Dosing regimens for treatment of multifocal motor neuropathy (MMN)

Abstract

Methods and dosing regimens are provided for treating multifocal motor neuropathy (MMN) using antibodies that specifically bind to the C2b moiety of complement component 2 (C2).

Description

Background Art

[0001] Multifocal motor neuropathy (MMN) is a rare chronic immune-mediated neuropathy that mainly involves progressive muscle weakness in the hands, forearms and lower legs. Multifocal motor neuropathy is clinically characterized by progressive asymmetric weakness and partial motor block involving 2 or more nerves. The estimated prevalence of MMN is 0.6 to 2 per 100,000 people, and it is usually manifested as asymmetric pure motor neuropathy of the upper limbs. Different from amyotrophic lateral sclerosis (ALS) that affects both upper motor neuron pathways and lower motor neuron pathways, MMN only involves the lower motor neuron pathway, particularly from the peripheral nerves of the lower motor neurons. The hallmark of the disease is the presence of multifocal motor block, i.e., the propagation of action potentials along axons is impaired, and patients usually show high serum levels of immunoglobulin M (IgM) antibodies against ganglioside GM1 (monosialyl tetrahexose-ganglioside). GM1 is widely expressed in the nervous system by neurons, especially around the nodes of Ranvier and Schwann cells. The prevailing view is that GM1 antibodies target the axonal membrane at the nodes of Ranvier. This is thought to interfere with axon-Schwann cell interactions, leading to enlargement of the nodes and direct damage to axons.

[0002] The presence and titer of IgM anti-ganglioside GM1 (anti-GM1) antibodies (observed in approximately 40% of MMN patients) and their complement activation properties are associated with clinical features such as weakness and axonal damage. Binding of these anti-GM1 antibodies to GM1 leads to activation of the classical complement pathway and subsequent deposition of the membrane attack complex (MAC). Consequently, this MAC deposition leads to disruption of Schwann cell-axonal membrane junctions, shifting of ion channel clusters, and perturbation of membrane integrity at the (para)nodal region, leading to demyelination. These findings suggest that complement plays an important role in the pathogenesis of MMN and that inhibition of complement activation may provide a new therapeutic option for this disease.

[0003] Currently, high-dose IV immunoglobulin (IVIg) treatment is the only approved treatment for MMN. IVIg treatment usually improves muscle strength, but the effectiveness of IVIg in alleviating MMN symptoms declines after several years, and many patients report progressive neurological deficits. Despite treatment with IVIg, the disability associated with MMN will continue to develop due to persistent axonal degeneration.

[0004] Therefore, there remains an unmet medical need for effective therapeutic options for the treatment of MMN. Summary of the invention

[0005] The present disclosure relates to methods for treating MMN with a complement component 2 (C2) inhibitor. Also provided herein are specific dosing regimens for administering a C2 inhibitor that results in a rapid reduction in free C2 levels in the blood of a subject with MMN. In one embodiment, the dosing regimen comprises a loading regimen that rapidly reduces free C2 in a subject, followed by a maintenance regimen that maintains reduced free C2 levels in the subject.

[0006] In one aspect, provided herein are methods of treating multifocal motor neuropathy (MMN) in a subject in need thereof, the method comprising administering to the subject an effective amount of a C2 inhibitor.

[0007] In one embodiment, the C2 inhibitor is administered at a dose of 0.1 mg / kg to 100 mg / kg. In one embodiment, the C2 inhibitor is administered at a dose of 10 mg / kg to 60 mg / kg. In one embodiment, the C2 inhibitor is administered at a dose of 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg or 80 mg / kg. In one embodiment, the C2 inhibitor is administered at a dose of 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg or 60 mg / kg. In one embodiment, the C2 inhibitor is administered at a dose of 5 mg / kg. In one embodiment, the C2 inhibitor is administered at a dose of 10 mg / kg. In one embodiment, the C2 inhibitor is administered at a dose of 15 mg / kg. In one embodiment, the C2 inhibitor is administered at a dose of 30 mg / kg. In one embodiment, the C2 inhibitor is administered at a dose of 60 mg / kg.

[0008] In one embodiment, the C2 inhibitor is administered at a fixed dose of 500 mg to 1500 mg. In one embodiment, the C2 inhibitor is administered at a fixed dose of 1200 mg.

[0009] In one embodiment, the C2 inhibitor is administered intravenously or subcutaneously. In one embodiment, the C2 inhibitor is administered intravenously. In one embodiment, the C2 inhibitor is administered subcutaneously.

[0010] In one embodiment, the C2 inhibitor is administered once a week. In one embodiment, the C2 inhibitor is administered once every 2 weeks. In one embodiment, the C2 inhibitor is administered once every 4 weeks. In one embodiment, the C2 inhibitor is administered once every 8 weeks.

[0011] In one embodiment, the C2 inhibitor is administered intravenously at a dose of 10 mg / kg once per week or every 2 weeks. In one embodiment, the C2 inhibitor is administered intravenously at a dose of 30 mg / kg once per week or every 2 weeks. In one embodiment, the C2 inhibitor is administered intravenously at a dose of 60 mg / kg once per week or every 2 weeks. In one embodiment, the C2 inhibitor is administered intravenously at a dose of 15 mg / kg once per week or every 2 weeks. In one embodiment, the C2 inhibitor is administered at a dose of 5 mg / kg once per week, every 2 weeks, or every 4 weeks.

[0012] In one embodiment, the C2 inhibitor is administered according to a loading regimen that reduces the level of free C2 in the subject's blood to or below a threshold level.

[0013] In one embodiment, the method further comprises a maintenance regimen following the loading regimen, wherein the maintenance regimen comprises administering the C2 inhibitor according to a regimen that maintains the level of free C2 in the subject's blood at or below a threshold level.

[0014] In one embodiment, the threshold level is 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7 or 0.8 μg / mL. In one embodiment, the threshold level is 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20% of the baseline level of free C2 in the subject.

[0015] In one embodiment, the loading regimen is a single initial dose followed by one or more subsequent doses. In one embodiment, the one or more subsequent doses are each a lower amount than the single initial dose.

[0016] In one embodiment, a single initial dose is followed by 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 subsequent doses. In one embodiment, subsequent doses are administered once a week, every 2 weeks or every 4 weeks.

[0017] In one embodiment, the single initial dose is followed by 4 subsequent doses, and wherein the subsequent doses are administered once a week. In one embodiment, the first subsequent dose is administered one week after the single initial dose.

[0018] In one embodiment, the single initial dose is 0.1 mg / kg to 100 mg / kg. In one embodiment, the single initial dose is 10 mg / kg to 60 mg / kg. In one embodiment, the single initial dose is 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg or 80 mg / kg. In one embodiment, the single initial dose is 15 mg / kg. In one embodiment, the single initial dose is 30 mg / kg. In one embodiment, the single initial dose is 60 mg / kg.

[0019] In one embodiment, the single initial dose is a fixed dose of 500 mg to 1500 mg. In one embodiment, the single initial dose is a fixed dose of 1200 mg.

