Methods for treating relapsing forms of multiple sclerosis

Abstract

To provide a method of treating multiple sclerosis, including relapsing forms of multiple sclerosis such as relapsing-remitting multiple sclerosis or relapsing-secondary progressive multiple sclerosis.SOLUTION: The present invention provides a method comprising administering a therapeutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds Repulsive Guidance Molecule A (RGMa).SELECTED DRAWING: None

Description

Technical Field

[0001] This application claims the benefit of U.S. Patent Application No. 62 / 217,672, filed on September 11, 2015; U.S. Patent Application No. 62 / 344,024, filed on June 1, 2016; U.S. Patent Application No. 62 / 362,931, filed on July 15, 2016; and U.S. Patent Application No. 62 / 381,322, filed on August 30, 2016. The entire content of each of the above applications is hereby incorporated by reference in its entirety. Sequence Listing This application includes a sequence listing submitted in ASCII format via EFS-Web, which is hereby incorporated by reference in its entirety. This ASCII copy, created on September 9, 2016, is named ABV12225WOO1_SEQ-LIST.txt and is 27,242 bytes in size.

[0002] The present invention relates to anti-RGMa antibodies and methods of using these antibodies for treating multiple sclerosis, including relapsing forms of multiple sclerosis such as relapsing-remitting multiple sclerosis or relapsing secondary progressive multiple sclerosis.

Background Art

[0003] Multiple sclerosis (MS) is a chronic autoimmune and neurodegenerative disorder of the central nervous system (CNS) characterized by inflammation, demyelination, axonal transection, and neuronal loss. It affects approximately 2.5 million people worldwide and is the most common cause of neurological disability in young adults. It is typically diagnosed between the ages of 20 and 40 and affects women twice as often as men.

[0004] Approximately 85% of patients with MS are initially diagnosed with relapsing-remitting MS (RRMS). Patients with RRMS experience discrete episodes of neurological dysfunction (referred to as relapses, exacerbations or attacks), each lasting from days to weeks, occurring intermittently over the years, and characterized by loss of neurological function separated by relatively stable periods. Neurological recovery after a relapse is variable but tends to be incomplete over time, and an estimated 42–57% of relapses are associated with sequelae of neurological deficits. Clinical symptoms are variable and include motor, sensory, visual, bladder and bowel dysfunction and imbalance. Brain atrophy, which symbolizes axonal and myelin loss, occurs early, coincides with loss of cognitive function and is progressive throughout the clinical course. Most patients with RRMS ultimately develop secondary progressive MS (SPMS), in which disability progresses independently of clinically distinct relapses. Relapses can occur in patients with SPMS, particularly during the transition from RRMS to SPMS and during the early course of SPMS (relapsing SPMS), and may be associated with acute inflammatory lesions detected by gadolinium enhancement on T1-weighted magnetic resonance imaging (MRI). Thus, the term relapsing form of MS (RFMS) refers to patients with RRMS or relapsing SPMS. However, over time, relapses become very infrequent and may occur in parallel with a decrease corresponding to acute inflammatory lesions detected by MRI (non-relapsing SPMS).

[0005] The main cause of irreversible damage in MS patients is due to time-dependent, cumulative axonal / neuronal and myelin / oligodendrocyte damage. Axonal injury, including axonal transection, begins early in MS and correlates with inflammatory activity but can occur in areas with little or no signs of inflammation. Several mechanisms result in axonal loss, such as inflammatory secretions, loss of support from oligodendrocytes, disruption of axonal ion concentrations, energy insufficiency, and calcium accumulation. Both the innate and adaptive arms of the immune system are involved in abnormal responses to several antigens associated with myelin sheaths and oligodendrocytes after activation of immune cells by self or cross-reactive microbial pathogens. Although cell markers on T cells (especially CD4+ Th1 cells) are involved, it is facilitated by various other cell types (CD8+ T cells, B cells, macrophages, and microglia) and soluble products (proteases, cytokines, and nitric oxide) that act both outside and inside the CNS. Axonal transection and axonal loss reported in postmortem studies have been shown to be associated with factors that inhibit remyelination and nerve regeneration. Furthermore, atrophy of the brain and spinal cord is a prominent feature in MS patients, and in end-stage disease, the estimated total axonal loss in spinal cord lesions reaches 70%.

Summary of the Invention

Problems to be Solved by the Invention

[0006] Thus, despite major therapeutic advances over the past 20 years in the development of more robust immunomodulatory anti-inflammatory drugs, there is a growing recognition that these treatment modalities are not very effective in preventing and improving the neurodegenerative components of axonal degeneration and oligodendrocyte apoptosis, which represent the main cause of permanent neurological disability in MS patients. Therefore, there is a need in the art for new methods of treating MS patients that are effective in preventing, improving, and reversing the neurodegenerative components of axonal degeneration and oligodendrocyte apoptosis.

Means for Solving the Problems

[0007] (Abstract) In one aspect, the present disclosure provides a method for treating relapsing multiple sclerosis in a subject in need thereof. The method comprises administering a therapeutically effective amount of an antibody or an antigen-binding fragment thereof that specifically binds to repulsive guidance molecule A (RGMa), wherein the antibody or antigen-binding fragment (a) a variable heavy chain comprising a complementarity-determining region (CDR)-1 comprising the amino acid sequence of SEQ ID NO: 2, a CDR-2 comprising the amino acid sequence of SEQ ID NO: 3, and a CDR-3 comprising the amino acid sequence of SEQ ID NO: 4; and (b) a variable light chain comprising a CDR-1 comprising the amino acid sequence of SEQ ID NO: 6, a CDR-2 comprising the amino acid sequence of SEQ ID NO: 7, and a CDR-3 comprising the amino acid sequence of SEQ ID NO: 8 .

[0008] The relapsing multiple sclerosis treated according to the above method can be relapsing-remitting multiple sclerosis (RRMS) or relapsing secondary progressive multiple sclerosis (SPMS).

[0009] In the above method, the antibody or the antigen-binding fragment thereof can be administered to the subject in an amount of about 50 mg to about 4000 mg, or in an amount of about 50 mg to about 2500 mg.

[0010] More specifically, the antibody or the antigen-binding fragment thereof can be administered to the subject in an amount of about 50 mg, 75 mg, 100 mg, 120 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 600 mg, 1000 mg, 1200 mg, 1600 mg, 1800 mg, 2400 mg or 3600 mg.

[0011] Such an antibody or antigen-binding fragment can be administered intravenously to the subject. Alternatively, such an antibody or antigen-binding fragment can be administered subcutaneously to the subject.

[0012] The antibody or antigen-binding fragment used in the above method has a variable heavy chain comprising the amino acid sequence of SEQ ID NO: 13 and a variable light chain comprising the amino acid sequence of SEQ ID NO: 14. Further, the antibody can be a human antibody, an immunoglobulin molecule, a disulfide-bonded Fv, a monoclonal antibody, an affinity matured antibody, an scFv, a chimeric antibody, a CDR-grafted antibody, a diabody, a humanized antibody, a multispecific antibody, a Fab, a dual specific antibody, a DVD, a Fab’, a bispecific antibody, an F(ab’) 2 and can be selected from the group consisting of Fv. In one embodiment, the antibody can be a human antibody. In another embodiment, the antibody can be a monoclonal antibody. In yet another embodiment, the antibody can be an affinity matured antibody. In still yet another embodiment, the antibody can be a chimeric antibody. In still further embodiments, the antibody is a humanized antibody. In yet another embodiment, the antibody is a Fab, a Fab’, an F(ab’) 2 or an Fv. In still further embodiments, the antibody is a dual specific antibody, a DVD or a bispecific antibody.

[0013] Furthermore, the antibody used in the above method can further comprise the constant sequence of SEQ ID NO: 12.

[0014] In certain embodiments, the methods disclosed herein include a plurality of variable dosing regimens, and the regimens include at least two phases. For example, the plurality of variable dosing regimens can include a first phase that includes administering at least one loading dose of the antibody or antigen-binding fragment thereof, followed by subsequent phases that include administering at least one therapeutic dose that is less than the loading dose. The therapeutic dose can be an amount that is at least 10% less, at least 20% less, at least 30% less, at least 40% less, at least 50% less, at least 60% less, at least 70% less, at least 80% less, or at least 90% less than the loading dose.

[0015] In another aspect, the methods disclosed herein further include administering an additional therapeutic agent to the subject. The additional therapeutic agent can be an immunosuppressant or an agent that treats one or more symptoms associated with multiple sclerosis. For example, the additional therapeutic agent can include alpha or beta interferon (e.g., Avonex or Betaseron), systemic corticosteroids such as methylprednisolone (Solu-Medrol) or prednisone (Deltasone), glatiramer (Copaxone), fingolimod (Gilenya), natalizumab (Tysabri), mitoxantrone (Novantrone), teriflunomide (Aubagio), BG-12 (Tecfidera), alemtuzumab (Lemtrada), daclizumab (Zinbryta), ocrelizumab (Ocrevus), amantadine (Symmetrel), amitriptyline (Elavil), nortriptyline, modafinil (Provigil), dalfampridine (Ampyra), cognition enhancers, immunomodulatory agents or neuroprotective agents.Cognitive enhancers may include acetylcholine receptor agonists, acetylcholinesterase inhibitors, butyrylcholinesterase inhibitors, N-methyl-D-aspartic acid (NMDA) receptor antagonists, activity-dependent neuroprotective protein (ADNP) agonists, serotonin 5-HT1A receptor agonists, 5-HT4 receptor agonists, 5-HT6 receptor antagonists, serotonin 1A receptor antagonists, histamine H3 receptor antagonists, calpain inhibitors, vascular endothelial growth factor (VEGF) proteins or agonists, trophic growth factors, anti-apoptotic compounds, AMPA-type glutamate receptor activators, L-type or N-type calcium channel blockers or regulators, potassium channel blockers, hypoxia-inducible factor (HIF) activators, HIF prolyl 4-hydroxylase inhibitors, anti-inflammatory agents, inhibitors of amyloid Aβ peptide or amyloid plaques, inhibitors of tau hyperphosphorylation, phosphodiesterase 5 inhibitors, phosphodiesterase 4 inhibitors, monoamine oxidase inhibitors, pharmaceutically acceptable salts thereof, or combinations thereof. For example, cognitive enhancers may include donepezil (Aricept®), rivastigmine (Exelon®), galantamine (Reminyl®), memantine (Namenda®), or combinations thereof. AE-12-1-Y-QL and other anti-RGMa antibodies disclosed herein may be used in combination with additional therapeutic agents. Anti-RGMa antibodies disclosed herein, including fully human monoclonal antibodies such as AE-12-1-Y-QL, represent novel molecular entities with specific and distinct new mechanisms of action from the aforementioned additional therapeutic agents. Furthermore, AE-12-1-Y-QL does not induce cytochrome enzyme activity and thus has a low potential for drug-drug interactions.

Brief Description of the Drawings

[0016]

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DETAILED DESCRIPTION OF THE INVENTION

[0017] Provided herein is a method for treating multiple sclerosis, particularly relapsing multiple sclerosis (e.g., relapsing-remitting multiple sclerosis and relapsing secondary progressive multiple sclerosis), by administering to a patient in need thereof a therapeutically effective amount of one or more anti-RGMa antibodies.

[0018] 1. Definitions Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, the present specification, including definitions, will control. Although preferred methods and materials are described below, methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting.

[0019] The terms "comprising," "including," "having," "has," "can," "containing," and derivatives thereof are intended to be open - ended transitional phrases, terms, or words when used herein, which do not exclude the possibility of adding operations or structures. The singular forms "a," "and," and "the" include plural references unless the context clearly dictates otherwise. The present disclosure also contemplates other embodiments that "comprise," "consist of," and "consist essentially of" the embodiments or elements presented herein, whether or not explicitly described.

[0020] "About," as used herein, can refer to a variation of approximately ±10% from the described value. Such variations are to be understood to be always included in any given value provided herein, whether or not a specific reference is made.

[0021] "Affinity - matured antibody" has an affinity of the antibody for the target antigen (i.e., K D , k d or k a) is used herein to refer to an antibody having one or more modifications in one or more CDRs that result in an improvement. Exemplary affinity matured antibodies have nanomolar or even picomolar affinity for the target antigen. Various means for producing affinity matured antibodies are known in the art and include screening of combinatorial antibody libraries produced using biopanning. For example, Marks et al., BioTechnology, 10:779-783 (1992) describe affinity maturation by VH and VL domain shuffling. Random mutagenesis of CDR and / or framework residues is described in Barbas et al., Proc. Nat. Acad. Sci. USA, 91:3809-3813 (1994); Schier et al., Gene, 169:147-155 (1995); Yelton et al., J. Immunol., 155:1994-2004 (1995); Jackson et al., J. Immunol., 154(7):3310-3319 (1995); and Hawkins et al., J. Mol. Biol., 226:889-896 (1992). Site-directed mutagenesis at selected mutagenesis sites and contact sites with activity enhancing amino acid residues or at hypermutation sites is described in U.S. Patent No. 6,914,128.

[0022] As used herein, the terms “antibody” and “antibodies” refer to monoclonal antibodies, multispecific antibodies, human antibodies, humanized antibodies (fully or partially humanized), avian (e.g., duck or goose), shark, whale, and mammalian, e.g., non-primate (e.g., cow, pig, camel, llama, horse, goat, rabbit, sheep, hamster, guinea pig, cat, dog, rat, mouse, etc.) or non-human primate (e.g., monkey, chimpanzee, etc.) antibodies, recombinant antibodies, chimeric antibodies, single-chain Fvs (“scFv”), single-chain antibodies, single domain antibodies, Fab fragments, F(ab’) fragments, F(ab’) 2Fragment, disulfide-bonded Fvs ("sdFv") and anti-idiotype antibodies ("anti-Id"), dual domain antibodies, dual variable domain (DVD) antibodies or triple variable domain (TVD) antibodies (dual variable domain immunoglobulins and methods for making them are described in Wu, C. et al., Nature Biotechnology, Vol. 25(11):1290-1297 (2007) and PCT International Application Publication No. WO2001 / 058956, the contents of each document being incorporated herein by reference), and any functionally active epitope-binding fragment as described above. In particular, an antibody includes an immunoglobulin molecule and an immunologically active fragment of an immunoglobulin molecule, i.e., a molecule containing an analyte-binding site. The immunoglobulin molecule can be of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass. For simplicity, an antibody against an analyte is often referred to herein as an "anti-analyte antibody" or simply an "analyte antibody" (e.g., an anti-RGMa antibody or an RGMa antibody).

[0023] As used herein, an "antibody fragment" refers to a portion of a complete antibody that includes an antigen-binding site or variable region. The portion does not include the constant heavy chain domains of the Fc region of the complete antibody (i.e., CH2, CH3 or CH4 depending on the antibody isotype). Examples of antibody fragments include, but are not limited to, Fab fragments, Fab' fragments, Fab'-SH fragments, F(ab' 2 fragments, Fd fragments, Fv fragments, diabodies, single-chain Fv (scFv) molecules, single-chain polypeptides containing only one light chain variable domain, single-chain polypeptides containing three CDRs of a light chain variable domain, single-chain polypeptides containing only one heavy chain variable region, and single-chain polypeptides containing three CDRs of a heavy chain variable region.

[0024] As used herein, "bispecific antibody" refers to a full-length antibody made by quadroma technology (see Milstein et al., Nature 305(5934):537-540 (1983)), by chemical linkage of two different monoclonal antibodies (see Staerz et al., Nature 314(6012):628-631 (1985)) or by a similar approach introducing mutations into the Fc region that results in a number of different immunoglobulin species that are knob-into-hole or monovalent-only functional bispecific antibodies (see Holliger et al., Proc. Natl. Acad. Sci. USA 90(14):6444-6448 (1993)). A bispecific antibody binds one antigen (or epitope) at one of the two binding arms (one pair of HC / LC) and a different antigen (or epitope) at the second arm (a different pair of HC / LC). By this definition, a bispecific antibody has two different antigen-binding arms (both in terms of specificity and CDR sequence) and is monovalent for each antigen to which it binds.

[0025] "CDR" is used herein to refer to "complementary determining regions" within antibody variable sequences. There are three CDRs in each of the variable regions of the heavy and light chains, which are designated "CDR1", "CDR2", and "CDR3" for each variable region. The term "CDR set", as used herein, refers to a group of the three CDRs present in a single variable region that binds an antigen. The exact boundaries of these CDRs are defined differently according to different systems. The system reported by Kabat (Kabat et al., Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md. (1987) and (1991))) not only provides a system for unambiguously numbering residues applicable to any variable region of an antibody, but also provides the exact residue boundaries that define the three CDRs. These CDRs may be referred to as "Kabat CDRs". Chothia and co-workers (Chothia and Lesk, J. Mol. Biol., 196:901-917 (1987); and Chothia et al., Nature, 342:877-883 (1989)) found that, despite being very diverse at the amino acid sequence level, certain small portions within the Kabat CDRs adopt nearly identical peptide backbone structures. These small portions are designated "L1", "L2", and "L3", or "H1", "H2", and "H3", where "L" and "H" refer to the light and heavy chain regions, respectively. These regions may be referred to as "Chothia CDRs" and have boundaries that overlap with the Kabat CDRs. Other boundaries that define CDRs overlapping with the Kabat CDRs have been reported by Padlan, FASEB J., 9:133-139 (1995); and MacCallum, J., Mol. Biol., 262(5):732-745 (1996). Still other definitions of CDR boundaries do not strictly follow one system of this specification but nevertheless overlap with the Kabat CDRs.However, these may be shortened or lengthened considering the prediction or experimental view that a particular residue or group of residues or even the entire CDR does not significantly affect antigen binding. Although certain embodiments use CDRs defined by Kabat or Chothia, the methods used herein can utilize CDRs defined according to either of these systems.

[0026] As used herein, an "antibody derivative" refers to an antibody having one or more modifications to the amino acid sequence, which may exhibit an altered domain structure, when compared to the native or parental antibody. This derivative can still adopt the typical domain configuration found in natural antibodies and an amino acid sequence capable of specifically binding to a target (antigen). Typical examples of antibody derivatives are antibodies linked to other polypeptides, reconstituted antibody domains, or fragments of antibodies. The derivative may also contain at least one additional compound, e.g., a protein domain, which is linked either covalently or non-covalently. This linkage can be based on gene fusion according to methods known in the art. The additional domain present in the fusion protein containing the antibody used in the present invention may preferably be linked by a flexible linker, advantageously a peptide linker, where the peptide linker contains a plurality of hydrophilic peptide-bonded amino acids of sufficient length to span the distance between the C-terminus of the additional protein domain and the N-terminus of the antibody or vice versa. The antibody can be linked to an effector molecule having biological activity or a structure suitable for selective binding to, e.g., a solid support, a biologically active substance (e.g., a cytokine or a growth hormone), a chemical substance, a peptide, a protein, or a drug.

[0027] As used herein, "bispecific antibody" refers to a full-length antibody capable of binding two different antigens (or epitopes) in each of its two binding arms (a pair of HC / LC) (see PCT Publication No. WO02 / 02773). Thus, a bispecific binding protein has two identical antigen-binding arms having the same specificity and the same CDR sequences and is bivalent with respect to each antigen to which it binds.

[0028] As used herein, "dual variable domain" refers to two or more antigen-binding sites in a binding protein, which can be a bivalent (two antigen-binding sites), tetravalent (four antigen-binding sites) or multivalent binding protein. A DVD can be monospecific, i.e., capable of binding one antigen (or one specific epitope), or multispecific, i.e., capable of binding two or more antigens (i.e., two or more epitopes of the same target antigen molecule or two or more epitopes of different target antigens). Preferred DVD binding proteins comprise two heavy chain DVD polypeptides and two light chain DVD polypeptides and are referred to as "DVD immunoglobulin" or "DVD-Ig". Thus, such a DVD-Ig binding protein is a tetramer, reminiscent of an IgG molecule but providing more antigen-binding sites than an IgG molecule. Thus, each half of the tetrameric DVD-Ig molecule is reminiscent of half of an IgG molecule and comprises a heavy chain DVD polypeptide and a light chain DVD polypeptide, but unlike a pair of heavy and light chains of an IgG molecule that provide a single antigen-binding domain, a pair of heavy and light chains of a DVD-Ig provides two or more antigen-binding sites.

[0029] Each antigen-binding site of the DVD-Ig binding protein can be derived from a donor (``parental'') monoclonal antibody and thus includes a heavy chain variable domain (VH) and a light chain variable domain (VL) each having a total of six CDRs involved in antigen binding per antigen-binding site. Thus, a DVD-Ig binding protein that binds two different epitopes (i.e., two different epitopes of two different antigen molecules or two different epitopes of the same antigen molecule) includes an antigen-binding site derived from a first parental monoclonal antibody and an antigen-binding site of a second parental monoclonal antibody.

[0030] The design, expression, and characterization of DVD-Ig binding molecules are provided in PCT Publication No. WO2007 / 024715, U.S. Patent No. 7,612,181, and Wu et al., Nature Biotech., Vol. 25:1290-1297 (2007). Preferred examples of such DVD-Ig molecules have the structural formula VD1-(X1)n-VD2-C-(X2)n, where VD1 is a first heavy chain variable domain, VD2 is a second heavy chain variable domain, C is a heavy chain constant domain, X1 is a linker provided that it is not CH1, X2 is an Fc region, and n is 0 or 1, preferably 1. It includes a heavy chain; and has the structural formula VD1-(X1)n-VD2-C-(X2)n, where VD1 is a first light chain variable domain, VD2 is a second light chain variable domain, C is a light chain constant domain, X1 is a linker provided that it is not CH1, X2 does not include an Fc region, and n is 0 or 1, preferably 1. It includes a light chain. Such a DVD-Ig can include two such heavy chains and two such light chains, and each chain includes tandemly linked variable domains without a constant region intervening between the variable regions, where the heavy and light chains bind to form a tandem functional antigen-binding site, and one pair of heavy and light chains can bind to another pair of heavy and light chains to form a tetrameric binding protein having four functional antigen-binding sites. In another example, the DVD-Ig molecule can include a heavy chain and a light chain, and each of the heavy and light chains includes three tandemly linked variable domains (VD1, VD2, VD3) without a constant region intervening between the variable domains, where one pair of heavy and light chains can bind to form three antigen-binding sites, and one pair of heavy and light chains can bind to another pair of heavy and light chains to form a tetrameric binding protein having six antigen-binding sites.

[0031] In one embodiment, the DVD-Ig binding protein according to the present invention not only binds to the same target molecule to which the parental monoclonal antibody binds, but also has one or more desirable properties of one or more of these parental monoclonal antibodies. For example, such additional properties are antibody parameters of one or more of the parental monoclonal antibodies. Antibody parameters that can contribute to the DVD-Ig binding protein from one or more of these parental monoclonal antibodies include, but are not limited to, antigen specificity, antigen affinity, efficacy, biological function, epitope recognition, protein stability, protein solubility, production efficiency, immunogenicity, pharmacokinetics, bioavailability, tissue cross-reactivity, and binding to orthologous antigens.

[0032] The DVD-Ig binding protein binds to at least one epitope of RGMa. Non-limiting examples of the DVD-Ig binding protein include a DVD-Ig binding protein that binds to one or more epitopes of RGMa, a DVD-Ig binding protein that binds to an epitope of human RGMa and an epitope of an RGMa peptide of another species (e.g., mouse), and a DVD-Ig binding protein that binds to an epitope of human RGMa and an epitope of another target molecule (VEGFR2 or VEGFR1).

[0033] "Epitope" or "epitopes" or "epitope of interest" refers to the site(s) in any molecule that can be recognized and bind to the complementary site(s) in a specific binding partner. The molecule and the specific binding partner are part of a pair of specific binding. For example, the epitope can be a polypeptide, protein, hapten, carbohydrate antigen (e.g., but not limited to, glycolipid, glycoprotein or lipopolysaccharide) or polysaccharide. The specific binding partner can be, but is not limited to, an antibody.

[0034] As used herein, "framework" (FR) or "framework array" can mean the remaining array of variable regions excluding the CDRs. Since the exact delineation of the CDR arrays can be determined by different systems (see, e.g., supra), the meaning of the framework array is subject to different interpretations accordingly. The six CDRs (CDR-L1, -L2, and -L3 of the light chain and CDR-H1, -H2, and -H3 of the heavy chain) also divide the framework regions of the light and heavy chains into four subregions (FR1, FR2, FR3, and FR4) in each chain, with CDR1 located between FR1 and FR2, CDR2 located between FR2 and FR3, and CDR3 located between FR3 and FR4. While not specifying a particular subregion as FR1, FR2, FR3, or FR4, as otherwise noted, the framework region represents the combined FRs within the variable region of a single, naturally occurring immunoglobulin chain. As used herein, FR represents one of the four subregions, and FR(s) represents two or more of the four subregions that make up the framework region.

[0035] Human heavy and light chain FR arrays are known in the art to be usable as heavy and light chain "acceptor" framework arrays (or simply "acceptor" arrays) for humanizing non-human antibodies using techniques known in the art. In one embodiment, the human heavy and light chain acceptor arrays are selected from framework arrays listed in publicly available databases such as V-base or in the International ImMunoGeneTics® (IMGT®) information system.

[0036] As used herein, "functional antigen-binding site" can mean a site on a binding protein (e.g., an antibody) that can bind to a target antigen. The antigen-binding affinity of the antigen-binding site may not be as strong as that of the parental binding protein, e.g., the parental antibody, from which the antigen-binding site is derived, but the ability to bind to the antigen can be measurable using any one of various methods known for evaluating proteins that bind to an antigen, e.g., antibodies. Further, the antigen-binding affinities of the respective antigen-binding sites of a multivalent protein, e.g., a multivalent antibody, need not be quantitatively the same herein.

[0037] As used herein, "human antibody" can include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies described herein can include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro, or mutations introduced by somatic mutation in vivo). However, the term "human antibody" as used herein is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been transplanted into human framework sequences.

[0038] The term "humanized antibody" is used herein to describe an antibody that contains variable region sequences of heavy and light chains from non-human species (e.g., mouse), but in which at least a portion of the VH and / or VL sequences have been modified to be more "human-like", i.e., more similar to human germline variable sequences. A "humanized antibody" is an antibody or a variant, derivative, analog or fragment thereof that immunospecifically binds to an antigen of interest and contains a framework (FR) region that substantially has the amino acid sequence of a human antibody and a complementarity determining region (CDR) that substantially has the amino acid sequence of a non-human antibody. As used herein, the term "substantially" in connection with a CDR refers to a CDR having an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98% or at least 99% identical to the amino acid sequence of a non-human antibody CDR. A humanized antibody contains substantially all of at least one, typically two variable domains (Fab, Fab’, F(ab’) 2 , FabC, Fv), wherein all or substantially all of the CDR regions correspond to the CDR regions of a non-human immunoglobulin (i.e., the donor antibody) and all or substantially all of the framework regions are framework regions of a human immunoglobulin consensus sequence. In one embodiment, a humanized antibody also contains at least a portion of an immunoglobulin constant region (Fc), typically at least a portion of the constant region of a human immunoglobulin. In some embodiments, a humanized antibody contains at least the variable domain of the heavy chain in addition to the light chain. The antibody may also include the CH1, hinge, CH2, CH3 and CH4 regions of the heavy chain. In some embodiments, a humanized antibody contains only a humanized light chain. In some embodiments, a humanized antibody contains only a humanized heavy chain. In certain embodiments, a humanized antibody contains only the humanized variable domain of the light chain and / or the humanized heavy chain.

[0039] The humanized antibody can be selected from any class of immunoglobulin including IgM, IgG, IgD, IgA, and IgE, and any isotype including, but not limited to, IgG1, IgG2, IgG3, and IgG4. The humanized antibody can include sequences from more than one class or isotype, and specific constant domains can be selected using techniques well known in the art to optimize the desired effector function.

[0040] The framework regions and CDRs of the humanized antibody need not exactly correspond to the parental sequences. For example, the donor antibody CDR or consensus framework can be mutated by at least one amino acid residue substitution, insertion, and / or deletion such that the CDR or framework residue at that site does not correspond to either the donor antibody or the consensus framework. However, in a preferred embodiment, such mutations are not extensive. Typically, at least 80%, preferably at least 85%, more preferably at least 90%, and most preferably at least 95% of the residues of the humanized antibody correspond to the residues of the humanized antibody of the parental FR and CDR sequences. As used herein, the term "consensus framework" refers to the framework region in an immunoglobulin consensus sequence. As used herein, the term "immunoglobulin consensus sequence" refers to a sequence formed from the amino acids (or nucleotides) that occur most frequently in a family of related immunoglobulin sequences (see, e.g., Winnaker, From Genes to Clones (Verlagsgesellschaft, Weinheim, 1987)). Thus, an "immunoglobulin consensus sequence" can include "consensus framework region(s)" and / or "consensus CDR(s)". In a family of immunoglobulins, each position in the consensus sequence is occupied by the amino acid that occurs most frequently at that position in the family. If two amino acids occur with equal frequency, either can be included in the consensus sequence.

[0041] The term "linker array" or "linker peptide array" refers to a natural or artificial polypeptide array connected to one or more polypeptide arrays of interest (e.g., full length, fragments, etc.). The term "connected" refers to the connection of the linker array to the polypeptide array of interest. Such polypeptide arrays are preferably connected by one or more peptide bonds. The linker array can have a length of about 4 to about 50 amino acids. Preferably, the length of the linker array is about 6 to about 30 amino acids. Natural linker arrays can be modified by amino acid substitution, addition or deletion to create artificial linker arrays. Exemplary linker arrays include, but are not limited to, the following: (i) A histidine (His) tag such as the 6×His tag (SEQ ID NO: 15) having the amino acid sequence HHHHHH (SEQ ID NO: 15) is useful as a linker array to facilitate the isolation and purification of the polypeptide of interest and antibodies; (ii) Enterokinase cleavage sites such as His tags are used for the isolation and purification of the protein and antibody of interest. In many cases, enterokinase cleavage sites are used together with His tags in the isolation and purification of the protein and antibody of interest. Various enterokinase cleavage sites are known in the art. Examples of enterokinase cleavage sites include, but are not limited to, the amino acid sequences DDDDK (SEQ ID NO: 16) and its derivatives (e.g., ADDDDK (SEQ ID NO: 17), etc.); (iii) Various sequences can be used to link or connect the light chain variable region and / or the heavy chain variable region of a single chain variable region fragment. Other examples of linker arrays can be found in Bird et al., Science 242:423-426 (1988); Huston et al., PNAS USA 85:5879-5883 (1988); and McCafferty et al., Nature 348:552-554 (1990). Also, the linker array can be modified for additional functions such as drug binding or binding to a solid support. In the context of the present disclosure, monoclonal antibodies can contain linker arrays such as, for example, His tags, enterokinase cleavage sites or both.

[0042] The "multiple variable dosing regimen" refers to a treatment schedule or regimen that includes the administration of different doses of the anti-RGMa antibody or an antigen-binding fragment thereof at various times throughout the course of treatment. For example, a multiple variable dosing regimen may include a loading dose administered first and one or more therapeutic doses administered thereafter. In one embodiment, the loading dose is a higher dose than the subsequent therapeutic dose(s).

[0043] The "loading dose" as used herein refers to the first dose(s) of the anti-RGMa antibody or an antigen-binding fragment thereof that is first used to treat relapsing multiple sclerosis in a subject. The loading dose may be larger compared to the subsequent therapeutic dose(s). The loading dose may be a single dose or a set of doses. For example, a 3600 mg dose can be administered as a single 3600 mg dose, as two 1800 mg doses each, or as four 900 mg doses each. In one embodiment, following the loading dose, administration of a lower dose, such as a therapeutic dose(s), follows.

[0044] The "therapeutic dose" as used herein refers to the subsequent dose(s) of the anti-RGMa antibody or an antigen-binding fragment thereof that is administered to a subject after the loading dose. The therapeutic dose is administered to the subject to maintain or continue the desired therapeutic effect. The therapeutic dose may be a single dose or a set of doses. In one embodiment, the therapeutic dose(s) is / are smaller than the loading dose(s), and each therapeutic dose may be equal to each other if administered consecutively.

[0045] The term "Columbia Suicide Severity Rating Scale" or "C-SSRS", when used interchangeably herein, refers to a systematically administered instrument developed to track suicide adverse events through treatment research. This instrument is designed to assess suicidal behavior and ideation and to track and evaluate all events related to suicide, not just the lethality of the attempt. Additional features that are evaluated include frequency, duration, controllability, reasons for the ideation, and deterrents. The C-SSRS is considered a low-burden instrument because it takes less than 5 minutes to administer.

[0046] The term "Expanded Disability Status Scale (EDSS)" or "EDSS", when used interchangeably herein, refers to a standardized rating scale that uses an ordered (ordinal) rating scale that requires human assessment. The EDSS quantifies impairments in eight functional systems (FS): pyramidal, cerebellar, brainstem, sensory, bowel and bladder, visual, cerebral, and other. With the EDSS, a neurologist can assign a functional system score (FSS) for each of these.

[0047] The term "Multiple Sclerosis Functional Composite" or "MFSC", when used interchangeably herein, refers to a performance measure using standardized procedures for testing human function, consisting of the Timed 25 Foot Walk (T25FW); the 9 Hole Peg Test (9HPT); and the Paced Auditory Serial Arithmetic Test (PASAT). Due to certain MSFC limitations, namely the abstract and dimensionless nature of the summary score, the fact that many clinicians are not familiar with z-scores, and the fact that the reference population affects the absolute values and weights of the components, MSFC scores are not clinically easy to interpret or compared across studies. Alternative analytical methods are used to define worsening as an increase in score by a pre-specified amount in any of the component tests, which can be reliably determined, have clinical relevance (e.g., 20%), and can demonstrate worsening in the same component at two consecutive time points.

[0048] The term "Multiple Sclerosis Impact Scale, Physical", "MSIS-29 PHYS" or "MSIS-29", when used interchangeably herein, refers to a disease-specific patient-reported assessment item used to evaluate the physical and psychological impact of MS. MSIS-29 includes a 20-item physical impact subscale (MSIS-29 PHYS) and a 9-item psychological impact subscale (MSIS-29 PSYCH). A worsening of ≥7.5 points from baseline in MSIS-29 PHYS has been shown to be clinically meaningful in clinical study populations. The proportion of patients in whom the physical impact of MS reported by the patient is accompanied by a clinically meaningful worsening (≥7.5 point worsening in MSIS-29 PHYS) is evaluated at consecutive time points over the course of the study.

[0049] As used herein, the term "Multiple Sclerosis Quality of Life-54" or "MSQOL-54" refers to a multidimensional health-related quality of life measure that combines both general and MS-specific items into a single instrument. The 54-item instrument generates 12 subscales along with two summary scores and two additional single-item scales. The subscales are physical function, role limitation - physical, role limitation - emotional, pain, emotional well-being, energy, health perceptions, social function, cognitive function, health distress, overall quality of life, and sexual function. The summary scores are the physical health composite summary and the mental health composite summary. The single-item scales are sexual function and satisfaction with changes in health.

