-synuclein-coated assay plate was washed three times with PBS-T using a 384-well automated plate washer, and 100 μl of blocking buffer was added to each well. The plate was then incubated at room temperature for 1 hour.

[0742] Before use, empty the test plate in the wells and tap it thoroughly on a paper towel to ensure the wells are completely emptied. Add two 50 μl aliquots of the pre-incubated sample to each well of the test plate and incubate the plate at room temperature for 10 minutes.

[0743] Wash the plate three times with PBS-T using a 384-well automated plate washer. Add 50 μl of goat anti-human-HRP secondary antibody (diluted 1:15,000 in blocking buffer) to each well, and then incubate at room temperature for 1 hour.

[0744] The plate was washed three times with PBS-T using a 384-well automated plate washer. The two ELISA substrate components were mixed at an appropriate volume ratio of 1:1, and 50 μl was added to all wells. Immediately after addition, the luminescence signal was quantified using an Envision microtiter plate reader.

[0745] Fit the IgG binding curve and calculate the IC50 value using the following equation: Sigmoidal, 4PL, X is log(concentration) Y = base value + (top value - base value) / (1 + ((X^Hill slope) / (IC50^Hill slope))).

[0746] result

[0747] The binding of GM37 variant 2 to monomeric and fibrillary α-synuclein was characterized in a competitive ELISA. The analysis was performed twice daily on three different days, using one monomeric α-synuclein formulation and three different α-synuclein fibrillary batches. Prior to this analysis, when wells were coated with a 1.4 μg / ml monomer solution, the antibody concentration used (finally 20 ng / ml or 133 pM) was shown to be within the dynamic range of the antibody titration curve. This allowed for the differentiation of free antibody levels.

[0748] Based on six independent competitive ELISA analyses, the mean IC50 value of GM37 variant 2 against monomeric α-synuclein was 183.9 ± 20.5 nM, and the mean IC50 value against fibrillary α-synuclein was 2.9 ± 4 nM (see table below). Based on these figures, the mean binding preference of GM37 variant 2 to fibrillary α-synuclein was 64.1 ± 5.2-fold, approximately 65-fold.

[0749] The table shows six specific experiments demonstrating the binding properties of GM37 variant 2 to monomeric and protofilament α-synuclein.

[0750] like Figure 3As shown, the IC50 values ​​for GM37 variant 2 were calculated using precise curve fitting and full titration curves for monomeric and α-synuclein fibrils. Furthermore, the reproducibility of the measurements was good, with IC50 CV (%) values ​​of 11.2% (monomeric α-synuclein) and 12.3% (fibril α-synuclein). Similarly, the calculated fold preference of GM37 variant 2 for aSN fibril binding exhibited a low CV value of 8.1%. Notably, these figures are based on the analysis of three different fibril batches, demonstrating the stability of the assay.

[0751] Similar analyses were performed using the Fab fragment derived from GM37v2 to distinguish between affinity contributions from the IgG form and the presence of fibril-induced conformational epitopes. The Fab fragment showed no preference for binding fibril α-synuclein. In summary, these data suggest that the preference of GM37v2 for binding fibril α-synuclein is solely driven by affinity and does not indicate fibril selectivity or specific conformational fibril epitopes.

[0752] In summary, the competitive ELISA experiments showed that GM37 variant 2 had a 65-fold preferred binding affinity to fibrils compared to the monomeric α-synuclein; this figure can be referred to as the affinity gain for binding and was used to develop the dosage regimen model described in Example 1.

[0753] Furthermore, the binding affinity / affinity of GM37var2 to MSA and PD brain homogenates enriched with insoluble α-synuclein was assessed by ELISA (data not shown). GM37var2 showed EC50 values ​​of approximately 0.09–0.16 nM for brain-derived α-synuclein oligomers and fibrils in these samples, supporting the clinical relevance of the sub-nanomolar fibril binding observed with recombinant materials in the aforementioned experimental setup.

[0754] Example 3 - Single-Augmentation (SAD) Study of the Antibody for Use According to the Invention, Illustrated by GM37 Variant 2

[0755] This is an interventional, randomized, double-blind, sequential, placebo-controlled study. Single-dose escalation study. This study aimed to determine the safety, tolerability, pharmacokinetic, and pharmacodynamic properties of GM37 variant 2 in healthy non-Japanese and Japanese subjects (Part A) and PD patients (Part B).

[0756] Part A consists of 6 sequential queues (queues A1 to A6): - Cohorts A1 to A3: 8 healthy subjects in each cohort: 6 were randomized to receive GM37v2 and 2 were randomized to receive placebo.

[0757] - Cohorts A4 to A6: Each cohort contains 11 to 12 healthy subjects, stratified by race, with an equal number of non-Japanese and Japanese subjects; per race group: up to 4 subjects are randomly assigned to receive GM37v2, and 1 to 2 subjects are randomly assigned to receive placebo.