[0020] In one embodiment, the subsequent dose is each 0.1mg / kg to 100mg / kg. In one embodiment, the subsequent dose is each 5mg / kg to 60mg / kg. In one embodiment, the subsequent dose is each 0.1mg / kg, 0.5mg / kg, 2.5mg / kg, 5mg / kg, 10mg / kg, 15mg / kg, 30mg / kg, 60mg / kg or 80mg / kg. In one embodiment, the subsequent dose is each 5mg / kg. In one embodiment, the subsequent dose is each 10mg / kg. In one embodiment, the subsequent dose is each 30mg / kg.

[0021] In one embodiment, subsequent doses are each a fixed dose of 500 mg to 1500 mg. In one embodiment, subsequent doses are each a fixed dose of 1200 mg.

[0022] In one embodiment, a single initial dose is 15 mg / kg and subsequent doses are each 5 mg / kg. In one embodiment, a single initial dose is 30 mg / kg and subsequent doses are each 10 mg / kg. In one embodiment, a single initial dose is 60 mg / kg and subsequent doses are each 30 mg / kg.

[0023] In one embodiment, the loading regimen is administered intravenously or subcutaneously. In one embodiment, the loading regimen is administered intravenously. In one embodiment, the loading regimen is administered subcutaneously.

[0024] In one embodiment, the loading regimen reduces the level of free C2 to a threshold level or below a threshold level within 1, 2, 3, 4, 5, 6 or 7 days. In one embodiment, the loading regimen reduces the level of free C2 to a threshold level or below a threshold level within 1, 2, 3, 4 or 5 weeks.

[0025] In one embodiment, the maintenance regimen is a dose of 0.1 to 100 mg / kg administered once per week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, or every 8 weeks.

[0026] In one embodiment, the maintenance regimen is a dosage of 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg administered once a week. In one embodiment, the maintenance regimen is a dosage of 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg administered once every 2 weeks. In one embodiment, the maintenance regimen is a dosage of 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg administered once every 3 weeks. In one embodiment, the maintenance regimen is a dosage of 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg once every 4 weeks. In one embodiment, the maintenance regimen is a dosage of 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg once every 5 weeks. In one embodiment, the maintenance regimen is a dosage of 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg once every 6 weeks. In one embodiment, the maintenance regimen is a dosage of 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg once every 7 weeks. In one embodiment, the maintenance regimen is a dosage of 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg once every 8 weeks.

[0027] In one embodiment, the maintenance regimen is a dose of 500 mg to 1500 mg administered once per week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, every 7 weeks or every 8 weeks. In one embodiment, subsequent doses are each a fixed dose of 1200 mg.

[0028] In one embodiment, the maintenance regimen is administered 1, 2, 3, 4, 5, 6, 7 or 8 weeks after the loading regimen. In one embodiment, if the level of free C2 in the subject's blood is above the threshold level, the maintenance regimen is administered. In one embodiment, the maintenance regimen is administered intravenously or subcutaneously. In one embodiment, the maintenance regimen is administered intravenously. In one embodiment, the maintenance regimen is administered subcutaneously.

[0029] In one embodiment, the loading regimen is: a single initial dose of 30 mg / kg; and four subsequent doses, each of which is 10 mg / kg administered once a week starting one week after the single initial dose; and the maintenance regimen is: a dose of 10 mg / kg administered once every two weeks.

[0030] In one embodiment, the loading regimen is: a single initial dose of 60 mg / kg; and four subsequent doses, each of which is 30 mg / kg administered once a week starting one week after the single initial dose; and the maintenance regimen is: a dose of 30 mg / kg administered once every two weeks.

[0031] In one embodiment, the loading regimen is: a single initial dose of 15 mg / kg; and four subsequent doses, each of which is 5 mg / kg administered once a week starting one week after the single initial dose; and the maintenance regimen is: a dose of 5 mg / kg administered once every four weeks.

[0032] In one embodiment, the maintenance regimen begins 1 week after the last subsequent dose of the loading regimen. In one embodiment, the maintenance regimen begins 2 weeks after the last subsequent dose of the loading regimen.

[0033] In one embodiment, the loading regimen is administered intravenously and the maintenance regimen is administered subcutaneously. In one embodiment, the loading regimen is administered subcutaneously and the maintenance regimen is administered intravenously. In one embodiment, both the loading regimen and the maintenance regimen are administered intravenously. In one embodiment, both the loading regimen and the maintenance regimen are administered subcutaneously.

[0034] In one embodiment, the subject's motor strength and / or the subject's sensory symptoms are improved as compared to that achieved with standard of care treatment using intravenous immunoglobulin (IVIg).

[0035] In one embodiment, the subject exhibits a reduction in the level of free C2 in the subject's blood after administration of a C2 inhibitor, compared to a baseline level of free C2 in the subject's blood. In one embodiment, the level of free C2 in the subject's blood is reduced by at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% compared to a baseline level of free C2 in the subject's blood.

[0036] In one embodiment, the method further comprises administering to the subject an additional therapeutic agent. In one embodiment, the additional therapeutic agent is IVIg. In one embodiment, the additional therapeutic agent is rituximab, eculizumab, cyclophosphamide, or mycophenolate mofetil.

[0037] In one embodiment, IVIg is administered to the subject once every two weeks, once every three weeks, once every four weeks, or once every five weeks.

[0038] In one embodiment, the subject has detectable baseline serum levels of anti-ganglioside IgM antibodies.

[0039] In one embodiment, the subject has been previously treated with IVIg. In one embodiment, the subject has been previously stabilized with IVIg. In one embodiment, the subject is dependent on IVIg.

[0040] In one embodiment, the subject does not concurrently receive IVIg. In one embodiment, the subject does not require IVIg retreatment following administration of the C2 inhibitor. In one embodiment, administration of the C2 inhibitor prolongs the time to IVIg retreatment.

[0041] In one embodiment, the subject shows an improvement in mMRC score after administration of a C2 inhibitor compared to the subject's baseline modified Medical Research Council (mMRC) score. In one embodiment, the mMRC score is an mMRC-10 sum score or an mMRC-14 sum score.

[0042] In one embodiment, the subject shows an improvement in grip strength following administration of the C2 inhibitor as compared to the subject's baseline grip strength.

[0043] In one embodiment, the overall disability scale constructed with the subject's baseline MMN Rasch Compared with the MMN Rasch-built Overall Disability Scale scores, subjects showed Rating improved.

[0044] In one embodiment, the C2 inhibitor is an antibody that specifically binds to C2.

[0045] In one embodiment, the antibody comprises: a heavy chain variable region (VH) and / or a light chain variable region (VL); the heavy chain variable region (VH) comprises the CDRH1, CDRH2 and CDRH3 amino acid sequences of the VH amino acid sequence shown in SEQ ID NO:7, or a variant thereof, wherein the variant comprises 1 to 5 amino acid changes in any one of the CDRH1, CDRH2 or CDRH3 amino acid sequences; the light chain variable region (VL) comprises the CDRL1, CDRL2 and CDRL3 amino acid sequences of the VL amino acid sequence shown in SEQ ID NO:8, or a variant thereof, wherein the variant comprises 1 to 5 amino acid changes in any one of the CDRL1, CDRL2 or CDRL3 amino acid sequences.