[0050] "Multiple sclerosis" (MS) refers to a chronic disease of the central nervous system characterized by progressive destruction of myelin, and often refers to a disabling disease. There are four internationally recognized forms of MS, namely, primary progressive multiple sclerosis (PPMS), relapsing remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS), and relapsing secondary progressive multiple sclerosis (RSPMS). Relapsing forms of MS include relapsing remitting multiple sclerosis and relapsing secondary progressive multiple sclerosis.

[0051] "Relapsing remitting multiple sclerosis" or "RRMS" is a relapsing form of multiple sclerosis characterized by distinct disease relapses (also known as exacerbations) that are followed by periods of recovery with sequelae and residual deficits during the recovery periods between relapses where there is complete recovery or no progression of the disease. The defining elements of RRMS are episodes of rapid worsening of neurological function, subsequent recovery to varying degrees, and a stable course between attacks (Lublin, F.D. and Reingold, S.O., Neurology (Vol. 46) pp. 907-911 (1996)). Relapses can last for days, weeks or months and recovery can be slow, gradual or almost instantaneous. The majority of subjects presenting with MS are initially diagnosed with RRMS. This typically occurs when they are in their 20s or 30s, although diagnoses are known to occur very early or late. Twice as many women as men are associated with this subtype of MS. During a relapse, the myelin, the protective insulating sheath around the nerve fibers (neurons) in the white matter regions of the central nervous system (CNS), can be damaged in an inflammatory reaction by the body's own immune system. This causes a variety of neurological symptoms that vary considerably depending on which areas of the CNS are damaged. Immediately after a relapse, the inflammatory reaction subsides and special glial cells in the CNS (called oligodendrocytes) promote remyelination, a process by which the myelin sheath around the axons is repaired. It is this remyelination that can be involved in the remission.

[0052] "Primary progressive multiple sclerosis" or "PPMS" occurs after a relapsing remitting disease course (RRMS). Of the 85% of people initially diagnosed with RRMS, most eventually transition to SPMS. This means that after a period of experiencing relapses and remissions, the disease begins to progress more steadily (not necessarily more rapidly) regardless of the presence or absence of any relapses (also called attacks or exacerbations). At any given point, SPMS accounts for approximately 30% of all subjects with multiple sclerosis. The natural course of MS indicates that 50% of subjects diagnosed with RRMS transition to secondary progressive MS (SPMS) within 10 years and 90% within 25 years.

[0053] A significant transition from RRMS to SPMS occurs in the absence of relapse when there is a progressive worsening of neurological function. In SPMS, people may or may not continue to experience relapses caused by inflammation; the disease changes from the inflammatory process seen in RRMS to a more steadily progressive stage characterized by nerve damage or loss. "Relapsing secondary progressive multiple sclerosis" or "relapsing SPMS" includes subjects during the initial stage after transition to SPMS that still exhibit features of relapse activity and inflammation, as documented in neuroimaging studies as new T1 gadolinium-enhancing lesions or new or newly enlarged T2 lesions on brain or spinal cord MRI.

[0054] "Multivalent binding protein" is used herein to refer to a binding protein that contains two or more antigen-binding sites (also referred to herein as "antigen-binding domains"). Multivalent binding proteins are preferably genetically engineered to have three or more antigen-binding sites and are generally not naturally occurring antibodies. The term "multispecific binding protein" refers to a binding protein that can bind to two or more related or unrelated targets, including binding proteins that can bind to two or more different epitopes of the same target molecule.

[0055] "Recombinant antibody" and "recombinant antibodies" refer to antibodies prepared by one or more processes including cloning a nucleic acid sequence encoding all or part of one or more monoclonal antibodies into a suitable expression vector by recombinant techniques and thereafter expressing the antibody in a suitable host cell. These terms include, but are not limited to, recombinantly produced monoclonal antibodies, chimeric antibodies, humanized antibodies (fully or partially humanized), multispecific or multivalent structures formed from antibody fragments, bispecific antibodies, heteroconjugate Abs, DVD-Ig and other antibodies described herein in (i). (Dual variable domain immunoglobulins and methods of making them are described in Wu, C. et al., Nature Biotechnology, Volume 25: pages 1290-1297 (2007).) The term "bispecific antibody" as used herein refers to an antibody that includes a first arm having specificity for one antigenic site and a second arm having specificity for a different antigenic site; that is, a bispecific antibody has dual specificity.

[0056] "Specific binding" or "binds specifically" as used herein can refer to the interaction of an antibody, protein or peptide with a second chemical species, where the interaction depends on the presence of a particular structure (e.g., an antigenic determinant or epitope) of the chemical species; for example, an antibody generally recognizes and binds to a particular protein structure rather than to a protein in general. If an antibody is specific for epitope "A", the presence of a molecule containing epitope A (or free, unlabeled A) will decrease the amount of labeled A bound to the antibody in a reaction containing labeled "A" and the antibody.

[0057] "Treat", "treating", or "treatment" are each used interchangeably herein to describe ameliorating, alleviating, or inhibiting the progression of a disease or one or more symptoms of such a disease to which such terms apply. Treatment can be effected by any acute or chronic means. The term also refers to reducing the severity of a disease or symptoms associated with such a disease before it becomes painful. Such a reduction in the severity of a disease before it becomes painful refers to administering an antibody or pharmaceutical composition described herein to a subject at a time other than the time of administration when the subject has become painful due to the disease. "Treatment" and "therapeutically" refer to the act of treating, as defined above for "treating".

[0058] "Variant" is used herein to describe a peptide or polypeptide whose amino acid sequence differs by an amino acid insertion, deletion, or conservative substitution, but which retains at least one biological activity. Representative examples of "biological activity" include the ability to bind to a specific antibody or the ability to promote an immune response. Variant is also used herein to describe a protein having an amino acid sequence that is substantially identical to a reference protein having an amino acid sequence that retains at least one biological activity. Conservative substitution of an amino acid, i.e., substitution of an amino acid with a different amino acid of similar properties (e.g., hydrophilicity, degree and distribution of charged regions), is typically recognized in the art as involving minor changes. These minor changes can, in part, be identified by considering the hydrophobicity index of the amino acid, as understood in the art. Kyte et al., J. Mol. Biol., 157:105-132 (1982). The hydrophobicity index of an amino acid is based on considerations of hydrophobicity and charge. It is known in the art that amino acids with similar hydrophobicity indices can be substituted and still retain protein function. In one embodiment, amino acids having a hydrophobicity index of ±2 are substituted. Also, the hydrophilicity of an amino acid can be used to reveal substitutions that result in a protein that retains biological function. Consideration of the hydrophilicity of amino acids in the context of a peptide allows calculation of the maximum local average hydrophilicity of the peptide, which is a useful means that has been reported to be well correlated with antigenicity and immunogenicity. U.S. Patent No. 4,554,101, which is incorporated herein by reference. Substitution of amino acids with similar hydrophilicity values can, as understood in the art, result in a peptide that retains biological activity, e.g., immunogenicity. The substitution can be made with amino acids having hydrophilicity values within ±2 of each other. Both the hydrophobicity index and the hydrophilicity value of an amino acid are affected by the specific side chain of that amino acid. Consistent with this observation, amino acid substitutions that are compatible with biological function are understood to depend on the relative similarity of the amino acids, particularly the relative similarity of their side chains, as revealed by hydrophobicity, hydrophilicity, charge, size, and other properties."Variant" can also be used to refer to an antigenically reactive fragment of an anti-RGMa antibody that differs from the corresponding fragment of the anti-RGMa antibody in the amino acid sequence, but is still antigenically reactive, and can compete with the corresponding fragment of the anti-RGMa antibody for binding to RGMa. "Variant" can also be used to describe a polypeptide or this fragment that has been differentially processed, e.g., by proteolysis, phosphorylation, or other post-translational modifications, but retains antigenic reactivity.

[0059] For the recitation of numerical ranges herein, each intervening number having the same degree of precision is explicitly considered. For example, for the range of 6-9, the numerical values of 7 and 8 are considered in addition to 6 and 9, and for the range of 6.0-7.0, the numerical values of 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly considered.

[0060] 2. Anti-RGMa Antibody Provided herein is a method of treating multiple sclerosis, particularly relapsing multiple sclerosis (e.g., relapsing-remitting multiple sclerosis and relapsing secondary progressive multiple sclerosis), by administering one or more anti-RGMa antibodies to a patient in need thereof. The anti-RGMa antibodies for use in the methods described herein bind to RGMa while minimizing or eliminating reactivity with repulsive guidance molecule c ("RGMc"). Antibodies produced against RGMa often cross-react with RGMc and result in iron accumulation in hepatocytes at high intravenous doses, so the specific binding of the antibodies to RGMa described herein provides a therapeutic benefit. Furthermore, the high selectivity of these antibodies provides a large therapeutic dose window or range for treatment.

[0061] RGMa exists in both membrane-bound and soluble forms. RGMa plays a role in neural tube development and further plays roles in cell adhesion, cell migration, cell polarity, and cell differentiation, which together affect early morphogenetic events. RGMa also inhibits nerve regeneration. The actions of RGMa (both membrane-bound and soluble forms) can be mediated by neogenin and / or bone morphogenetic protein (BMP) receptors. For example, the RGMa-BMP interaction can enhance neurite outgrowth inhibition (e.g., via neuronal BMP receptors) and inhibit remyelination (e.g., via glial BMP receptors). As another example, the RGMa-neogenin interaction can inhibit axon growth.

[0062] In certain embodiments, the anti-RGMa antibodies provided herein can bind to and neutralize human RGMa. In certain embodiments, the anti-RGMa antibodies provided herein have a unique combination of nerve regeneration properties and nerve recovery properties, demonstrating axon regeneration, neuroprotection, and remyelination in animal models. From the perspective of the multifaceted role of RGMa, it is desirable to establish a safety range with anti-RGMa antibodies in mammals, particularly humans.

[0063] a. RGMa recognition antibody Antibodies that can be used to treat patients with multiple sclerosis, particularly relapsing forms of multiple sclerosis (e.g., relapsing-remitting multiple sclerosis and relapsing secondary progressive multiple sclerosis), are antibodies that bind to RGMa, this fragment, or variant. The antibody may be a fragment of an anti-RGMa antibody or this variant or derivative. The antibody may be a polyclonal antibody or a monoclonal antibody. The antibody may be a chimeric antibody, a single-chain antibody, an affinity matured antibody, a human antibody, a humanized antibody, a fully human antibody, or an antibody fragment such as a Fab fragment or a mixture thereof. The antibody fragment or derivative may 2 include F(ab’), Fv, or scFv fragments. The antibody derivative can be generated by peptidomimetics. Further, techniques reported for the generation of single-chain antibodies can be adapted to generate single-chain antibodies.

[0064] Human antibodies can be derived from phage display technology or transgenic mice expressing human immunoglobulin genes. Human antibodies can be generated and isolated as a result of the immune response in humans in vivo. See, for example, Funaro et al., BMC Biotechnology, 2008 (8): 85. Thus, the antibody can be a human product rather than an animal repertoire. Since this is of human origin, the risk of reactivity to self-antigens can be minimized. Alternatively, standard yeast display libraries and display technologies can be used to select and isolate human anti-RGMa antibodies. For example, a naive human single-chain variable fragment (scFv) library can be used to select human anti-RGMa antibodies. Transgenic animals can be used to express human antibodies.

[0065] A humanized antibody can be an antibody molecule derived from a non-human species antibody that binds to a desired antigen and has one or more complementarity-determining regions (CDRs) from a non-human species and a framework region from a human immunoglobulin molecule.

[0066] The antibody can specifically bind to RGMa. The RGMa-specific RGMa antibody can include SEQ ID NOs: 2-4 and 6-8, SEQ ID NOs: 13-14, or SEQ ID NOs: 2-4, 6-8, and 13-14. The antibody can bind to SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, or a fragment or variant thereof. The antibody can recognize and specifically bind to an epitope present in the RGMa polypeptide or the above variant. The epitope is SEQ ID NO: 18 (full-length human RGMa), SEQ ID NO: 19 (a human RGMa fragment corresponding to amino acids 47-168 of SEQ ID NO: 18), SEQ ID NO: 20 (a human RGMa fragment), or a variant thereof, and their sequences are provided below.

[0067]

Chemical formula

[0068] [Chem.]

[0069] [Chem.]

[0070] (1) Antibody structure (a) Heavy and light chain CDRs The antibody can immunospecifically bind to RGMa (SEQ ID NO: 18), SEQ ID NO: 19, SEQ ID NO: 20, this fragment or this variant, and may include the variable heavy chain and / or variable light chain shown in Table 1. The antibody can immunospecifically bind to RGMa, this fragment, derivative or variant, and may include one or more heavy chain or light chain CDR sequences also shown in Table 1. The light chain of the antibody can be a kappa chain or a lambda chain. For example, see Table 1. The method for producing the antibody shown in Table 1 is described in WO2013 / 112922, the content of which is incorporated herein by reference.

[0071]

Table 1

[0072] The antibody or this variant or derivative may contain one or more amino acid sequences that are more than 95%, more than 90%, more than 85%, more than 80%, more than 75%, more than 70%, more than 65%, more than 60%, more than 55% or more than 50% identical to one or more of SEQ ID NOs: 1-8 or 13-14. The antibody or this variant or derivative may be encoded by one or more nucleic acid sequences that are more than 95%, more than 90%, more than 85%, more than 80%, more than 75%, more than 70%, more than 65%, more than 60%, more than 55% or more than 50% identical to one or more of SEQ ID NOs: 1-8 or 13-14. The identity and homology of polypeptides can be determined, for example, by the algorithm described in the report by Wilbur, W.J. and Lipman, D.J., Proc. Natl. Acad. Sci. USA, Vol. 80, pp. 726-730 (1983).

[0073] The antibody may be of the IgG, IgE, IgM, IgD, IgA and IgY molecular classes (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclasses. For example, the antibody may be an IgG1 molecule having the following constant region sequence.

[0074]

Chemical formula

[0075] The above constant region of SEQ ID NO: 9 contains two (2) mutations of the wild-type constant region sequence at positions 234 and 235. In particular, these mutations are the change from leucine to alanine at positions 234 and 235 respectively (this is referred to as the "LLAA" mutation). These mutations are shown in bold and underlined above. The purpose of these mutations is to eliminate effector function.

[0076] Alternatively, the IgG1 molecule can have the above constant region sequence (SEQ ID NO: 9) containing one or more mutations. For example, the constant region sequence of SEQ ID NO: 9 may contain a mutation at amino acid 250 where threonine is replaced by glutamine (SEQ ID NO: 10), a mutation at amino acid 428 where methionine is replaced by leucine (SEQ ID NO: 11) or a mutation at amino acid 250 where threonine is replaced by glutamine and a mutation at amino acid 428 where methionine is replaced by leucine (SEQ ID NO: 12) as shown in Table 2 below.

[0077]

Table 2

[0078] Alternatively, the IgG1 molecule can contain a heavy chain comprising AE12-1(VH)CDR-H1 (SEQ ID NO: 2), AE12-1(VH)CDR-H2 (SEQ ID NO: 3), AE12-1(VH)CDR-H3 (SEQ ID NO: 4), and a light chain comprising AE12-1(VL)CDR-L1 (SEQ ID NO: 6), AE12-1(VL)CDR-L2 (SEQ ID NO: 7), and AE12-1-Y(VL)CDR-L3 (SEQ ID NO: 8), as well as the constant sequence of SEQ ID NO: 12 (this antibody is designated AE12-1-Y-QL and has the light chain sequence of SEQ ID NO: 13 and the heavy chain sequence of SEQ ID NO: 14).

[0079]

Table 3

[0080] 3. Pharmaceutical Composition The antibody can be a component in a pharmaceutical composition. The pharmaceutical composition can also contain a pharmaceutically acceptable carrier. The pharmaceutical composition containing the antibody described herein is for use in the treatment of multiple sclerosis, particularly relapsing forms of multiple sclerosis such as relapsing-remitting multiple sclerosis and relapsing secondary progressive multiple sclerosis. In certain embodiments, the composition contains one or more antibodies described herein. In another embodiment, the pharmaceutical composition contains one or more antibodies described herein and one or more prophylactic or therapeutic agents other than the antibodies described herein for the treatment of multiple sclerosis, particularly relapsing forms of multiple sclerosis such as relapsing-remitting multiple sclerosis and relapsing secondary progressive multiple sclerosis. In a further embodiment, the prophylactic or therapeutic agent is known to be useful in the prevention, treatment, management, or improvement of multiple sclerosis or one or more of its symptoms and is being used or is currently being used. According to these embodiments, the composition can further contain a carrier, diluent, or excipient.

[0081] The antibodies described herein can be incorporated into pharmaceutical compositions suitable for administration to a subject. Typically, the pharmaceutical composition comprises an antibody described herein (such as AE-12-1-Y-QL for example) and a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coating agents, antibacterial and antifungal agents, isotonic agents and absorption delaying agents, etc. that are physiologically compatible. Examples of pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, etc., and combinations thereof. In many cases, it is preferred to include an isotonic agent, such as a sugar, a polyalcohol such as mannitol, sorbitol, or sodium chloride in the composition. The pharmaceutically acceptable carrier may further include auxiliary substances such as a small amount of wetting or emulsifying agent, preservative or buffer that enhance the shelf life or effectiveness of the antibody.

[0082] In a further embodiment, the pharmaceutical composition comprises at least one additional therapeutic agent for treating multiple sclerosis described herein, particularly relapsing forms of multiple sclerosis (such as relapsing-remitting multiple sclerosis and relapsing secondary progressive multiple sclerosis).

[0083] A variety of delivery systems are known, such as encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing antibodies or antibody fragments, receptor-mediated endocytosis (see, e.g., Wu and Wu, J. Biol. Chem. 262:4429-4432 (1987)), construction of nucleic acids as part of a retroviral vector or other vector, and can be used to administer one or more antibodies described herein, or a combination of prophylactic or therapeutic agents useful for the prevention, management, treatment or amelioration of multiple sclerosis or one or more of its symptoms such as relapsing forms of multiple sclerosis (such as relapsing-remitting multiple sclerosis and relapsing secondary progressive multiple sclerosis). Methods of administering prophylactic or therapeutic agents include, but are not limited to, parenteral administration (e.g., intradermal, intramuscular, intraperitoneal, intravenous, intrathecal and subcutaneous), epidural administration, intratumoral administration and mucosal administration (e.g., intranasal and oral routes). Further, pulmonary administration can be employed, for example, by use of an inhaler or nebulizer, and formulations containing aerosolizing agents. See, for example, U.S. Patent Nos. 6,019,968; 5,985,320; 5,985,309; 5,934,272; 5,874,064; 5,855,913; 5,290,540; and 4,880,078; and PCT Application Publication Nos. WO92 / 19244; WO97 / 32572; WO97 / 44013; WO98 / 31346; and WO99 / 66903. Each of these is hereby incorporated by reference in its entirety. In one embodiment, the antibodies, combination therapies or compositions described herein are administered using the Alkermes AIR® pulmonary drug delivery technology (Alkermes, Inc., Cambridge, Mass.). In certain embodiments, the prophylactic or therapeutic agent of the antibody described herein is administered intramuscularly, intravenously, intratumorally, orally, intranasally, intrapulmonary or subcutaneously.The prophylactic or therapeutic agent may be administered by any convenient route, for example, by infusion or bolus injection, by absorption through the epithelium or the inner membrane of the skin mucosa (e.g., oral mucosa, rectal and intestinal mucosa, etc.), and may be administered together with other biologically active agents. The administration may be systemic or local.

[0084] In certain embodiments, it may be desirable to locally administer the antibodies described herein to the area in need of treatment; this can be accomplished, for example, but not by way of limitation, by local infusion, by injection, or using an implant that is a porous or non-porous material including membranes and matrices such as the sialast membrane, polymers, fibrous matrices (e.g., Tissuel®) or collagen matrices. In one embodiment, an effective amount of one or more of the antibodies described herein is locally administered to the affected area of the subject to prevent, treat, manage and / or ameliorate the disorder or the condition. In another embodiment, an effective amount of the antibody described herein is locally administered to the affected area of the subject in combination with an effective amount of one or more therapeutic agents (e.g., one or more prophylactic or therapeutic agents) other than the antibody described herein to prevent, treat, manage and / or ameliorate the disorder or the one or more conditions.

[0085] In another embodiment, the antibody can be delivered in a release control system or a sustained release system. In one embodiment, a pump can be used to effect release control or sustained release (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng., 14:20; Buchwald et al., 1980, Surgery 88:507; Saudek et al., 1989, N. Engl., J. Med., 321:574). In another embodiment, a polymeric material can be used to effect release control or sustained release of the therapeutic agents described herein (see, e.g., Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, 1983, J. Macromol. Sci. Rev. Macromol. Chem., 23:61. See also Levy et al., 1985, Science, 228:190; During et al., 1989, Ann. Neurol., 25:351; Howard et al., 1989, J. Neurosurg., 71:105); U.S. Patent Nos. 5,679,377; 5,916,597; 5,912,015; 5,989,463; 5,128,326; PCT Publication No. WO99 / 15154; and PCT Publication No. WO99 / 20253).Examples of polymers used in sustained release formulations include, but are not limited to, poly(2-hydroxyethyl methacrylate), poly(methyl methacrylate), poly(acrylic acid), poly(ethylene-co-vinyl acetate), poly(methacrylic acid), polyglycolide (PLG), polyanhydrides, poly(N-vinyl pyrrolidone), poly(vinyl alcohol), polyacrylamide, poly(ethylene glycol), polylactide (PLA), poly(lactide-co-glycolide (PLGA) and polyorthoesters. In certain embodiments, the polymers used in sustained release formulations are inert, free of leachable impurities, stable in storage, sterilized, and biodegradable. In yet another embodiment, the release control system or sustained release system is placed in proximity to the prophylactic or therapeutic target and thus requires only a small systemic dose (see, for example, Goodson, Medical Applications of Controlled Release, supra, Volume 2, pages 115-138 (1984)).

[0086] The release control system is described in a review by Langer (1990, Science, 249:1527-1533). Any technique known to those skilled in the art can be used to manufacture sustained-release formulations containing one or more of the antibodies described herein. See, for example, U.S. Patent No. 4,526,938, PCT Application Publication No. WO91 / 05548, PCT Application Publication No. WO96 / 20698, Ning et al., 1996, "Intratumoral Radioimmunotheraphy of a Human Colon Cancer Xenograft Using a Sustained-Release Gel", Radiotherapy & Oncology, 39:179-189; Song et al., 1995, "Antibody Mediated Lung Targeting of Long-Circulating Emulsions", PDA Journal of Pharmaceutical Science & Technology, 50:372-397; Cleek et al., 1997, "Biodegradable Polymeric Carriers for a bFGF Antibody for Cardiovascular Application", Pro.Int’l.Symp.Control.Rel.Bioact.Mater., 24:853-854; Lam et al., 1997, "Microencapsulation of Recombinant Humanized Monoclonal Antibody for Local Delivery", Proc.Int’l.Symp.Control Rel.Bioact.Mater., 24:759-760. Each is hereby incorporated by reference in its entirety.).

[0087] The pharmaceutical composition is formulated to be compatible with the intended route of administration. Examples of routes of administration include, but are not limited to, parenteral, such as intravenous, intrathecal, intradermal, subcutaneous, oral, intranasal (e.g., inhalation), transdermal (e.g., topical), transmucosal and rectal administration. In certain embodiments, the composition is formulated according to routine procedures as a pharmaceutical composition suitable for intravenous, subcutaneous, intramuscular, oral, intranasal or topical administration to humans. Typically, the composition for intravenous administration is a solution in a sterile isotonic aqueous buffer. Optionally, the composition may also contain solubilizing agents and local anesthetics such as lignocaine to relieve pain at the injection site.

[0088] The methods described herein may include the administration of a composition formulated for parenteral administration by injection (e.g., by bolus injection or continuous infusion). Injectable formulations may be presented in unit dosage form (e.g., in ampoules or in multi-dose containers), together with an added preservative. The composition may take the form of a suspension, solution or emulsion in an oily or aqueous vehicle and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution before use with a suitable vehicle (e.g., sterile pyrogen-free water). The methods described herein may additionally include the administration of a composition formulated as a depot formulation. Such long-acting formulations may be administered by implantation (e.g., subcutaneously, intrathecally or intramuscularly) or by intramuscular injection. Thus, for example, the composition may be formulated using a suitable polymeric material or hydrophobic material (e.g., as an emulsion in a tolerated oil) or an ion exchange resin, or as a poorly soluble derivative (e.g., as a poorly soluble salt).

[0089] The methods described herein include the administration of compositions formulated as the neutral or salt form. Pharmaceutically acceptable salts include salts formed with anions such as those derived from hydrochloric acid, phosphoric acid, acetic acid, oxalic acid, tartaric acid, etc., and salts formed with cations such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxide, isopropylamine, triethylamine, 2-ethylaminoethanol, histidine, procaine, etc.

[0090] Generally, the components of the composition are provided separately or mixed together in unit dosage forms as a lyophilized powder or a water-free concentrate in a sealed container, such as an ampoule or sachette, indicating the amount of the active agent. If the mode of administration is infusion, the composition can be dispensed in an infusion bottle containing pharmaceutical-grade sterilized water or physiological saline. If the mode of administration is by injection, an ampoule of sterile water for injection or physiological saline can be provided so that the components can be mixed before administration.

[0091] In particular, the methods described herein also contemplate that one or more antibodies or pharmaceutical compositions described herein are packaged in a sealed container such as an ampoule or sachet indicating the amount of antibody. In one embodiment, one or more antibodies or pharmaceutical compositions described herein are provided in a sealed container as a lyophilized powder that has been dry sterilized or as a concentrate that does not contain water and can be reconstituted to an appropriate concentration for administration to a subject (e.g., using water or saline). In one embodiment, one or more antibodies or pharmaceutical compositions described herein are provided as a dry sterilized lyophilized powder in a sealed container in unit doses of at least 5 mg, such as at least 10 mg, at least 15 mg, at least 25 mg, at least 35 mg, at least 45 mg, at least 50 mg, at least 75 mg or at least 100 mg. The lyophilized antibodies or pharmaceutical compositions described herein need to be stored in this original container between 2°C and 8°C, and the antibodies or pharmaceutical compositions described herein need to be administered within one week, such as within 5 days, within 72 hours, within 48 hours, within 24 hours, within 12 hours, within 6 hours, within 5 hours, within 3 hours or within 1 hour after reconstitution. In an alternative embodiment, one or more antibodies or pharmaceutical compositions described herein are provided in a liquid dosage form in a sealed container indicating the amount and concentration of the antibody. In a further embodiment, the liquid dosage form of the administered composition is provided in a sealed container at at least 0.25 mg / ml, such as at least 0.5 mg / ml, at least 1 mg / ml, at least 2.5 mg / ml, at least 5 mg / ml, at least 8 mg / ml, at least 10 mg / ml, at least 15 mg / ml, at least 25 mg / ml, at least 50 mg / ml, at least 75 mg / ml or at least 100 mg / ml. The liquid dosage form needs to be stored in this original container between 2°C and 8°C.

[0092] The antibodies described herein can be incorporated into pharmaceutical compositions suitable for parenteral administration. In one aspect, the antibody is prepared as an injection solution containing 0.1 - 500 mg / ml antibody. The injection solution can be constituted in either a liquid or lyophilized dosage form in a flint or amber vial, ampule or prefilled syringe. The buffer can be L - histidine (1 - 50 mM), optimally 5 - 10 mM, at pH 5.0 - 7.0 (optimally pH 6.0). Other suitable buffers include, but are not limited to, sodium succinate, sodium citrate, sodium phosphate or potassium phosphate. Sodium chloride can be used at a concentration of 0 - 300 mM (optimally 150 mM for liquid dosage forms) to adjust the tonicity of the solution. Antifreeze agents, mainly 0 - 10% sucrose (optimally 0.5 - 1.0%), can be included for lyophilized dosage forms. Other suitable antifreeze agents include trehalose and lactose. Filling agents, mainly 1 - 10% mannitol (optimally 2 - 4%), can be included for lyophilized dosage forms. Stabilizers, mainly 1 - 50 mM L - methionine (optimally 5 - 10 mM), can be used in both liquid and lyophilized dosage forms. Other suitable filling agents include glycine, arginine and can be included as 0 - 0.05% polysorbate - 80 (optimally 0.005 - 0.01%). Additional surfactants include, but are not limited to, polysorbate 20 and BRIJ surfactants. The pharmaceutical composition containing the antibodies described herein, prepared as an injection solution for parenteral administration, can further contain an agent useful as an adjuvant, such as those used to increase the absorption or dispersion of the antibody. A particularly useful adjuvant is hyaluronidase such as Hylenex® (recombinant human hyaluronidase). The addition of hyaluronidase in the injection solution improves the bioavailability after parenteral administration, particularly subcutaneous administration. Also, it is possible to make the injection site volume larger (i.e., greater than 1 ml) with less pain and discomfort, and a minimal incidence of injection site reactions. (See International Application Publication No. WO04 / 078140 and U.S. Patent Application Publication No. 2006 / 104968, which are incorporated herein by reference.))。

[0093] The compositions described herein can be in various forms. These include, for example, liquid solutions (e.g., injectable and infusible solutions), dispersants or suspensions, tablets, pills, powders, liposomes, and liquid, semi-solid and solid dosage forms such as suppositories. The preferred form depends on the intended mode of administration and therapeutic application. The composition can be in the form of an injectable or infusible solution, similar to those used for human passive immunization, together with other antibodies. In one embodiment, the antibody can be administered by intravenous infusion or injection. In another embodiment, the antibody is administered by intramuscular or subcutaneous injection.

[0094] Therapeutic compositions typically need to be sterile and stable under manufacturing and storage conditions. The composition can be formulated as a solution, microemulsion, dispersant, liposome, or other regular structure suitable for high drug concentrations. Sterile injectable solutions can be prepared by incorporating the active compound (i.e., the binding protein, e.g., the antibodies described herein) in the required amounts, together with one or a combination of the ingredients listed above, in a suitable solvent, and subsequently, if necessary, by filtration sterilization. Generally, dispersants are prepared by incorporating the active compound in a sterile vehicle containing a basic dispersion medium and the other necessary ingredients from those listed above. In the case of a sterile powder that has been sterilized and lyophilized to prepare a sterile injectable solution, the preparation method includes vacuum drying and spray drying that yield a powder of the active ingredient to which any additional desired ingredients have been added from its previously sterile filtered solution. The appropriate fluidity of the solution can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersants, and by the use of surfactants. Sustained absorption of injectable compositions can be brought about by including in the composition agents that delay absorption, such as monostearates and gelatin.

[0095] The antibodies described herein can be administered by a variety of methods known in the art. For example, the route / mode of administration can be subcutaneous injection, intravenous injection or infusion. As will be appreciated by those skilled in the art, the route and / or mode of administration will vary depending on the desired result. In certain embodiments, the active compound can be prepared using a carrier that protects the compound against rapid release, such as a controlled release formulation including implants, transdermal patches and microencapsulated delivery systems. Biodegradable biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid can be used. Numerous methods for preparing such formulations are patented or generally known to those skilled in the art. See, for example, Sustained and Controlled Release Drug Delivery Systems, edited by J.R. Robinson, Marcel Dekker, Inc., New York, 1978.

[0096] In certain embodiments, the antibodies described herein can be administered orally, for example, using an inert diluent or an absorbable edible carrier. The antibody (and, optionally, other components) can also be enclosed in a hard or soft shell gelatin capsule, compressed into tablets or incorporated directly into the subject's diet. For oral therapeutic administration, the antibody can be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc. In order to administer the antibodies described herein by means other than parenteral administration, it may be necessary to coat the antibody with a substance to prevent inactivation, or co-administer this with the antibody.

[0097] The supplementary active compounds can also be incorporated into the composition. In certain embodiments, the antibodies described herein are formulated and / or co-administered with one or more additional therapeutic agents useful for the treatment of the disorders or diseases described herein. For example, the anti-RGMa antibodies described herein can be formulated and / or co-administered with one or more additional antibodies that bind to other targets (e.g., antibodies that bind to other soluble antigens or cell surface molecules). Furthermore, one or more of the antibodies described herein can be used in combination with two or more of the above therapeutic agents. Such combination therapies can advantageously utilize lower dosages of the administered therapeutic agents and thus avoid the toxicities or complications that may be associated with various monotherapies.

[0098] In certain embodiments, the antibodies described herein are conjugated to half-life extending vehicles known in the art. Such vehicles include, but are not limited to, the Fc domain, polyethylene glycol, and dextran. Such vehicles are described, for example, in U.S. patent application Ser. No. 09 / 428,082 and published PCT application WO99 / 25044. These are incorporated herein by reference for any purpose.

[0099] The antibodies described herein can be used alone or in combination with one or more additional agents, such as therapeutic agents (e.g., small molecules or biological agents), and the additional agents are selected by those skilled in the art for the intended purpose. For example, the additional therapeutic agent can be an immunosuppressive agent or an agent that treats one or more symptoms associated with multiple sclerosis. The additional agent can be alpha or beta interferon. Alpha or beta interferons such as Avonex, Betaseron, Extavia, and Rebif may slow the rate at which the symptoms of multiple sclerosis worsen over time. The additional agent can be a corticosteroid such as methylprednisolone (Solu-Medrol) or prednisone (Delta-Cortef). The additional agent can be glatiramer (Copaxone) which can block the immune system's attack on myelin. The additional agent can be fingolimod (Gilenya) which can capture immune cells in lymph nodes. The additional agent can be natalizumab (Tysabri) which can interfere with the movement of potentially harmful immune cells from the bloodstream to the brain and spinal cord. The additional agent can be mitoxantrone (Novantrone), an immunosuppressive agent. The additional agent can be teriflunomide (Aubagio). The additional agent can be BG-12 (Tecfidera). The additional agent can be alemtuzumab (Lemtrada). The additional agent can be daclizumab (Zinbryta), an interleukin-2 receptor blocking antibody. The additional agent can be ocrelizumab (Ocrevus), an anti-CD20 antibody. The additional agent can be amantadine (Symmetrel). The additional agent can be amitriptyline (Elavil). The additional agent can be nortriptyline, modafinil (Provigil). The additional agent can be dalfampridine (Ampyra).