[0758] Part B consists of two queues (queues B1 and B2): - Cohorts B1 and B2: 7 to 8 patients with Parkinson's disease (PD): 6 patients were randomized to receive GM37v2 and 1 to 2 patients were randomized to receive placebo.

[0759] The dosage range is 75 to 9000 mg; the exact dose increment will be determined at the dosing meeting. Part A: 6 doses tested; healthy subjects 75 mg-225 mg-750 mg-2250 mg-4500 mg-9000 mg. Part B: 2 doses tested; PD patients 2250 mg and 9000 mg.

[0760] GM37v2 and placebo doses were administered via intravenous (IV) infusion over 60 minutes (±10 minutes).

[0761] In each cohort, the first two subjects / patients received either GM37v2 or placebo (1:1) and thus served as sentinel subjects / patients to assess safety and tolerability before the remaining subjects / patients were administered the drug.

[0762] In cohorts A1, A2, A3, B1, and B2, following the sentinel subjects: up to 6 subjects received GM37v2 or placebo (5:1) at least 14 days after the sentinel subjects were administered and their safety data were reviewed. The 6 subjects were administered at staggered intervals, with up to 3 subjects starting administration on the same day (with a maximum overlap of 30 minutes between infusions) and at least 1 day before the start of the next staggered group.

[0763] In cohorts A4, A5, and A6, following the sentinel subjects: 9 to 10 subjects received GM37v2 or placebo at least 14 days after the sentinel subjects were administered and their safety data were reviewed (7:2 for cohort A4, 7:3 for cohort A5, and 6:3 for cohort A6). The 10 subjects were administered at staggered intervals, with a maximum of 3 subjects starting administration on the same day (with a maximum overlap of 30 minutes between infusions) and at least 1 day before the start of the next staggered group.

[0764] Parts A and B were run in parallel. However, the dose administered to PD patients in cohort B1 did not exceed the test dose for healthy subjects in part A. Cohort B1 was initiated based on safety and tolerability assessments of the first 6 subjects in cohort A4 (i.e., at the same dose).

[0765] All subjects / patients were screened 3 weeks and 7 weeks prior to GM37v2 administration. Eligible subjects / patients were confined to the clinic from day 2 before administration (day -2) to day 3 after administration (afternoon of day 4). Subjects / patients then returned to the clinic regularly until a final evaluation was performed 12 weeks after IMP administration.

[0766] Safety and tolerability were assessed throughout the study.

[0767] Prior to dose escalation and the start of each cohort in Part A, blinded safety and tolerability data, preliminary pharmacokinetic data, and preliminary peripheral blood and CSF pharmacodynamic (target binding) data for Part A were evaluated and discussed at a dosing meeting. Dose escalation for the second cohort in Part A (Cohort A2) was based on an evaluation of 4 weeks of safety data from the first cohort (Cohort A1); for each subsequent cohort in Part A, dose escalation was based on at least 2 weeks of safety data from the previous cohort in Part A.

[0768] Pharmacokinetic results: Following IV infusion of GM37v2, the median tmax for non-Japanese subjects occurred within 8 to 90 minutes after the end of the infusion (individual range: 1.00 to 5.00 hours after infusion initiation), slightly later for Japanese subjects, within 15 to 150 minutes after the end of the infusion (individual range: 1.00 to 5.00 hours after infusion initiation), and for PD patients, within 38 to 45 minutes after the end of the infusion (individual range: 1.00 to 5.00 hours after infusion initiation). By the end of the infusion (1 hour after administration), the Cmax had not been reached in most subjects / patients (i.e., 35 out of 41 subjects receiving GM37v2 in Part A and 10 out of 12 patients receiving GM37v2 in Part B). For healthy subjects (Japanese or non-Japanese) or PD patients, the GM37v2 dose had no significant effect on tmax, with similar median values ​​and overlapping ranges across dose groups.

[0769] After Cmax, the “free” concentration of GM37v2 in plasma decreased in a multi-stage manner and could be quantified down to the last pharmacokinetic sample collected from all subjects / patients in portions A and B (except for one subject in cohort A5 whose last sample was collected on day 63, all others were collected on day 84).

[0770] The clearance was found to be approximately 0.01 L / h (0.24 L / d) for all dose groups and study portions, with an overall mean clearance (range 0.00883 to 0.0121 L / h) and an overall mean t1 / 2 of approximately 700 hours (29 days; range 565 to 843 hours); in contrast, endogenous immunoglobulin G1 had a clearance of 0.21 L / d and a t1 / 2 of 21 days.

[0771] GM37v2 exposure (Cmax and AUC) was comparable between Japanese and non-Japanese subjects, as well as between healthy subjects and PD patients. Half-life, clearance, and volume of distribution were comparable at all doses and between Japanese and non-Japanese subjects, as well as between healthy subjects and PD patients.