[0046] In one embodiment, (a) VH comprises the following CDRH1, CDRH2 and CDRH3 amino acid sequences, respectively: SEQ ID NO: 1 or a variant thereof containing 1 to 5 amino acid changes, SEQ ID NO: 2 or a variant thereof containing 1 to 5 amino acid changes, SEQ ID NO: 3 or a variant thereof containing 1 to 5 amino acid changes; and / or (b) VL comprises the following CDRL1, CDRL2 and CDRL3 amino acid sequences, respectively: SEQ ID NO: 4 or a variant thereof containing 1 to 5 amino acid changes, SEQ ID NO: 5 or a variant thereof containing 1 to 5 amino acid changes, SEQ ID NO: 6 or a variant thereof containing 1 to 5 amino acid changes.

[0047] In one embodiment, the antibody comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences set forth in SEQ ID NOs: 1, 2, 3, 4, 5 and 6, respectively.

[0048] In one embodiment, the antibody comprises: a VH comprising an amino acid sequence that is at least 75%, 80%, 85%, 90%, 95% or 99% identical to the amino acid sequence shown in SEQ ID NO:7; and / or a VL comprising an amino acid sequence that is at least 75%, 80%, 85%, 90%, 95% or 99% identical to the amino acid sequence shown in SEQ ID NO:8.

[0049] In one embodiment, the antibody comprises a VH comprising the amino acid sequence shown in SEQ ID NO: 7 and a VL comprising the amino acid sequence shown in SEQ ID NO: 8. In one embodiment, the amino acid sequence of VH consists of the amino acid sequence shown in SEQ ID NO: 7 and the amino acid sequence of VL consists of the amino acid sequence shown in SEQ ID NO: 8.

[0050] In one embodiment, the antibody comprises: a heavy chain comprising an amino acid sequence that is at least 75%, 80%, 85%, 90%, 95% or 99% identical to the amino acid sequence shown in SEQ ID NO:9; and / or a light chain comprising an amino acid sequence that is at least 75%, 80%, 85%, 90%, 95% or 99% identical to the amino acid sequence shown in SEQ ID NO:10.

[0051] In one embodiment, the antibody comprises a heavy chain comprising the amino acid sequence shown in SEQ ID NO: 9 and a light chain comprising the amino acid sequence shown in SEQ ID NO: 10. In one embodiment, the amino acid sequence of the heavy chain consists of the amino acid sequence shown in SEQ ID NO: 9 and the amino acid sequence of the light chain consists of the amino acid sequence shown in SEQ ID NO: 10.

[0052] In one aspect, provided herein is a C2 inhibitor for use in treating multifocal motor neuropathy, wherein the treatment is performed according to a method disclosed herein.

[0053] In one aspect, provided herein is a C2 inhibitor for use in the preparation of a medicament for treating multifocal motor neuropathy, wherein the treatment is performed according to the methods disclosed herein.

[0054] In one aspect, provided herein is the use of a C2 inhibitor for treating multifocal motor neuropathy, wherein the treatment is performed according to the methods disclosed herein. DETAILED DESCRIPTION

[0055] The present disclosure relates to methods for treating MMN with a C2 inhibitor (e.g., an anti-C2 antibody). Also provided herein are specific dosing regimens for administering a C2 inhibitor that results in a rapid reduction in free C2 levels in the blood of a subject with MMN. In one embodiment, the dosing regimen comprises a loading regimen that rapidly reduces free C2 in a subject, followed by a maintenance regimen that maintains reduced free C2 levels in the subject.

[0056] definition

[0057] As used herein, the term "antibody" and variations thereof include full-length antibodies, antigen-binding fragments of full-length antibodies, and molecules comprising antibody CDRs, VH regions, and / or VL regions. Examples of antibodies include, but are not limited to, monoclonal antibodies, recombinantly produced antibodies, monospecific antibodies, multispecific antibodies (including bispecific antibodies), human antibodies, humanized antibodies, chimeric antibodies, immunoglobulins, synthetic antibodies, tetrameric antibodies comprising two heavy chains and two light chain molecules, antibody light chain monomers, antibody heavy chain monomers, antibody light chain dimers, antibody heavy chain dimers, antibody light chain-antibody heavy chain pairs, intrabodies, heteroconjugate antibodies, antibody-drug conjugates, single domain antibodies, monovalent antibodies, single-chain antibodies or single-chain Fv (single-chain Fv, scFv), camelized antibodies, affibodies, Fab fragments, F(ab')2 fragments, disulfide-linked Fv (sdFv), anti-idiotypic antibodies (including, for example, anti-anti-Id antibodies), and any of the above antigen-binding fragments. In certain embodiments, the antibodies described herein refer to polyclonal antibody populations. The antibody can be any type of immunoglobulin molecule (e.g., IgG, IgE, IgM, IgD, IgA or IgY), any class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 or IgA2) or any subclass (e.g., IgG2a or IgG2b). In certain embodiments, the antibody described herein is an IgG antibody or its class (e.g., human IgG1 or IgG4) or subclass. In one embodiment, the antibody is a humanized monoclonal antibody. In one embodiment, the antibody is a human monoclonal antibody.

[0058] As used herein, the term "CDR" or "complementarity determining region" means non-adjacent antigen binding sites present in the variable regions of heavy and light chain polypeptides. These specific regions have been described, for example, by Kabat et al., J. Biol. Chem. 252, 6609-6616 (1977) and Kabat et al., Sequences of Proteins of Immunological Interest. (1991); Chothia et al., J. Mol. Biol. 196: 901-917 (1987); and MacCallum et al., J. Mol. Biol. 262: 732-745 (1996), all of which are incorporated herein by reference in their entirety, wherein the definitions include overlaps or subsets of amino acid residues when compared to each other (see Table 1 below). In certain embodiments, the term "CDR" is a CDR defined by MacCallum et al., J. Mol. Biol. 262: 732-745 (1996) and Martin A. "Protein Sequence and Structure Analysis of Antibody Variable Domains," in Antibody Engineering, Kontermann and Dübel, eds., Chapter 31, pp. 422 to 439, Springer-Verlag, Berlin (2001). In certain embodiments, the term "CDR" is a CDR defined by Kabat et al., J. Biol. Chem. 252, 6609-6616 (1977) and Kabat et al., Sequences of Proteins of Immunological Interest. (1991). In certain embodiments, the heavy chain CDR and light chain CDR of an antibody are defined using different conventions. In certain embodiments, the heavy chain CDR and / or light chain CDR are defined by structural analysis of the antibody and identification of residues in the variable region that are predicted to contact the epitope region of the target molecule (e.g., human C2). CDRH1, CDRH2, and CDRH3 represent the heavy chain CDR, and CDRL1, CDRL2, and CDRL3 represent the light chain CDR.

[0059] Table 1: CDR Definition

[0060]

[0061] The terms "variable region" and "variable domain" used herein are interchangeable and are common in the art. A variable region generally refers to a part of an antibody, generally speaking, a part of a light chain or a heavy chain, generally about 110 to 120 amino acids or 110 to 125 amino acids at the amino terminal in a mature heavy chain and about 90 to 115 amino acids in a mature light chain, which differ greatly in sequence between antibodies and are used for the binding and specificity of a particular antibody for its specific antigen. The variability of the sequence is concentrated in those regions known as complementarity determining regions (CDRs), while the more highly conserved regions in the variable region are known as framework regions (FRs). Without wishing to be bound by any particular mechanism or theory, it is believed that the CDRs of light and heavy chains are primarily responsible for the interaction and specificity of antibodies with antigens. In certain embodiments, the variable region is a human variable region. In certain embodiments, the variable region comprises rodent or mouse CDRs and human framework regions (FRs). In one embodiment, the variable region is a primate (e.g., non-human primate) variable region. In one embodiment, the variable region comprises rodent or murine CDRs and primate (eg, non-human primate) framework regions (FRs).