[0100] The additional therapeutic agent can be a "cognitive enhancer", which is a drug that improves disorders of human cognitive abilities in the brain (i.e., thinking, learning, and memory). Cognitive enhancers act by altering the availability of neurochemical substances (e.g., neurotransmitters, enzymes, and hormones), improving oxygen supply, stimulating nerve growth, or inhibiting nerve damage. Examples of cognitive enhancers include compounds that increase the activity of acetylcholine, including, but not limited to, acetylcholine receptor agonists (e.g., nicotinic α-7 receptor agonists or allosteric modulators, α4β2 nicotinic receptor agonists or allosteric modulators), acetylcholinesterase inhibitors (e.g., donepezil, rivastigmine, and galantamine), butyrylcholinesterase inhibitors, N-methyl-D-aspartic acid (NMDA) receptor antagonists (e.g., memantine), activity-dependent neuroprotective protein (ADNP) agonists, serotonin 5-HT1A receptor agonists (e.g., xaliproden), 5-HT4 receptor agonists, 5-HT6 receptor antagonists, serotonin 1A receptor antagonists, histamine H3 receptor antagonists, calpain inhibitors, vascular endothelial growth factor (VEGF) protein or agonists, trophic growth factors, anti-apoptotic compounds, AMPA-type glutamate receptor activators, L-type or N-type calcium channel blockers or modulators, potassium channel blockers, hypoxia-inducible factor (HIF) activators, HIF prolyl 4-hydroxylase inhibitors, anti-inflammatory drugs, inhibitors of amyloid Aβ peptide or amyloid plaques, inhibitors of tau hyperphosphorylation, phosphodiesterase 5 inhibitors (e.g., tadalafil, sildenafil), phosphodiesterase 4 inhibitors, monoamine oxidase inhibitors, or pharmaceutically acceptable salts of these medications. Specific examples of such cognitive enhancers include, but are not limited to, cholinesterase inhibitors such as donepezil (Aricept®), rivastigmine (Exelon®), galantamine (Reminyl®), and N-methyl-D-aspartic acid antagonists such as memantine (Namenda®).At least one cognitive enhancer can be administered simultaneously with, or sequentially (in any order) with, the antibodies described herein, and includes agents currently recognized or recognized in the future as being useful for treating a disease or condition treated by the antibodies described herein. Further, the combinations described herein are considered to have additive or synergistic effects when used in the above treatment. The additional agent can also be an agent that imparts beneficial properties to the therapeutic composition, such as an agent that affects the viscosity of the composition.

[0101] It should be further understood that the combinations are combinations useful for their intended purposes. The above agents are for illustrative purposes and are not intended to be limiting. The combination can include an antibody and at least one additional agent selected from the following list. The combination can also include more than one additional agent, such as two or three additional agents, as long as the resulting composition can perform its intended function.

[0102] The pharmaceutical composition can include an antibody in a "therapeutically effective amount" or "prophylactically effective amount". "Therapeutically effective amount" refers to an effective amount at a dosage and for a period required to achieve a desired therapeutic result. The therapeutically effective amount of an antibody can be determined by one of ordinary skill in the art and can vary depending on factors such as the individual's disease state, age, gender and weight, as well as the ability of the antibody to elicit a desired response in the individual. The therapeutically effective amount is also such that, if there are any toxic or adverse effects of the antibody, these are outweighed by the therapeutically beneficial effects. In certain embodiments, the therapeutically effective amount is an amount that neutralizes RGMa. In certain embodiments, the therapeutically effective amount is an amount that reduces the inhibitory effect of RGMa in nerve regeneration. "Prophylactically effective amount" refers to an effective amount at a dosage and for a period required to achieve a desired prophylactic result. Typically, since prophylactic dosages are used in a subject before or at the initial stage of a disease, the prophylactically effective amount is less than the therapeutically effective amount.

[0103] For therapeutic purposes, the antibody is administered to a patient in a therapeutically effective amount in a pharmaceutically acceptable carrier. In certain embodiments, a "therapeutically effective amount" is physiologically significant. An antibody is physiologically significant if its presence results in a detectable change in the physiology of the recipient patient. In this context, an antibody may be physiologically significant if its presence, for example, decreases the secretion of interferon-γ (INF-γ), interleukin-2 (IL-2), IL-4 and / or IL-17 from CD4+ T cells. A drug is physiologically significant if its presence results in, for example, a decrease in the proliferative response in peripheral blood mononuclear cells (PBMC) and / or the expression of pro-inflammatory cytokines. In certain embodiments, the amount of anti-RGMa antibody is physiologically significant if it results in a decrease in the level of free RGMa, such as a decrease in the free RGMa level in CSF.

[0104] The dosage regimen may be adjusted to provide the optimal desired response (e.g., a therapeutic or prophylactic response). For example, a single bolus may be administered, several divided doses may be administered over time, or the dosage may be proportionally decreased or increased as indicated by the exigencies of the therapeutic situation. For ease of administration and uniformity of dosage, it is particularly advantageous to formulate parenteral compositions in dosage unit form. As used herein, a dosage unit form refers to physically discrete units suitable as unitary dosages for the mammalian subject to be treated; each unit contains a predetermined quantity of the active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specifications for the dosage unit forms are determined by and directly dependent on (a) the particular properties of the active compound and the specific therapeutic or prophylactic effect to be achieved and (b) the limitations inherent in the art of compounding such active compounds for the treatment of sensitivity in individuals.

[0105] 4. Methods of treating, preventing, modulating or reducing relapsing multiple sclerosis a. Relapsing-remitting multiple sclerosis (RRMS) In a patient diagnosed with multiple sclerosis, it is possible to evaluate whether the subject has relapsing-remitting multiple sclerosis. The evaluation may indicate an appropriate treatment course such as preventive therapy, maintenance therapy or modulating therapy. Thus, provided herein is a method of treating, preventing, modulating or alleviating relapsing-remitting multiple sclerosis by administering to a patient in need thereof a therapeutically effective amount of one or more antibodies (such as antibody AE12-1-Y-QL) described herein.

[0106] In one embodiment, a fixed dose of one or more of the antibodies described herein can be administered to a subject. Exemplary and non-limiting ranges of a therapeutically effective amount or a prophylactically effective amount of an antibody or antibody portion described herein are from about 50 mg to about 4000 mg, from about 50 mg to about 3900 mg, from about 50 mg to about 3800 mg, from about 50 mg to about 3700 mg, from about 50 mg to about 3600 mg, from about 50 mg to about 3500 mg, from about 50 mg to about 3400 mg, from about 50 mg to about 3300 mg, from about 50 mg to about 3200 mg, from about 50 mg to about 3100 mg, from about 50 mg to about 3000 mg, from about 50 mg to about 2900 mg, from about 50 mg to about 2800 mg, from about 50 mg to about 2700 mg, from about 50 mg to about 2600 mg, from about 50 mg to about 2500 mg, from about 50 mg to about 2400 mg, from about 50 mg to about 2300 mg, from about 50 mg to about 2200 mg, from about 50 mg to about 2100 mg, from about 50 mg to about 2000 mg, from about 50 mg to about 1900 mg, from about 50 mg to about 1800 mg, from about 50 mg to about 1700 mg, from about 50 mg to about 1600 mg, from about 50 mg to about 1500 mg, from about 50 mg to about 1400 mg, from about 50 mg to about 1300 mg, from about 50 mg to about 1200 mg, from about 50 mg to about 1100 mg, from about 50 mg to about 1000 mg, from about 50 mg to about 900 mg, from about 50 mg to about 800 mg, from about 50 mg to about 700 mg, from about 50 mg to about 600 mg, from about 50 mg to about 500 mg, from about 50 mg to about 400 mg, from about 50 mg to about 300 mg, from about 100 mg to about 4000 mg, from about 100 mg to about 3900 mg, from about 100 mg to about 3800 mg, from about 100 mg to about 3700 mg, from about 100 mg to about 3600 mg, from about 100 mg to about 3500 mg, from about 100 mg to about 3400 mg, from about 100 mg to about 3300 mg, from about 100 mg to about 3200 mg, from about 100 mg to about 3100 mg, from about 100 mg to about 3000 mg, from about 100 mg to about 2900 mg, from about 100 mg to about 2800 mg, from about 100 mg to about 2700 mg, from about 100 mg to about 2600 mg, from about 100 mg to about 2500 mg, from about 100 mg to about 2400 mg, from about 100 mg to about 2300 mg, from about 100 mg to about 2200 mg, from about 100 mg to about 2100 mg, from about 100 mg to about 2000 mg,From about 100 mg to about 1900 mg, from about 100 mg to about 1800 mg, from about 100 mg to about 1700 mg, from about 100 mg to about 1600 mg, from about 100 mg to about 1500 mg, from about 100 mg to about 1400 mg, from about 100 mg to about 1300 mg, from about 100 mg to about 1200 mg, from about 100 mg to about 1100 mg, from about 100 mg to about 1000 mg, from about 100 mg to about 900 mg, from about 100 mg to about 800 mg, from about 100 mg to about 700 mg, from about 100 mg to about 600 mg, from about 100 mg to about 500 mg, from about 100 mg to about 400 mg, from about 100 mg to about 300 mg, from about 150 mg to about 4000 mg, from about 150 mg to about 3900 mg, from about 150 mg to about 3800 mg, from about 150 mg to about 3700 mg, from about 150 mg to about 3600 mg, from about 150 mg to about 3500 mg, from about 150 mg to about 3400 mg, from about 150 mg to about 3300 mg, from about 150 mg to about 3200 mg, from about 150 mg to about 3100 mg, from about 150 mg to about 3000 mg, from about 150 mg to about 2900 mg, from about 150 mg to about 2800 mg, from about 150 mg to about 2700 mg, from about 150 mg to about 2600 mg, from about 150 mg to about 2500 mg, from about 150 mg to about 2400 mg, from about 150 mg to about 2300 mg, from about 150 mg to about 2200 mg, from about 150 mg to about 2100 mg, from about 150 mg to about 2000 mg, from about 150 mg to about 1900 mg, from about 150 mg to about 1800 mg, from about 150 mg to about 1700 mg, from about 150 mg to about 1600 mg, from about 150 mg to about 1500 mg, from about 150 mg to about 1400 mg, from about 150 mg to about 1300 mg, from about 150 mg to about 1200 mg, from about 150 mg to about 1100 mg, from about 150 mg to about 1000 mg, from about 150 mg to about 900 mg, from about 150 mg to about 800 mg, from about 150 mg to about 700 mg, from about 150 mg to about 600 mg, from about 150 mg to about 500 mg, from about 150 mg to about 400 mg, from about 150 mg to about 300 mg, from about 200 mg to about 4000 mg, from about 200 mg to about 3900 mg, from about 200 mg to about 3800 mg, from about 200 mg to about 3700 mg, from about 200 mg to about 3600 mg, from about 200 mg to about 3500 mg, from about 200 mg to about 3400 mg, from about 200 mg to about 3300 mgFrom about 200 mg to about 3200 mg, from about 200 mg to about 3100 mg, from about 200 mg to about 3000 mg, from about 200 mg to about 2900 mg, from about 200 mg to about 2800 mg, from about 200 mg to about 2700 mg, from about 200 mg to about 2600 mg, from about 200 mg to about 2500 mg, from about 200 mg to about 2400 mg, from about 200 mg to about 2300 mg, from about 200 mg to about 2200 mg, from about 200 mg to about 2100 mg, from about 200 mg to about 2000 mg, from about 200 mg to about 1900 mg, from about 200 mg to about 1800 mg, from about 200 mg to about 1700 mg, from about 200 mg to about 1600 mg, from about 200 mg to about 1500 mg, from about 200 mg to about 1400 mg, from about 200 mg to about 1300 mg, from about 200 mg to about 1200 mg, from about 200 mg to about 1100 mg, from about 200 mg to about 1000 mg, from about 200 mg to about 900 mg, from about 200 mg to about 800 mg, from about 200 mg to about 700 mg, from about 200 mg to about 600 mg, from about 200 mg to about 500 mg, from about 200 mg to about 400 mg, from about 200 mg to about 300 mg, from about 250 mg to about 4000 mg, from about 250 mg to about 3900 mg, from about 250 mg to about 3800 mg, from about 250 mg to about 3700 mg, from about 250 mg to about 3600 mg, from about 250 mg to about 3500 mg, from about 250 mg to about 3400 mg, from about 250 mg to about 3300 mg, from about 250 mg to about 3200 mg, from about 250 mg to about 3100 mg, from about 250 mg to about 3000 mg, from about 250 mg to about 2900 mg, from about 250 mg to about 2800 mg, from about 250 mg to about 2700 mg, from about 250 mg to about 2600 mg, from about 250 mg to about 2500 mg, from about 250 mg to about 2400 mg, from about 250 mg to about 2300 mg, from about 250 mg to about 2200 mg, from about 250 mg to about 2100 mg, from about 250 mg to about 2000 mg, from about 250 mg to about 1900 mg, from about 250 mg to about 1800 mg, from about 250 mg to about 1700 mg, from about 250 mg to about 1600 mg, from about 250 mg to about 1500 mg, from about 250 mg to about 1400 mg, from about 250 mg to about 1300 mg, from about 250 mg to about 1200 mg, from about 250 mg to about 1100 mg, from about 250 mg to about 1000 mg, from about 250 mg to about 900 mg, from about 250 mg to about 800 mgfrom about 250 mg to about 700 mg, from about 250 mg to about 600 mg, from about 250 mg to about 500 mg, from about 250 mg to about 400 mg, from about 250 mg to about 300 mg, from about 300 mg to about 4000 mg, from about 300 mg to about 3900 mg, from about 300 mg to about 3800 mg, from about 300 mg to about 3700 mg, from about 300 mg to about 3600 mg, from about 300 mg to about 3500 mg, from about 300 mg to about 3400 mg, from about 300 mg to about 3300 mg, from about 300 mg to about 3200 mg, from about 300 mg to about 3100 mg, from about 300 mg to about 3000 mg, from about 300 mg to about 2900 mg, from about 300 mg to about 2800 mg, from about 300 mg to about 2700 mg, from about 300 mg to about 2600 mg, from about 300 mg to about 2500 mg, from about 300 mg to about 2400 mg, from about 300 mg to about 2300 mg, from about 300 mg to about 2200 mg, from about 300 mg to about 2100 mg, from about 300 mg to about 2000 mg, from about 300 mg to about 1900 mg, from about 300 mg to about 1800 mg, from about 300 mg to about 1700 mg, from about 300 mg to about 1600 mg, from about 300 mg to about 1500 mg, from about 300 mg to about 1400 mg, from about 300 mg to about 1300 mg, from about 300 mg to about 1200 mg, from about 300 mg to about 1100 mg, from about 300 mg to about 1000 mg, from about 300 mg to about 900 mg, from about 300 mg to about 800 mg, from about 300 mg to about 700 mg, from about 300 mg to about 600 mg, from about 300 mg to about 500 mg, from about 300 mg to about 400 mg, from about 350 mg to about 4000 mg, from about 350 mg to about 3900 mg, from about 350 mg to about 3800 mg, from about 350 mg to about 3700 mg, from about 350 mg to about 3600 mg, from about 350 mg to about 3500 mg, from about 350 mg to about 3400 mg, from about 350 mg to about 3300 mg, from about 350 mg to about 3200 mg, from about 350 mg to about 3100 mg, from about 350 mg to about 3000 mg, from about 350 mg to about 2900 mg, from about 350 mg to about 2800 mg, from about 350 mg to about 2700 mg, from about 350 mg to about 2600 mg, from about 350 mg to about 2500 mg, from about 350 mg to about 2400 mg, from about 350 mg to about 2300 mg, from about 350 mg to about 2200 mg, from about 350 mg to about 2100 mg, from about 350 mg to about 2000 mg,From about 350 mg to about 1900 mg, from about 350 mg to about 1800 mg, from about 350 mg to about 1700 mg, from about 350 mg to about 1600 mg, from about 350 mg to about 1500 mg, from about 350 mg to about 1400 mg, from about 350 mg to about 1300 mg, from about 350 mg to about 1200 mg, from about 350 mg to about 1100 mg, from about 350 mg to about 1000 mg, from about 350 mg to about 900 mg, from about 350 mg to about 800 mg, from about 350 mg to about 700 mg, from about 350 mg to about 600 mg, from about 350 mg to about 500 mg, from about 350 mg to about 400 mg, from about 400 mg to about 4000 mg, from about 400 mg to about 3900 mg, from about 400 mg to about 3800 mg, from about 400 mg to about 3700 mg, from about 400 mg to about 3600 mg, from about 400 mg to about 3500 mg, from about 400 mg to about 3400 mg, from about 400 mg to about 3300 mg, from about 400 mg to about 3200 mg, from about 400 mg to about 3100 mg, from about 400 mg to about 3000 mg, from about 400 mg to about 2900 mg, from about 400 mg to about 2800 mg, from about 400 mg to about 2700 mg, from about 400 mg to about 2600 mg, from about 400 mg to about 2500 mg, from about 400 mg to about 2400 mg, from about 400 mg to about 2300 mg, from about 400 mg to about 2200 mg, from about 400 mg to about 2100 mg, from about 400 mg to about 2000 mg, from about 400 mg to about 1900 mg, from about 400 mg to about 1800 mg, from about 400 mg to about 1700 mg, from about 400 mg to about 1600 mg, from about 400 mg to about 1500 mg, from about 400 mg to about 1400 mg, from about 400 mg to about 1300 mg, from about 400 mg to about 1200 mg, from about 400 mg to about 1100 mg, from about 400 mg to about 1000 mg, from about 400 mg to about 900 mg, from about 400 mg to about 800 mg, from about 400 mg to about 700 mg, from about 400 mg to about 600 mg, from about 400 mg to about 500 mg, from about 450 mg to about 4000 mg, from about 450 mg to about 3900 mg, from about 450 mg to about 3800 mg, from about 450 mg to about 3700 mg, from about 450 mg to about 3600 mg, from about 450 mg to about 3500 mg, from about 450 mg to about 3400 mg, from about 450 mg to about 3300 mg, from about 450 mg to about 3200 mg, from about 450 mg to about 3100 mg, from about 450 mg to about 3000 mgFrom about 450 mg to about 2900 mg, from about 450 mg to about 2800 mg, from about 450 mg to about 2700 mg, from about 450 mg to about 2600 mg, from about 450 mg to about 2500 mg, from about 450 mg to about 2400 mg, from about 450 mg to about 2300 mg, from about 450 mg to about 2200 mg, from about 450 mg to about 2, 100 mg, from about 450 mg to about 2000 mg, from about 450 mg to about 1900 mg, from about 450 mg to about 1800 mg, from about 450 mg to about 1700 mg, from about 450 mg to about 1600 mg, from about 450 mg to about 1500 mg, from about 450 mg to about 1400 mg, from about 450 mg to about 1300 mg, from about 450 mg to about 1200 mg, from about 450 mg to about 1100 mg, from about 450 mg to about 1000 mg, from about 450 mg to about 900 mg, from about 450 mg to about 800 mg, from about 450 mg to about 700 mg, from about 450 mg to about 600 mg or from about 450 mg to about 500 mg.

[0107] Specifically, the targets are 50mg, 75mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1000mg, 1025mg, 1050mg, 1075mg, 1100mg, 1125mg, 1150mg, 1175mg, 1200mg, 1225mg, 1250mg, 1275mg, 1300mg, 1325mg, 1350mg, 1375mg, 1400mg, 1425mg, 1450mg, 1475mg, 1500mg, 1525mg, 1550mg, 1575mg, 1600mg, 1625mg, 1650mg, 1675mg, 1700mg, 1725mg, 1750mg, 1775mg, 1800mg, 1825mg, 1850mg, 1875mg, 1900mg, 1925mg, 1950mg, 1975mg, 2000mg, 2025mg, 2050mg, 2075mg, 2100mg, 2125mg, 2150mg, 2175mg, 2200mg, 2225mg, 2250mg, 2275mg, 2300mg, 2325mg, 2350mg, 2375mg, 2400mg, 2425mg, 2450mg, 2475mg, 2500mg, 2525mg, 2550mg, 2575mg, 2600mg, 2625mg, 2650mg, 2675mg, 2700mg, 2725mg, 2750mg, 2775mg, 2800mg, 2825mg, 2850mg, 2875mg, 2900mg, 2925mg, 2950mg, 2975mg, 3000mg, 3025mg, 3050mg, 3075mg, 3100mg, 3125mg, 3150mg, 3175mg, 3200mg, 3225mg, 3250mg, 3275mg, 3300mg, 3325mg, 3350mg, 3375mg, 3400mg, 3425mg, 3450mg, 3475mg, 3500mg, 3525mg, 3550mg, 3575mg, 3600mg, 3625mg, 3650mg, 3675mg, 3700mg, 3725mg,It may be administered at 3750 mg, 3775 mg, 3800 mg, 3825 mg, 3850 mg, 3875 mg, 3900 mg, 3925 mg, 3950 mg, 3975 mg, or 4000 mg.

[0108] The dosage of the antibody or antibody portion described herein may be administered once a week, once every other week, once every two weeks, once every three weeks, once every four weeks, once a month, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every two months, once every nine weeks, once every ten weeks, once every eleven weeks, or once every twelve weeks, depending on the needs of the individual and the professional judgment of the person administering the composition or directing the administration of the composition. The dosage ranges described herein are merely exemplary and are not intended to limit the scope or practice of the claimed composition.

[0109] In one embodiment, a fixed dosage of one or more of the antibodies described herein may be administered to a subject. Exemplary and non-limiting amounts of the antibody or antibody portion described herein that are therapeutically or prophylactically effective include up to about 200 mg / kg, up to about 190 mg / kg, up to about 180 mg / kg, up to about 170 mg / kg, up to about 160 mg / kg, up to about 150 mg / kg, up to about 140 mg / kg, up to about 130 mg / kg, up to about 120 mg / kg, up to about 110 mg / kg, up to about 100 mg / kg, up to about 90 mg / kg, up to about 80 mg / kg, up to about 70 mg / kg, up to about 60 mg / kg, up to about 50 mg / kg, up to about 40 mg / kg, up to about 30 mg / kg, up to about 20 mg / kg, up to about 10 mg / kg, up to about 5 mg / kg, or up to about 2.5 mg / kg.

[0110] Administration of the antibody to the patient can be intravenous, intra-arterial, intraperitoneal, intramuscular, subcutaneous, intrathoracic, intrathecal, intraocular, intravitreal, perfusion by local catheter or direct intralesional injection. When administering a therapeutic protein by injection, the administration can be by continuous infusion or by single or multiple boluses. Intravenous injection provides a useful mode of administration due to thorough circulation in the rapidly distributing antibody. The antibody can be administered orally, for example, with an inert diluent or assimilable edible carrier. Optionally, the antibody and other components can be enclosed in hard or soft shell gelatin capsules and compressed into tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc.

[0111] In one embodiment, when one or more of the antibodies described herein are administered intravenously to a patient as a fixed dose, the therapeutically effective amount or prophylactically effective amount of the antibody or antibody portion that can be administered is from about 50 mg to 4000 mg, from about 50 mg to about 3900 mg, from about 50 mg to about 3800 mg, from about 50 mg to about 3700 mg, from about 50 mg to about 3600 mg, from about 50 mg to about 3500 mg, from about 50 mg to about 3400 mg, from about 50 mg to about 3300 mg, from about 50 mg to about 3200 mg, from about 50 mg to about 3100 mg, from about 50 mg to about 3000 mg, from about 50 mg to about 2900 mg, from about 50 mg to about 2800 mg, from about 50 mg to about 2700 mg, from about 50 mg to about 2600 mg, from about 50 mg to about 2500 mg, from about 50 mg to about 2400 mg, from about 50 mg to about 2300 mg, from about 50 mg to about 2200 mg, from about 50 mg to about 2100 mg, from about 50 mg to about 2000 mg, from about 50 mg to about 1900 mg, from about 50 mg to about 1800 mg, from about 50 mg to about 1700 mg, from about 50 mg to about 1600 mg, from about 50 mg to about 1500 mg, from about 50 mg to about 1400 mg, from about 50 mg to about 1300 mg, from about 50 mg to about 1200 mg, from about 50 mg to about 1100 mg, from about 50 mg to about 1000 mg, from about 50 mg to about 900 mg, from about 50 mg to about 800 mg, from about 50 mg to about 700 mg, from about 50 mg to about 600 mg, from about 50 mg to about 500 mg, from about 50 mg to about 400 mg, from about 50 mg to about 300 mg, from about 100 mg to about 4000 mg, from about 100 mg to about 3900 mg, from about 100 mg to about 3800 mg, from about 100 mg to about 3700 mg, from about 100 mg to about 3600 mg, from about 100 mg to about 3500 mg, from about 100 mg to about 3400 mg, from about 100 mg to about 3300 mg, from about 100 mg to about 3200 mg, from about 100 mg to about 3100 mg, from about 100 mg to about 3000 mg, from about 100 mg to about 2900 mg, from about 100 mg to about 2800 mg, from about 100 mg to about 2700 mg, from about 100 mg to about 2600 mg, from about 100 mg to about 2500 mg, from about 100 mg to about 2400 mg, from about 100 mg to about 2300 mg, from about 100 mg to about 2200 mg, from about 100 mg to about 2100 mg, from about 100 mg to about 2000 mg, from about 100 mg to about 1900 mg,From about 100 mg to about 1800 mg, from about 100 mg to about 1700 mg, from about 100 mg to about 1600 mg, from about 100 mg to about 1500 mg, from about 100 mg to about 1400 mg, from about 100 mg to about 1300 mg, from about 100 mg to about 1200 mg, from about 100 mg to about 1100 mg, from about 100 mg to about 1000 mg, from about 100 mg to about 900 mg, from about 100 mg to about 800 mg, from about 100 mg to about 700 mg, from about 100 mg to about 600 mg, from about 100 mg to about 500 mg, from about 100 mg to about 400 mg, from about 100 mg to about 300 mg, from about 150 mg to about 4000 mg, from about 150 mg to about 3900 mg, from about 150 mg to about 3800 mg, from about 150 mg to about 3700 mg, from about 150 mg to about 3600 mg, from about 150 mg to about 3500 mg, from about 150 mg to about 3400 mg, from about 150 mg to about 3300 mg, from about 150 mg to about 3200 mg, from about 150 mg to about 3100 mg, from about 150 mg to about 3000 mg, from about 150 mg to about 2900 mg, from about 150 mg to about 2800 mg, from about 150 mg to about 2700 mg, from about 150 mg to about 2600 mg, from about 150 mg to about 2500 mg, from about 150 mg to about 2400 mg, from about 150 mg to about 2300 mg, from about 150 mg to about 2200 mg, from about 150 mg to about 2100 mg, from about 150 mg to about 2000 mg, from about 150 mg to about 1900 mg, from about 150 mg to about 1800 mg, from about 150 mg to about 1700 mg, from about 150 mg to about 1600 mg, from about 150 mg to about 1500 mg, from about 150 mg to about 1400 mg, from about 150 mg to about 1300 mg, from about 150 mg to about 1200 mg, from about 150 mg to about 1100 mg, from about 150 mg to about 1000 mg, from about 150 mg to about 900 mg, from about 150 mg to about 800 mg, from about 150 mg to about 700 mg, from about 150 mg to about 600 mg, from about 150 mg to about 500 mg, from about 150 mg to about 400 mg, from about 150 mg to about 300 mg, from about 200 mg to about 4000 mg, from about 200 mg to about 3900 mg, from about 200 mg to about 3800 mg, from about 200 mg to about 3700 mg, from about 200 mg to about 3600 mg, from about 200 mg to about 3500 mg, from about 200 mg to about 3400 mg, from about 200 mg to about 3300 mg, from about 200 mg to about 3200 mgFrom about 200 mg to about 3100 mg, from about 200 mg to about 3000 mg, from about 200 mg to about 2900 mg, from about 200 mg to about 2800 mg, from about 200 mg to about 2700 mg, from about 200 mg to about 2600 mg, from about 200 mg to about 2500 mg, from about 200 mg to about 2400 mg, from about 200 mg to about 2300 mg, from about 200 mg to about 2200 mg, from about 200 mg to about 2100 mg, from about 200 mg to about 2000 mg, from about 200 mg to about 1900 mg, from about 200 mg to about 1800 mg, from about 200 mg to about 1700 mg, from about 200 mg to about 1600 mg, from about 200 mg to about 1500 mg, from about 200 mg to about 1400 mg, from about 200 mg to about 1300 mg, from about 200 mg to about 1200 mg, from about 200 mg to about 1100 mg, from about 200 mg to about 1000 mg, from about 200 mg to about 900 mg, from about 200 mg to about 800 mg, from about 200 mg to about 700 mg, from about 200 mg to about 600 mg, from about 200 mg to about 500 mg, from about 200 mg to about 400 mg, from about 200 mg to about 300 mg, from about 250 mg to about 4000 mg, from about 250 mg to about 3900 mg, from about 250 mg to about 3800 mg, from about 250 mg to about 3700 mg, from about 250 mg to about 3600 mg, from about 250 mg to about 3500 mg, from about 250 mg to about 3400 mg, from about 250 mg to about 3300 mg, from about 250 mg to about 3200 mg, from about 250 mg to about 3100 mg, from about 250 mg to about 3000 mg, from about 250 mg to about 2900 mg, from about 250 mg to about 2800 mg, from about 250 mg to about 2700 mg, from about 250 mg to about 2600 mg, from about 250 mg to about 2500 mg, from about 250 mg to about 2400 mg, from about 250 mg to about 2300 mg, from about 250 mg to about 2200 mg, from about 250 mg to about 2100 mg, from about 250 mg to about 2000 mg, from about 250 mg to about 1900 mg, from about 250 mg to about 1800 mg, from about 250 mg to about 1700 mg, from about 250 mg to about 1600 mg, from about 250 mg to about 1500 mg, from about 250 mg to about 1400 mg, from about 250 mg to about 1300 mg, from about 250 mg to about 1200 mg, from about 250 mg to about 1100 mg, from about 250 mg to about 1000 mg, from about 250 mg to about 900 mg, from about 250 mg to about 800 mg, from about 250 mg to about 700 mgFrom about 250 mg to about 600 mg, from about 250 mg to about 500 mg, from about 250 mg to about 400 mg, from about 250 mg to about 300 mg, from about 300 mg to about 4000 mg, from about 300 mg to about 3900 mg, from about 300 mg to about 3800 mg, from about 300 mg to about 3700 mg, from about 300 mg to about 3600 mg, from about 300 mg to about 3500 mg, from about 300 mg to about 3400 mg, from about 300 mg to about 3300 mg, from about 300 mg to about 3200 mg, from about 300 mg to about 3100 mg, from about 300 mg to about 3000 mg, from about 300 mg to about 2900 mg, from about 300 mg to about 2800 mg, from about 300 mg to about 2700 mg, from about 300 mg to about 2600 mg, from about 300 mg to about 2500 mg, from about 300 mg to about 2400 mg, from about 300 mg to about 2300 mg, from about 300 mg to about 2200 mg, from about 300 mg to about 2100 mg, from about 300 mg to about 1900 mg, from about 300 mg to about 1800 mg, from about 300 mg to about 1700 mg, from about 300 mg to about 1600 mg, from about 300 mg to about 1500 mg, from about 300 mg to about 1400 mg, from about 300 mg to about 1300 mg, from about 300 mg to about 1200 mg, from about 300 mg to about 1100 mg, from about 300 mg to about 1000 mg, from about 300 mg to about 900 mg, from about 300 mg to about 800 mg, from about 300 mg to about 700 mg, from about 300 mg to about 600 mg, from about 300 mg to about 500 mg, from about 300 mg to about 400 mg, from about 350 mg to about 4000 mg, from about 350 mg to about 3900 mg, from about 350 mg to about 3800 mg, from about 350 mg to about 3700 mg, from about 350 mg to about 3600 mg, from about 350 mg to about 3500 mg, from about 350 mg to about 3400 mg, from about 350 mg to about 3300 mg, from about 350 mg to about 3200 mg, from about 350 mg to about 3100 mg, from about 350 mg to about 3000 mg, from about 350 mg to about 2900 mg, from about 350 mg to about 2800 mg, from about 350 mg to about 2700 mg, from about 350 mg to about 2600 mg, from about 350 mg to about 2500 mg, from about 350 mg to about 2400 mg, from about 350 mg to about 2300 mg, from about 350 mg to about 2200 mg, from about 350 mg to about 2100 mg, from about 350 mg to about 2000 mg, from about 350 mg to about 1900 mg, from about 350 mg to about 1800 mgfrom about 350 mg to about 1700 mg, from about 350 mg to about 1600 mg, from about 350 mg to about 1500 mg, from about 350 mg to about 1400 mg, from about 350 mg to about 1300 mg, from about 350 mg to about 1200 mg, from about 350 mg to about 1100 mg, from about 350 mg to about 1000 mg, from about 350 mg to about 900 mg, from about 350 mg to about 800 mg, from about 350 mg to about 700 mg, from about 350 mg to about 600 mg, from about 350 mg to about 500 mg, from about 350 mg to about 400 mg, from about 400 mg to about 4000 mg, from about 400 mg to about 3900 mg, from about 400 mg to about 3800 mg, from about 400 mg to about 3700 mg, from about 400 mg to about 3600 mg, from about 400 mg to about 3500 mg, from about 400 mg to about 3400 mg, from about 400 mg to about 3300 mg, from about 400 mg to about 3200 mg, from about 400 mg to about 3100 mg, from about 400 mg to about 3000 mg, from about 400 mg to about 2900 mg, from about 400 mg to about 2800 mg, from about 400 mg to about 2700 mg, from about 400 mg to about 2600 mg, from about 400 mg to about 2500 mg, from about 400 mg to about 2400 mg, from about 400 mg to about 2300 mg, from about 400 mg to about 2200 mg, from about 400 mg to about 2100 mg, from about 400 mg to about 2000 mg, from about 400 mg to about 1900 mg, from about 400 mg to about 1800 mg, from about 400 mg to about 1700 mg, from about 400 mg to about 1600 mg, from about 400 mg to about 1500 mg, from about 400 mg to about 1400 mg, from about 400 mg to about 1300 mg, from about 400 mg to about 1200 mg, from about 400 mg to about 1100 mg, from about 400 mg to about 1000 mg, from about 400 mg to about 900 mg, from about 400 mg to about 800 mg, from about 400 mg to about 700 mg, from about 400 mg to about 600 mg, from about 400 mg to about 500 mg, from about 450 mg to about 4000 mg, from about 450 mg to about 3900 mg, from about 450 mg to about 3800 mg, from about 450 mg to about 3700 mg, from about 450 mg to about 3600 mg, from about 450 mg to about 3500 mg, from about 450 mg to about 3400 mg, from about 450 mg to about 3300 mg, from about 450 mg to about 3200 mg, from about 450 mg to about 3100 mg, from about 450 mg to about 3000 mg, from about 450 mg to about 2900 mg, from about 450 mg to about 2800 mgFrom about 450 mg to about 2700 mg, from about 450 mg to about 2600 mg, from about 450 mg to about 2500 mg, from about 450 mg to about 2400 mg, from about 450 mg to about 2300 mg, from about 450 mg to about 2200 mg, from about 450 mg to about 2100 mg, from about 450 mg to about 2000 mg, from about 450 mg to about, 1900 mg, from about 450 mg to about 1800 mg, from about 450 mg to about 1700 mg, from about 450 mg to about 1600 mg, from about 450 mg to about 1500 mg, from about 450 mg to about 1400 mg, from about 450 mg to about 1300 mg, from about 450 mg to about 1200 mg, from about 450 mg to about 1100 mg, from about 450 mg to about 1000 mg, from about 450 mg to about 900 mg, from about 450 mg to about 800 mg, from about 450 mg to about 700 mg, from about 450 mg to about 600 mg or from about 450 mg to about 500 mg.