[0772] The pharmacokinetics of “free” GM37v2 are linear, with dose increases in part A ranging from 75 to 9000 mg and in part B from 2250 to 9000 mg, resulting in roughly dose-proportional increases in exposure.

[0773] Free GM37v2 crossed the blood-brain barrier and was detectable in all CSF samples collected from subjects / patients in subsets A and B on days 3 and 21, with the exception of one subject (75 mg GM37v2), in whom free GM37v2 was below the limit of quantitation in CSF on both days 3 and 21. CSF: plasma ratios were between 0.0955% and 0.137% on day 3 and between 0.164% and 0.512% on day 21. CSF: plasma ratios were comparable across all doses and between healthy subjects and PD patients.

[0774] Figures 4a and 4b depict the relationship between median (including quartile) plasma concentrations (ng / mL) of GM37 variant 2 and time at each dose level in healthy subjects (cohorts A1 to A6) and patients (cohorts B1 to B2).

[0775] Pharmacodynamic results

[0776] In portions A and B, a dose-dependent decrease in plasma “free” α-synuclein was observed immediately following GM37v2 infusion due to GM37v2 binding. A similar pattern was also evident in total α-synuclein, but with significantly less...

Claims

1. A method for treating early multiple system atrophy (MSA) or MSA-C, wherein the method comprises administering an effective amount of a monoclonal anti-α-synuclein antibody to a human subject in need, wherein the monoclonal anti-α-synuclein antibody binds to an epitope within amino acids 112-117 (SEQ ID NO: 9 (ILEDMP)) of human α-synuclein (SEQ ID NO: 10), and wherein the monoclonal antibody comprises: a. Heavy chain CDR1 having the amino acid sequence of SEQ ID NO:1; b. Heavy chain CDR2 having the amino acid sequence of SEQ ID NO:34; c. Heavy chain CDR3 having the amino acid sequence of SEQ ID NO:3; d. The light chain CDR1 having the amino acid sequence of SEQ ID NO:4; e. The light chain CDR2 having the amino acid sequence of SEQ ID NO:5; and f. Light chain CDR3 having the amino acid sequence of SEQ ID NO:

6.

2. The method for treating MSA according to claim 1, wherein the human subject had a total UMSARS score of less than 40 at the start of treatment.

3. The method of treating MSA according to any one of claims 1-2, wherein the human subject has early MSA-C.

4. The method of treating MSA according to any one of claims 1-3, wherein the human subject has MSA-C and a total UMSARS score of less than 40 at the start of treatment.

5. The method for treating MSA according to any one of claims 1-4, wherein the monoclonal antibody comprises a heavy chain variable domain having the amino acid sequence of SEQ ID NO:31 and a light chain variable domain having the amino acid sequence of SEQ ID NO:

8.

6. The method for treating MSA according to any one of claims 1-5, wherein the monoclonal antibody is a human IgG1 antibody.

7. The method for treating MSA according to any one of claims 1-6, wherein the monoclonal antibody comprises a constant heavy chain domain having the amino acid sequence of SEQ ID NO:18 and a κ light chain constant domain having the amino acid sequence of SEQ ID NO:

17.

8. The method for treating MSA according to any one of claims 1-7, wherein the monoclonal antibody is elenetatumab.

9. The method of treating MSA according to any one of claims 1-8, wherein the monoclonal antibody is administered intravenously about every 4 weeks.

10. The method of treating MSA according to any one of claims 1-8, wherein the monoclonal antibody is administered intravenously about once a month.

11. The method of treating MSA according to any one of claims 1-10, wherein the monoclonal antibody is administered intravenously at a dose of about 2100 mg.

12. The method of treating MSA according to any one of claims 1-10, wherein the monoclonal antibody is administered intravenously at a dose of about 4200 mg.

13. The method of treating MSA according to any one of claims 1-12, wherein the treatment comprises: Slowing clinical progress by at least 5%, for example at least 10%, for example at least 15%, for example at least 20%, for example at least 25%, for example at least 30%, for example at least 35%, for example at least 40%, for example at least 45%, for example at least 50%, for example at least 55%, for example at least 60%, for example at least 65%, for example at least 70%, for example at least 75%, for example at least 80%, for example at least 85%, or for example at least 90%.

14. The method of treating MSA according to any one of claims 1-13, wherein the therapeutic effect is quantified by longitudinal change relative to baseline score using the Unified Multisystem Atrophy Rating Scale Total Score (UMSARS TS) or a modified UMSARS (mUMSARS).

15. The method of treating MSA according to any one of claims 1-14, wherein the therapeutic effect is quantified by longitudinal changes in brain volume relative to baseline, such as by volumetric MRI (vMRI).

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