[0062] As used herein, the terms "VH" and "VL" refer to the antibody heavy chain variable region and light chain variable region, respectively, as described in Kabat et al., (1991) Sequences of Proteins of Immunological Interest (NIH Publication No. 91-3242, Bethesda), which is incorporated herein by reference in its entirety.

[0063] The term "constant region" used herein is commonly used in the art. The constant region is a part of an antibody, for example, the carboxyl terminal portion of a light chain and / or a heavy chain, which is not directly involved in the binding of the antibody to an antigen, but may exhibit a variety of effector functions, such as interaction with an Fc receptor (e.g., an Fcγ receptor).

[0064] As used herein, the term "heavy chain" when used in reference to antibodies may refer to any of the different types, e.g., alpha (α), delta (δ), epsilon (ε), gamma (γ), and mu (μ) (based on the amino acid sequence of the constant region), which give rise to the IgA, IgD, IgE, IgG, and IgM classes of antibodies, respectively, including the IgG subclasses, e.g., IgG1, IgG2, IgG3, and IgG4.

[0065] As used herein, the term "light chain" when used in reference to an antibody can refer to any of the different types, e.g., kappa (κ) or lambda (λ) (based on the amino acid sequence of the constant region). Light chain amino acid sequences are well known in the art. In one embodiment, the light chain is a human light chain.

[0066] As used herein, the terms "specific binding", "specific recognition", "immunospecific binding", and "immunospecific recognition" are analogous terms in the context of antibodies and refer to molecules that bind to an antigen (e.g., an epitope or immune complex), such binding being understood by those skilled in the art. For example, a molecule that specifically binds to an antigen can often be identified by, for example, immunoassays, The molecule that specifically binds to an antigen binds to the antigen with a KA that is at least 2 logs (e.g., a factor of 10), 2.5 logs, 3 logs, 4 logs, or more greater than the KA when the molecule nonspecifically binds to another antigen.

[0067] The term "EU numbering system" as used herein refers to the EU numbering convention for antibody constant regions as described in Edelman G.M. et al., Proc. Natl. Acad. USA, 63, 78-85 (1969) and Kabat et al., Sequences of Proteins of Immunological Interest, U. Sept. Health and Human Services, 5th Edition, 1991, each of which is incorporated herein by reference in its entirety.

[0068] The term "subject" as used herein includes any human or non-human animal. In one embodiment, the subject is a human.

[0069] As used herein, the term "baseline" refers to a measurement (e.g., free C2 level) in a subject (e.g., in the subject's blood) prior to the first administration (e.g., intravenous or subcutaneous administration) of a treatment (e.g., a C2 inhibitor).

[0070] As used herein, the term "effective amount" in the context of administering a treatment to a subject refers to that amount of the treatment which achieves the desired prophylactic or therapeutic effect.

[0071] The term "IVIg retreatment" as used herein refers to the administration of IVIg treatment to a subject that has been previously treated with IVIg. In one embodiment, IVIg retreatment is given to a subject based on clinical worsening. In one embodiment, clinical worsening is defined as a decrease in grip strength of any hand of >30% (based on an average calculation of 3 days) and / or a decrease in the mMRC-10 total score of at least 2 points observed for at least 2 consecutive days compared to the day of randomization.

[0072] As used herein, the term "IVIg-dependent" or "dependent on IVIg" means that a subject shows clinical worsening if IVIg treatment is stopped, or shows clinical improvement if IVIg treatment is initiated. In one embodiment, a subject is considered IVIg-dependent if the subject is stable on IVIg for longer than 3 months and a clinically significant worsening is confirmed. In one embodiment, a subject is considered IVIg-dependent if the subject is stable on IVIg for less than 3 months and shows clinical improvement after initiating IVIg treatment.

[0073] As used herein, the term "about" when referring to a measurable value (e.g., a dosage) encompasses variations of ±20%, ±15%, ±10%, ±5%, ±1%, or ±0.1% of a given value or range as it is suitable for performing the methods disclosed herein.

[0074] Multifocal Motor Neuropathy (MMN)

[0075] Diagnosis of MMN

[0076] The diagnosis of MMN depends on showing that the patient has a pure motor disorder affecting an individual nerve, no upper motor neuron (UMN) signs, only mild or no sensory loss, and evidence of conduction block. These criteria are designed to distinguish the condition from ALS (pure motor but with UMN signs), the Lewis-Sumner syndrome variant of chronic inflammatory demyelinating polyneuropathy (CIDP) (similar to MMN, but usually with significant sensory loss), and "vasculitis" (a type of multiple mononeuropathy syndrome caused by inflammatory damage to the blood vessels in the nerves, which also causes sensory and motor symptoms).

[0077] A neurologist is usually required to determine the diagnosis based on the history and physical examination, as well as electrodiagnostic studies, including nerve conduction studies (NCS) and needle electromyography (EMG). NCS usually indicates conduction block. This can be achieved by showing that the nerve signal cannot be conducted through the "lesion" at some points along the nerve. For example, if the nerve is blocked in the forearm, the electrical impulse can easily pass from the wrist to the hand if the stimulator is placed at the wrist. However, if the stimulator is applied at the elbow, the signal will be blocked and cannot reach the hand. In MMN, sensory conduction along the same path should be normal. The EMG part of the test looks for signals in the way that the muscles fire. In MMN, the EMG will most likely reveal abnormalities, indicating that a certain percentage of motor axons have been damaged. Laboratory tests for GM1 antibodies are frequently performed, and if they are abnormal, they can be very helpful. However, since only one-third of patients with MMN have these antibodies, a negative test does not rule out the disease. Spinal fluid examination is usually not helpful.

[0078] Standard of care treatment

[0079] In 2012, the U.S. Food and Drug Administration (FDA) approved Gammagard Liquid 10% for the treatment of MMN. The drug is intravenous immunoglobulin (IVIg), and most affected individuals respond to the treatment with IVIg. When treatment begins, muscle weakness is usually improved quickly. The effect of IVIg treatment eventually weakens, and affected individuals need to take the drug again every 2 to 6 weeks (maintenance treatment). Sometimes, the response of affected individuals to the drug becomes low, and higher doses or more frequent maintenance treatments will be required. If the affected individual does not respond to the treatment with IVIg or stops responding to the treatment, other drugs can be tried. A variety of other drugs for the treatment of MMN have been tested, including cyclophosphamide, rituximab, beta-interferon, mycophenolate mofetil, cyclosporine, azathioprine and infliximab.

[0080] C2 inhibitors

[0081] C2 inhibitors that can be used in the methods and uses provided herein include, but are not limited to, any anti-C2 antibody.