[0112] Specifically, the patient takes 50mg, 75mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1000mg, 1025mg, 1050mg, 1075mg, 1100mg, 1125mg, 1150mg, 1175mg, 1200mg, 1225mg, 1250mg, 1275mg, 1300mg, 1325mg, 1350mg, 1375mg, 1400mg, 1425mg, 1450mg, 1475mg, 1500mg, 1525mg, 1550mg, 1575mg, 1600mg, 1625mg, 1650mg, 1675mg, 1700mg, 1725mg, 1750mg, 1775mg, 1800mg, 1825mg, 1850mg, 1875mg, 1900mg, 1925mg, 1950mg, 1975mg, 2000mg, 2025mg, 2050mg, 2075mg, 2100mg, 2125mg, 2150mg, 2175mg, 2200mg, 2225mg, 2250mg, 2275mg, 2300mg, 2325mg, 2350mg, 2375mg, 2400mg, 2425mg, 2450mg, 2475mg, 2500mg, 2525mg, 2550mg, 2575mg, 2600mg, 2625mg, 2650mg, 2675mg, 2700mg, 2725mg, 2750mg, 2775mg, 2800mg, 2825mg, 2850mg, 2875mg, 2900mg, 2925mg, 2950mg, 2975mg, 3000mg, 3025mg, 3050mg, 3075mg, 3100mg, 3125mg, 3150mg, 3175mg, 3200mg, 3225mg, 3250mg, 3275mg, 3300mg, 3325mg, 3350mg, 3375mg, 3400mg, 3425mg, 3450mg, 3475mg, 3500mg, 3525mg, 3550mg, 3575mg, 3600mg, 3625mg, 3650mg, 3675mg, 3700mg, 3725mg,It may be administered at 3750 mg, 3775 mg, 3800 mg, 3825 mg, 3850 mg, 3875 mg, 3900 mg, 3925 mg, 3950 mg, 3975 mg, or 4000 mg.

[0113] The dosage of the antibody or antibody portion described herein may be administered once a week, once every other week, once every two weeks, once every three weeks, once every four weeks, once a month, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every two months, once every nine weeks, once every ten weeks, once every eleven weeks, or once every twelve weeks, depending on the needs of the individual and the professional judgment of the person administering the composition or directing the administration of the composition. The dosage ranges described herein are merely exemplary and are not intended to limit the scope or practice of the claimed composition.

[0114] In another embodiment, when one or more of the antibodies described herein are administered subcutaneously to a patient as a fixed dose, the therapeutically effective amount or prophylactically effective amount of the antibody or antibody portion that can be administered is from about 50 mg to about 500 mg, from 50 mg to about 400 mg, from about 50 mg to about 300 mg, from about 50 mg to about 200 mg, from about 50 mg to about 100 mg, from about 75 mg to about 500 mg, from 75 mg to about 400 mg, from about 75 mg to about 300 mg, from about 75 mg to about 200 mg, from about 75 mg to about 100 mg, from about 100 mg to about 500 mg, from about 100 mg to about 400 mg, from about 100 mg to about 300 mg, from about 100 mg to about 200 mg, from about 125 mg to about 500 mg, from 125 mg to about 400 mg, from about 125 mg to about 300 mg, from about 125 mg to about 200 mg, from about 150 mg to about 500 mg, from 150 mg to about 400 mg, from about 150 mg to about 300 mg, from about 150 mg to about 200 mg, from about 175 mg to about 500 mg, from 175 mg to about 400 mg, from about 175 mg to about 300 mg, from about 175 mg to about 200 mg, from about 200 mg to about 500 mg, from 200 mg to about 400 mg or from about 200 mg to about 300 mg. Specifically, the subject can be administered 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg or 500 mg.

[0115] The dosage of the antibody or antibody portion described herein can be administered once a week, once every other week, once every two weeks, once every three weeks, once every four weeks, once a month, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every two months, once every nine weeks, once every ten weeks, once every eleven weeks or once every twelve weeks, at the professional judgment of the person administering the composition or the person directing the administration of the composition, depending on the needs of the individual, and the dosage ranges described herein are merely exemplary and are not intended to limit the scope or practice of the claimed composition.

[0116] In one embodiment, the treatment regimen of one or more antibodies described herein can be administered to a subject. Exemplary and non-limiting regimens are multiple variable dosing regimens. For example, a multiple variable dosing regimen can include a loading dose, followed by at least one therapeutic dose that is less than the loading dose.

[0117] Anti-RGMa antibodies may undergo elimination via target-mediated pharmacokinetics. In certain embodiments, the loading dose is effective to overcome target-mediated pharmacokinetics.

[0118] In certain embodiments, the method includes achieving an early steady-state level of the antibody by providing a loading dose of the anti-RGMa antibody, followed by subsequent doses of a smaller amount of the antibody.

[0119] In certain embodiments, the method includes achieving an early effective target trough serum concentration by providing a loading dose of the anti-RGMa antibody, followed by subsequent doses of a smaller amount of the antibody.

[0120] In certain embodiments, the method includes achieving an early clinical effect by providing a loading dose of the anti-RGMa antibody, followed by subsequent doses of a smaller amount of the antibody.

[0121] For example, the steady-state level, effective target trough serum concentration, and / or clinical effect are reached within 4 weeks, preferably within 3 weeks, more preferably within 2 weeks, most preferably within 1 week, such as within 6 days, within 5 days, within 4 days, within 3 days, within 2 days, or within 1 day. Thereafter, the steady-state level is maintained by administration of a smaller maintenance dose for the remainder of the treatment regimen or until suppression of the disease symptoms is achieved.

[0122] In one embodiment, the therapeutic dose is an amount that is at least 10% less, at least 20% less, at least 30% less, at least 40% less, at least 50% less, at least 60% less, at least 70% less, at least 80% less, or at least 90% less than the loading dose. Alternatively, the therapeutic dose can be about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% of the loading dose.

[0123] In one embodiment, the loading dose is from about 100 mg to about 4000 mg, from about 100 mg to about 3900 mg, from about 100 mg to about 3800 mg, from about 100 mg to about 3700 mg, from about 100 mg to about 3600 mg, from about 100 mg to about 3500 mg, from about 100 mg to about 3400 mg, from about 100 mg to about 3300 mg, from about 100 mg to about 3200 mg, from about 100 mg to about 3100 mg, from about 100 mg to about 3000 mg, from about 100 mg to about 2900 mg, from about 100 mg to about 2800 mg, from about 100 mg to about 2700 mg, from about 100 mg to about 2600 mg, from about 100 mg to about 2500 mg, from about 100 mg to about 2400 mg, from about 100 mg to about 2300 mg, from about 100 mg to about 2200 mg, from about 100 mg to about 2100 mg, from about 100 mg to about 2000 mg, from about 100 mg to about 1900 mg, from about 100 mg to about 1800 mg, from about 100 mg to about 1700 mg, from about 100 mg to about 1600 mg, from about 100 mg to about 1500 mg, from about 100 mg to about 1400 mg, from about 100 mg to about 1300 mg, from about 100 mg to about 1200 mg, from about 100 mg to about 1100 mg, from about 100 mg to about 1000 mg, from about 100 mg to about 900 mg, from about 100 mg to about 800 mg, from about 100 mg to about 700 mg, from about 100 mg to about 600 mg, from about 100 mg to about 500 mg, from about 100 mg to about 400 mg, from about 100 mg to about 300 mg, from about 150 mg to about 4000 mg, from about 150 mg to about 3900 mg, from about 150 mg to about 3800 mg, from about 150 mg to about 3700 mg, from about 150 mg to about 3600 mg, from about 150 mg to about 3500 mg, from about 150 mg to about 3400 mg, from about 150 mg to about 3300 mg, from about 150 mg to about 3200 mg, from about 150 mg to about 3100 mg, from about 150 mg to about 3000 mg, from about 150 mg to about 2900 mg, from about 150 mg to about 2800 mg, from about 150 mg to about 2700 mg, from about 150 mg to about 2600 mg, from about 150 mg to about 2500 mg, from about 150 mg to about 2400 mg, from about 150 mg to about 2300 mg, from about 150 mg to about 2200 mg, from about 150 mg to about 2100 mg, from about 150 mg to about 2000 mg, from about 150 mg to about 1900 mg, from about 150 mg to about 1800 mg, from about 150 mg to about 1700 mg,from about 150 mg to about 1600 mg, from about 150 mg to about 1500 mg, from about 150 mg to about 1400 mg, from about 150 mg to about 1300 mg, from about 150 mg to about 1200 mg, from about 150 mg to about 1100 mg, from about 150 mg to about 1000 mg, from about 150 mg to about 900 mg, from about 150 mg to about 800 mg, from about 150 mg to about 700 mg, from about 150 mg to about 600 mg, from about 150 mg to about 500 mg, from about 150 mg to about 400 mg, from about 150 mg to about 300 mg, from about 200 mg to about 4000 mg, from about 200 mg to about 3900 mg, from about 200 mg to about 3800 mg, from about 200 mg to about 3700 mg, from about 200 mg to about 3600 mg, from about 200 mg to about 3500 mg, from about 200 mg to about 3400 mg, from about 200 mg to about 3300 mg, from about 200 mg to about 3200 mg, from about 200 mg to about 3100 mg, from about 200 mg to about 3000 mg, from about 200 mg to about 2900 mg, from about 200 mg to about 2800 mg, from about 200 mg to about 2700 mg, from about 200 mg to about 2600 mg, from about 200 mg to about 2500 mg, from about 200 mg to about 2400 mg, from about 200 mg to about 2300 mg, from about 200 mg to about 2200 mg, from about 200 mg to about 2100 mg, from about 200 mg to about 2000 mg, from about 200 mg to about 1900 mg, from about 200 mg to about 1800 mg, from about 200 mg to about 1700 mg, from about 200 mg to about 1600 mg, from about 200 mg to about 1500 mg, from about 200 mg to about 1400 mg, from about 200 mg to about 1300 mg, from about 200 mg to about 1200 mg, from about 200 mg to about 1100 mg, from about 200 mg to about 1000 mg, from about 200 mg to about 900 mg, from about 200 mg to about 800 mg, from about 200 mg to about 700 mg, from about 200 mg to about 600 mg, from about 200 mg to about 500 mg, from about 200 mg to about 400 mg, from about 200 mg to about 300 mg, from about 250 mg to about 4000 mg, from about 250 mg to about 3900 mg, from about 250 mg to about 3800 mg, from about 250 mg to about 3700 mg, from about 250 mg to about 3600 mg, from about 250 mg to about 3500 mg, from about 250 mg to about 3400 mg, from about 250 mg to about 3300 mg, from about 250 mg to about 3200 mg, from about 250 mg to about 3100 mg, from about 250 mg to about 3000 mgFrom about 250 mg to about 2900 mg, from about 250 mg to about 2800 mg, from about 250 mg to about 2700 mg, from about 250 mg to about 2600 mg, from about 250 mg to about 2500 mg, from about 250 mg to about 2400 mg, from about 250 mg to about 2300 mg, from about 250 mg to about 2200 mg, from about 250 mg to about 2100 mg, from about 250 mg to about 2000 mg, from about 250 mg to about 1900 mg, from about 250 mg to about 1800 mg, from about 250 mg to about 1700 mg, from about 250 mg to about 1600 mg, from about 250 mg to about 1500 mg, from about 250 mg to about 1400 mg, from about 250 mg to about 1300 mg, from about 250 mg to about 1200 mg, from about 250 mg to about 1100 mg, from about 250 mg to about 1000 mg, from about 250 mg to about 900 mg, from about 250 mg to about 800 mg, from about 250 mg to about 700 mg, from about 250 mg to about 600 mg, from about 250 mg to about 500 mg, from about 250 mg to about 400 mg, from about 250 mg to about 300 mg, from about 300 mg to about 2500 mg, from about 300 mg to about 2400 mg, from about 300 mg to about 2300 mg, from about 300 mg to about 2200 mg, from about 300 mg to about 2100 mg, from about 300 mg to about 2000 mg, from about 300 mg to about 1900 mg, from about 300 mg to about 1800 mg, from about 300 mg to about 1700 mg, from about 300 mg to about 1600 mg, from about 300 mg to about 1500 mg, from about 300 mg to about 1400 mg, from about 300 mg to about 1300 mg, from about 300 mg to about 1200 mg, from about 300 mg to about 1100 mg, from about 300 mg to about 1000 mg, from about 300 mg to about 900 mg, from about 300 mg to about 800 mg, from about 300 mg to about 700 mg, from about 300 mg to about 600 mg, from about 300 mg to about 500 mg, from about 300 mg to about 400 mg, from about 350 mg to about 4000 mg, from about 350 mg to about 3900 mg, from about 350 mg to about 3800 mg, from about 350 mg to about 3700 mg, from about 350 mg to about 3600 mg, from about 350 mg to about 3500 mg, from about 350 mg to about 3400 mg, from about 350 mg to about 3300 mg, from about 350 mg to about 3200 mg, from about 350 mg to about 3100 mg, from about 350 mg to about 3000 mg, from about 350 mg to about 2900 mg, from about 350 mg to about 2800 mg, from about 350 mg to about 2700 mgfrom about 350 mg to about 2600 mg, from about 350 mg to about 2500 mg, from about 350 mg to about 2400 mg, from about 350 mg to about 2300 mg, from about 350 mg to about 2200 mg, from about 350 mg to about 2100 mg, from about 350 mg to about 2000 mg, from about 350 mg to about 1900 mg, from about 350 mg to about 1800 mg, from about 350 mg to about 1700 mg, from about 350 mg to about 1600 mg, from about 350 mg to about 1500 mg, from about 350 mg to about 1400 mg, from about 350 mg to about 1300 mg, from about 350 mg to about 1200 mg, from about 350 mg to about 1100 mg, from about 350 mg to about 1000 mg, from about 350 mg to about 900 mg, from about 350 mg to about 800 mg, from about 350 mg to about 700 mg, from about 350 mg to about 600 mg, from about 350 mg to about 500 mg, from about 350 mg to about 400 mg, from about 400 mg to about 4000 mg, from about 400 mg to about 3900 mg, from about 400 mg to about 3800 mg, from about 400 mg to about 3700 mg, from about 400 mg to about 3600 mg, from about 400 mg to about 3500 mg, from about 400 mg to about 3400 mg, from about 400 mg to about 3300 mg, from about 400 mg to about 3200 mg, from about 400 mg to about 3100 mg, from about 400 mg to about 3000 mg, from about 400 mg to about 2900 mg, from about 400 mg to about 2800 mg, from about 400 mg to about 2700 mg, from about 400 mg to about 2600 mg, from about 400 mg to about 2500 mg, from about 400 mg to about 2400 mg, from about 400 mg to about 2300 mg, from about 400 mg to about 2200 mg, from about 400 mg to about 2100 mg, from about 400 mg to about 2000 mg, from about 400 mg to about 1900 mg, from about 400 mg to about 1800 mg, from about 400 mg to about 1700 mg, from about 400 mg to about 1600 mg, from about 400 mg to about 1500 mg, from about 400 mg to about 1400 mg, from about 400 mg to about 1300 mg, from about 400 mg to about 1200 mg, from about 400 mg to about 1100 mg, from about 400 mg to about 1000 mg, from about 400 mg to about 900 mg, from about 400 mg to about 800 mg, from about 400 mg to about 700 mg, from about 400 mg to about 600 mg, from about 400 mg to about 500 mg, from about 450 mg to about 4000 mg, from about 450 mg to about 3900 mg, from about 450 mg to about 3800 mg, from about 450 mg to about 3700 mgFrom about 450 mg to about 3600 mg, from about 450 mg to about 3500 mg, from about 450 mg to about 3400 mg, from about 450 mg to about 3300 mg, from about 450 mg to about 3200 mg, from about 450 mg to about 3100 mg, from about 450 mg to about 3000 mg, from about 450 mg to about 2900 mg, from about 450 mg to about 2800 mg, from about 450 mg to about 2700 mg, from about 450 mg to about 2600 mg, from about 450 mg to about 2500 mg, from about 450 mg to about 2400 mg, from about 450 mg to about 2300 mg, from about 450 mg to about 2200 mg, from about 450 mg to about 2100 mg, from about 450 mg to about 2000 mg, from about 450 mg to about 1900 mg, from about 450 mg to about 1800 mg, from about 450 mg to about 1700 mg, from about 450 mg to about 1600 mg, from about 450 mg to about 1500 mg, from about 450 mg to about 1400 mg, from about 450 mg to about 1300 mg, from about 450 mg to about 1200 mg, from about 450 mg to about 1100 mg, from about 450 mg to about 1000 mg, from about 450 mg to about 900 mg, from about 450 mg to about 800 mg, from about 450 mg to about 700 mg, from about 450 mg to about 600 mg or from about 450 mg to about 500 mg.

[0124] Specifically, the targets are 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1000mg, 1025mg, 1050mg, 1075mg, 1100mg, 1125mg, 1150mg, 1175mg, 1200mg, 1225mg, 1250mg, 1275mg, 1300mg, 1325mg, 1350mg, 1375mg, 1400mg, 1425mg, 1450mg, 1475mg, 1500mg, 1525mg, 1550mg, 1575mg, 1600mg, 1625mg, 1650mg, 1675mg, 1700mg, 1725mg, 1750mg, 1775mg, 1800mg, 1825mg, 1850mg, 1875mg, 1900mg, 1925mg, 1950mg, 1975mg, 2000mg, 2025mg, 2050mg, 2075mg, 2100mg, 2125mg, 2150mg, 2175mg, 2200mg, 2225mg, 2250mg, 2275mg, 2300mg, 2325mg, 2350mg, 2375mg, 2400mg, 2425mg, 2450mg, 2475mg, 2500mg, 2525mg, 2550mg, 2575mg, 2600mg, 2625mg, 2650mg, 2675mg, 2700mg, 2725mg, 2750mg, 2775mg, 2800mg, 2825mg, 2850mg, 2875mg, 2900mg, 2925mg, 2950mg, 2975mg, 3000mg, 3025mg, 3050mg, 3075mg, 3300mg, 3325mg, 3350mg, 3375mg, 3200mg, 3225mg, 3250mg, 3275mg, 3300mg, 3325mg, 3350mg, 3375mg, 3400mg, 3425mg, 3450mg, 3475mg, 3500mg, 3525mg, 3550mg, 3575mg, 3600mg, 3625mg, 3650mg, 3675mg, 3700mg, 3725mg, 3750mg,Loading doses of 3775 mg, 3800 mg, 3825 mg, 3850 mg, 3875 mg, 3900 mg, 3925 mg, 3950 mg, 3975 mg, or 4000 mg may be administered.

[0125] In certain embodiments, the loading dose comprises one or more doses, which may be administered over one or more days. In certain embodiments, the loading dose comprises two or more doses, each dose being administered on a separate day. Thus, the loading dose may be administered as one, two, or more doses, each dose being administered during the loading dose phase. The loading dose phase may include about 14 days, about 13 days, about 12 days, about 11 days, about 10 days, about 9 days, about 8 days, about 7 days, about 6 days, about 5 days, about 4 days, about 3 days, about 2 days, or about 1 day. For example, the loading dose may be administered as two doses over two consecutive days. In certain embodiments, the loading dose comprises a first dose of about 1800 mg and a second dose of about 1800 mg, optionally administered one or more days apart during the loading dose phase. In certain other embodiments, the loading dose comprises a single dose, such as a single dose of about 100 mg, about 300 mg, or about 1200 mg.

[0126] In certain embodiments, more than one loading dose is administered. For example, the first loading dose may be administered at a first time point (over one or more days), and subsequent loading doses may be administered at subsequent time points (over one or more days). In certain embodiments, the interval between the first time point and the subsequent time points is at least one week, at least two weeks, at least three weeks, at least four weeks, at least one month, at least five weeks, at least six weeks, at least seven weeks, at least eight weeks, at least two months, at least nine weeks, at least ten weeks, at least eleven weeks, or at least twelve weeks. In certain embodiments, the interval between the first time point and the subsequent time points is about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, about eight weeks, about nine weeks, about ten weeks, about eleven weeks, or about twelve weeks.

[0127] In one embodiment, the therapeutic dose is from about 50 mg to about 2500 mg, from about 50 mg to about 2400 mg, from about 50 mg to about 2300 mg, from about 50 mg to about 2200 mg, from about 50 mg to about 2100 mg, from about 50 mg to about 2000 mg, from about 50 mg to about 1900 mg, from about 50 mg to about 1800 mg, from about 50 mg to about 1700 mg, from about 50 mg to about 1600 mg, from about 50 mg to about 1500 mg, from about 50 mg to about 1400 mg, from about 50 mg to about 1300 mg, from about 50 mg to about 1200 mg, from about 50 mg to about 1100 mg, from about 50 mg to about 1000 mg, from about 50 mg to about 900 mg, from about 50 mg to about 800 mg, from about 50 mg to about 700 mg, from about 50 mg to about 600 mg, from about 50 mg to about 500 mg, from about 50 mg to about 400 mg, from about 50 mg to about 300 mg, from 100 mg to about 2500 mg, from about 100 mg to about 2400 mg, from about 100 mg to about 2300 mg, from about 100 mg to about 2200 mg, from about 100 mg to about 2100 mg, from about 100 mg to about 2000 mg, from about 100 mg to about 1900 mg, from about 100 mg to about 1800 mg, from about 100 mg to about 1700 mg, from about 100 mg to about 1600 mg, from about 100 mg to about 1500 mg, from about 100 mg to about 1400 mg, from about 100 mg to about 1300 mg, from about 100 mg to about 1200 mg, from about 100 mg to about 1100 mg, from about 100 mg to about 1000 mg, from about 100 mg to about 900 mg, from about 100 mg to about 800 mg, from about 100 mg to about 700 mg, from about 100 mg to about 600 mg, from about 100 mg to about 500 mg, from about 100 mg to about 400 mg, from about 100 mg to about 300 mg, from about 150 mg to about 2500 mg, from about 150 mg to about 2400 mg, from about 150 mg to about 2300 mg, from about 150 mg to about 2200 mg, from about 150 mg to about 2100 mg, from about 150 mg to about 2000 mg, from about 150 mg to about 1900 mg, from about 150 mg to about 1800 mg, from about 150 mg to about 1700 mg, from about 150 mg to about 1600 mg, from about 150 mg to about 1500 mg, from about 150 mg to about 1400 mg, from about 150 mg to about 1300 mg, from about 150 mg to about 1200 mg, from about 150 mg to about 1100 mg, from about 150 mg to about 1000 mg, from about 150 mg to about 900 mg, from about 150 mg to about 800 mg,From about 150 mg to about 700 mg, from about 150 mg to about 600 mg, from about 150 mg to about 500 mg, from about 150 mg to about 400 mg, from about 150 mg to about 300 mg, from about 200 mg to about 2500 mg, from about 200 mg to about 2400 mg, from about 200 mg to about 2300 mg, from about 200 mg to about 2200 mg, from about 200 mg to about 2100 mg, from about 200 mg to about 2000 mg, from about 200 mg to about 1900 mg, from about 200 mg to about 1800 mg, from about 200 mg to about 1700 mg, from about 200 mg to about 1600 mg, from about 200 mg to about 1500 mg, from about 200 mg to about 1400 mg, from about 200 mg to about 1300 mg, from about 200 mg to about 1200 mg, from about 200 mg to about 1100 mg, from about 200 mg to about 1000 mg, from about 200 mg to about 900 mg, from about 200 mg to about 800 mg, from about 200 mg to about 700 mg, from about 200 mg to about 600 mg, from about 200 mg to about 500 mg, from about 200 mg to about 400 mg, from about 200 mg to about 300 mg, from about 250 mg to about 2500 mg, from about 250 mg to about 2400 mg, from about 250 mg to about 2300 mg, from about 250 mg to about 2200 mg, from about 250 mg to about 2100 mg, from about 250 mg to about 2000 mg, from about 250 mg to about 1900 mg, from about 250 mg to about 1800 mg, from about 250 mg to about 1700 mg, from about 250 mg to about 1600 mg, from about 250 mg to about 1500 mg, from about 250 mg to about 1400 mg, from about 250 mg to about 1300 mg, from about 250 mg to about 1200 mg, from about 250 mg to about 1100 mg, from about 250 mg to about 1000 mg, from about 250 mg to about 900 mg, from about 250 mg to about 800 mg, from about 250 mg to about 700 mg, from about 250 mg to about 600 mg, from about 250 mg to about 500 mg, from about 250 mg to about 400 mg, from about 250 mg to about 300 mg, from about 300 mg to about 2500 mg, from about 300 mg to about 2400 mg, from about 300 mg to about 2300 mg, from about 300 mg to about 2200 mg, from about 300 mg to about 2100 mg, from about 300 mg to about 2000 mg, from about 300 mg to about 1900 mg, from about 300 mg to about 1800 mg, from about 300 mg to about 1700 mg, from about 300 mg to about 1600 mg, from about 300 mg to about 1500 mg, from about 300 mg to about 1400 mg,from about 300 mg to about 1300 mg, from about 300 mg to about 1200 mg, from about 300 mg to about 1100 mg, from about 300 mg to about 1000 mg, from about 300 mg to about 900 mg, from about 300 mg to about 800 mg, from about 300 mg to about 700 mg, from about 300 mg to about 600 mg, from about 300 mg to about 500 mg, from about 300 mg to about 400 mg, from about 350 mg to about 4000 mg, from about 350 mg to about 3900 mg, from about 350 mg to about 3800 mg, from about 350 mg to about 3700 mg, from about 350 mg to about 3600 mg, from about 350 mg to about 3500 mg, from about 350 mg to about 3400 mg, from about 350 mg to about 3300 mg, from about 350 mg to about 3200 mg, from about 350 mg to about 3100 mg, from about 350 mg to about 3000 mg, from about 350 mg to about 2900 mg, from about 350 mg to about 2800 mg, from about 350 mg to about 2700 mg, from about 350 mg to about 2600 mg, from about 350 mg to about 2500 mg, from about 350 mg to about 2400 mg, from about 350 mg to about 2300 mg, from about 350 mg to about 2200 mg, from about 350 mg to about 2100 mg, from about 350 mg to about 2000 mg, from about 350 mg to about 1900 mg, from about 350 mg to about 1800 mg, from about 350 mg to about 1700 mg, from about 350 mg to about 1600 mg, from about 350 mg to about 1500 mg, from about 350 mg to about 1400 mg, from about 350 mg to about 1300 mg, from about 350 mg to about 1200 mg, from about 350 mg to about 1100 mg, from about 350 mg to about 1000 mg, from about 350 mg to about 900 mg, from about 350 mg to about 800 mg, from about 350 mg to about 700 mg, from about 350 mg to about 600 mg, from about 350 mg to about 500 mg, from about 350 mg to about 400 mg, from about 400 mg to about 4000 mg, from about 400 mg to about 3900 mg, from about 400 mg to about 3800 mg, from about 400 mg to about 3700 mg, from about 400 mg to about 3600 mg, from about 400 mg to about 3500 mg, from about 400 mg to about 3400 mg, from about 400 mg to about 3300 mg, from about 400 mg to about 3200 mg, from about 400 mg to about 3100 mg, from about 400 mg to about 3000 mg, from about 400 mg to about 2900 mg, from about 400 mg to about 2800 mg, from about 400 mg to about 2700 mg, from about 400 mg to about 2600 mg, from about 400 mg to about 2500 mg,from about 400 mg to about 2400 mg, from about 400 mg to about 2300 mg, from about 400 mg to about 2200 mg, from about 400 mg to about 2100 mg, from about 400 mg to about 2000 mg, from about 400 mg to about 1900 mg, from about 400 mg to about 1800 mg, from about 400 mg to about 1700 mg, from about 400 mg to about 1600 mg, from about 400 mg to about 1500 mg, from about 400 mg to about 1400 mg, from about 400 mg to about 1300 mg, from about 400 mg to about 1200 mg, from about 400 mg to about 1100 mg, from about 400 mg to about 1000 mg, from about 400 mg to about 900 mg, from about 400 mg to about 800 mg, from about 400 mg to about 700 mg, from about 400 mg to about 600 mg, from about 400 mg to about 500 mg, from about 450 mg to about 4000 mg, from about 450 mg to about 3900 mg, from about 450 mg to about 3800 mg, from about 450 mg to about 3700 mg, from about 450 mg to about 3600 mg, from about 450 mg to about 3500 mg, from about 450 mg to about 3400 mg, from about 450 mg to about 3300 mg, from about 450 mg to about 3200 mg, from about 450 mg to about 3100 mg, from about 450 mg to about 3000 mg, from about 450 mg to about 2900 mg, from about 450 mg to about 2800 mg, from about 450 mg to about 2700 mg, from about 450 mg to about 2600 mg, from about 450 mg to about 2500 mg, from about 450 mg to about 2400 mg, from about 450 mg to about 2300 mg, from about 450 mg to about 2200 mg, from about 450 mg to about 2100 mg, from about 450 mg to about 2000 mg, from about 450 mg to about 1900 mg, from about 450 mg to about 1800 mg, from about 450 mg to about 1700 mg, from about 450 mg to about 1600 mg, from about 450 mg to about 1500 mg, from about 450 mg to about 1400 mg, from about 450 mg to about 1300 mg, from about 450 mg to about 1200 mg, from about 450 mg to about 1100 mg, from about 450 mg to about 1000 mg, from about 450 mg to about 900 mg, from about 450 mg to about 800 mg, from about 450 mg to about 700 mg, from about 450 mg to about 600 mg or from about 450 mg to about 500 mg.,

[0128] Specifically, the subject may be administered a therapeutic dose of 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1025 mg, 1050 mg, 1075 mg, 1100 mg, 1125 mg, 1150 mg, 1175 mg, 1200 mg, 1225 mg, 1250 mg, 1275 mg, 1300 mg, 1325 mg, 1350 mg, 1375 mg, 1400 mg, 1425 mg, 1450 mg, 1475 mg, 1500 mg, 1525 mg, 1550 mg, 1575 mg, 1600 mg, 1625 mg, 1650 mg, 1675 mg, 1700 mg, 1725 mg, 1750 mg, 1775 mg, 1800 mg, 1825 mg, 1850 mg, 1875 mg, 1900 mg, 1925 mg, 1950 mg, 1975 mg, 2000 mg, 2025 mg, 2050 mg, 2075 mg, 2100 mg, 2125 mg, 2150 mg, 2175 mg, 2200 mg, 2225 mg, 2250 mg, 2275 mg, 2300 mg, 2325 mg, 2350 mg, 2375 mg, 2400 mg, 2425 mg, 2450 mg, 2475 mg, or 2500 mg.

[0129] In one embodiment, the loading dose is twice the therapeutic dose. For example, the loading dose may be 100 mg of the antibody or antigen-binding fragment thereof, and the subsequent therapeutic dose may be 50 mg. As another example, the loading dose may be 300 mg of the antibody or antigen-binding fragment thereof, and the subsequent therapeutic dose may be 150 mg. As yet another example, the loading dose may be 1200 mg of the antibody or antigen-binding fragment thereof, and the subsequent therapeutic dose may be 600 mg. As yet another example, the loading dose may be 3600 mg of the antibody or antigen-binding fragment thereof, and the subsequent therapeutic dose may be 1800 mg.

[0130] The therapeutic dosages of the antibodies or antibody portions described herein may be administered once a week, once every other week, once every two weeks, once every three weeks, once every four weeks, once a month, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every two months, once every nine weeks, once every ten weeks, once every eleven weeks, or once every twelve weeks, depending on the needs of the individual and the professional judgment of the person administering the composition or directing the administration of the composition, and the dosage ranges described herein are merely exemplary and are not intended to limit the scope or practice of the claimed composition.

[0131] In certain exemplary embodiments, the method comprises administering from about 150 mg to about 1000 mg of the antibody once every 28 days.

[0132] In certain exemplary embodiments, the method comprises administering from about 300 mg to about 1200 mg of the antibody per month. For example, the method may comprise administering about 450 mg of the antibody per month.

[0133] In certain exemplary embodiments, the method comprises administering a loading dose of the antibody or antigen-binding fragment thereof, followed by administering at least one therapeutic dose of the antibody or antigen-binding fragment thereof.

[0134] In some such embodiments, the loading dose is administered all at once in one day. In other such embodiments, the loading dose is divided over multiple days (e.g., divided over two days). For example, the loading dose may be administered as two or more doses over two or more days.

[0135] In some such embodiments, the therapeutic dose is administered at least 1 week after administration of the loading dose. For example, the therapeutic dose can be administered 1 week after administration of the loading dose, 2 weeks after administration of the loading dose, 3 weeks after administration of the loading dose, 4 weeks after administration of the loading dose, 5 weeks after administration of the loading dose, 6 weeks after administration of the loading dose, 7 weeks after administration of the loading dose, 8 weeks after administration of the loading dose, 9 weeks after administration of the loading dose, 10 weeks after administration of the loading dose, 11 weeks after administration of the loading dose, or 12 weeks after administration of the loading dose.

[0136] In some such embodiments, the method includes administering one or more therapeutic doses. For example, the method can include administering a loading dose followed by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 subsequent therapeutic doses. In certain embodiments, the method can include administering a loading dose followed by a total of 4 administrations with 3 therapeutic doses. The interval between the loading dose and the first therapeutic dose can be at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 1 month, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 2 months, at least 9 weeks, at least 10 weeks, at least 11 weeks, or at least 12 weeks. In particular, the interval between the loading dose and the first therapeutic dose can be about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, or about 12 weeks. The one or more therapeutic doses can be administered once a week, once every other week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once a month, once every 5 weeks, once every 6 weeks, once every 7 weeks, once every 8 weeks, once every 2 months, once every 9 weeks, once every 10 weeks, once every 11 weeks, or once every 12 weeks, depending on the needs of the individual and the professional judgment of the person administering the composition or directing the administration of the composition. The dosage ranges described herein are merely exemplary and are not intended to limit the scope or practice of the claimed composition.

[0137] The antibody may be administered alone or conjugated to liposomes and formulated according to known methods for preparing pharmaceutically useful compositions, whereby the antibody is combined by mixing with a pharmaceutically acceptable carrier. A "pharmaceutically acceptable carrier" may be tolerated by the recipient patient. Sterile phosphate buffered saline is an example of a pharmaceutically acceptable carrier. Other suitable carriers are well known to those skilled in the art. See, for example, REMINGTON’S PHARMACEUTICAL SCIENCES, 19th Edition (1995).

[0138] Additional methods of treatment may be used to control the duration of action of the antibody in therapeutic applications. Controlled release preparations can be prepared by complexing or adsorbing the antibody using polymers. For example, biocompatible polymers include matrices of poly(ethylene-co-vinyl acetate) and matrices of polyanhydride copolymers of stearic acid dimer and sebacic acid. Sherwood et al., Bio / Technology, 10:1446 (1992). The rate of release of the antibody from such matrices depends on the molecular weight of the protein, the amount of antibody within the matrix, and the size of the dispersed particles. Saltzman et al., Biophys. J., 55:163 (1989); Sherwood et al., supra. Other solid dosage forms are described in REMINGTON’S PHARMACEUTICAL SCIENCES, 19th Edition (1995).

[0139] b. Secondary progressive multiple sclerosis (SPMS) In a patient diagnosed with multiple sclerosis, it is possible to evaluate whether the subject has secondary progressive multiple sclerosis. The evaluation may indicate an appropriate course of treatment such as prophylactic, maintenance, or modulating therapy. Thus, provided herein is a method of treating, preventing, modulating, or alleviating secondary progressive multiple sclerosis by administering to a patient in need thereof a therapeutically effective amount of one or more (e.g., such as antibody AE12-1-Y-QL) antibodies described herein.

[0140] In one embodiment, a fixed dose of one or more of the antibodies described herein can be administered to a subject. Exemplary and non-limiting ranges of a therapeutically effective amount or a prophylactically effective amount of an antibody or antibody portion described herein are from about 50 mg to about 4000 mg, from about 50 mg to about 3900 mg, from about 50 mg to about 3800 mg, from about 50 mg to about 3700 mg, from about 50 mg to about 3600 mg, from about 50 mg to about 3500 mg, from about 50 mg to about 3400 mg, from about 50 mg to about 3300 mg, from about 50 mg to about 3200 mg, from about 50 mg to about 3100 mg, from about 50 mg to about 3000 mg, from about 50 mg to about 2900 mg, from about 50 mg to about 2800 mg, from about 50 mg to about 2700 mg, from about 50 mg to about 2600 mg, from about 50 mg to about 2500 mg, from about 50 mg to about 2400 mg, from about 50 mg to about 2300 mg, from about 50 mg to about 2200 mg, from about 50 mg to about 2100 mg, from about 50 mg to about 2000 mg, from about 50 mg to about 1900 mg, from about 50 mg to about 1800 mg, from about 50 mg to about 1700 mg, from about 50 mg to about 1600 mg, from about 50 mg to about 1500 mg, from about 50 mg to about 1400 mg, from about 50 mg to about 1300 mg, from about 50 mg to about 1200 mg, from about 50 mg to about 1100 mg, from about 50 mg to about 1000 mg, from about 50 mg to about 900 mg, from about 50 mg to about 800 mg, from about 50 mg to about 700 mg, from about 50 mg to about 600 mg, from about 50 mg to about 500 mg, from about 50 mg to about 400 mg, from about 50 mg to about 300 mg, from about 100 mg to about 4000 mg, from about 100 mg to about 3900 mg, from about 100 mg to about 3800 mg, from about 100 mg to about 3700 mg, from about 100 mg to about 3600 mg, from about 100 mg to about 3500 mg, from about 100 mg to about 3400 mg, from about 100 mg to about 3300 mg, from about 100 mg to about 3200 mg, from about 100 mg to about 3100 mg, from about 100 mg to about 3000 mg, from about 100 mg to about 2900 mg, from about 100 mg to about 2800 mg, from about 100 mg to about 2700 mg, from about 100 mg to about 2600 mg, from about 100 mg to about 2500 mg, from about 100 mg to about 2400 mg, from about 100 mg to about 2300 mg, from about 100 mg to about 2200 mg, from about 100 mg to about 2100 mg, from about 100 mg to about 2000 mg,from about 100 mg to about 1900 mg, from about 100 mg to about 1800 mg, from about 100 mg to about 1700 mg, from about 100 mg to about 1600 mg, from about 100 mg to about 1500 mg, from about 100 mg to about 1400 mg, from about 100 mg to about 1300 mg, from about 100 mg to about 1200 mg, from about 100 mg to about 1100 mg, from about 100 mg to about 1000 mg, from about 100 mg to about 900 mg, from about 100 mg to about 800 mg, from about 100 mg to about 700 mg, from about 100 mg to about 600 mg, from about 100 mg to about 500 mg, from about 100 mg to about 400 mg, from about 100 mg to about 300 mg, from about 150 mg to about 4000 mg, from about 150 mg to about 3900 mg, from about 150 mg to about 3800 mg, from about 150 mg to about 3700 mg, from about 150 mg to about 3600 mg, from about 150 mg to about 3500 mg, from about 150 mg to about 3400 mg, from about 150 mg to about 3300 mg, from about 150 mg to about 3200 mg, from about 150 mg to about 3100 mg, from about 150 mg to about 3000 mg, from about 150 mg to about 2900 mg, from about 150 mg to about 2800 mg, from about 150 mg to about 2700 mg, from about 150 mg to about 2600 mg, from about 150 mg to about 2500 mg, from about 150 mg to about 2400 mg, from about 150 mg to about 2300 mg, from about 150 mg to about 2200 mg, from about 150 mg to about 2100 mg, from about 150 mg to about 2000 mg, from about 150 mg to about 1900 mg, from about 150 mg to about 1800 mg, from about 150 mg to about 1700 mg, from about 150 mg to about 1600 mg, from about 150 mg to about 1500 mg, from about 150 mg to about 1400 mg, from about 150 mg to about 1300 mg, from about 150 mg to about 1200 mg, from about 150 mg to about 1100 mg, from about 150 mg to about 1000 mg, from about 150 mg to about 900 mg, from about 150 mg to about 800 mg, from about 150 mg to about 700 mg, from about 150 mg to about 600 mg, from about 150 mg to about 500 mg, from about 150 mg to about 400 mg, from about 150 mg to about 300 mg, from about 200 mg to about 4000 mg, from about 200 mg to about 3900 mg, from about 200 mg to about 3800 mg, from about 200 mg to about 3700 mg, from about 200 mg to about 3600 mg, from about 200 mg to about 3500 mg, from about 200 mg to about 3400 mg, from about 200 mg to about 3300 mgFrom about 200 mg to about 3200 mg, from about 200 mg to about 3100 mg, from about 200 mg to about 3000 mg, from about 200 mg to about 2900 mg, from about 200 mg to about 2800 mg, from about 200 mg to about 2700 mg, from about 200 mg to about 2600 mg, from about 200 mg to about 2500 mg, from about 200 mg to about 2400 mg, from about 200 mg to about 2300 mg, from about 200 mg to about 2200 mg, from about 200 mg to about 2100 mg, from about 200 mg to about 2000 mg, from about 200 mg to about 1900 mg, from about 200 mg to about 1800 mg, from about 200 mg to about 1700 mg, from about 200 mg to about 1600 mg, from about 200 mg to about 1500 mg, from about 200 mg to about 1400 mg, from about 200 mg to about 1300 mg, from about 200 mg to about 1200 mg, from about 200 mg to about 1100 mg, from about 200 mg to about 1000 mg, from about 200 mg to about 900 mg, from about 200 mg to about 800 mg, from about 200 mg to about 700 mg, from about 200 mg to about 600 mg, from about 200 mg to about 500 mg, from about 200 mg to about 400 mg, from about 200 mg to about 300 mg, from about 250 mg to about 4000 mg, from about 250 mg to about 3900 mg, from about 250 mg to about 3800 mg, from about 250 mg to about 3700 mg, from about 250 mg to about 3600 mg, from about 250 mg to about 3500 mg, from about 250 mg to about 3400 mg, from about 250 mg to about 3300 mg, from about 250 mg to about 3200 mg, from about 250 mg to about 3100 mg, from about 250 mg to about 3000 mg, from about 250 mg to about 2900 mg, from about 250 mg to about 2800 mg, from about 250 mg to about 2700 mg, from about 250 mg to about 2600 mg, from about 250 mg to about 2500 mg, from about 250 mg to about 2400 mg, from about 250 mg to about 2300 mg, from about 250 mg to about 2200 mg, from about 250 mg to about 2100 mg, from about 250 mg to about 2000 mg, from about 250 mg to about 1900 mg, from about 250 mg to about 1800 mg, from about 250 mg to about 1700 mg, from about 250 mg to about 1600 mg, from about 250 mg to about 1500 mg, from about 250 mg to about 1400 mg, from about 250 mg to about 1300 mg, from about 250 mg to about 1200 mg, from about 250 mg to about 1100 mg, from about 250 mg to about 1000 mg, from about 250 mg to about 900 mg, from about 250 mg to about 800 mgFrom about 250 mg to about 700 mg, from about 250 mg to about 600 mg, from about 250 mg to about 500 mg, from about 250 mg to about 400 mg, from about 250 mg to about 300 mg, from about 300 mg to about 4000 mg, from about 300 mg to about 3900 mg, from about 300 mg to about 3800 mg, from about 300 mg to about 3700 mg, from about 300 mg to about 3600 mg, from about 300 mg to about 3500 mg, from about 300 mg to about 3400 mg, from about 300 mg to about 3300 mg, from about 300 mg to about 3200 mg, from about 300 mg to about 3100 mg, from about 300 mg to about 3000 mg, from about 300 mg to about 2900 mg, from about 300 mg to about 2800 mg, from about 300 mg to about 2700 mg, from about 300 mg to about 2600 mg, from about 300 mg to about 2500 mg, from about 300 mg to about 2400 mg, from about 300 mg to about 2300 mg, from about 300 mg to about 2200 mg, from about 300 mg to about 2100 mg, from about 300 mg to about 2000 mg, from about 300 mg to about 1900 mg, from about 300 mg to about 1800 mg, from about 300 mg to about 1700 mg, from about 300 mg to about 1600 mg, from about 300 mg to about 1500 mg, from about 300 mg to about 1400 mg, from about 300 mg to about 1300 mg, from about 300 mg to about 1200 mg, from about 300 mg to about 1100 mg, from about 300 mg to about 1000 mg, from about 300 mg to about 900 mg, from about 300 mg to about 800 mg, from about 300 mg to about 700 mg, from about 300 mg to about 600 mg, from about 300 mg to about 500 mg, from about 300 mg to about 400 mg, from about 350 mg to about 4000 mg, from about 350 mg to about 3900 mg, from about 350 mg to about 3800 mg, from about 350 mg to about 3700 mg, from about 350 mg to about 3600 mg, from about 350 mg to about 3500 mg, from about 350 mg to about 3400 mg, from about 350 mg to about 3300 mg, from about 350 mg to about 3200 mg, from about 350 mg to about 3100 mg, from about 350 mg to about 3000 mg, from about 350 mg to about 2900 mg, from about 350 mg to about 2800 mg, from about 350 mg to about 2700 mg, from about 350 mg to about 2600 mg, from about 350 mg to about 2500 mg, from about 350 mg to about 2400 mg, from about 350 mg to about 2300 mg, from about 350 mg to about 2200 mg, from about 350 mg to about 2100 mg, from about 350 mg to about 2000 mg,From about 350 mg to about 1900 mg, from about 350 mg to about 1800 mg, from about 350 mg to about 1700 mg, from about 350 mg to about 1600 mg, from about 350 mg to about 1500 mg, from about 350 mg to about 1400 mg, from about 350 mg to about 1300 mg, from about 350 mg to about 1200 mg, from about 350 mg to about 1100 mg, from about 350 mg to about 1000 mg, from about 350 mg to about 900 mg, from about 350 mg to about 800 mg, from about 350 mg to about 700 mg, from about 350 mg to about 600 mg, from about 350 mg to about 500 mg, from about 350 mg to about 400 mg, from about 400 mg to about 4000 mg, from about 400 mg to about 3900 mg, from about 400 mg to about 3800 mg, from about 400 mg to about 3700 mg, from about 400 mg to about 3600 mg, from about 400 mg to about 3500 mg, from about 400 mg to about 3400 mg, from about 400 mg to about 3300 mg, from about 400 mg to about 3200 mg, from about 400 mg to about 3100 mg, from about 400 mg to about 3000 mg, from about 400 mg to about 2900 mg, from about 400 mg to about 2800 mg, from about 400 mg to about 2700 mg, from about 400 mg to about 2600 mg, from about 400 mg to about 2500 mg, from about 400 mg to about 2400 mg, from about 400 mg to about 2300 mg, from about 400 mg to about 2200 mg, from about 400 mg to about 2100 mg, from about 400 mg to about 2000 mg, from about 400 mg to about 1900 mg, from about 400 mg to about 1800 mg, from about 400 mg to about 1700 mg, from about 400 mg to about 1600 mg, from about 400 mg to about 1500 mg, from about 400 mg to about 1400 mg, from about 400 mg to about 1300 mg, from about 400 mg to about 1200 mg, from about 400 mg to about 1100 mg, from about 400 mg to about 1000 mg, from about 400 mg to about 900 mg, from about 400 mg to about 800 mg, from about 400 mg to about 700 mg, from about 400 mg to about 600 mg, from about 400 mg to about 500 mg, from about 450 mg to about 4000 mg, from about 450 mg to about 3900 mg, from about 450 mg to about 3800 mg, from about 450 mg to about 3700 mg, from about 450 mg to about 3600 mg, from about 450 mg to about 3500 mg, from about 450 mg to about 3400 mg, from about 450 mg to about 3300 mg, from about 450 mg to about 3200 mg, from about 450 mg to about 3100 mg, from about 450 mg to about 3000 mgFrom about 450 mg to about 2900 mg, from about 450 mg to about 2800 mg, from about 450 mg to about 2700 mg, from about 450 mg to about 2600 mg, from about 450 mg to about 2500 mg, from about 450 mg to about 2400 mg, from about 450 mg to about 2300 mg, from about 450 mg to about 2200 mg, from about 450 mg to about, 2100 mg, from about 450 mg to about 2000 mg, from about 450 mg to about 1900 mg, from about 450 mg to about 1800 mg, from about 450 mg to about 1700 mg, from about 450 mg to about 1600 mg, from about 450 mg to about 1500 mg, from about 450 mg to about 1400 mg, from about 450 mg to about 1300 mg, from about 450 mg to about 1200 mg, from about 450 mg to about 1100 mg, from about 450 mg to about 1000 mg, from about 450 mg to about 900 mg, from about 450 mg to about 800 mg, from about 450 mg to about 700 mg, from about 450 mg to about 600 mg or from about 450 mg to about 500 mg.

[0141] Specifically, the targets are 50mg, 75mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1000mg, 1025mg, 1050mg, 1075mg, 1100mg, 1125mg, 1150mg, 1175mg, 1200mg, 1225mg, 1250mg, 1275mg, 1300mg, 1325mg, 1350mg, 1375mg, 1400mg, 1425mg, 1450mg, 1475mg, 1500mg, 1525mg, 1550mg, 1575mg, 1600mg, 1625mg, 1650mg, 1675mg, 1700mg, 1725mg, 1750mg, 1775mg, 1800mg, 1825mg, 1850mg, 1875mg, 1900mg, 1925mg, 1950mg, 1975mg, 2000mg, 2025mg, 2050mg, 2075mg, 2100mg, 2125mg, 2150mg, 2175mg, 2200mg, 2225mg, 2250mg, 2275mg, 2300mg, 2325mg, 2350mg, 2375mg, 2400mg, 2425mg, 2450mg, 2475mg, 2500mg, 2525mg, 2550mg, 2575mg, 2600mg, 2625mg, 2650mg, 2675mg, 2700mg, 2725mg, 2750mg, 2775mg, 2800mg, 2825mg, 2850mg, 2875mg, 2900mg, 2925mg, 2950mg, 2975mg, 3000mg, 3025mg, 3050mg, 3075mg, 3100mg, 3125mg, 3150mg, 3175mg, 3200mg, 3225mg, 3250mg, 3275mg, 3300mg, 3325mg, 3350mg, 3375mg, 3400mg, 3425mg, 3450mg, 3475mg, 3500mg, 3525mg, 3550mg, 3575mg, 3600mg, 3625mg, 3650mg, 3675mg, 3700mg, 3725mg,3750 mg, 3775 mg, 3800 mg, 3825 mg, 3850 mg, 3875 mg, 3900 mg, 3925 mg, 3950 mg, 3975 mg, or 4000 mg may be administered.

[0142] The dosage of the antibody or antibody portion described herein may be administered once a week, once every other week, once every two weeks, once every three weeks, once every four weeks, once a month, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every two months, once every nine weeks, once every ten weeks, once every eleven weeks, or once every twelve weeks, at the discretion of the person administering the composition or the person directing the administration of the composition, according to the needs of the individual. The dosage ranges described herein are merely exemplary and are not intended to limit the scope or practice of the claimed composition.

[0143] In one embodiment, a fixed dosage of one or more of the antibodies described herein may be administered to a subject. Exemplary and non-limiting amounts of the antibody or antibody portion described herein that are therapeutically or prophylactically effective include up to about 200 mg / kg, up to about 190 mg / kg, up to about 180 mg / kg, up to about 170 mg / kg, up to about 160 mg / kg, up to about 150 mg / kg, up to about 140 mg / kg, up to about 130 mg / kg, up to about 120 mg / kg, up to about 110 mg / kg, up to about 100 mg / kg, up to about 90 mg / kg, up to about 80 mg / kg, up to about 70 mg / kg, up to about 60 mg / kg, up to about 50 mg / kg, up to about 40 mg / kg, up to about 30 mg / kg, up to about 20 mg / kg, up to about 10 mg / kg, up to about 5 mg / kg, or up to about 2.5 mg / kg.

[0144] Administration of the antibody to the patient can be intravenous, intraarterial, intraperitoneal, intramuscular, subcutaneous, intrathoracic, intrathecal, intraocular, intravitreal, perfusion by local catheter or direct intralesional injection. When administering a therapeutic protein by injection, the administration can be by continuous infusion or by single or multiple boluses. Intravenous injection provides a useful mode of administration due to thorough circulation in the rapidly distributing antibody. The antibody can be administered orally, for example, with an inert diluent or assimilable edible carrier. Optionally, the antibody and other components can be enclosed in hard or soft shell gelatin capsules and compressed into tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc.

[0145] In one embodiment, when one or more of the antibodies described herein are administered intravenously to a patient as a fixed dose, the therapeutically effective amount or prophylactically effective amount of the antibody or antibody portion that can be administered is from about 50 mg to about 4000 mg, from about 50 mg to about 3900 mg, from about 50 mg to about 3800 mg, from about 50 mg to about 3700 mg, from about 50 mg to about 3600 mg, from about 50 mg to about 3500 mg, from about 50 mg to about 3400 mg, from about 50 mg to about 3300 mg, from about 50 mg to about 3200 mg, from about 50 mg to about 3100 mg, from about 50 mg to about 3000 mg, from about 50 mg to about 2900 mg, from about 50 mg to about 2800 mg, from about 50 mg to about 2700 mg, from about 50 mg to about 2600 mg, from about 50 mg to about 2500 mg, from about 50 mg to about 2400 mg, from about 50 mg to about 2300 mg, from about 50 mg to about 2200 mg, from about 50 mg to about 2100 mg, from about 50 mg to about 2000 mg, from about 50 mg to about 1900 mg, from about 50 mg to about 1800 mg, from about 50 mg to about 1700 mg, from about 50 mg to about 1600 mg, from about 50 mg to about 1500 mg, from about 50 mg to about 1400 mg, from about 50 mg to about 1300 mg, from about 50 mg to about 1200 mg, from about 50 mg to about 1100 mg, from about 50 mg to about 1000 mg, from about 50 mg to about 900 mg, from about 50 mg to about 800 mg, from about 50 mg to about 700 mg, from about 50 mg to about 600 mg, from about 50 mg to about 500 mg, from about 50 mg to about 400 mg, from about 50 mg to about 300 mg, from about 100 mg to about 4000 mg, from about 100 mg to about 3900 mg, from about 100 mg to about 3800 mg, from about 100 mg to about 3700 mg, from about 100 mg to about 3600 mg, from about 100 mg to about 3500 mg, from about 100 mg to about 3400 mg, from about 100 mg to about 3300 mg, from about 100 mg to about 3200 mg, from about 100 mg to about 3100 mg, from about 100 mg to about 3000 mg, from about 100 mg to about 2900 mg, from about 100 mg to about 2800 mg, from about 100 mg to about 2700 mg, from about 100 mg to about 2600 mg, from about 100 mg to about 2500 mg, from about 100 mg to about 2400 mg, from about 100 mg to about 2300 mg, from about 100 mg to about 2200 mg, from about 100 mg to about 2100 mg, from about 100 mg to about 2000 mg, from about 100 mg to about 1900 mg,From about 100 mg to about 1800 mg, from about 100 mg to about 1700 mg, from about 100 mg to about 1600 mg, from about 100 mg to about 1500 mg, from about 100 mg to about 1400 mg, from about 100 mg to about 1300 mg, from about 100 mg to about 1200 mg, from about 100 mg to about 1100 mg, from about 100 mg to about 1000 mg, from about 100 mg to about 900 mg, from about 100 mg to about 800 mg, from about 100 mg to about 700 mg, from about 100 mg to about 600 mg, from about 100 mg to about 500 mg, from about 100 mg to about 400 mg, from about 100 mg to about 300 mg, from about 150 mg to about 4000 mg, from about 150 mg to about 3900 mg, from about 150 mg to about 3800 mg, from about 150 mg to about 3700 mg, from about 150 mg to about 3600 mg, from about 150 mg to about 3500 mg, from about 150 mg to about 3400 mg, from about 150 mg to about 3300 mg, from about 150 mg to about 3200 mg, from about 150 mg to about 3100 mg, from about 150 mg to about 3000 mg, from about 150 mg to about 2900 mg, from about 150 mg to about 2800 mg, from about 150 mg to about 2700 mg, from about 150 mg to about 2600 mg, from about 150 mg to about 2500 mg, from about 150 mg to about 2400 mg, from about 150 mg to about 2300 mg, from about 150 mg to about 2200 mg, from about 150 mg to about 2100 mg, from about 150 mg to about 2000 mg, from about 150 mg to about 1900 mg, from about 150 mg to about 1800 mg, from about 150 mg to about 1700 mg, from about 150 mg to about 1600 mg, from about 150 mg to about 1500 mg, from about 150 mg to about 1400 mg, from about 150 mg to about 1300 mg, from about 150 mg to about 1200 mg, from about 150 mg to about 1100 mg, from about 150 mg to about 1000 mg, from about 150 mg to about 900 mg, from about 150 mg to about 800 mg, from about 150 mg to about 700 mg, from about 150 mg to about 600 mg, from about 150 mg to about 500 mg, from about 150 mg to about 400 mg, from about 150 mg to about 300 mg, from about 200 mg to about 4000 mg, from about 200 mg to about 3900 mg, from about 200 mg to about 3800 mg, from about 200 mg to about 3700 mg, from about 200 mg to about 3600 mg, from about 200 mg to about 3500 mg, from about 200 mg to about 3400 mg, from about 200 mg to about 3300 mg, from about 200 mg to about 3200 mgFrom about 200 mg to about 3100 mg, from about 200 mg to about 3000 mg, from about 200 mg to about 2900 mg, from about 200 mg to about 2800 mg, from about 200 mg to about 2700 mg, from about 200 mg to about 2600 mg, from about 200 mg to about 2500 mg, from about 200 mg to about 2400 mg, from about 200 mg to about 2300 mg, from about 200 mg to about 2200 mg, from about 200 mg to about 2100 mg, from about 200 mg to about 2000 mg, from about 200 mg to about 1900 mg, from about 200 mg to about 1800 mg, from about 200 mg to about 1700 mg, from about 200 mg to about 1600 mg, from about 200 mg to about 1500 mg, from about 200 mg to about 1400 mg, from about 200 mg to about 1300 mg, from about 200 mg to about 1200 mg, from about 200 mg to about 1100 mg, from about 200 mg to about 1000 mg, from about 200 mg to about 900 mg, from about 200 mg to about 800 mg, from about 200 mg to about 700 mg, from about 200 mg to about 600 mg, from about 200 mg to about 500 mg, from about 200 mg to about 400 mg, from about 200 mg to about 300 mg, from about 250 mg to about 4000 mg, from about 250 mg to about 3900 mg, from about 250 mg to about 3800 mg, from about 250 mg to about 3700 mg, from about 250 mg to about 3600 mg, from about 250 mg to about 3500 mg, from about 250 mg to about 3400 mg, from about 250 mg to about 3300 mg, from about 250 mg to about 3200 mg, from about 250 mg to about 3100 mg, from about 250 mg to about 3000 mg, from about 250 mg to about 2900 mg, from about 250 mg to about 2800 mg, from about 250 mg to about 2700 mg, from about 250 mg to about 2600 mg, from about 250 mg to about 2500 mg, from about 250 mg to about 2400 mg, from about 250 mg to about 2300 mg, from about 250 mg to about 2200 mg, from about 250 mg to about 2100 mg, from about 250 mg to about 2000 mg, from about 250 mg to about 1900 mg, from about 250 mg to about 1800 mg, from about 250 mg to about 1700 mg, from about 250 mg to about 1600 mg, from about 250 mg to about 1500 mg, from about 250 mg to about 1400 mg, from about 250 mg to about 1300 mg, from about 250 mg to about 1200 mg, from about 250 mg to about 1100 mg, from about 250 mg to about 1000 mg, from about 250 mg to about 900 mg, from about 250 mg to about 800 mg, from about 250 mg to about 700 mgFrom about 250 mg to about 600 mg, from about 250 mg to about 500 mg, from about 250 mg to about 400 mg, from about 250 mg to about 300 mg, from about 300 mg to about 4000 mg, from about 300 mg to about 3900 mg, from about 300 mg to about 3800 mg, from about 300 mg to about 3700 mg, from about 300 mg to about 3600 mg, from about 300 mg to about 3500 mg, from about 300 mg to about 3400 mg, from about 300 mg to about 3300 mg, from about 300 mg to about 3200 mg, from about 300 mg to about 3100 mg, from about 300 mg to about 3000 mg, from about 300 mg to about 2900 mg, from about 300 mg to about 2800 mg, from about 300 mg to about 2700 mg, from about 300 mg to about 2600 mg, from about 300 mg to about 2500 mg, from about 300 mg to about 2400 mg, from about 300 mg to about 2300 mg, from about 300 mg to about 2200 mg, from about 300 mg to about 2100 mg, from about 300 mg to about 2000 mg, from about 300 mg to about 1900 mg, from about 300 mg to about 1800 mg, from about 300 mg to about 1700 mg, from about 300 mg to about 1600 mg, from about 300 mg to about 1500 mg, from about 300 mg to about 1400 mg, from about 300 mg to about 1300 mg, from about 300 mg to about 1200 mg, from about 300 mg to about 1100 mg, from about 300 mg to about 1000 mg, from about 300 mg to about 900 mg, from about 300 mg to about 800 mg, from about 300 mg to about 700 mg, from about 300 mg to about 600 mg, from about 300 mg to about 500 mg, from about 300 mg to about 400 mg, from about 350 mg to about 4000 mg, from about 350 mg to about 3900 mg, from about 350 mg to about 3800 mg, from about 350 mg to about 3700 mg, from about 350 mg to about 3600 mg, from about 350 mg to about 3500 mg, from about 350 mg to about 3400 mg, from about 350 mg to about 3300 mg, from about 350 mg to about 3200 mg, from about 350 mg to about 3100 mg, from about 350 mg to about 3000 mg, from about 350 mg to about 2900 mg, from about 350 mg to about 2800 mg, from about 350 mg to about 2700 mg, from about 350 mg to about 2600 mg, from about 350 mg to about 2500 mg, from about 350 mg to about 2400 mg, from about 350 mg to about 2300 mg, from about 350 mg to about 2200 mg, from about 350 mg to about 2100 mg, from about 350 mg to about 2000 mg, from about 350 mg to about 1900 mgfrom about 350 mg to about 1800 mg, from about 350 mg to about 1700 mg, from about 350 mg to about 1600 mg, from about 350 mg to about 1500 mg, from about 350 mg to about 1400 mg, from about 350 mg to about 1300 mg, from about 350 mg to about 1200 mg, from about 350 mg to about 1100 mg, from about 350 mg to about 1000 mg, from about 350 mg to about 900 mg, from about 350 mg to about 800 mg, from about 350 mg to about 700 mg, from about 350 mg to about 600 mg, from about 350 mg to about 500 mg, from about 350 mg to about 400 mg, from about 400 mg to about 4000 mg, from about 400 mg to about 3900 mg, from about 400 mg to about 3800 mg, from about 400 mg to about 3700 mg, from about 400 mg to about 3600 mg, from about 400 mg to about 3500 mg, from about 400 mg to about 3400 mg, from about 400 mg to about 3300 mg, from about 400 mg to about 3200 mg, from about 400 mg to about 3100 mg, from about 400 mg to about 3000 mg, from about 400 mg to about 2900 mg, from about 400 mg to about 2800 mg, from about 400 mg to about 2700 mg, from about 400 mg to about 2600 mg, from about 400 mg to about 2500 mg, from about 400 mg to about 2400 mg, from about 400 mg to about 2300 mg, from about 400 mg to about 2200 mg, from about 400 mg to about 2100 mg, from about 400 mg to about 2000 mg, from about 400 mg to about 1900 mg, from about 400 mg to about 1800 mg, from about 400 mg to about 1700 mg, from about 400 mg to about 1600 mg, from about 400 mg to about 1500 mg, from about 400 mg to about 1400 mg, from about 400 mg to about 1300 mg, from about 400 mg to about 1200 mg, from about 400 mg to about 1100 mg, from about 400 mg to about 1000 mg, from about 400 mg to about 900 mg, from about 400 mg to about 800 mg, from about 400 mg to about 700 mg, from about 400 mg to about 600 mg, from about 400 mg to about 500 mg, from about 450 mg to about 4000 mg, from about 450 mg to about 3900 mg, from about 450 mg to about 3800 mg, from about 450 mg to about 3700 mg, from about 450 mg to about 3600 mg, from about 450 mg to about 3500 mg, from about 450 mg to about 3400 mg, from about 450 mg to about 3300 mg, from about 450 mg to about 3200 mg, from about 450 mg to about 3100 mg, from about 450 mg to about 3000 mg, from about 450 mg to about 2900 mgFrom about 450 mg to about 2800 mg, from about 450 mg to about 2700 mg, from about 450 mg to about 2600 mg, from about 450 mg to about 2500 mg, from about 450 mg to about 2400 mg, from about 450 mg to about 2300 mg, from about 450 mg to about 2200 mg, from about 450 mg to about 2100 mg, from about 450 mg to, about 2000 mg, from about 450 mg to about 1900 mg, from about 450 mg to about 1800 mg, from about 450 mg to about 1700 mg, from about 450 mg to about 1600 mg, from about 450 mg to about 1500 mg, from about 450 mg to about 1400 mg, from about 450 mg to about 1300 mg, from about 450 mg to about 1200 mg, from about 450 mg to about 1100 mg, from about 450 mg to about 1000 mg, from about 450 mg to about 900 mg, from about 450 mg to about 800 mg, from about 450 mg to about 700 mg, from about 450 mg to about 600 mg or from about 450 mg to about 500 mg.

[0146] Specifically, the patient takes 50mg, 75mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1000mg, 1025mg, 1050mg, 1075mg, 1100mg, 1125mg, 1150mg, 1175mg, 1200mg, 1225mg, 1250mg, 1275mg, 1300mg, 1325mg, 1350mg, 1375mg, 1400mg, 1425mg, 1450mg, 1475mg, 1500mg, 1525mg, 1550mg, 1575mg, 1600mg, 1625mg, 1650mg, 1675mg, 1700mg, 1725mg, 1750mg, 1775mg, 1800mg, 1825mg, 1850mg, 1875mg, 1900mg, 1925mg, 1950mg, 1975mg, 2000mg, 2025mg, 2050mg, 2075mg, 2100mg, 2125mg, 2150mg, 2175mg, 2200mg, 2225mg, 2250mg, 2275mg, 2300mg, 2325mg, 2350mg, 2375mg, 2400mg, 2425mg, 2450mg, 2475mg, 2500mg, 2525mg, 2550mg, 2575mg, 2600mg, 2625mg, 2650mg, 2675mg, 2700mg, 2725mg, 2750mg, 2775mg, 2800mg, 2825mg, 2850mg, 2875mg, 2900mg, 2925mg, 2950mg, 2975mg, 3000mg, 3025mg, 3050mg, 3075mg, 3100mg, 3125mg, 3150mg, 3175mg, 3200mg, 3225mg, 3250mg, 3275mg, 3300mg, 3325mg, 3350mg, 3375mg, 3400mg, 3425mg, 3450mg, 3475mg, 3500mg, 3525mg, 3550mg, 3575mg, 3600mg, 3625mg, 3650mg, 3675mg, 3700mg, 3725mg,Doses of 3750 mg, 3775 mg, 3800 mg, 3825 mg, 3850 mg, 3875 mg, 3900 mg, 3925 mg, 3950 mg, 3975 mg, or 4000 mg may be administered.

[0147] The dosage of the antibodies or antibody portions described herein may be administered once a week, once every other week, once every two weeks, once every three weeks, once every four weeks, once a month, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every two months, once every nine weeks, once every ten weeks, once every eleven weeks, or once every twelve weeks, at the discretion of the person administering the composition or the person directing the administration of the composition, depending on the needs of the individual. The dosage ranges described herein are merely exemplary and are not intended to limit the scope or practice of the claimed composition.

[0148] In another embodiment, when one or more of the antibodies described herein are administered subcutaneously to a patient as a fixed dose, the therapeutically effective or prophylactically effective amount of the antibody or antibody portion that can be administered is from about 50 mg to about 500 mg, from 50 mg to about 400 mg, from about 50 mg to about 300 mg, from about 50 mg to about 200 mg, from about 50 mg to about 100 mg, from about 75 mg to about 500 mg, from 75 mg to about 400 mg, from about 75 mg to about 300 mg, from about 75 mg to about 200 mg, from about 75 mg to about 100 mg, from about 100 mg to about 500 mg, from about 100 mg to about 400 mg, from about 100 mg to about 300 mg, from about 100 mg to about 200 mg, from about 125 mg to about 500 mg, from 125 mg to about 400 mg, from about 125 mg to about 300 mg, from about 125 mg to about 200 mg, from about 150 mg to about 500 mg, from 150 mg to about 400 mg, from about 150 mg to about 300 mg, from about 150 mg to about 200 mg, from about 175 mg to about 500 mg, from 175 mg to about 400 mg, from about 175 mg to about 300 mg, from about 175 mg to about 200 mg, from about 200 mg to about 500 mg, from 200 mg to about 400 mg or from about 200 mg to about 300 mg. Specifically, the subject can be administered 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg or 500 mg.