[0082] In one embodiment, the C2 inhibitor is an antibody that specifically binds to the C2b portion of C2 in a pH-dependent and Ca2+-dependent manner. In one embodiment, the C2 inhibitor is an anti-C2b antibody. C2b as used herein refers to a smaller 30 kDa fragment of complement protein C2. In one embodiment, the antibody inhibits the function of C2 and blocks downstream complement activation.

[0083] In one embodiment, the antibody comprises: a heavy chain variable region (VH) and / or a light chain variable region (VL); the heavy chain variable region (VH) comprises the CDRH1, CDRH2 and CDRH3 amino acid sequences of the VH amino acid sequence shown in SEQ ID NO:7, or a variant thereof, wherein the variant comprises 1 to 5 amino acid changes in any one of the CDRH1, CDRH2 or CDRH3 amino acid sequences; the light chain variable region (VL) comprises the CDRL1, CDRL2 and CDRL3 amino acid sequences of the VL amino acid sequence shown in SEQ ID NO:8, or a variant thereof, wherein the variant comprises 1 to 5 amino acid changes in any one of the CDRL1, CDRL2 or CDRL3 amino acid sequences.

[0084] In one embodiment, (a) VH comprises the following CDRH1, CDRH2 and CDRH3 amino acid sequences, respectively: SEQ ID NO: 1 or a variant thereof containing 1 to 5 amino acid changes, SEQ ID NO: 2 or a variant thereof containing 1 to 5 amino acid changes, and SEQ ID NO: 3 or a variant thereof containing 1 to 5 amino acid changes; and / or (b) VL comprises the following CDRL1, CDRL2 and CDRL3 amino acid sequences, respectively: SEQ ID NO: 4 or a variant thereof containing 1 to 5 amino acid changes, SEQ ID NO: 5 or a variant thereof containing 1 to 5 amino acid changes, and SEQ ID NO: 6 or a variant thereof containing 1 to 5 amino acid changes.

[0085] In one embodiment, the antibody comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3 amino acid sequences set forth in SEQ ID NOs: 1, 2, 3, 4, 5 and 6, respectively.

[0086] In one embodiment, the antibody comprises: a VH comprising an amino acid sequence that is at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in SEQ ID NO:7; and / or a VL comprising an amino acid sequence that is at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in SEQ ID NO:8.

[0087] In one embodiment, the antibody comprises a VH comprising the amino acid sequence shown in SEQ ID NO: 7 and a VL comprising the amino acid sequence shown in SEQ ID NO: 8. In one embodiment, the amino acid sequence of VH consists of the amino acid sequence shown in SEQ ID NO: 7 and the amino acid sequence of VL consists of the amino acid sequence shown in SEQ ID NO: 8.

[0088] In one embodiment, the antibody comprises: a heavy chain comprising an amino acid sequence that is at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in SEQ ID NO:9; and / or a light chain comprising an amino acid sequence that is at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in SEQ ID NO:10.

[0089] In one embodiment, the antibody comprises a heavy chain comprising the amino acid sequence shown in SEQ ID NO: 9 and a light chain comprising the amino acid sequence shown in SEQ ID NO: 10. In one embodiment, the amino acid sequence of the heavy chain consists of the amino acid sequence shown in SEQ ID NO: 9 and the amino acid sequence of the light chain consists of the amino acid sequence shown in SEQ ID NO: 10.

[0090] In one embodiment, the antibody is ARGX-117, the sequence of which is provided in Table 2 below.

[0091] Table 2: Amino Acid Sequence of ARGX-117

[0092]

[0093] ARGX-117 is pH-dependent and Ca 2+ In one embodiment of any of the methods disclosed herein, the C2 inhibitor binds to human C2 and cynomolgus monkey C2 in a pH-dependent and Ca-dependent manner, with an affinity for human C2 ranging from 0.109 nM to 2.02 nM and an affinity for cynomolgus monkey C2 ranging from 0.056 nM to 0.13 nM, respectively. 2+ARGX-117 binds to human C2 and cynomolgus monkey C2 in a dependent manner, with an affinity for human C2 ranging from 0.109 nM to 2.02 nM, and an affinity for cynomolgus monkey C2 ranging from 0.056 nM to 0.13 nM, respectively. ARGX-117 does not cross-react with C2 from rat, rabbit, hamster, mouse, and guinea pig. Epitope mapping revealed that ARGX-117 primarily binds to the sushi 2 domain of C2. In one embodiment of any of the methods disclosed herein, the C2 inhibitor binds to the sushi 2 domain of C2.

[0094] ARGX-117 inhibits the classical and lectin pathways of the complement system, but does not affect the alternative pathway. In one embodiment of any of the methods disclosed herein, the C2 inhibitor inhibits the classical and lectin pathways of the complement system. In one embodiment of any of the methods disclosed herein, the C2 inhibitor does not inhibit the alternative pathway.

[0095] Methods and dosing regimen

[0096] The present disclosure shows that C2 inhibitors are highly effective in treating multifocal motor neuropathy (MMN). Therefore, the present disclosure broadly relates to methods of treating MMN with C2 inhibitors. Also provided herein are specific dosing regimens for administering C2 inhibitors that result in a rapid reduction in free C2 levels in the blood of subjects with MMN.

[0097] In one aspect, provided herein are methods of treating multifocal motor neuropathy (MMN) in a subject in need thereof, the method comprising administering to the subject an effective amount of a C2 inhibitor.

[0098] In one embodiment, the C2 inhibitor is administered at a dose of about 0.1 mg / kg to 100 mg / kg. In one embodiment, the C2 inhibitor is administered at a dose of about 5 mg / kg to 60 mg / kg. In one embodiment, the C2 inhibitor is administered at a dose of:

[0099] About 0.1mg / kg, 0.5mg / kg, 2.5mg / kg, 5mg / kg, 7.5mg / kg, 10mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg , 45mg / kg, 50mg / kg, 55mg / kg, 60mg / kg, 65mg / kg, 70mg / kg, 75mg / kg, 80mg / kg, 85mg / kg, 90mg / kg, 95mg / kg, or 100mg / kg.

[0100] In one embodiment, the C2 inhibitor is administered at a dose of about 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg. In one embodiment, the C2 inhibitor is administered at a dose of about 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, or 60 mg / kg. In one embodiment, the C2 inhibitor is administered at a dose of about 5 mg / kg. In one embodiment, the C2 inhibitor is administered at a dose of about 10 mg / kg. In one embodiment, the C2 inhibitor is administered at a dose of about 15 mg / kg. In one embodiment, the C2 inhibitor is administered at a dose of about 30 mg / kg. In one embodiment, the C2 inhibitor is administered at a dose of about 60 mg / kg.

[0101] In one embodiment, the C2 inhibitor is administered at a dose of 0.1 mg / kg to 100 mg / kg. In one embodiment, the C2 inhibitor is administered at a dose of 5 mg / kg to 60 mg / kg. In one embodiment, the C2 inhibitor is administered at a dose of:

[0102] 0.1mg / kg, 0.5mg / kg, 2.5mg / kg, 5mg / kg, 7.5mg / kg, 10mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg , 45mg / kg, 50mg / kg, 55mg / kg, 60mg / kg, 65mg / kg, 70mg / kg, 75mg / kg, 80mg / kg, 85mg / kg, 90mg / kg, 95mg / kg, or 100mg / kg.

[0103] In one embodiment, the C2 inhibitor is administered at a dose of 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg. In one embodiment, the C2 inhibitor is administered at a dose of 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, or 60 mg / kg.

[0104] In one embodiment, the C2 inhibitor is administered at a fixed dose of about 500 mg to 1500 mg. In one embodiment, the C2 inhibitor is administered at a fixed dose of about 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, or 1500 mg.

[0105] In one embodiment, the C2 inhibitor is administered at a fixed dose of 500 mg to 1500 mg. In one embodiment, the C2 inhibitor is administered at a fixed dose of 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg or 1500 mg.

[0106] In one embodiment, the C2 inhibitor is administered intravenously or subcutaneously. In one embodiment, the C2 inhibitor is administered intravenously. In one embodiment, the C2 inhibitor is administered subcutaneously.

[0107] In one embodiment, the C2 inhibitor is administered once a week. In one embodiment, the C2 inhibitor is administered once every 2 weeks. In one embodiment, the C2 inhibitor is administered once every 4 weeks. In one embodiment, the C2 inhibitor is administered once every 5 weeks. In one embodiment, the C2 inhibitor is administered once every 6 weeks. In one embodiment, the C2 inhibitor is administered once every 7 weeks. In one embodiment, the C2 inhibitor is administered once every 8 weeks.

[0108] In one embodiment, the C2 inhibitor is administered once weekly at a dose of about 0.1 mg / kg to 100 mg / kg. In one embodiment, the C2 inhibitor is administered once weekly at a dose of about 5 mg / kg to 60 mg / kg. In one embodiment, the C2 inhibitor is administered once weekly at a dose of about 0.1 mg / kg,

[0109] 0.5mg / kg, 2.5mg / kg, 5mg / kg, 7.5mg / kg, 10mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg, 45mg / kg, 50mg / kg, 55mg / kg, 60mg / kg, 65mg / kg, 70mg / kg, 75mg / kg, 80mg / kg, 85mg / kg, 90mg / kg, 95mg / kg, or 100mg / kg.

[0110] In one embodiment, the C2 inhibitor is administered once a week at a dose of about 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg. In one embodiment, the C2 inhibitor is administered once a week at a dose of about 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, or 60 mg / kg. In one embodiment, the C2 inhibitor is administered once a week at a dose of about 5 mg / kg. In one embodiment, the C2 inhibitor is administered once a week at a dose of about 10 mg / kg. In one embodiment, the C2 inhibitor is administered once a week at a dose of about 15 mg / kg. In one embodiment, the C2 inhibitor is administered once a week at a dose of about 30 mg / kg. In one embodiment, the C2 inhibitor is administered once a week at a dose of about 60 mg / kg.

[0111] In one embodiment, the C2 inhibitor is administered once a week at a dose of 0.1 mg / kg to 100 mg / kg. In one embodiment, the C2 inhibitor is administered once a week at a dose of 5 mg / kg to 60 mg / kg. In one embodiment, the C2 inhibitor is administered once a week at a dose of:

[0112] 0.1mg / kg, 0.5mg / kg, 2.5mg / kg5mg / kg, 7.5mg / kg, 10mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg , 45mg / kg, 50mg / kg, 55mg / kg, 60mg / kg, 65mg / kg, 70mg / kg, 75mg / kg, 80mg / kg, 85mg / kg, 90mg / kg, 95mg / kg, or 100mg / kg.

[0113] In one embodiment, the C2 inhibitor is administered once a week at a dose of 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg. In one embodiment, the C2 inhibitor is administered once a week at a dose of 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, or 60 mg / kg.

[0114] In one embodiment, the C2 inhibitor is administered once weekly at a fixed dose of about 500 mg to 1500 mg. In one embodiment, the C2 inhibitor is administered once weekly at a fixed dose of about 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg or 1500 mg.

[0115] In one embodiment, the C2 inhibitor is administered once weekly at a fixed dose of 500 mg to 1500 mg. In one embodiment, the C2 inhibitor is administered once weekly at a fixed dose of 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg or 1500 mg.

[0116] In one embodiment, the C2 inhibitor is administered once every 2 weeks at a dose of about 0.1 mg / kg to 100 mg / kg. In one embodiment, the C2 inhibitor is administered once every 2 weeks at a dose of about 5 mg / kg to 60 mg / kg. In one embodiment, the C2 inhibitor is administered once every 2 weeks at the following doses:

[0117] About 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 7.5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 445 mg / kg, 50 mg / kg, 55 mg / kg, 60 mg / kg, 65 mg / kg, 70 mg / kg, 75 mg / kg, 80 mg / kg, 85 mg / kg, 90 mg / kg, 95 mg / kg, or 100 mg / kg. In one embodiment, the C2 inhibitor is administered once every 2 weeks at a dose of about 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg or 80 mg / kg. In one embodiment, the C2 inhibitor is administered at a dose of about 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, or 60 mg / kg once every 2 weeks. In one embodiment, the C2 inhibitor is administered at a dose of about 5 mg / kg once every 2 weeks. In one embodiment, the C2 inhibitor is administered at a dose of about 10 mg / kg once every 2 weeks. In one embodiment, the C2 inhibitor is administered at a dose of about 15 mg / kg once every 2 weeks. In one embodiment, the C2 inhibitor is administered at a dose of about 30 mg / kg once every 2 weeks. In one embodiment, the C2 inhibitor is administered at a dose of about 60 mg / kg once every 2 weeks.

[0118] In one embodiment, the C2 inhibitor is administered once every 2 weeks at a dose of 0.1 mg / kg to 100 mg / kg. In one embodiment, the C2 inhibitor is administered once every 2 weeks at a dose of 5 mg / kg to 60 mg / kg. In one embodiment, the C2 inhibitor is administered once every 2 weeks at a dose of:

[0119] 0.1mg / kg, 0.5mg / kg, 2.5mg / kg, 5mg / kg, 7.5mg / kg, 10mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg , 45mg / kg, 50mg / kg, 55mg / kg, 60mg / kg, 65mg / kg, 70mg / kg, 75mg / kg, 80mg / kg, 85mg / kg, 90mg / kg, 95mg / kg, or 100mg / kg.

[0120] In one embodiment, the C2 inhibitor is administered at a dose of 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg once every 2 weeks. In one embodiment, the C2 inhibitor is administered at a dose of 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, or 60 mg / kg once every 2 weeks.

[0121] In one embodiment, the C2 inhibitor is administered once every 2 weeks at a fixed dose of about 500 mg to 1500 mg. In one embodiment, the C2 inhibitor is administered once every 2 weeks at a fixed dose of about 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, or 1500 mg.

[0122] In one embodiment, the C2 inhibitor is administered once every 2 weeks at a fixed dose of 500 mg to 1500 mg. In one embodiment, the C2 inhibitor is administered once every 2 weeks at a fixed dose of 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg or 1500 mg.

[0123] In one embodiment, the C2 inhibitor is administered once every 3 weeks at a dose of about 0.1 mg / kg to 100 mg / kg. In one embodiment, the C2 inhibitor is administered once every 3 weeks at a dose of about 5 mg / kg to 60 mg / kg. In one embodiment, the C2 inhibitor is administered once every 3 weeks at the following doses:

[0124] About 0.1mg / kg, 0.5mg / kg, 2.5mg / kg, 5mg / kg, 7.5mg / kg, 10mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg , 45mg / kg, 50mg / kg, 55mg / kg, 60mg / kg, 65mg / kg, 70mg / kg, 75mg / kg, 80mg / kg, 85mg / kg, 90mg / kg, 95mg / kg, or 100mg / kg.