[0149] The dosage of the antibody or antibody portion described herein can be administered once a week, once every other week, once every two weeks, once every three weeks, once every four weeks, once a month, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every two months, once every nine weeks, once every ten weeks, once every eleven weeks or once every twelve weeks, at the professional judgment of the person administering the composition or the person directing the administration of the composition, depending on the needs of the individual. The dosage ranges described herein are merely exemplary and are not intended to limit the scope or practice of the claimed composition.

[0150] In one embodiment, the treatment regimen of one or more antibodies described herein can be administered to a subject. Exemplary and non-limiting regimens are multiple variable dosing regimens. For example, a multiple variable dosing regimen can include a loading dose followed by at least one therapeutic dose that is less than the loading dose.

[0151] Anti-RGMa antibodies may undergo elimination via target-mediated pharmacokinetics. In certain embodiments, the loading dose is effective to overcome target-mediated pharmacokinetics.

[0152] In certain embodiments, the method includes achieving an early steady-state level of the antibody by providing a loading dose of the anti-RGMa antibody followed by subsequent doses of a smaller amount of the antibody.

[0153] In certain embodiments, the method includes achieving an early effective target trough serum concentration by providing a loading dose of the anti-RGMa antibody followed by subsequent doses of a smaller amount of the antibody.

[0154] In certain embodiments, the method includes achieving an early clinical effect by providing a loading dose of the anti-RGMa antibody followed by subsequent doses of a smaller amount of the antibody.

[0155] For example, the steady-state level, effective target trough serum concentration, and / or clinical effect are reached within 4 weeks, preferably within 3 weeks, more preferably within 2 weeks, most preferably within 1 week, such as within 6 days, within 5 days, within 4 days, within 3 days, within 2 days, or within 1 day. Thereafter, the steady-state level is maintained by administration of a smaller maintenance dose for the remainder of the treatment regimen or until suppression of the disease symptoms is achieved.

[0156] In one embodiment, the therapeutic dose is an amount that is at least 10% less, at least 20% less, at least 30% less, at least 40% less, at least 50% less, at least 60% less, at least 70% less, at least 80% less, or at least 90% less than the loading dose. Alternatively, the therapeutic dose can be about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% of the loading dose.

[0157] In one embodiment, the loading dose is from about 100 mg to about 4000 mg, from about 100 mg to about 3900 mg, from about 100 mg to about 3800 mg, from about 100 mg to about 3700 mg, from about 100 mg to about 3600 mg, from about 100 mg to about 3500 mg, from about 100 mg to about 3400 mg, from about 100 mg to about 3300 mg, from about 100 mg to about 3200 mg, from about 100 mg to about 3100 mg, from about 100 mg to about 3000 mg, from about 100 mg to about 2900 mg, from about 100 mg to about 2800 mg, from about 100 mg to about 2700 mg, from about 100 mg to about 2600 mg, from about 100 mg to about 2500 mg, from about 100 mg to about 2400 mg, from about 100 mg to about 2300 mg, from about 100 mg to about 2200 mg, from about 100 mg to about 2100 mg, from about 100 mg to about 2000 mg, from about 100 mg to about 1900 mg, from about 100 mg to about 1800 mg, from about 100 mg to about 1700 mg, from about 100 mg to about 1600 mg, from about 100 mg to about 1500 mg, from about 100 mg to about 1400 mg, from about 100 mg to about 1300 mg, from about 100 mg to about 1200 mg, from about 100 mg to about 1100 mg, from about 100 mg to about 1000 mg, from about 100 mg to about 900 mg, from about 100 mg to about 800 mg, from about 100 mg to about 700 mg, from about 100 mg to about 600 mg, from about 100 mg to about 500 mg, from about 100 mg to about 400 mg, from about 100 mg to about 300 mg, from about 150 mg to about 4000 mg, from about 150 mg to about 3900 mg, from about 150 mg to about 3800 mg, from about 150 mg to about 3700 mg, from about 150 mg to about 3600 mg, from about 150 mg to about 3500 mg, from about 150 mg to about 3400 mg, from about 150 mg to about 3300 mg, from about 150 mg to about 3200 mg, from about 150 mg to about 3100 mg, from about 150 mg to about 3000 mg, from about 150 mg to about 2900 mg, from about 150 mg to about 2800 mg, from about 150 mg to about 2700 mg, from about 150 mg to about 2600 mg, from about 150 mg to about 2500 mg, from about 150 mg to about 2400 mg, from about 150 mg to about 2300 mg, from about 150 mg to about 2200 mg, from about 150 mg to about 2100 mg, from about 150 mg to about 2000 mg, from about 150 mg to about 1900 mg, from about 150 mg to about 1800 mg, from about 150 mg to about 1700 mg,From about 150 mg to about 1600 mg, from about 150 mg to about 1500 mg, from about 150 mg to about 1400 mg, from about 150 mg to about 1300 mg, from about 150 mg to about 1200 mg, from about 150 mg to about 1100 mg, from about 150 mg to about 1000 mg, from about 150 mg to about 900 mg, from about 150 mg to about 800 mg, from about 150 mg to about 700 mg, from about 150 mg to about 600 mg, from about 150 mg to about 500 mg, from about 150 mg to about 400 mg, from about 150 mg to about 300 mg, from about 200 mg to about 4000 mg, from about 200 mg to about 3900 mg, from about 200 mg to about 3800 mg, from about 200 mg to about 3700 mg, from about 200 mg to about 3600 mg, from about 200 mg to about 3400 mg, from about 200 mg to about 3300 mg, from about 200 mg to about 3200 mg, from about 200 mg to about 3100 mg, from about 200 mg to about 3000 mg, from about 200 mg to about 2900 mg, from about 200 mg to about 2800 mg, from about 200 mg to about 2700 mg, from about 200 mg to about 2600 mg, from about 200 mg to about 2500 mg, from about 200 mg to about 2400 mg, from about 200 mg to about 2300 mg, from about 200 mg to about 2200 mg, from about 200 mg to about 2100 mg, from about 200 mg to about 2000 mg, from about 200 mg to about 1900 mg, from about 200 mg to about 1800 mg, from about 200 mg to about 1700 mg, from about 200 mg to about 1600 mg, from about 200 mg to about 1500 mg, from about 200 mg to about 1400 mg, from about 200 mg to about 1300 mg, from about 200 mg to about 1200 mg, from about 200 mg to about 1100 mg, from about 200 mg to about 1000 mg, from about 200 mg to about 900 mg, from about 200 mg to about 800 mg, from about 200 mg to about 700 mg, from about 200 mg to about 600 mg, from about 200 mg to about 500 mg, from about 200 mg to about 400 mg, from about 200 mg to about 300 mg, from about 250 mg to about 4000 mg, from about 250 mg to about 3900 mg, from about 250 mg to about 3800 mg, from about 250 mg to about 3700 mg, from about 250 mg to about 3600 mg, from about 250 mg to about 3500 mg, from about 250 mg to about 3400 mg, from about 250 mg to about 3300 mg, from about 250 mg to about 3200 mg, from about 250 mg to about 3100 mg, from about 250 mg to about 3000 mg, from about 250 mg to about 2900 mgFrom about 250 mg to about 2800 mg, from about 250 mg to about 2700 mg, from about 250 mg to about 2600 mg, from about 250 mg to about 2500 mg, from about 250 mg to about 2400 mg, from about 250 mg to about 2300 mg, from about 250 mg to about 2200 mg, from about 250 mg to about 2100 mg, from about 250 mg to about 2000 mg, from about 250 mg to about 1900 mg, from about 250 mg to about 1800 mg, from about 250 mg to about 1700 mg, from about 250 mg to about 1600 mg, from about 250 mg to about 1500 mg, from about 250 mg to about 1400 mg, from about 250 mg to about 1300 mg, from about 250 mg to about 1200 mg, from about 250 mg to about 1100 mg, from about 250 mg to about 1000 mg, from about 250 mg to about 900 mg, from about 250 mg to about 800 mg, from about 250 mg to about 700 mg, from about 250 mg to about 600 mg, from about 250 mg to about 500 mg, from about 250 mg to about 400 mg, from about 250 mg to about 300 mg, from about 300 mg to about 2500 mg, from about 300 mg to about 2400 mg, from about 300 mg to about 2300 mg, from about 300 mg to about 2200 mg, from about 300 mg to about 2100 mg, from about 300 mg to about 2000 mg, from about 300 mg to about 1900 mg, from about 300 mg to about 1800 mg, from about 300 mg to about 1700 mg, from about 300 mg to about 1600 mg, from about 300 mg to about 1500 mg, from about 300 mg to about 1400 mg, from about 300 mg to about 1300 mg, from about 300 mg to about 1200 mg, from about 300 mg to about 1100 mg, from about 300 mg to about 1000 mg, from about 300 mg to about 900 mg, from about 300 mg to about 800 mg, from about 300 mg to about 700 mg, from about 300 mg to about 600 mg, from about 300 mg to about 500 mg, from about 300 mg to about 400 mg, from about 350 mg to about 4000 mg, from about 350 mg to about 3900 mg, from about 350 mg to about 3800 mg, from about 350 mg to about 3700 mg, from about 350 mg to about 3600 mg, from about 350 mg to about 3500 mg, from about 350 mg to about 3400 mg, from about 350 mg to about 3300 mg, from about 350 mg to about 3200 mg, from about 350 mg to about 3100 mg, from about 350 mg to about 3000 mg, from about 350 mg to about 2900 mg, from about 350 mg to about 2800 mg, from about 350 mg to about 2700 mg, from about 350 mg to about 2600 mgfrom about 350 mg to about 2500 mg, from about 350 mg to about 2400 mg, from about 350 mg to about 2300 mg, from about 350 mg to about 2200 mg, from about 350 mg to about 2100 mg, from about 350 mg to about 2000 mg, from about 350 mg to about 1900 mg, from about 350 mg to about 1800 mg, from about 350 mg to about 1700 mg, from about 350 mg to about 1600 mg, from about 350 mg to about 1500 mg, from about 350 mg to about 1400 mg, from about 350 mg to about 1300 mg, from about 350 mg to about 1200 mg, from about 350 mg to about 1100 mg, from about 350 mg to about 1000 mg, from about 350 mg to about 900 mg, from about 350 mg to about 800 mg, from about 350 mg to about 700 mg, from about 350 mg to about 600 mg, from about 350 mg to about 500 mg, from about 350 mg to about 400 mg, from about 400 mg to about 4000 mg, from about 400 mg to about 3900 mg, from about 400 mg to about 3800 mg, from about 400 mg to about 3700 mg, from about 400 mg to about 3600 mg, from about 400 mg to about 3500 mg, from about 400 mg to about 3400 mg, from about 400 mg to about 3300 mg, from about 400 mg to about 3200 mg, from about 400 mg to about 3100 mg, from about 400 mg to about 3000 mg, from about 400 mg to about 2900 mg, from about 400 mg to about 2800 mg, from about 400 mg to about 2700 mg, from about 400 mg to about 2600 mg, from about 400 mg to about 2500 mg, from about 400 mg to about 2400 mg, from about 400 mg to about 2300 mg, from about 400 mg to about 2200 mg, from about 400 mg to about 2100 mg, from about 400 mg to about 2000 mg, from about 400 mg to about 1900 mg, from about 400 mg to about 1800 mg, from about 400 mg to about 1700 mg, from about 400 mg to about 1600 mg, from about 400 mg to about 1500 mg, from about 400 mg to about 1400 mg, from about 400 mg to about 1300 mg, from about 400 mg to about 1200 mg, from about 400 mg to about 1100 mg, from about 400 mg to about 1000 mg, from about 400 mg to about 900 mg, from about 400 mg to about 800 mg, from about 400 mg to about 700 mg, from about 400 mg to about 600 mg, from about 400 mg to about 500 mg, from about 450 mg to about 4000 mg, from about 450 mg to about 3900 mg, from about 450 mg to about 3800 mg, from about 450 mg to about 3700 mg, from about 450 mg to about 3600 mgFrom about 450 mg to about 3500 mg, from about 450 mg to about 3400 mg, from about 450 mg to about 3300 mg, from about 450 mg to about 3200 mg, from about 450 mg to about 3100 mg, from about 450 mg to about 3000 mg, from about 450 mg to about 2900 mg, from about 450 mg to about 2800 mg, from about 450 mg to about 2700 mg, from about 450 mg to about 2600 mg, from about 450 mg to about 2500 mg, from about 450 mg to about 2400 mg, from about 450 mg to about 2300 mg, from about 450 mg to about 2200 mg, from about 450 mg to about 2100 mg, from about 450 mg to about 2000 mg, from about 450 mg to about 1900 mg, from about 450 mg to about 1800 mg, from about 450 mg to about 1700 mg, from about 450 mg to about 1600 mg, from about 450 mg to about 1500 mg, from about 450 mg to about 1400 mg, from about 450 mg to about 1300 mg, from about 450 mg to about 1200 mg, from about 450 mg to about 1100 mg, from about 450 mg to about 1000 mg, from about 450 mg to about 900 mg, from about 450 mg to about 800 mg, from about 450 mg to about 700 mg, from about 450 mg to about 600 mg or from about 450 mg to about 500 mg.

[0158] Specifically, the targets are 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1000mg, 1025mg, 1050mg, 1075mg, 1100mg, 1125mg, 1150mg, 1175mg, 1200mg, 1225mg, 1250mg, 1275mg, 1300mg, 1325mg, 1350mg, 1375mg, 1400mg, 1425mg, 1450mg, 1475mg, 1500mg, 1525mg, 1550mg, 1575mg, 1600mg, 1625mg, 1650mg, 1675mg, 1700mg, 1725mg, 1750mg, 1775mg, 1800mg, 1825mg, 1850mg, 1875mg, 1900mg, 1925mg, 1950mg, 1975mg, 2000mg, 2025mg, 2050mg, 2075mg, 2100mg, 2125mg, 2150mg, 2175mg, 2200mg, 2225mg, 2250mg, 2275mg, 2300mg, 2325mg, 2350mg, 2375mg, 2400mg, 2425mg, 2450mg, 2475mg, 2500mg, 2525mg, 2550mg, 2575mg, 2600mg, 2625mg, 2650mg, 2675mg, 2700mg, 2725mg, 2750mg, 2775mg, 2800mg, 2825mg, 2850mg, 2875mg, 2900mg, 2925mg, 2950mg, 2975mg, 3000mg, 3025mg, 3050mg, 3075mg, 3300mg, 3325mg, 3350mg, 3375mg, 3200mg, 3225mg, 3250mg, 3275mg, 3300mg, 3325mg, 3350mg, 3375mg, 3400mg, 3425mg, 3450mg, 3475mg, 3500mg, 3525mg, 3550mg, 3575mg, 3600mg, 3625mg, 3650mg, 3675mg, 3700mg, 3725mg, 3750mg,Loading doses of 3775 mg, 3800 mg, 3825 mg, 3850 mg, 3875 mg, 3900 mg, 3925 mg, 3950 mg, 3975 mg, or 4000 mg may be administered.

[0159] In certain embodiments, the loading dose comprises more than one dose, which may be administered over one or more days. In certain embodiments, the loading dose comprises more than two doses, and each dose is administered on a separate day. Thus, the loading dose may be administered as one, two, or more doses, and each dose is administered during the loading dose phase. The loading dose phase may include about 14 days, about 13 days, about 12 days, about 11 days, about 10 days, about 9 days, about 8 days, about 7 days, about 6 days, about 5 days, about 4 days, about 3 days, about 2 days, or about 1 day. For example, the loading dose may be administered as two doses over two consecutive days. In certain embodiments, the loading dose comprises a first dose of about 1800 mg and a second dose of about 1800 mg, optionally administered one or more days apart during the loading dose phase. In certain other embodiments, the loading dose comprises a single dose, such as a single dose of about 100 mg, about 300 mg, or about 1200 mg.

[0160] In certain embodiments, more than one loading dose is administered. For example, the first loading dose may be administered at a first time point (over one or more days), and subsequent loading doses may be administered at subsequent time points (over one or more days). In certain embodiments, the interval between the first time point and the subsequent time point is at least one week, at least two weeks, at least three weeks, at least four weeks, at least one month, at least five weeks, at least six weeks, at least seven weeks, at least eight weeks, at least two months, at least nine weeks, at least ten weeks, at least eleven weeks, or at least twelve weeks. In certain embodiments, the interval between the first time point and the subsequent time point is about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, about eight weeks, about nine weeks, about ten weeks, about eleven weeks, or about twelve weeks.

[0161] In one embodiment, the therapeutic dose is from about 50 mg to about 2500 mg, from about 50 mg to about 2400 mg, from about 50 mg to about 2300 mg, from about 50 mg to about 2200 mg, from about 50 mg to about 2100 mg, from about 50 mg to about 2000 mg, from about 50 mg to about 1900 mg, from about 50 mg to about 1800 mg, from about 50 mg to about 1700 mg, from about 50 mg to about 1600 mg, from about 50 mg to about 1500 mg, from about 50 mg to about 1400 mg, from about 50 mg to about 1300 mg, from about 50 mg to about 1200 mg, from about 50 mg to about 1100 mg, from about 50 mg to about 1000 mg, from about 50 mg to about 900 mg, from about 50 mg to about 800 mg, from about 50 mg to about 700 mg, from about 50 mg to about 600 mg, from about 50 mg to about 500 mg, from about 50 mg to about 400 mg, from about 50 mg to about 300 mg, from 100 mg to about 2500 mg, from about 100 mg to about 2400 mg, from about 100 mg to about 2300 mg, from about 100 mg to about 2200 mg, from about 100 mg to about 2100 mg, from about 100 mg to about 2000 mg, from about 100 mg to about 1900 mg, from about 100 mg to about 1800 mg, from about 100 mg to about 1700 mg, from about 100 mg to about 1600 mg, from about 100 mg to about 1500 mg, from about 100 mg to about 1400 mg, from about 100 mg to about 1300 mg, from about 100 mg to about 1200 mg, from about 100 mg to about 1100 mg, from about 100 mg to about 1000 mg, from about 100 mg to about 900 mg, from about 100 mg to about 800 mg, from about 100 mg to about 700 mg, from about 100 mg to about 600 mg, from about 100 mg to about 500 mg, from about 100 mg to about 400 mg, from about 100 mg to about 300 mg, from about 150 mg to about 2500 mg, from about 150 mg to about 2400 mg, from about 150 mg to about 2300 mg, from about 150 mg to about 2200 mg, from about 150 mg to about 2100 mg, from about 150 mg to about 2000 mg, from about 150 mg to about 1900 mg, from about 150 mg to about 1800 mg, from about 150 mg to about 1700 mg, from about 150 mg to about 1600 mg, from about 150 mg to about 1500 mg, from about 150 mg to about 1400 mg, from about 150 mg to about 1300 mg, from about 150 mg to about 1200 mg, from about 150 mg to about 1100 mg, from about 150 mg to about 1000 mg, from about 150 mg to about 900 mg, from about 150 mg to about 800 mg,from about 150 mg to about 700 mg, from about 150 mg to about 600 mg, from about 150 mg to about 500 mg, from about 150 mg to about 400 mg, from about 150 mg to about 300 mg, from about 200 mg to about 2500 mg, from about 200 mg to about 2400 mg, from about 200 mg to about 2300 mg, from about 200 mg to about 2200 mg, from about 200 mg to about 2100 mg, from about 200 mg to about 2000 mg, from about 200 mg to about 1900 mg, from about 200 mg to about 1800 mg, from about 200 mg to about 1700 mg, from about 200 mg to about 1600 mg, from about 200 mg to about 1500 mg, from about 200 mg to about 1400 mg, from about 200 mg to about 1300 mg, from about 200 mg to about 1200 mg, from about 200 mg to about 1100 mg, from about 200 mg to about 1000 mg, from about 200 mg to about 900 mg, from about 200 mg to about 800 mg, from about 200 mg to about 700 mg, from about 200 mg to about 600 mg, from about 200 mg to about 500 mg, from about 200 mg to about 400 mg, from about 200 mg to about 300 mg, from about 250 mg to about 2500 mg, from about 250 mg to about 2400 mg, from about 250 mg to about 2300 mg, from about 250 mg to about 2200 mg, from about 250 mg to about 2100 mg, from about 250 mg to about 2000 mg, from about 250 mg to about 1900 mg, from about 250 mg to about 1800 mg, from about 250 mg to about 1700 mg, from about 250 mg to about 1600 mg, from about 250 mg to about 1500 mg, from about 250 mg to about 1400 mg, from about 250 mg to about 1300 mg, from about 250 mg to about 1200 mg, from about 250 mg to about 1100 mg, from about 250 mg to about 1000 mg, from about 250 mg to about 900 mg, from about 250 mg to about 800 mg, from about 250 mg to about 700 mg, from about 250 mg to about 600 mg, from about 250 mg to about 500 mg, from about 250 mg to about 400 mg, from about 250 mg to about 300 mg, from about 300 mg to about 2500 mg, from about 300 mg to about 2400 mg, from about 300 mg to about 2300 mg, from about 300 mg to about 2200 mg, from about 300 mg to about 2100 mg, from about 300 mg to about 2000 mg, from about 300 mg to about 1900 mg, from about 300 mg to about 1800 mg, from about 300 mg to about 1700 mg, from about 300 mg to about 1600 mg, from about 300 mg to about 1500 mg, from about 300 mg to about 1400 mg,From about 300 mg to about 1300 mg, from about 300 mg to about 1200 mg, from about 300 mg to about 1100 mg, from about 300 mg to about 1000 mg, from about 300 mg to about 900 mg, from about 300 mg to about 800 mg, from about 300 mg to about 700 mg, from about 300 mg to about 600 mg, from about 300 mg to about 500 mg, from about 300 mg to about 400 mg, from about 350 mg to about 4000 mg, from about 350 mg to about 3900 mg, from about 350 mg to about 3800 mg, from about 350 mg to about 3700 mg, from about 350 mg to about 3600 mg, from about 350 mg to about 3500 mg, from about 350 mg to about 3400 mg, from about 350 mg to about 3300 mg, from about 350 mg to about 3200 mg, from about 350 mg to about 3100 mg, from about 350 mg to about 3000 mg, from about 350 mg to about 2900 mg, from about 350 mg to about 2800 mg, from about 350 mg to about 2700 mg, from about 350 mg to about 2600 mg, from about 350 mg to about 2500 mg, from about 350 mg to about 2400 mg, from about 350 mg to about 2300 mg, from about 350 mg to about 2200 mg, from about 350 mg to about 2100 mg, from about 350 mg to about 2000 mg, from about 350 mg to about 1900 mg, from about 350 mg to about 1800 mg, from about 350 mg to about 1700 mg, from about 350 mg to about 1600 mg, from about 350 mg to about 1500 mg, from about 350 mg to about 1400 mg, from about 350 mg to about 1300 mg, from about 350 mg to about 1200 mg, from about 350 mg to about 1100 mg, from about 350 mg to about 1000 mg, from about 350 mg to about 900 mg, from about 350 mg to about 800 mg, from about 350 mg to about 700 mg, from about 350 mg to about 600 mg, from about 350 mg to about 500 mg, from about 350 mg to about 400 mg, from about 400 mg to about 4000 mg, from about 400 mg to about 3900 mg, from about 400 mg to about 3800 mg, from about 400 mg to about 3700 mg, from about 400 mg to about 3600 mg, from about 400 mg to about 3500 mg, from about 400 mg to about 3400 mg, from about 400 mg to about 3300 mg, from about 400 mg to about 3200 mg, from about 400 mg to about 3100 mg, from about 400 mg to about 3000 mg, from about 400 mg to about 2900 mg, from about 400 mg to about 2800 mg, from about 400 mg to about 2700 mg, from about 400 mg to about 2600 mg, from about 400 mg to about 2500 mg,From about 400 mg to about 2400 mg, from about 400 mg to about 2300 mg, from about 400 mg to about 2200 mg, from about 400 mg to about 2100 mg, from about 400 mg to about 2000 mg, from about 400 mg to about 1900 mg, from about 400 mg to about 1800 mg, from about 400 mg to about 1700 mg, from about 400 mg to about 1600 mg, from about 400 mg to about 1500 mg, from about 400 mg to about 1400 mg, from about 400 mg to about 1300 mg, from about 400 mg to about 1200 mg, from about 400 mg to about 1100 mg, from about 400 mg to about 1000 mg, from about 400 mg to about 900 mg, from about 400 mg to about 800 mg, from about 400 mg to about 700 mg, from about 400 mg to about 600 mg, from about 400 mg to about 500 mg, from about 450 mg to about 4000 mg, from about 450 mg to about 3900 mg, from about 450 mg to about 3800 mg, from about 450 mg to about 3700 mg, from about 450 mg to about 3600 mg, from about 450 mg to about 3500 mg, from about 450 mg to about 3400 mg, from about 450 mg to about 3300 mg, from about 450 mg to about 3200 mg, from about 450 mg to about 3100 mg, from about 450 mg to about 3000 mg, from about 450 mg to about 2900 mg, from about 450 mg to about 2800 mg, from about 450 mg to about 2700 mg, from about 450 mg to about 2600 mg, from about 450 mg to about 2500 mg, from about 450 mg to about 2400 mg, from about 450 mg to about 2300 mg, from about 450 mg to about 2200 mg, from about 450 mg to about 2100 mg, from about 450 mg to about 2000 mg, from about 450 mg to about 1900 mg, from about 450 mg to about 1800 mg, from about 450 mg to about 1700 mg, from about 450 mg to about 1600 mg, from about 450 mg to about 1500 mg, from about 450 mg to about 1400 mg, from about 450 mg to about 1300 mg, from about 450 mg to about 1200 mg, from about 450 mg to about 1100 mg, from about 450 mg to about 1000 mg, from about 450 mg to about 900 mg, from about 450 mg to about 800 mg, from about 450 mg to about 700 mg, from about 450 mg to about 600 mg or from about 450 mg to about 500 mg.,

[0162] Specifically, the subject can be administered a therapeutic dose of 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1025 mg, 1050 mg, 1075 mg, 1100 mg, 1125 mg, 1150 mg, 1175 mg, 1200 mg, 1225 mg, 1250 mg, 1275 mg, 1300 mg, 1325 mg, 1350 mg, 1375 mg, 1400 mg, 1425 mg, 1450 mg, 1475 mg, 1500 mg, 1525 mg, 1550 mg, 1575 mg, 1600 mg, 1625 mg, 1650 mg, 1675 mg, 1700 mg, 1725 mg, 1750 mg, 1775 mg, 1800 mg, 1825 mg, 1850 mg, 1875 mg, 1900 mg, 1925 mg, 1950 mg, 1975 mg, 2000 mg, 2025 mg, 2050 mg, 2075 mg, 2100 mg, 2125 mg, 2150 mg, 2175 mg, 2200 mg, 2225 mg, 2250 mg, 2275 mg, 2300 mg, 2325 mg, 2350 mg, 2375 mg, 2400 mg, 2425 mg, 2450 mg, 2475 mg, or 2500 mg.

[0163] In one embodiment, the loading dose is twice the therapeutic dose. For example, the loading dose can be 100 mg of the antibody or antigen-binding fragment thereof, and the subsequent therapeutic dose can be 50 mg. As another example, the loading dose can be 300 mg of the antibody or antigen-binding fragment thereof, and the subsequent therapeutic dose can be 150 mg. As yet another example, the loading dose can be 1200 mg of the antibody or antigen-binding fragment thereof, and the subsequent therapeutic dose can be 600 mg. As yet another example, the loading dose can be 3600 mg of the antibody or antigen-binding fragment thereof, and the subsequent therapeutic dose can be 1800 mg.

[0164] The therapeutic dosage of the antibodies or antibody portions described herein can be administered once a week, once every other week, once every two weeks, once every three weeks, once every four weeks, once a month, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every two months, once every nine weeks, once every ten weeks, once every eleven weeks, or once every twelve weeks, at the sole discretion of the person administering the composition or the person directing the administration of the composition, depending on the needs of the individual, and the dosage ranges described herein are merely exemplary and are not intended to limit the scope or practice of the claimed composition.

[0165] In certain exemplary embodiments, the method comprises administering from about 150 mg to about 1000 mg of the antibody once every 28 days.

[0166] In certain exemplary embodiments, the method comprises administering from about 300 mg to about 1200 mg of the antibody per month. For example, the method can comprise administering about 450 mg of the antibody per month.

[0167] In certain exemplary embodiments, the method comprises administering a loading dose of the antibody or antigen-binding fragment thereof, followed by administering at least one therapeutic dose of the antibody or antigen-binding fragment thereof.

[0168] In some such embodiments, the loading dose is administered all at once in one day. In other such embodiments, the loading dose is divided over multiple days (e.g., divided over two days). For example, the loading dose can be administered as two or more doses over two or more days.

[0169] In some such embodiments, the therapeutic dose is administered at least 1 week after administration of the loading dose. For example, the therapeutic dose can be administered 1 week after administration of the loading dose, 2 weeks after administration of the loading dose, 3 weeks after administration of the loading dose, 4 weeks after administration of the loading dose, 5 weeks after administration of the loading dose, 6 weeks after administration of the loading dose, 7 weeks after administration of the loading dose, 8 weeks after administration of the loading dose, 9 weeks after administration of the loading dose, 10 weeks after administration of the loading dose, 11 weeks after administration of the loading dose, or 12 weeks after administration of the loading dose.

[0170] In some such embodiments, the method includes administering one or more therapeutic doses. For example, the method can include administering a loading dose followed by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 subsequent therapeutic doses. In certain embodiments, the method can include administering a loading dose followed by a total of 4 administrations with 3 therapeutic doses. The interval between the loading dose and the first therapeutic dose can be at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 1 month, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 2 months, at least 9 weeks, at least 10 weeks, at least 11 weeks, or at least 12 weeks. In particular, the interval between the loading dose and the first therapeutic dose can be about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, or about 12 weeks. The one or more therapeutic doses can be administered once a week, once every other week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once a month, once every 5 weeks, once every 6 weeks, once every 7 weeks, once every 8 weeks, once every 2 months, once every 9 weeks, once every 10 weeks, once every 11 weeks, or once every 12 weeks, depending on the needs of the individual and the professional judgment of the person administering the composition or directing the administration of the composition. The dosage ranges described herein are merely illustrative and are not intended to limit the scope or practice of the claimed composition.

[0171] The antibody may be administered alone or conjugated to liposomes and formulated according to known methods for preparing pharmaceutically useful compositions, whereby the antibody is combined by mixing with a pharmaceutically acceptable carrier. A "pharmaceutically acceptable carrier" may be tolerated by the recipient patient. Sterile phosphate buffered saline is an example of a pharmaceutically acceptable carrier. Other suitable carriers are well known to those skilled in the art. See, for example, REMINGTON’S PHARMACEUTICAL SCIENCES, 19th Edition (1995).

[0172] Additional therapeutic methods may be used to control the duration of action of the antibody in therapeutic applications. Controlled release preparations can be prepared by complexing or adsorbing the antibody using a polymer. For example, biocompatible polymers include matrices of poly(ethylene-co-vinyl acetate) and matrices of polyanhydride copolymers of stearic acid dimer and sebacic acid. Sherwood et al., Bio / Technology, Vol. 10:1446 (1992). The rate of release of the antibody from such matrices depends on the molecular weight of the protein, the amount of antibody within the matrix, and the size of the dispersed particles. Saltzman et al., Biophys. J., Vol. 55:163 (1989); Sherwood et al., supra. Other solid dosage forms are described in REMINGTON’S PHARMACEUTICAL SCIENCES, 19th Edition (1995).

Example

[0173] The present invention has a plurality of aspects illustrated by the following non-limiting examples.

[0174] [Example 1] Single-dose study to evaluate the safety, tolerability, pharmacokinetics, and immunogenicity of AE12-1-Y-QL in healthy subjects Study Design: This is a single-dose, randomized, double-blind, placebo-controlled, single-site study. Up to 56 healthy male and female subjects will be enrolled in this study. The purpose of the study was to evaluate the safety, tolerability, pharmacokinetics, and immunogenicity of single intravenous and subcutaneous administrations of AE12-1-Y-QL in healthy subjects, namely healthy adult male and female subjects.

[0175] Methodology: There are seven dosing groups consisting of eight subjects per group. In each group of eight subjects, six subjects will be randomly assigned to receive a single dose of AE12-1-Y-QL and two subjects will receive placebo. The administrations in groups 1 to 6 are administered by intravenous injection (IV). The administration in group 7 is administered by subcutaneous injection (SC). The doses administered are shown in Table 4.

[0176]

Table 4

[0177] In each group, the dose is administered on the morning of day 1. The administrations in one group are separated by at least a 5-week interval until the administration of the next group. The high dose is administered only after the safety, tolerability, and pharmacokinetic data obtained at the low dose have been reviewed and evaluated. In groups 1 to 7, on day 1, one subject is administered the active drug and one subject is administered placebo, and later, among the additional six subjects, five are administered the active drug and one is administered placebo. In each group, a maximum of two subjects are administered per day. Assuming no delay in replenishment, the administrations are carried out on consecutive days. The administration in group 7 can be started immediately 5 weeks after the administration in group 2 is completed.

[0178] For the determination of AE12-1-Y-QL concentration, a series of blood samples are collected by venipuncture as follows: before administration (0 hours), 2, 4, 6, 10, 14, 24, 48, 72, 96, 120, 144, and 168 hours after administration, and on days 14, 28, 42, 56, 70, 84, 112, and 140. Blood samples for the determination of anti-drug antibodies are collected before administration (0 hours) on day 1, and on days 8, 14, 28, 42, 56, and 84 after administration.

[0179] The subject undergoes two magnetic resonance imaging (MRI) scans: the baseline scan is performed before administration and before the baseline lumbar puncture.

[0180] For the determination of AE12-1-Y-QL concentration and biomarker analysis, two lumbar punctures are performed and cerebrospinal fluid (CSF) is collected. The first lumbar puncture (baseline) is performed before administration, and the second lumbar puncture is performed on day 7, approximately simultaneously with the baseline lumbar puncture.

[0181] Diagnostic and major criteria for inclusion / exclusion: Major inclusion criteria: A subject is eligible to participate in the study if the following criteria are met: 1. Male or female, age at screening is between 18 and 55 years inclusive.

[0182] 2. In the case of females, the subject is: · Definitely not pregnant as determined by the following; · The subject is postmenopausal (absence of menstruation for at least 1 year and of the appropriate age). · The subject is surgically sterile, confirmed by bilateral oophorectomy and / or hysterectomy, or has tubal occlusion (ligation and occlusion methods, e.g., Essure® etc.) since at least 3 months before screening.

[0183] 3. Females must have a negative pregnancy test result at the time of urine sample screening and before administration of the serum sample obtained on the day of check-in.

[0184] 4. For males, the subject must be surgically infertile (vasectomized) or, from the first study drug administration until 140 days after the final study drug administration, must agree to use at least one of the following contraceptive methods: · Complete abstinence from sexual intercourse as the subject's preferred lifestyle; natural family planning is not allowed; · The partner uses an IUD; · The partner uses hormonal contraceptives by oral, injection, or implant methods; · The subject and / or the partner use the dual barrier method (male condom and occlusive cap [pessary or cervical cap] or contraceptive sponge [used in combination with all spermicidal jelly or cream]).