[0125] In one embodiment, the C2 inhibitor is administered once every 3 weeks at a dose of about 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg or 80 mg / kg. In one embodiment, the C2 inhibitor is administered once every 3 weeks at a dose of about 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg or 60 mg / kg. In one embodiment, the C2 inhibitor is administered once every 3 weeks at a dose of about 5 mg / kg. In one embodiment, the C2 inhibitor is administered once every 3 weeks at a dose of about 10 mg / kg. In one embodiment, the C2 inhibitor is administered once every 3 weeks at a dose of about 15 mg / kg. In one embodiment, the C2 inhibitor is administered once every 3 weeks at a dose of about 30 mg / kg. In one embodiment, the C2 inhibitor is administered once every 3 weeks at a dose of about 60 mg / kg.

[0126] In one embodiment, the C2 inhibitor is administered once every 3 weeks at a dose of 0.1 mg / kg to 100 mg / kg. In one embodiment, the C2 inhibitor is administered once every 3 weeks at a dose of 5 mg / kg to 60 mg / kg. In one embodiment, the C2 inhibitor is administered once every 3 weeks at a dose of:

[0127] 0.1mg / kg, 0.5mg / kg, 2.5mg / kg, 5mg / kg, 7.5mg / kg, 10mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg , 45mg / kg, 50mg / kg, 55mg / kg, 60mg / kg, 65mg / kg, 70mg / kg, 75mg / kg, 80mg / kg, 85mg / kg, 90mg / kg, 95mg / kg, or 100mg / kg.

[0128] In one embodiment, the C2 inhibitor is administered once every 3 weeks at a dose of 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg. In one embodiment, the C2 inhibitor is administered once every 3 weeks at a dose of 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, or 60 mg / kg.

[0129] In one embodiment, the C2 inhibitor is administered once every 3 weeks at a fixed dose of about 500 mg to 1500 mg. In one embodiment, the C2 inhibitor is administered once every 3 weeks at a fixed dose of about 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, or 1500 mg.

[0130] In one embodiment, the C2 inhibitor is administered once every 3 weeks at a fixed dose of 500 mg to 1500 mg. In one embodiment, the C2 inhibitor is administered once every 3 weeks at a fixed dose of 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, or 1500 mg.

[0131] In one embodiment, the C2 inhibitor is administered once every 4 weeks at a dose of about 0.1 mg / kg to 100 mg / kg. In one embodiment, the C2 inhibitor is administered once every 4 weeks at a dose of about 4 mg / kg to 60 mg / kg. In one embodiment, the C2 inhibitor is administered once every 4 weeks at a dose of:

[0132] About 0.1mg / kg, 0.5mg / kg, 2.5mg / kg, 5mg / kg, 7.5mg / kg, 10mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg , 45mg / kg, 50mg / kg, 55mg / kg, 60mg / kg, 65mg / kg, 70mg / kg, 75mg / kg, 80mg / kg, 85mg / kg, 90mg / kg, 95mg / kg, or 100mg / kg.

[0133] In one embodiment, the C2 inhibitor is administered once every 4 weeks at a dose of about 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg or 80 mg / kg. In one embodiment, the C2 inhibitor is administered once every 4 weeks at a dose of about 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg or 60 mg / kg. In one embodiment, the C2 inhibitor is administered once every 4 weeks at a dose of about 5 mg / kg. In one embodiment, the C2 inhibitor is administered once every 4 weeks at a dose of about 10 mg / kg. In one embodiment, the C2 inhibitor is administered once every 4 weeks at a dose of about 15 mg / kg. In one embodiment, the C2 inhibitor is administered once every 4 weeks at a dose of about 30 mg / kg. In one embodiment, the C2 inhibitor is administered once every 4 weeks at a dose of about 60 mg / kg.

[0134] In one embodiment, the C2 inhibitor is administered once every 4 weeks at a dose of 0.1 mg / kg to 100 mg / kg. In one embodiment, the C2 inhibitor is administered once every 4 weeks at a dose of 5 mg / kg to 60 mg / kg. In one embodiment, the C2 inhibitor is administered once every 4 weeks at a dose of:

[0135] 0.1mg / kg, 0.5mg / kg, 2.5mg / kg, 5mg / kg, 7.5mg / kg, 10mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg , 45mg / kg, 50mg / kg, 55mg / kg, 60mg / kg, 65mg / kg, 70mg / kg, 75mg / kg, 80mg / kg, 85mg / kg, 90mg / kg, 95mg / kg, or 100mg / kg.

[0136] In one embodiment, the C2 inhibitor is administered at a dose of 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg once every 4 weeks. In one embodiment, the C2 inhibitor is administered at a dose of 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, or 60 mg / kg once every 4 weeks.

[0137] In one embodiment, the C2 inhibitor is administered once every 4 weeks at a fixed dose of about 500 mg to 1500 mg. In one embodiment, the C2 inhibitor is administered once every 4 weeks at a fixed dose of about 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, or 1500 mg.

[0138] In one embodiment, the C2 inhibitor is administered once every 4 weeks at a fixed dose of 500 mg to 1500 mg. In one embodiment, the C2 inhibitor is administered once every 4 weeks at a fixed dose of 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, or 1500 mg.

[0139] In one embodiment, the C2 inhibitor is administered once every 5 weeks at a dose of about 0.1 mg / kg to 100 mg / kg. In one embodiment, the C2 inhibitor is administered once every 5 weeks at a dose of about 5 mg / kg to 60 mg / kg. In one embodiment, the C2 inhibitor is administered once every 5 weeks at the following doses:

[0140] About 0.1mg / kg, 0.5mg / kg, 2.5mg / kg, 5mg / kg, 7.5mg / kg, 10mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg , 45mg / kg, 50mg / kg, 55mg / kg, 60mg / kg, 65mg / kg, 70mg / kg, 75mg / kg, 80mg / kg, 85mg / kg, 90mg / kg, 95mg / kg, or 100mg / kg.

[0141] In one embodiment, the C2 inhibitor is administered once every 5 weeks at a dose of about 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg. In one embodiment, the C2 inhibitor is administered once every 5 weeks at a dose of about 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, or 60 mg / kg. In one embodiment, the C2 inhibitor is administered once every 5 weeks at a dose of about 5 mg / kg. In one embodiment, the C2 inhibitor is administered once every 10 weeks at a dose of about 5 mg / kg. In one embodiment, the C2 inhibitor is administered once every 15 weeks at a dose of about 5 mg / kg. In one embodiment, the C2 inhibitor is administered once every 30 weeks at a dose of about 5 mg / kg. In one embodiment, the C2 inhibitor is administered once every 60 weeks at a dose of about 5 mg / kg.