[0185] 5. The body mass index (BMI) is between 18.0 and 29.9, inclusive. BMI is calculated by dividing the weight in kg by the square of the height in meters.

[0186] 6. In a generally healthy state based on the results of medical history, physical examination, vital signs, laboratory profile, neurological examination, and 12-lead electrocardiogram (ECG).

[0187] Major exclusion criteria: If any of the following criteria are met, the subject is not eligible to participate in the study: 1. Regularly requires any over-the-counter and / or prescription medications, vitamins, and / or herbal supplements. 2. Use of any medications (prescription or over-the-counter), vitamins, and / or herbal supplements within 14 days before study drug administration or within 10 half-lives of each drug, whichever is longer, unless prior approval has been obtained from an AbbVie study-designated physician. 3. Receives any depot medications by injection within 30 days before study drug administration. 4. Receives investigational medicinal products within a period equal to 10 half-lives or within 6 weeks before study drug administration, whichever is longer, if known. 5. Positive urine screening for drug abuse, alcohol, or cotinine. 6. Alcohol consumption within 72 hours before the administration of the investigational drug. 7. History of malignant tumors; however, subjects with a history of excision or treatment of basal cell carcinoma or three or fewer squamous cell carcinomas are eligible to participate in this study. 8. Known to be hypersensitive to the investigational drug or its excipients. 9. History of drug or alcohol abuse within 2 years before the administration of the investigational drug. 10. History of severe allergic or anaphylactic reactions. 11. History of seizure disorders or unexplained fainting, or a seizure history within 6 months. 12. Answering "yes" to questions 4 or 5 of the suicidal ideation part of the Columbia Suicide Severity Rating Scale (C-SSRS) completed at the time of screening, or a history of suicidal ideation or a clinically severe depressive episode within 1 month before the administration of the investigational drug, as evidenced by any history of suicidal behavior. 13. Positive test results for hepatitis A virus immunoglobulin M (HAV-IgM), hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab), or human immunodeficiency virus antibody (HIV Ab). A negative HIV status is confirmed at the time of screening, and the results are confidentially managed by the study facility. 14. Chickenpox or varicella-zoster virus infection within 6 weeks before screening, or any severe viral infection. 15. Exposure to varicella-zoster virus within 21 days before screening. 16. History of human immunodeficiency virus (HIV) or other immunodeficiency conditions. 17. Receiving any type of live virus vaccine, including but not limited to measles / mumps / rubella vaccine, varicella-zoster virus vaccine, oral polio vaccine, and intranasal influenza vaccine, starting 4 weeks before administration. 18. Hospitalization or an infection (viral, fungal, bacterial) requiring intravenous (IV) antibiotics within 8 weeks before administration. 19. Performance of a planned elective surgery starting 2 weeks before randomization or until the end of the study. 20. History of abnormal test results indicating any serious heart disease, endocrine disease, blood disease, liver disease, immune disease, metabolic disease, urinary disease, lung disease, gastrointestinal disease, skin disease, mental disease, kidney disease, neurological disease, and / or other major diseases, as considered by the principal investigator of the clinical trial. 21. Any of the following abnormal blood tests at the time of screening: · Hemoglobin ≤ 10.0 g / dL · Platelets < 150 × 10 9 / L · Lymphocytes ≤ 1.0 × 10 9 / L · Neutrophils ≤ 1.5 × 10 9 / L · Alanine aminotransferase / serum glutamate pyruvate transaminase (ALT / SGPT), or aspartate aminotransferase / serum glutamate oxaloacetate transaminase (AST / SGOT) > 1 × upper limit of normal (ULN) · Serum creatinine ≥ 1 × ULN · Serum iron, ferritin, transferrin saturation > 1 × ULN 22. Contraindications to lumbar puncture (e.g., lumbar spinal scoliosis, coagulation disorders, infected skin at the needle puncture site) or use of blood thinning compounds including non-steroidal anti-inflammatory agents (e.g., aspirin, ibuprofen, naproxen), clopidogrel, warfarin, heparin (or heparin-like substances), fondaparinux (or related compounds), or thrombin inhibitors (dabigatran) and factor Xa inhibitors (rivaroxaban and apixaban) within 14 days of lumbar puncture. 23. Subjects for whom MRI is contraindicated (i.e., those with an intracranial aneurysm clip, metal piece, cochlear implant, spinal cord stimulator, or other electromotive device in the body such as a pacemaker) are allergic to gadolinium or have claustrophobia. 24. Baseline brain MRI scan shows the presence of an intracranial tumor or other evidence precluding the subject from undergoing lumbar puncture. 25. Transfusion or loss of more than 450 mL of blood volume (including plasma exchange) or receiving an infusion of any blood product within 8 weeks prior to administration of the study drug. 26. Women who are pregnant or breastfeeding.

[0188] Pharmacokinetic variables: The following pharmacokinetic parameters of AE12-1-Y-QL are determined using the non-compartmental method. The observed maximum serum concentration (C max ), C max time to reach (peak time, T max ), terminal elimination rate constant (β), terminal elimination half-life (T 1 / 2 ), area under the plasma concentration-time curve from time 0 to the time of the last measurable concentration (AUC) (AUC t ), AUC from time 0 to infinite time (AUC∞), and clearance (CL for IV administration and CL / F for SC administration) are determined. Additionally, the absolute bioavailability (F abs ) after SC administration is estimated. Antidrug antibody titers are determined for the assessment of immunogenicity. Additional parameters may be calculated if useful for the interpretation of the data.

[0189] Pharmacogenetic variables: DNA samples labeled "PG-DNA blood" can be analyzed for pharmacokinetics, pharmacodynamics, tolerability, and safety regarding AE12-1-Y-QL or genetic factors contributing to the response of subjects to treatments in other studies. Such genetic factors may include drug-metabolizing enzymes, genes of drug transport proteins, genes within the target pathway, or other genes thought to be related to drug response. Some genes that have been insufficiently characterized or are unknown to date may be understood to be important at the time of analysis. The samples can be analyzed as part of a comprehensive research evaluation of genetic factors involved in the response to AE12-1-Y-QL or drugs of this class. The samples can also be used for the development of diagnostic tests related to AE12-1-Y-QL (or drugs of this class). The results of pharmacogenetic analysis are not reported with the study summary.

[0190] DNA samples labeled as "PGDM-DNA blood" are analyzed to characterize genes of drug-metabolizing enzymes or drug-transporting proteins, genes within target pathways, or other genes thought to be related to drug response to any pharmaceutical. Analysis of samples for pharmacogenetic variables can be performed by non-Good Laboratory Practice (GLP) laboratories.

[0191] Safety: The safety assessment includes the following: adverse event monitoring, vital signs, physical examination, neurological examination, electrocardiogram, laboratory tests, Columbia Suicide Severity Rating Scale, and brain MRI. The MRI is performed at baseline and 28 days after dosing. The following MRI sequences are performed: T1-weighted; T2-weighted FLAIR; T1 with gadolinium; T2-weighted; diffusion-weighted; and gradient echo (GRE).

[0192] Adverse events are coded by the Medical Dictionary for Regulatory Activities (MedDRA). The number and percentage of subjects reporting treatment-emergent adverse events are tabulated by System Organ Class (SOC) by MedDRA Preferred Term and pathway and dose level classification. Tabulation is also provided where the number of subjects reporting an adverse event (MedDRA term) is further classified by severity (mild, moderate, or severe) and whether it may be related to the investigational drug. Deaths, other serious adverse events, and other significant adverse events are identified separately. Clinically significant potential vital sign and laboratory test values and measurements of quantitative ECG variables are identified according to the criteria defined previously.

[0193] [Example 2] Single-dose study to evaluate the safety, tolerability, pharmacokinetics, and immunogenicity of AE12-1-Y-QL in healthy subjects

[0194] Study design: This was a single-dose, randomized, double-blind, placebo-controlled, single-site study. Forty-seven healthy male and female subjects were enrolled in this study. The purpose of the study was to evaluate the safety, tolerability, pharmacokinetics, and immunogenicity of single intravenous and subcutaneous administrations of AE12-1-Y-QL in healthy subjects, namely healthy adult male and female subjects.

[0195] Methodology: There were six dosing groups consisting of 7 or 8 subjects per group. Each of groups 1 to 5 included 8 subjects; 6 subjects were randomly assigned to receive a single dose of AE12-1-Y-QL and 2 subjects received placebo. The administrations in groups 1 to 5 were administered by intravenous infusion (IV). Group 7 included 7 subjects; 5 subjects were randomly assigned to receive a single dose of AE12-1-Y-QL and 2 subjects received placebo. The administration in group 7 was administered by subcutaneous injection (SC). The doses administered are shown in Table 5.

[0196]

Table 5

[0197] In each group, the dose was administered on the morning of day 1. The administrations in one group were separated by at least a 5-week interval until the administration in the next group. The high dose was administered only after the safety, tolerability, and pharmacokinetic data obtained at the low dose had been reviewed and evaluated. On day 1, 1 active drug subject and 1 placebo subject were administered, and later, 6 additional subjects were divided into 5 active drug and 1 placebo and administered. In each group, a maximum of 2 subjects were administered per day. The administrations were carried out on consecutive days. The administration of group 7 was started immediately 5 weeks after the administration of group 2 was completed.

[0198] In Groups 1 - 3, and 7, a series of blood samples for determination of AE12 - 1 - Y - QL concentration were collected by venipuncture as follows: before dosing (0 hours), 2, 4, 6, 10, 14, 24, 48, 72, 96, 120, 144, and 168 hours after dosing, and on Days 14, 28, 42, 56, 70, 84, 112, and 140. In Group 4, a series of blood samples for determination of AE12 - 1 - Y - QL concentration were collected by venipuncture as follows: before dosing (0 hours), 2, 4, 6, 10, 14, 24, 48, 72, 96, 120, 144, and 168 hours after dosing, and on Days 14, 28, 42, 56, 70, 84, 112, 140, and >196. In Group 5, a series of blood samples for determination of AE12 - 1 - Y - QL concentration were collected by venipuncture as follows: before dosing (0 hours), 2, 4, 6, 10, 14, 24, 48, 72, 96, 120, 144, and 168 hours after dosing, and on Days 14, 28, 42, 56, 70, 84, 112, 140, 168, and 196. Blood samples for determination of anti - drug antibodies were collected before dosing (0 hours) on Day 1, and on Days 8, 14, 28, 42, 56, and 84 after dosing.

[0199] The subjects had two magnetic resonance imaging (MRI) scans: the baseline scan was performed before dosing and before the baseline lumbar puncture.

[0200] For determination of AE12 - 1 - Y - QL concentration; total sRGMa level (see Figure 7), free sRGMa level (see Figure 6), and bound sRGMa level (see Figure 5) and for biomarker analysis, two lumbar punctures were performed and CSF was collected. The first lumbar puncture (baseline) was performed before dosing (baseline lumbar puncture), and the second lumbar puncture was performed on Day 7, approximately simultaneously with the baseline lumbar puncture.

[0201] Diagnostic and major criteria for selection / exclusion: Major selection criteria: Subjects were eligible to participate in the study if they met the following criteria: 1. Male or female, age at screening was between 18 and 55 years inclusive of that age.

[0202] 2. For females, the subjects are: · It is confirmed by the following that there is no possibility of pregnancy; · The subject is postmenopausal (no menstruation for at least one year and at the corresponding age). · The subject is surgically infertile, confirmed by bilateral oophorectomy and / or hysterectomy, or has tubal occlusion (including ligation and occlusion methods such as Essure®) since at least 3 months before screening.

[0203] 3. Females must have a negative pregnancy test result at the time of urine sample screening and before administration to the serum sample obtained on the day of check-in.

[0204] 4. For males, the subjects are surgically infertile (vasectomized), or must agree to perform at least one of the following contraceptive methods from the first administration of the study drug to 140 days after the final administration of the study drug: · Complete abstinence from sexual intercourse as the subject's preferred lifestyle; natural family planning is not allowed; · The partner uses an IUD; · The partner uses oral, injectable, or implantable hormonal contraceptives; · The subject and / or the partner use a double barrier method (male condom and occlusive cap [pessary or cervical cap] or contraceptive sponge [used in combination with all spermicidal jelly or cream]).

[0205] 5. The body mass index (BMI) is from 18.0 to 29.9, including the value. BMI is calculated by dividing the body weight (kg) by the square of the height (m).

[0206] 6. In a normal healthy state based on the medical history, physical examination, vital signs, laboratory profile, neurological examination, and the results of a 12-lead electrocardiogram (ECG).

[0207] Major exclusion criteria: The subject was not eligible to participate in the study if any of the following criteria were met: 1. Regularly requires any over-the-counter and / or prescription medications, vitamins, and / or herbal supplements. 2. Use of any medications (prescription or over-the-counter), vitamins, and / or herbal supplements within 14 days prior to study drug administration or within 10 half-lives of each drug, whichever is longer, unless prior approval has been obtained from an AbbVie study-designated physician. 3. Receives any depot medications by injection within 30 days prior to study drug administration. 4. Receives investigational medications for a clinical trial within a period equal to 10 half-lives or within 6 weeks prior to study drug administration, whichever is longer, if known. 5. Positive urine screening for drug abuse, alcohol, or cotinine. 6. Alcohol consumption within 72 hours prior to study drug administration. 7. History of malignancy; however, subjects with a history of excision or treatment of basal cell carcinoma or three or fewer squamous cell carcinomas are eligible to participate in this study. 8. Known to be hypersensitive to the study drug or its excipients. 9. History of drug or alcohol abuse within 2 years prior to study drug administration. 10. History of severe allergy or anaphylactic reaction. 11. History of seizure disorder or unexplained fainting, or a seizure within 6 months. 12. Answering "yes" to question 4 or 5 in the suicidal ideation section of the Columbia-Suicide Severity Rating Scale (C-SSRS) completed at screening, or a history of suicidal ideation or a clinically significant depressive episode within 1 month prior to study drug administration, as evidenced by any history of suicidal behavior. 13. Positive test results for hepatitis A virus immunoglobulin M (HAV-IgM), hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab), or human immunodeficiency virus antibody (HIV Ab). A negative HIV status is confirmed at screening, and the results are kept confidential at the study site. 14. Chickenpox or herpes zoster virus infection, or any severe viral infection within 6 weeks before screening. 15. Exposure to varicella-zoster virus within 21 days before screening. 16. History of human immunodeficiency virus (HIV) or other immunodeficiency conditions. 17. Receiving any type of live virus vaccine, including but not limited to measles / mumps / rubella vaccine, varicella-zoster virus vaccine, oral polio vaccine, and nasal influenza vaccine, starting 4 weeks before administration. 18. Hospitalization or intravenous (IV) antibiotic treatment for an infection (viral, fungal, bacterial) within 8 weeks before administration. 19. Performing a planned elective surgery starting 2 weeks before randomization or until the end of the study. 20. Abnormal laboratory results indicating any severe heart disease, endocrine disease, blood disease, liver disease, immune disease, metabolic disease, urinary disease, lung disease, gastrointestinal disease, skin disease, mental disease, kidney disease, neurological disease, and / or other major diseases, in the opinion of the principal investigator of the clinical trial. 21. Any of the following abnormal blood tests at screening: · Hemoglobin ≤ 10.0 g / dL · Platelets < 150 × 10 9 / L · Lymphocytes ≤ 1.0 × 10 9 / L · Neutrophils ≤ 1.5 × 10 9 / L · Alanine aminotransferase / serum glutamate pyruvate transaminase (ALT / SGPT), or aspartate aminotransferase / serum glutamate oxaloacetate transaminase (AST / SGOT) > 1 × upper limit of normal (ULN) · Serum creatinine ≥ 1 × ULN · Serum iron, ferritin, transferrin saturation > 1 × ULN 22. Contraindications for lumbar puncture (e.g., lumbar scoliosis, coagulation disorders, infected skin at the needle puncture site) or within 14 days of lumbar puncture, use of blood-diluting compounds including non-steroidal anti-inflammatory drugs (e.g., aspirin, ibuprofen, naproxen), clopidogrel, warfarin, heparin (or heparin-like substances), fondaparinux (or related compounds), or thrombin inhibitors (dabigatran) and factor Xa inhibitors (rivaroxaban and apixaban). 23. Subjects for whom MRI is contraindicated (i.e., those with an intracranial aneurysm clip, metal pieces, cochlear implant, spinal cord stimulator, or an implantable cardioverter defibrillator) are allergic to gadolinium or have claustrophobia. 24. Baseline brain MRI scan shows the presence of an intracranial tumor or other evidence that would preclude the subject from undergoing lumbar puncture. 25. Transfusion or loss of more than 450 mL of blood volume (including plasma exchange) or receiving an infusion of any blood product within 8 weeks prior to the administration of the study drug. 26. Women who are pregnant or breastfeeding.

[0208] Pharmacokinetic variables: The following pharmacokinetic parameters of AE12-1-Y-QL are determined using the non-compartmental method. Observed maximum serum concentration (C max ), C max time to reach (peak time, T max ), terminal elimination rate constant (β), terminal elimination half-life (T 1 / 2 ), area under the plasma concentration-time curve from time 0 to the time of the last measurable concentration (AUC) (AUC t ), AUC from time 0 to infinite time (AUC∞), coefficient of variation expressed as % (%CV) and clearance (CL for IV administration and CL / F for SC administration) were determined. Additionally, the absolute bioavailability (F abs ) after SC administration was estimated. Antidrug antibody titers were determined for the assessment of immunogenicity. Additional parameters may be calculated if useful for the interpretation of the data.

[0209] Preliminary results: The preliminary mean (%CV) pharmacokinetic parameters of AE12-1-Y-QL are shown in Table 6.

[0210]

Table 6

[0211] a. IV administration; b. SC administration; c. harmonic mean (pseudo CV); d. Estimation based on N = 5.

[0212] C max Values increased proportionally with dose, but the AUC values increased more than proportionally with dose up to 1600 mg, indicating non-linear PK. The harmonic mean half-life ranged from 19 to 50 days, and within the dose range of 50 to 1600 mg, the higher values were at the 1000 mg and 1600 mg doses. The variability of AE12-1-Y-QL exposure was low (15 - 22% CV) based on C max and AUC.

[0213] The preliminary mean (+SD) concentration-time profile of AE12-1-Y-QL is shown in Figure 1.

[0214] The preliminary mean (+SD) concentration-time profile of AE12-1-Y-QL 150 mg is shown in Figure 2. The relative bioavailability after a single SC dose of AE12-1-Y-QL 150 mg was approximately 65% based on the exposure in both the 150 mg IV and SC dosing groups.

[0215] C max and AUC ∞ normalized by the preliminary mean (±SD) dose versus the AE12-1-Y-QL dose is shown in Figure 3.

[0216] CSF and serum samples were assayed for AE12-1-Y-QL levels on day 7. The detection limit of the assay was 16.3 ng / mL. AE12-1-Y-QL exposure after a single dose of AE12-1-Y-QL is shown in Table 7. The AE12-1-Y-QL concentrations in serum and CSF on day 7 are shown in Figure 4. The total CSF exposure of AE12-1-Y-QL on day 7 after dosing was approximately 0.2% of the serum exposure.

[0217]

Table 7

[0218] The variability of CSF relative to serum concentration was low in groups 3 - 5 (CV < 35%), and group 2 had an outlier with very high variability. The AE12-1-Y-QL concentration in CSF continued to increase with dose (the increase was less than dose-proportional), but the ratio of CSF to serum increased with increasing dose.

[0219] At baseline and on day 7, CSF samples were assayed for bound, free, and total RGMa. Bound RGMa from CSF samples is shown in Figure 5. Free RGMa from CSF samples is shown in Figure 6. Total RGMa from CSF samples is shown in Figure 7.

[0220] AE12-1-Y-QL produces a statistically significant dose-dependent decrease in the concentration of free RGMa in CSF from healthy volunteers 7 days after dosing in the dose range of 50 to 1600 mg. AE12-1-Y-QL produces a statistically significant dose-dependent increase in the concentration of antibody-bound RGMa in CSF from healthy volunteers 7 days after dosing in the dose range of 50 to 1600 mg. There was no sign of an effect on the overall concentration of total RGMa. These results indicate that AE12-1-Y-QL decreases the concentration of free RGMa in CSF.

[0221] Safety: Safety evaluations include the following: Adverse event (AE) monitoring, sequential assessment of vital signs, physical examinations, neurological examinations, psychological evaluations using the Columbia Suicide Severity Rating Scale, electrocardiograms, laboratory tests, including comprehensive blood chemistry as well as complete blood count and differential, CSF parameters, and brain MRI. MRI is performed at baseline and on day 28 after dosing.

[0222] Four (33%) of 12 placebo-treated subjects and 25 (71%) of 35 subjects treated with AE12-1-Y-QL had at least one AE with no apparent trend in the frequency of AEs by each dose-escalation group. The most frequently reported AEs for AE12-1-Y-QL-treated subjects were headache, treatment pain, treatment headache, and nausea. A summary of adverse events is shown in Table 8.

[0223]

Table 8

[0224] Most treatment-related AEs evaluated by the principal investigator of the clinical trial were of low severity (mild to moderate) and resolved spontaneously without treatment. There were no major dose-related biochemical or hematological changes. There were no treatment-related AE discontinuations.

[0225] Two subjects who experienced SAEs died, and both were determined to be unrelated to AE12-1-Y-QL. In both cases, autopsy and toxicology reports concluded that death was due to other causes unrelated to AE12-1-Y-QL. Each SAE was considered not to affect the overall risk / benefit profile of AE12-1-Y-QL.

[0226] Conclusion. AE12-1-Y-QL was tolerated up to 1600 mg in healthy subjects. The most frequently reported AEs were associated with lumbar puncture. PK results showed increased serum exposure more than dose-proportionally and a CSF-to-serum ratio similar to other monoclonal antibodies. From the currently estimated half-life of AE12-1-Y-QL, it is expected that effective exposure will be achieved with monthly dosing. The safety profile and serum / CSF PK data support the use of AE12-1-Y-QL as a treatment for relapsing multiple sclerosis.

[0227] [Example 3] Administration Study of AE12-1-Y-QL in Subjects with Relapsing Multiple Sclerosis The primary objective of this study was to evaluate the safety, tolerability, pharmacokinetics, and immunogenicity of AE12-1-Y-QL in subjects with relapsing multiple sclerosis (RMS) managed with glatiramer acetate (GA) treatment. The secondary objective was to evaluate the effect of AE12-1-Y-QL on clinical and neuroimaging parameters of multiple sclerosis (MS) disease activity.

[0228] Study Population: Adult male and female subjects with RMS managed with GA treatment.

[0229] Methodology: This is a double-blind, placebo-controlled, randomized, escalating multiple-dose study. Approximately 48 - 56 subjects will participate in this study. There are four treatment groups. Groups 1 and 2 each consist of 8 subjects who are currently receiving GA. In each group of 8 subjects, 6 subjects are randomly assigned to receive 4 doses of AE12 - 1 - Y - QL co-administered with the current dose of GA, and 2 subjects receive the corresponding placebo co-administered with the current dose of GA. Group 3a includes a minimum of 8 and a maximum of 16 subjects, with 6 to a maximum of 12 subjects randomly assigned to receive 4 doses of AE12 - 1 - Y - QL co-administered with the current dose of GA, and 2 to a maximum of 4 subjects receiving the corresponding placebo co-administered with the current dose of GA. Group 3b consists of approximately 12 subjects randomly assigned to receive 4 doses of AE12 - 1 - Y - QL co-administered with the current dose of GA, and 12 subjects receiving the corresponding placebo co-administered with the current dose of GA.

[0230] Subjects in Groups 1 through 3a have conventional MRI performed at the study baseline and on Days 57, 112, and 175 to monitor disease activity and safety. The conventional MRI performed on subjects in Groups 1 through 3a includes T1 - weighted (with and without gadolinium contrast), T2 - weighted, T2 - weighted fluid - attenuated inversion recovery (FLAIR), proton density (PD) - weighted, T2 * / susceptibility - weighted, and diffusion - weighted images. The total number enrolled in Group 3b may be increased to provide 12 subjects in each treatment group that completes by Day 112.

[0231] For the subjects in Group 3b, as described for Groups 1 - 3a, perform baseline MRI as well as conventional MRI on Days 57, 112, and 175 to monitor disease activity and safety. Additionally, for the subjects in Group 3b, perform non - conventional MRI sequences at baseline and Day 112 of the study to evaluate the effect of AE12 - 1 - Y - QL on the pathophysiology of white matter. A sufficient number of subjects are enrolled so that up to 12 subjects in each treatment group of Group 3b complete the Day 112 visit with available MRI data. Non - conventional MRI includes magnetization transfer and diffusion tensor imaging.

[0232] Non - conventional MRI analysis. Non - conventional brain MRI is incorporated into this MAD study to explore the potential effect of AE12 - 1 - Y - QL on remyelination and axonal regeneration in patients with RFMS.

[0233] GA - managed patients treated in Group 3b receiving AE12 - 1 - Y - QL 1200 mg (n = 12) or placebo (n = 12) are evaluated by quantitative MRI assessment items sensitive to remyelination and axonal regeneration (in addition to conventional MRI). The patients are from the Stanford University and University of California, San Francisco (UCSF) clinical trial sites. Quantitative MRI at baseline and 112 days post - dosing was performed on a 3T MRI at one of the UCSF clinical trial sites. The primary endpoints are magnetization transfer ratio (MTR) and radial diffusivity (RD) in lesions defined by baseline T2 / FLAIR MRI.

[0234] An increase in MTR and a decrease in RD within existing lesions in subjects treated with AE12 - 1 - Y - QL compared to placebo are interpreted as evidence of improvement associated with AE12 - 1 - Y - QL in axonal and myelin pathophysiology. Twelve RFMS patients per group enable the detection of a 5% increase in T2 lesion MTR in a baseline - adjusted analysis of a placebo - controlled parallel - group study with 80% power at α = 0.05 (one - sided).

[0235] Primary MRI endpoints: · Mean differences from placebo adjusted to baseline for each AE12-1-Y-QL regimen in lesions identified by baseline T2 / FLAIR MRI in magnetization transfer ratio (MTR) at baseline and day 112 · Radial diffusivity (RD) (axial diffusivity (AD)) at baseline and day 112 in lesions identified by baseline T2 / FLAIR MRI is also performed.

[0236] For each evaluation item, the mean difference from placebo adjusted to the baseline of each AE12-1-Y-QL regimen is expressed based on the ANCOVA framework. The primary statistical inference is performed in the estimation of the effect at a significance level of 0.05.

[0237] The assumptions for the power analysis were based on the MTR in T2 lesions from RRMS patients (Altmann DR et al., 2013) for a one-sided comparison (ANCOVA) of the baseline tracking the change in MTR between the test groups. The baseline mean in T2 lesions is 30.3. The population standard deviation is the same for both the baseline measurement and the post-dose measurement. The standard deviation in T2 lesions is 1.91. The correlation coefficient between the baseline and the post-dose measurement is 0.70 (data from Altmann DR et al., 2013).

[0238] All doses of AE12-1-Y-QL are administered intravenously (IV) in the morning. Subjects continue on their current GA regimen, i.e., Copaxone® 20 mg administered subcutaneously once daily, or Copaxone® 40 mg administered subcutaneously three times a week, or generic GA 20 mg administered subcutaneously once daily. Subjects must have received Copaxone® for at least 2 weeks prior to randomization and must maintain the same regimen throughout the study. For each group, subjects receive a total of 4 administrations, with each administration separated by a 4-week interval. The high dose is administered only after the safety, tolerability, and pharmacokinetic data obtained at the low dose have been reviewed and evaluated by the sponsor in consultation with the investigators.

[0239] The doses administered are shown in Table 9.

[0240]

Table 9

[0241] A series of serum samples for the determination of AE12-1-Y-QL are collected by day 175 after the start of dosing. A series of serum samples for the determination of anti-drug antibodies are collected by day 112 after the start of dosing.

[0242] Two lumbar punctures are performed to collect CSF for the following: routine laboratory tests consisting of cell count and differential, glucose, total protein, albumin, immunoglobulins; determination of AE12-1-Y-QL concentration; total, free, and bound sRGMa levels; availability of AE12-1-Y-QL for interaction with membrane-bound BMP receptors using a reporter gene assay; and biomarker analysis. The first lumbar puncture is performed before the first dose (baseline) but after baseline brain MRI; the second lumbar puncture is performed 27 days after the fourth dose.

[0243] After successful completion of the screening visit, eligible subjects undergo a baseline brain magnetic resonance imaging (MRI). The baseline MRI can be performed at any time after the screening visit and at least 7 days before the start of incarceration (-10 days). If the most recent MRI (within 6 weeks before screening) is not available from the subject's medical history at screening, the baseline MRI is used to determine the subject's eligibility. Subjects who show evidence of obvious vascular lesions, tumors, tumor effects, or other abnormalities other than those consistent with MS on brain MRI are excluded. All subjects undergo MRI at baseline, day 57, day 112, and day 175.

[0244] Safety and tolerability are evaluated through the study. This includes adverse event collection, experimental tests, neurological examinations, vital sign and electrocardiogram (ECG) measurements, and MRI scans. If necessary, unscheduled relapse evaluation visits occur within 72 hours of the onset of any new neurological symptoms that may indicate the onset of clinical relapse. These visits consist of neurological examinations, Expanded Disability Status Scale (EDSS), vital signs, blood chemistry and hematology, and urine tests. Subjects who experience a suspected MS relapse may be treated with 1000 mg / day of IV methylprednisolone for 3 to 5 days.

[0245] Multiple sclerosis disease activity is monitored during a planned series of outpatient visits and at unscheduled visits if necessary. Clinical events captured and recorded include relapses and progression of disability measured on the Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC) as well as the individual domains of the MSFC, Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9HPT), and Paced Auditory Serial Addition Test (PASAT). Additionally, patients recorded assessment items obtained using the Multiple Sclerosis Impact Scale (MSIS-29) and the Multiple Sclerosis Quality of Life-54 (MSQOL-54).

[0246] No formal statistical analysis by means of a comparison of annual relapse rate (ARR) and the proportion of relapse-free patients is performed, and results are summarized as descriptive statistics by treatment group and visit. Progression of disability can only be ascertained from EDSS scores obtained according to a protocol-defined assessment schedule at regular visits. If a subject experiences at least a 1.0-point increase in EDSS from a baseline EDSS ≥ 1.0 that persists for 12 weeks, the nurse administering the treatment must notify the neurologist administering the treatment. The subject must be informed that they are experiencing a worsening of physical disability.

[0247] Diagnostic and major criteria for inclusion / exclusion: Main inclusion criteria: To be eligible for this study, candidates must meet the following eligibility criteria at the time specified in the individual criteria listed before or below randomization: 1. Male or female, aged between 18 and 60 years inclusive.

[0248] 2. The subject is currently receiving Copaxone® 20 mg administered subcutaneously once daily for at least 2 weeks before randomization, or Copaxone® 40 mg administered subcutaneously three times a week, or generic glatiramer acetate 20 mg administered subcutaneously once daily, for the treatment of MS.

[0249] 3. In the case of females, the subject is: · Not at risk of pregnancy [surgically sterile (oophorectomy, total hysterectomy, tubal ligation), postmenopausal for at least 2 years (hormone replacement therapy is permitted)], or · If at risk of pregnancy, the subject must practice complete abstinence from sexual intercourse as their preferred lifestyle; natural family planning is not permitted; have a vasectomized male partner at least 6 months prior to the study or consent to use an effective method of contraception (copper or hormonal intrauterine device (IUD), oral hormonal contraception, or double barrier protection method) throughout the treatment and follow-up period.

[0250] 4. Females must have a negative pregnancy test result before study drug administration.

[0251] 5. In the case of males, the subject is: · Must have a diagnosis of having undergone male contraceptive surgery, such as vasectomy, or · Consent to having a low sex drive, or consent to use a barrier method of contraception or practice complete abstinence from sexual intercourse as their preferred lifestyle until 90 days after the final dose of study drug; natural family planning is not permitted.

[0252] 6. Diagnosis of relapsing-remitting MS (RRMS) or secondary progressive MS (SPMS), known as relapsing form of MS (RFMS).

[0253] 7. Subjects with RRMS must have a definite diagnosis according to the revised McDonald diagnostic criteria, and subjects with RFMS must have no evidence of ongoing disease activity as demonstrated below.

[0254] · At least one relapse within 12 months prior to randomization, with a head MRI showing lesions consistent with MS (if a scan performed within 6 months prior to screening is available from the subject's medical history, a current scan is not required, and if no scan is available from the subject's medical history, a baseline scan may be used). The relapse is defined as a new or recurrent neurological symptom without fever or infection lasting at least 24 hours, and with new objective neurological findings upon examination by the neurologist performing the examination. The subject must have no objective signs at the time of examination by the neurologist confirming the event. The time from the relapse should be measured from the start time of the relapse, or · Evidence of gadolinium-enhancing lesions in the brain on MRI performed within 6 months prior to randomization (if a scan is not available from the subject's medical history, a baseline scan may be used).

[0255] 8. At the screening visit, be neurologically stable at the discretion of the principal investigator of the clinical trial and have not experienced or recovered from a recent relapse 30 days prior to the screening visit.

[0256] 9. The baseline EDSS must be between 1.0 and 6.0, inclusive.

[0257] 10. The body mass index (BMI) is between 18.0 and 32.0, inclusive. The BMI is calculated by dividing the weight (kg) by the square of the height (m).

[0258] 11. Have a brain MRI scan interpreted by a radiologist that shows no obvious vascular lesions, tumors, tumor effects, or evidence of other abnormalities other than those consistent with MS that would preclude the subject from undergoing lumbar puncture / spinal tap for CSF collection. A baseline MRI scan interpreted by a radiologist may be used at least 7 days prior to incarceration.

[0259] 12. In the absence of MS, in a generally healthy state based on medical history, physical examination, vital signs, laboratory profile, neurological examination, and results of a 12-lead electrocardiogram (ECG).

[0260] Exclusion criteria: A subject is not eligible to participate in the study if any of the following criteria are met: Medical history: 1. Diagnosis of primary progressive MS. 2. Abnormal test result history indicating any severe heart disease, endocrine disease, blood disease, liver disease, immune disease, metabolic disease, urinary disease, lung disease, gastrointestinal disease, skin disease, mental disease, kidney disease, neurological disease (other than MS), and / or other major diseases that make administration of AE12-1-Y-QL or GA impossible, in the opinion of the treating physician. 3. MS relapse occurring within 30 days prior to randomization and / or the subject not being stabilized from a previous relapse prior to randomization. 4. Subjects for whom MRI is contraindicated (i.e., subjects with an intracranial aneurysm clip, metal pieces, cochlear implant, spinal cord stimulator, or other internal electrical device such as a pacemaker), for whom gadolinium is contraindicated or allergic to gadolinium (previously diagnosed with renal dysfunction, abnormal eGFR, nephrogenic systemic fibrosis, and including allergies), medically unmanageable, or claustrophobic such that they cannot lie still for more than 1 hour for imaging procedures. 5. Received any depot medication by injection within 30 days prior to study drug administration. 6. Received an investigational medicinal product within a period equal to 10 half-lives or within 6 weeks prior to study drug administration, if known. 7. Positive drug abuse or alcohol screening detected at screening or on Day - 3. 8. History of malignant tumor; however, subjects with a history of excision or treatment of basal cell carcinoma or with three or fewer squamous cell carcinomas are eligible to participate in this study. 9. Known to be hypersensitive to the study drug or its excipients. 10. History of drug or alcohol abuse within two years prior to study drug administration. 11. History of severe allergic or anaphylactic reactions. 12. History of seizure disorders or unexplained fainting, or a seizure history within six months. 13. Answering "yes" to question 4 or 5 in the suicidal ideation part of the Columbia-Suicide Severity Rating Scale (C-SSRS) completed at screening, or a history of suicidal ideation or a clinically severe depressive episode within one month prior to study drug administration, as evidenced by any history of suicidal behavior. 14. Known history of hepatitis C virus or hepatitis B virus, or positive screening test results. 15. Varicella or herpes zoster virus infection within six weeks prior to screening, or any severe viral infection. 16. Exposure to varicella-zoster virus within 21 days prior to screening. 17. History of human immunodeficiency virus (HIV) or other immunodeficiency conditions. 18. Administration of any type of live virus vaccine, including but not limited to measles / mumps / rubella vaccine, varicella-zoster virus vaccine, oral polio vaccine, and nasal influenza vaccine, within less than four weeks prior to randomization. 19. Hospitalization or an infection (viral, fungal, bacterial) requiring intravenous (IV) antibiotics within eight weeks prior to randomization. 20. Performance of a planned elective surgery from two weeks prior to randomization until the end of the study. 21. Findings on brain MRI scan showing clinically significant brain abnormalities other than MS. 22. Any of the following abnormal blood tests at screening: · Hemoglobin ≤ 10.0 g / dL · Platelets ≤ 100 × 10 9 / L · Lymphocytes ≤ 1.0×10 9 / L · Neutrophils ≤ 1.5×10 9 / L · Alanine aminotransferase / serum glutamate pyruvate transaminase (ALT / SGPT), aspartate aminotransferase / serum glutamate oxaloacetate transaminase (AST / SGOT), or gamma-glutamyl transferase ≥ 2 times the upper limit of normal (ULN) · Serum iron, ferritin, transferrin saturation > ULN · Serum creatinine ≥ ULN 23. Contraindications for lumbar puncture (e.g., lumbar spinal scoliosis, coagulation disorders, or anticoagulant medications, infected skin at the needle puncture site). 24. Transfusion or loss of a blood volume of 550 mL or more (including plasma exchange) or receipt of any blood product infusion within 8 weeks before the study drug administration.

[0261] Treatment history 25. Pretreatment with any of the following: · Total body lymphoid irradiation · Cladribine or mitoxantrone · T cell or T cell receptor vaccination 26. Pretreatment with cyclophosphamide or alemtuzumab within 1 year before randomization. 27. Pretreatment with any of the following medications or procedures within 6 months before randomization: · Natalizumab · Rituximab · Daclizumab · Cyclosporine · Azathioprine · Methotrexate · Mycophenolate mofetil · Intravenous immunoglobulin (IVIg) · Plasma exchange or immunoadsorption 28. Treatment with any of the following medications within 30 days before randomization: · IV corticosteroid treatment · Oral corticosteroid treatment · Beta interferon · Fingolimod · Dimethyl fumarate · Teriflunomide 29. Initiation of treatment or dose adjustment of commercially available Fampridine-SR within the last 90 days. This is acceptable if the patient has already received a stable dose of Fampridine-SR prior to randomization and if the plan is to maintain this dose and regimen during the study.

[0262] Pharmacokinetics: The following values of pharmacokinetic parameters are estimated using the non-compartmental method. The observed maximum serum concentration (C max ), C max time to reach (peak time, T max ), area under the concentration-time curve (AUC) from time 0 to the time of the last measurable concentration (AUC t ) are estimated after the first and fourth administrations. The observed serum concentration before administration (C through ), terminal elimination rate constant (β), terminal elimination half-life (t 1 / 2 ), and apparent clearance (CL / F) are estimated after the fourth administration. Anti-drug antibodies are determined for the assessment of immunogenicity. Additional parameters can be calculated if useful for the interpretation of the data.

[0263] CSF Biomarkers: A panel of biomarkers representing markers of pro-inflammatory and anti-inflammatory, neuroregeneration / neuroprotection, neurodegeneration, and / or remyelination is evaluated.

[0264] Pharmacodynamics: Results of brain MRI examinations (Group 3b) The study includes, as endpoints of the examination, MRI evaluation items sensitive to the pathophysiology of axons and myelin in the brain and changes in disease activity. The following evaluation items are evaluated: Primary MRI Endpoints: · Magnetization transfer ratio (MTR) at baseline and day 112 in lesions identified by baseline T2 / FLAIR MRI ·Radiation diffusion (RD) at baseline and day 112 in lesions identified by baseline T2 / FLAIR MRI ·Total number of new gadolinium-enhanced T1 lesions from day 57 to day 112 ·Total number of new or newly enlarged T2 hyperintense lesions at day 112 ·Total lesion volume of new or newly enlarged T2 hyperintense lesions at day 112 Secondary MRI endpoints: Fractional anisotropy (FA) and axial diffusivity (AD) at baseline and day 112 in lesions identified by baseline T2 / FLAIR MRI MTR in normal-appearing gray matter (NAGM) identified by baseline MRI at baseline and day 112 MTR and FA in normal-appearing white matter (NAWM) identified by baseline MRI at baseline and day 112

[0265] Safety: Safety variables include the following: adverse event monitoring, vital signs, physical examination, neurological examination, electrocardiogram, laboratory test evaluations, and C-SSRS and MRI scans. Unscheduled relapse evaluations occur within 72 hours of the onset of any new neurological symptoms that may indicate the onset of clinical relapse, if necessary. These evaluations consist of neurological examination, EDSS, vital signs, blood chemistry and hematology, urine tests, and MRI if necessary. Subjects experiencing suspected MS relapse, or subjects found to have at least two new T1 gadolinium-enhanced lesions in important areas or one new T1 gadolinium-enhanced lesion on the safety MRI at day 57 may be treated with IV methylprednisolone 1000 mg / day for 3 to 5 days.

[0266] Adverse events are coded by the Medical Dictionary for Regulatory Activities (MedDRA). For each of the individual groups, the number and percentage of subjects reporting treatment-emergent adverse events are tabulated by MedDRA preferred terms and high-level organ classifications. Tabulations are also provided where the number of subjects reporting an adverse event (MedDRA term) is further classified by severity (mild, moderate, or severe) and likelihood of being related to the investigational drug. Deaths, other serious adverse events, and other significant adverse events are identified separately. Clinically significant laboratory test values and vital sign measurements are identified according to the criteria defined above.

[0267] [Example 4] A [11C]-PBR28 positron emission tomography study to evaluate the effect of AE12-1-Y-QL on central nervous system inflammation in subjects with relapsing multiple sclerosis 11 [11C]-PBR28 positron emission tomography study Study design: An open-label positron emission tomography study to examine the effect of AE12-1-Y-QL on the expression of the translocator protein (TSPO) in the central nervous system of subjects with relapsing multiple sclerosis. Approximately 24 subjects with relapsing multiple sclerosis with stable disease will be enrolled in this study. The purpose of this study is to examine the effect of a single dose of AE12-1-Y-QL on [11C]-PBR28 radioligand binding to the translocator protein (TSPO) in the brains of subjects with relapsing multiple sclerosis (RFMS), as well as to evaluate the safety and tolerability of a single dose of AE12-1-Y-QL in this subject population. 11 [11C]-PBR28 radioligand binding, and to evaluate the safety and tolerability of a single dose of AE12-1-Y-QL in this subject population.

[0268] Background and principle of PET imaging method: The 18-kilodalton translocator protein (TSPO) is a mitochondrial protein, first described for its ability to bind various benzodiazepine drugs and thus previously known as the peripheral benzodiazepine receptor (PBR). TSPO expression is present throughout the body and CNS and is relatively high in microglia, macrophages, and myeloid cells mobilized to the periphery (monocyte-derived macrophages). In the MS brain, focal areas of CNS inflammation are characterized by increased density of activated microglia and macrophage immune cells with increased expression of TSPO compared to normal healthy brain tissue. It has been demonstrated that the magnitude of TSPO density in these focal lesions of the MS brain is closely related to the density of microglia and macrophage immune cells and the severity of the MS disease. Therefore, 11 [11C]-PK11195, 11 [18F]-PBR28, [18F]-PBR111 and other TSPO-targeted positron emission tomography (PET) radioligands have been applied to study disease processes involving microglial activation or macrophage mobilization such as MS, and to investigate the effect of novel therapeutic agents on the innate immune system in the brains of patients with CNS diseases.

[0269] 11 [11C]-PBR28 is a PET radioligand that is selective and has a high binding affinity for TSPO. 11 Dosimetry and whole-body distribution measurements of [11C]-PBR28 have been completed in human subjects, demonstrating an effective radiation exposure dose of 6.6 μSv / MBq that is acceptable for human use. 11 ​C]-PBR28 has the characteristics of an optimal PET radioligand and has been successfully used to quantify changes in TSPO levels in healthy volunteers and patients with multiple sclerosis, Alzheimer's disease, and Parkinson's disease, thus supporting the use of this radioligand in clinical studies. A relatively low dose is required to detect binding in the brain, enabling multiple brain PET scans of good image quality to be performed on individual subjects. Test-retest studies in healthy volunteers demonstrated an intraclass correlation of equilibrium volume distribution (V T ) greater than 0.9 in most regions of the brain.

[0270] Selective high-affinity TSPO radioligand 11 This open-label PET study using [C]-PBR28 was designed to determine the effect of AE12-1-Y-QL on TSPO expression levels in the central nervous system (CNS) of subjects with relapsing multiple sclerosis. The findings from this study can demonstrate whether AE12-1-Y-QL has an immunomodulatory effect in the CNS and provide information on the safety and tolerability of AE12-1-Y-QL as monotherapy in MS patients.

[0271] Methodology: This is an open-label positron emission tomography (PET) study using a selective high-affinity transport protein (TSPO) radioligand 11 [C]-PBR28 to examine the effect of AE12-1-Y-QL on TSPO expression in the central nervous system of subjects with relapsing multiple sclerosis (RFMS). Approximately 24 subjects with RFMS with stable disease are enrolled in the study according to selection criteria ensuring that at least 18 subjects complete all study visits and have evaluable image data at all time points (4 in Part I and 14 in Part II). Subjects participating in Part I of the study are not eligible to participate in Part II of the study. The study is divided into two parts as shown below.

[0272] Part I (Test-Retest Evaluation): In Part I, measurements were taken at intervals of 15 + / - 5 days 11 C]-PBR28 PET within the scope of the main items was examined for test-retest variability. The subjects did not receive AE12-1-Y-QL. Four subjects of RFMS completed all study visits and had evaluable image data at all time points in Part I. Evaluable subjects were defined as those who completed baseline magnetic resonance imaging (MRI) and two planned PET image sessions with available quality MRI, PET images, and arterial data, as determined by the investigator at each time point. Subjects completed two dynamic PET scans of the brain by arterial sampling and one MRI scan of the brain over four visit courses as follows.

[0273] · Visit 1: Screening · Visit 2: Baseline MRI scan · Visit 3: Baseline PET scan · Visit 4: Follow-up PET scan

[0274] Part II (AE12-1-Y-QL Treatment Group): Part II began after the completion of Part I and examined the effect of a single intravenous administration of AE12-1-Y-QL on TSPO expression in the central nervous system of subjects of RFMS. Based on the information obtained, an AE12-1-Y-QL dose of 1600 mg was selected for this study. The dose of this study could be lowered or raised up to 2400 mg based on the safety and pharmacokinetic information obtained from Example 1. The dose could also be adjusted based on the safety and pharmacodynamic results obtained from all the aforementioned subjects in this study. At least 14 subjects of RFMS completed all study visits and had evaluable image data at all time points in Part II. Subjects completed two dynamic PET scans of the brain by arterial sampling and two MRI scans of the brain over six visit courses as follows.

[0275] · Visit 1: Screening · Visit 2: Baseline MRI ·Visit 3: Baseline PET scan ·Visit 4: AE12-1-Y-QL administration ·Visit 5: Follow-up PET scan ·Visit 6: Follow-up clinical and safety assessment including MRI

[0276] Screening: In both Part I and Part II, the eligibility of subjects is evaluated at Visit 1 that occurs within 30 days prior to Visit 3. Visit 2 can be conducted at any time after Screening (Visit 1) and at least 7 days prior to the PET scan (Visit 3).

[0277] The following procedures are performed to determine the eligibility of subjects for the study: medical history, physical examination (including height, weight, and BMI), neurological examination, Columbia Suicide Severity Rating Scale (C-SSRS), clinical laboratory evaluation (standard hematology, clinical chemistry, and urine tests), hepatitis screening, urine tests for HIV, drug abuse, and alcohol screening, 12-lead ECG, vital signs (blood pressure, heart rate), review of concomitant medications, pregnancy test, allergy test, and blood sampling to determine the genetic polymorphism of TSPO.

[0278] Magnetic resonance imaging (MRI). After successful completion of Screening (Visit 1), all eligible subjects undergo a baseline brain MRI (Visit 2). Visit 2 can be conducted at any time after Screening (Visit 1) and at least 7 days prior to the PET scan (Visit 3). All planned MRIs are performed on a 3-tesla system at the Imanova Image Center. Subjects showing evidence of other abnormalities other than obvious vascular lesions, tumors, tumor effects, or those corresponding to MS on the brain MRI are excluded. The baseline MRI is further used to depict demyelinating lesions and anatomical regions of interest (ROIs) for individual PET images. For MRI images, an intravenous catheter (for gadolinium contrast agent injection) is inserted in all subjects according to standard clinical practice. The following image sequence types are performed on all eligible subjects at Visit 2 (Part I); Visit 2 and Visit 6 (Part II): ·T1-weighted ·Diffusion-weighted image ·T2-weighted FLAIR ·PD-weighted ·T2-weighted ·Gadolinium-enhanced T1-weighted Additional image sequences may be included. The total imaging session is expected to be approximately 60 minutes in duration and not to exceed 90 minutes. Detailed scan parameters, sequences, imaging planes, and the order in which acquisitions need to be performed are provided in the study imaging manual.

[0279] Intra-arterial catheter placement and monitoring: At the Imanova Imaging Centre, prior to the planned PET scan, a radial artery catheter for blood sampling is inserted into all subjects. The procedure should be performed by an anaesthetist or a duly trained physician and monitored by a registered nurse during the study. The risks of radial artery cannulation are minimised by having the procedure performed by an experienced physician. Pain is minimised by using local anaesthesia. Bleeding is prevented by applying local pressure or a pressure dressing for at least 10 minutes after catheter removal. After arterial cannulation, the subject's blood supply to their hand and fingers is examined and the catheter is removed again. Subjects are also asked to avoid the use of aspirin, non-steroidal anti-inflammatory drugs (NSAIDs) or anticoagulants. Subjects are provided with the telephone number of the 24-hour emergency doctor to call if they experience pain, pallor, numbness, tingling, coldness, or any other abnormal symptoms in the wrist or hand, fever, chills or drainage from the vascular access site after the procedure. Subjects are given verbal instructions regarding the points to watch out for and the procedures to follow if such problems occur. Infection should be avoided by thorough skin cleansing prior to intravascular line insertion.

[0280] The cannulation site may be alternated between the two wrists during subsequent PET scan visits, at the discretion of the anaesthetist or physician performing the procedure. Re-cannulation at the same site in the patient may be performed if the interval between procedures is at least one week.

[0281] Positron emission tomography (PET). In Part I, the subjects were not administered AE12-1-Y-QL and received PET imaging sessions at two time points (Visit 3 and Visit 4) for test and retest scans. Visit 4 was 15 + / - 5 days after Visit 3.

[0282] In Part II, the subjects were administered AE12-1-Y-QL and received PET imaging sessions at two time points: once at baseline (Visit 3) and another scan (Visit 5) 15 + / - 5 days after the AE12-1-Y-QL administration (Visit 4). The interval between Visit 4 and 5 in Part II can be adjusted by the sponsor based on the pharmacokinetic information obtained from the single escalating dose in Example 1 and the pharmacodynamic results obtained from the subjects previously scanned in this study.

[0283] For PET imaging, an intravenous catheter (for injection of the radioligand) and a radial artery catheter (for measurement of the radioligand) are inserted according to standard clinical practice in all subjects.

[0284] Low-dose computed tomography (CT) scans are obtained to correct for attenuation of the positron emission signal. After completion of the CT scan, the subject receives an intravenous bolus injection of 11 C]-PBR28 (injected over a period of approximately 20 seconds) at a dose of 400 MBq or less. The exact amount of 11 C]-PBR28 administered is determined immediately prior to administration but does not exceed 10 μg. Acquisition of dynamic brain PET data begins simultaneously with the administration of the radioligand and continues for approximately 90 minutes.

[0285] 11 A series of blood samples for the pharmacokinetic assay of

[0286] 11 ​​C]-PBR28 Administration and Dosage: Subjects in Parts I and II each received two administrations of the PET radioligand 11 C]-PBR28, one immediately prior to each PET scan. Due to the relatively short half-life of carbon-11 (approximately 20 minutes), 11 C]-PBR28 was prepared on-site at the Imanova Imaging Centre immediately before administration.

[0287] Each subject was exposed to a maximum radiation dose of 400 MBq of 11 C]-PBR28 in their respective PET scans. Additionally, a single low-dose CT scan of the head was obtained at each PET visit and attenuation correction was estimated. The effective dose from this study for each subject consists of 0.72 mSv from the low-dose CT scans combined with up to 5.28 mSv from the two 11 C]-PBR28 administrations, resulting in a total of 6 mSv. In the rare event of equipment failure or unusable data, subjects could undergo up to three PET / CT imaging sessions, and the maximum effective dose from this study consists of 1.08 mSv from the three low-dose CT scans combined with up to 7.92 mSv from the three 11 C]-PBR28 administrations, resulting in a total of 9 mSv. Therefore, this study falls into International Commission on Radiological Protection (ICRP) category IIb: less than 10 mSv in addition to natural background radiation over the last three years, including the doses from this study.

[0288] Image Analysis and PET Pharmacokinetic Modelling: PET images were reconstructed with scatter and attenuation correction, and body motion was automatically corrected by frame-to-frame alignment. PET images were co-registered with individual structural MRI images. Anatomical regions of interest (ROIs) were delineated based on the MRI data and applied to the individual dynamic PET data to create local time-activity curves. For each ROI, the volume distribution (V t) is estimated using an appropriate pharmacokinetic model with the arterial plasma input function. For the primary analysis, the optimal pharmacokinetic modeling approach (two tissue compartment model or graphic model) is determined from Part I and applied to Part II. The two tissue compartment model is preferred for the primary analysis. However, if the fit is poor or the model cannot be identified, the graphic model approach is pursued. Data from all subjects at all time points are subjected to a single analysis approach. Appropriate alternative pharmacokinetic modeling approaches (in particular, two tissue compartment model vs. graphic model) are applied to the data from Parts I and II, as in the sensitivity analysis identified previously. The volume distribution ratio (DVR) of each ROI is also estimated based on the selection of a pseudo-reference region to account for variability in the blood.

[0289] PET images from both Parts I and II are examined to identify an appropriate reference region among all subjects. The reference region is selected based on the following criteria: · Consistent among all subjects · Identified within gray matter or apparently normal white matter · Stable V between two PET scans T value · The mean difference between two PET scans is not statistically significant, and · The mean absolute variability between two PET scans is < 20% among all subjects and the absolute variability is

[0290]

Number

[0291] In Part II, all subjects visit the study facility on Day 70 + / - 5 after administration of AE12 - 1 - Y - QL for clinical and safety evaluations. The following procedures are performed: physical examination, neurological examination, C - SSRS (Part II only), clinical laboratory evaluations (standard hematology, clinical chemistry, and urine tests), 12 - lead ECG, vital signs (blood pressure, heart rate), MRI, and pregnancy test.

[0292] Safety: Safety is evaluated through the study. If necessary, unscheduled relapse evaluation visits occur within 72 hours of the onset of any new neurological symptoms that may indicate the onset of a clinical relapse, if possible. This includes adverse event collection, laboratory tests, physical examinations, neurological examinations, vital sign, and ECG measurements.

[0293] Diagnostic and Major Criteria for Selection / Exclusion: Major Selection Criteria: Subjects are eligible to participate in the study if they meet the following criteria: 1. Male or female, aged 18 to 60 years inclusive at the time of screening.

[0294] 2. For females: · Not likely to be pregnant (surgically sterile [ovariectomy, total hysterectomy, tubal ligation], postmenopausal for at least 2 years [hormone replacement therapy is permitted], or · Likely to be pregnant: · At the time of screening, each 11 C]-PBR28 dose, and negative pregnancy test within 24 hours of study drug administration; and · The subject must practice complete abstinence from sexual intercourse as their preferred lifestyle; (natural family planning is not permitted; or the sexual partner of a male couple who has had a vasectomy at least 6 months before the study; or agree to use an effective method of contraception (copper or hormonal intrauterine device [IUD]) throughout the treatment and follow-up period.

[0295] 3. For males, must have a diagnosis of male contraceptive surgery, such as vasectomy, or agree to have a low libido, or agree to use barrier contraception until 90 days after study drug administration.

[0296] 4. Diagnosis of relapsing remitting MS (RRMS) or relapsing secondary progressive MS (SPMS), known as relapsing forms of MS (RFMS). Patients with RRMS must have a confirmed diagnosis according to the Revised McDonald Diagnostic Criteria, and patients with RFMS must have evidence of ongoing disease activity as demonstrated below: · Experienced at least one relapse within 12 months prior to randomization, with a head MRI showing lesions consistent with MS (if a prior MRI scan performed within 6 months prior to screening is available from the subject's medical history, a current scan is not required). For selection, a relapse is defined as neurological signs and / or symptoms confirmed by a neurologist in the medical record and lasting at least 24 hours as determined by the principal investigator of the clinical trial or the treating neurologist. The time from relapse should be measured from the start time of the relapse, or · Show evidence of gadolinium (Gd)-enhancing lesions in the brain on an MRI performed within 6 months prior to screening.

[0297] 5. At the screening visit, be neurologically stable at the discretion of the principal investigator of the clinical trial and not have experienced or recovered from a recent relapse within 30 days prior to the screening visit.

[0298] 6. The score on the Kurtzke Expanded Disability Status Scale (EDSS) is between 1.0 and 6.0, inclusive, at the screening visit.

[0299] 7. A TSPO high or mixed affinity binder, as determined by rs6971 polymorphism genotyping at screening.

[0300] 8. At screening, the body mass index (BMI) is between 18.0 and 35.0, inclusive.

[0301] 9. Except for MS, the subject is otherwise healthy based on medical history, physical examination, vital signs, laboratory profile, and results of 12-lead electrocardiogram.

[0302] Major exclusion criteria: The subject is not eligible to participate in the study if any of the following criteria are met: 1. Diagnosis of primary progressive or non-relapsing secondary progressive MS. 2. Receiving any depot medication (except contraceptives) by injection within 30 days prior to study drug administration. 3. Receiving an investigational medicinal product within a period equal to 10 half-lives or within 6 weeks prior to study drug administration, if known. 4. Substance abuse or positive alcohol screening. 5. Smoking more than 10 cigarettes per day or using a nicotine patch. 6. History of malignancy; however, subjects with a history of excision or treatment of basal cell carcinoma or 3 or fewer squamous cell carcinomas are eligible to participate in this study. 7. Known to be hypersensitive to the study drug or its excipients. 8. History of substance or alcohol abuse within 2 years prior to study drug administration. 9. History of severe allergy or anaphylactic reaction. 10. History of seizure disorder or unexplained fainting, or seizure history within 6 months prior to screening. 11. Answering "yes" to question 4 or 5 in the suicidal ideation section of the Columbia-Suicide Severity Rating Scale (C-SSRS) completed at screening, or a history of suicidal ideation or clinically severe depressive episode within 1 month prior to study drug administration, as evidenced by any history of suicidal behavior. 12. Known history of hepatitis B virus or hepatitis C virus, or positive screening test results. 13. Varicella or herpes zoster virus infection within 6 weeks prior to screening, or any severe viral infection. 14. Exposure to varicella-zoster virus within 21 days prior to screening. 15. History of human immunodeficiency virus (HIV) or other immunodeficiency states. 16. Any live virus vaccine of any type, including but not limited to measles / mumps / rubella vaccine, varicella zoster virus vaccine, oral polio vaccine, and nasal influenza vaccine, starting 4 weeks before Visit 2. 17. Hospitalization or an infection (viral, fungal, bacterial) requiring intravenous (IV) antibiotics within 8 weeks before Visit 2. 18. Performance of a planned elective surgery starting 14 days before Visit 2 or until the end of the study. 19. Any abnormal laboratory result history indicating any severe heart disease, endocrine disease, blood disease, liver disease, immune disease, metabolic disease, urinary disease, lung disease, gastrointestinal disease, skin disease, mental disease, kidney disease, neurological disease (other than MS), and / or any other major disease that makes administration of AE12-1-Y-QL impossible, in the opinion of the principal investigator of the clinical trial. 20. Any of the following abnormal blood tests at screening: · Hemoglobin ≤ 10.0 g / dL · Platelets ≤ 100 × 10 9 / L · Lymphocytes ≤ 1.0 × 10 9 / L · Neutrophils ≤ 1.5 × 10 9 / L · Alanine aminotransferase / serum glutamate pyruvate transaminase (ALT / SGPT), aspartate aminotransferase / serum glutamate oxaloacetate transaminase (AST / SGOT), or gamma-glutamyl transferase ≥ 2 times the upper limit of normal (ULN) · Serum creatinine ≥ ULN · APTT ≥ ULN · INR ≥ ULN · eGFR ≤ 30 mL / min / 1.73 m 2 21. Transfusion or loss of more than 550 mL of blood volume (including plasma exchange) or receiving an infusion of any blood product within 8 weeks before administration of the study drug. 22. An MS relapse occurring within 30 days before screening and / or the subject has not been stabilized from a previous relapse before screening. 23. Subjects who cannot or do not wish to undergo MRI or PET procedures. 24. The subject has a contraindication to arterial line insertion as determined by an abnormal Allen's test or coagulation profile at screening. 25. Subjects for whom MRI is contraindicated (i.e., those with an intracranial aneurysm clip, metal piece, cochlear implant, spinal cord stimulator, or other in vivo electrical device such as a pacemaker), gadolinium is contraindicated or the subject is allergic to gadolinium (including those previously diagnosed with renal dysfunction, abnormal eGFR, nephrogenic systemic fibrosis), medically unmanageable, or has claustrophobia such that they cannot lie flat for more than one hour for an imaging procedure. 26. Subjects with a pre-radiation exposure history within the past year for the purposes of the study that exceeds the International Commission on Radiological Protection (ICRP) / Radiopharmaceutical Research Committee (RDRC) limits for annual radiation exposure due to participation in this study. These guidelines are for an effective dose of 10 mSv per year. 27. Findings on a brain MRI scan show any clinically significant brain abnormalities other than MS. 28. The subject has a past medical history of cerebrovascular disease or vasculitis. 29. Homozygosity for the low-affinity binding form of TSPO as determined by TSPO genotype analysis (Ala147Thr polymorphism of the rs6971 SNP in exon 4 of the TSPO gene) at screening. 30. Use of high-dose diazepam within 5 half-lives prior to a PET imaging session. 31. Pretreatment by any of the following: · Total body lymph node irradiation · Cladribine or mitoxantrone · T cell or T cell receptor vaccination 32. Pretreatment with cyclophosphamide or alemtuzumab within one year prior to Visit 2. 33. Pretreatment by any of the following medications or procedures within six months prior to Visit 2: · Natalizumab · Rituximab · Daclizumab · Cyclosporine · Azathioprine · Methotrexate · Mycophenolate mofetil · Intravenous immunoglobulin (IVIg) · Plasma exchange or cell adsorption removal method 34. Treatment by any of the following medications within 30 days before Visit 2: · IV corticosteroid treatment · Oral corticosteroid treatment · Glatiramer acetate · Fingolimod · Dimethyl fumarate · Teriflunomide · Beta interferon 35. Initiation of treatment and dose adjustment of commercially available famciclovir-SR within at least 90 days before screening (Subjects who have been stably administered commercially available famciclovir-SR for more than 90 days are not exclud...

Claims

1. 1. A method for treating relapsing forms of multiple sclerosis in a subject in need of such treatment, comprising administering a therapeutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds to Repulsive Guidance Molecule A (RGMa), wherein the antibody or antigen-binding fragment: (a) a variable heavy chain comprising a complementarity determining region (CDR)-1 comprising the amino acid sequence of SEQ ID NO:2, a CDR-2 comprising the amino acid sequence of SEQ ID NO:3, and a CDR-3 comprising the amino acid sequence of SEQ ID NO:4; and (b) a variable light chain comprising a CDR-1 comprising the amino acid sequence of SEQ ID NO:6, a CDR-2 comprising the amino acid sequence of SEQ ID NO:7, and a CDR-3 comprising the amino acid sequence of SEQ ID NO:

8. A method comprising:

2. 10. The method of claim 1, wherein the antibody or antigen-binding fragment thereof is administered to the subject in an amount of about 50 mg to about 4000 mg, or in an amount of about 50 mg to about 2500 mg.

3. 3. The method of claim 2, wherein the antibody or antigen-binding fragment thereof is administered in an amount of about 50 mg, 100 mg, 150 mg, 300 mg, 450 mg, 600 mg, 1000 mg, 1200 mg, 1600 mg, 1800 mg, 2400 mg or 3600 mg.

4. 3. The method of claim 2, wherein the antibody or antigen-binding fragment thereof is administered in an amount of about 50 mg, 75 mg, 100 mg, 120 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg or 500 mg.

5. The method of claim 3 , wherein the antibody or antigen-binding fragment thereof is administered intravenously (IV).

6. The method of claim 4 , wherein the antibody or antigen-binding fragment thereof is administered subcutaneously.

7. 7. The method of any one of claims 1 to 6, wherein the variable heavy chain comprises the amino acid sequence of SEQ ID NO: 13 and the variable light chain comprises the amino acid sequence of SEQ ID NO:

14.

8. The antibody may be a human antibody, an immunoglobulin molecule, a disulfide-linked Fv, a monoclonal antibody, an affinity matured antibody, an scFv, a chimeric antibody, a CDR-grafted antibody, a diabody, a humanized antibody, a multispecific antibody, a Fab, a dual specific antibody, a DVD, a Fab', a bispecific antibody, a F(ab') ２ The method of any one of claims 1 to 7, wherein the Fv is selected from the group consisting of Fv and Fv.

9. The method of claim 8 , wherein the antibody is a human antibody.

10. The method of claim 8 , wherein the antibody is a monoclonal antibody.

11. The method of claim 8 , wherein the antibody is an affinity matured antibody.

12. The method of claim 8 , wherein the antibody is a chimeric antibody.

13. The method of claim 8 , wherein the antibody is a humanized antibody.

14. The antibody is Fab, Fab', or F(ab'). ２ or Fv.

15. The method of claim 8, wherein the antibody is a dual specific antibody, a DVD or a bispecific antibody.

16. The method of claim 7, further comprising the constant sequence of SEQ ID NO:

12.

17. 17. The method of any one of claims 1 to 16, further comprising administering an additional therapeutic agent.

18. 18. The method of claim 17, wherein the additional therapeutic agent is an immunosuppressant or an agent that treats one or more symptoms associated with multiple sclerosis.

19. Additional therapeutic agents include beta interferon, glatiramer (Copaxone), fingolimod (Gilenya), natalizumab (Tysabri), mitoxantrone (Novantrone), teriflunimide (Aubagio), BG-12 (Tecfidera), alemtuzumab (Lemtrada). , daclizumab (Zinbryta), ocrelizumab (Ocrevus), amantadine (Symmetrel), amitriptyline (Elavil), nortriptyline, modafinil (Provigil), dalfampyridine (Ampyra), a cognitive enhancer, an immunomodulator or a neuroprotectant.

20. Cognitive enhancing drugs include acetylcholine receptor agonists, acetylcholinesterase inhibitors, butyrylcholinesterase inhibitors, N-methyl-D-aspartate (NMDA) receptor antagonists, activity-dependent neuroprotective protein (ADNP) agonists, serotonin 5-HT1A receptor agonists, 5-HT4 receptor agonists, 5-HT6 receptor antagonists, serotonin 1A receptor antagonists, histamine H3 receptor antagonists, calpain inhibitors, vascular endothelial growth factor (VEGF) proteins or agonists, trophic growth factors, 20. The method of claim 19, comprising administering to a subject a therapeutically effective amount of a medicament for treating or preventing the development of a medicament for treating or preventing the development of a medicament for treating or preventing the development of a medicament for treating or preventing the development of a medicament for treating or preventing the development of a medicament for treating or preventing the development of a medicament for treating the treatment of a subject ...

21. 21. The method of claim 20, wherein the cognitive enhancing agent comprises donepezil (Aricept®), rivastigmine (Exelon®), galantamine (Reminyl®), memantine (Namenda®), or a combination thereof.

22. 22. The method of any one of claims 1 to 21, wherein the relapsing form of multiple sclerosis is relapsing remitting multiple sclerosis (RRMS) or relapsing secondary progressive multiple sclerosis (SPMS).

23. 23. The method of any one of claims 1 to 22, wherein the antibody or antigen-binding fragment thereof is administered according to a multiple variable dosing regimen.

24. 24. The method of claim 23, wherein the multiple variable dosing regimen comprises a loading dose and a therapeutic dose that is lower than the loading dose.

25. 25. The method of claim 24, wherein the loading dose is selected from the group consisting of 100 mg, 300 mg, 1200 mg and 3600 mg.

26. 25. The method of claim 24, wherein the therapeutic dose is selected from the group consisting of 50 mg, 150 mg, 600 mg and 1800 mg.

27. 25. The method of claim 24, wherein the time interval between the loading dose and the first treatment dose is at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 1 month, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 2 months, at least 9 weeks, at least 10 weeks, at least 11 weeks, or at least 12 weeks.

28. 2. The method of claim 1, wherein the antibody or antigen-binding fragment thereof is administered once a week, once every other week, once every two weeks, once every three weeks, once every four weeks, once a month, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every two months, once every nine weeks, once every ten weeks, once every eleven weeks, or once every twelve weeks.

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