[0142] In one embodiment, the C2 inhibitor is administered once every 5 weeks at a dose of 0.1 mg / kg to 100 mg / kg. In one embodiment, the C2 inhibitor is administered once every 5 weeks at a dose of 5 mg / kg to 60 mg / kg. In one embodiment, the C2 inhibitor is administered once every 5 weeks at the following doses:

[0143] 0.1mg / kg, 0.5mg / kg, 2.5mg / kg, 5mg / kg, 7.5mg / kg, 10mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg , 45mg / kg, 50mg / kg, 55mg / kg, 60mg / kg, 65mg / kg, 70mg / kg, 75mg / kg, 80mg / kg, 85mg / k, 90mg / kg, 95mg / kg, or 100mg / kg.

[0144] In one embodiment, the C2 inhibitor is administered once every 5 weeks at a dose of 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg. In one embodiment, the C2 inhibitor is administered once every 5 weeks at a dose of 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, or 60 mg / kg.

[0145] In one embodiment, the C2 inhibitor is administered once every 5 weeks at a fixed dose of about 500 mg to 1500 mg. In one embodiment, the C2 inhibitor is administered once every 5 weeks at a fixed dose of about 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, or 1500 mg.

[0146] In one embodiment, the C2 inhibitor is administered once every 5 weeks at a fixed dose of 500 mg to 1500 mg. In one embodiment, the C2 inhibitor is administered once every 5 weeks at a fixed dose of 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg or 1500 mg.

[0147] In one embodiment, the C2 inhibitor is administered once every 6 weeks at a dose of about 0.1 mg / kg to 100 mg / kg. In one embodiment, the C2 inhibitor is administered once every 6 weeks at a dose of about 5 mg / kg to 60 mg / kg. In one embodiment, the C2 inhibitor is administered once every 6 weeks at the following doses:

[0148] About 0.1mg / kg, 0.5mg / kg, 2.5mg / kg, 5mg / kg, 7.5mg / kg, 10mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg , 45mg / kg, 50mg / kg, 55mg / kg, 60mg / kg, 65mg / kg, 70mg / kg, 75mg / kg, 80mg / kg, 85mg / kg, 90mg / kg, 95mg / kg, or 100mg / kg.

[0149] In one embodiment, the C2 inhibitor is administered once every 6 weeks at a dose of about 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg or 80 mg / kg. In one embodiment, the C2 inhibitor is administered once every 6 weeks at a dose of about 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg or 60 mg / kg. In one embodiment, the C2 inhibitor is administered once every 6 weeks at a dose of about 5 mg / kg. In one embodiment, the C2 inhibitor is administered once every 6 weeks at a dose of about 10 mg / kg. In one embodiment, the C2 inhibitor is administered once every 6 weeks at a dose of about 15 mg / kg. In one embodiment, the C2 inhibitor is administered once every 6 weeks at a dose of about 30 mg / kg. In one embodiment, the C2 inhibitor is administered once every 6 weeks at a dose of about 60 mg / kg.

[0150] In one embodiment, the C2 inhibitor is administered once every 6 weeks at a dose of 0.1 mg / kg to 100 mg / kg. In one embodiment, the C2 inhibitor is administered once every 6 weeks at a dose of 5 mg / kg to 60 mg / kg. In one embodiment, the C2 inhibitor is administered once every 6 weeks at the following doses:

[0151] 0.1mg / kg, 0.5mg / kg, 2.5mg / kg, 5mg / kg, 7.5mg / kg, 10mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg , 45mg / kg, 50mg / kg, 55mg / kg, 60mg / kg, 65mg / kg, 70mg / kg, 75mg / kg, 80mg / kg, 85mg / kg, 90mg / kg, 95mg / kg, or 100mg / kg.

[0152] In one embodiment, the C2 inhibitor is administered at a dose of 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg once every 6 weeks. In one embodiment, the C2 inhibitor is administered at a dose of 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, or 60 mg / kg once every 6 weeks.

[0153] In one embodiment, the C2 inhibitor is administered once every 6 weeks at a fixed dose of about 500 mg to 1500 mg. In one embodiment, the C2 inhibitor is administered once every 6 weeks at a fixed dose of about 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, or 1500 mg.

[0154] In one embodiment, the C2 inhibitor is administered once every 6 weeks at a fixed dose of 500 mg to 1500 mg. In one embodiment, the C2 inhibitor is administered once every 6 weeks at a fixed dose of 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, or 1500 mg.

[0155] In one embodiment, the C2 inhibitor is administered once every 7 weeks at a dose of about 0.1 mg / kg to 100 mg / kg. In one embodiment, the C2 inhibitor is administered once every 7 weeks at a dose of about 5 mg / kg to 60 mg / kg. In one embodiment, the C2 inhibitor is administered once every 7 weeks at the following doses:

[0156] About 0.1mg / kg, 0.5mg / kg, 2.5mg / kg, 5mg / kg, 7.5mg / kg, 10mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg , 45mg / kg, 50mg / kg, 55mg / kg, 60mg / kg, 65mg / kg, 70mg / kg, 75mg / kg, 80mg / kg, 85mg / kg, 90mg / kg, 95mg / kg, or 100mg / kg.

[0157] In one embodiment, the C2 inhibitor is administered once every 7 weeks at a dose of about 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg or 80 mg / kg. In one embodiment, the C2 inhibitor is administered once every 7 weeks at a dose of about 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg or 60 mg / kg. In one embodiment, the C2 inhibitor is administered once every 7 weeks at a dose of about 5 mg / kg. In one embodiment, the C2 inhibitor is administered once every 7 weeks at a dose of about 10 mg / kg. In one embodiment, the C2 inhibitor is administered once every 7 weeks at a dose of about 15 mg / kg. In one embodiment, the C2 inhibitor is administered once every 7 weeks at a dose of about 30 mg / kg. In one embodiment, the C2 inhibitor is administered once every 7 weeks at a dose of about 60 mg / kg.

[0158] In one embodiment, the C2 inhibitor is administered once every 7 weeks at a dose of 0.1 mg / kg to 100 mg / kg. In one embodiment, the C2 inhibitor is administered once every 7 weeks at a dose of 5 mg / kg to 60 mg / kg. In one embodiment, the C2 inhibitor is administered once every 7 weeks at the following doses:

[0159] 0.1mg / kg, 0.5mg / kg, 2.5mg / kg, 5mg / kg, 7.5mg / kg, 10mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg , 45mg / kg, 50mg / kg, 55mg / kg, 60mg / kg, 65mg / kg, 70mg / kg, 75mg / kg, 80mg / kg, 85mg / kg, 90mg / kg, 95mg / kg, or 100mg / kg.

[0160] In one embodiment, the C2 inhibitor is administered at a dose of 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg once every 7 weeks. In one embodiment, the C2 inhibitor is administered at a dose of 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, or 60 mg / kg once every 7 weeks.

[0161] In one embodiment, the C2 inhibitor is administered once every 7 weeks at a fixed dose of about 500 mg to 1500 mg. In one embodiment, the C2 inhibitor is administered once every 7 weeks at a fixed dose of about 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, or 1500 mg.

[0162] In one embodiment, the C2 inhibitor is administered once every 7 weeks at a fixed dose of 500 mg to 1500 mg. In one embodiment, the C2 inhibitor is administered once every 7 weeks at a fixed dose of 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, or 1500 mg.

[0163] In one embodiment, the C2 inhibitor is administered once every 8 weeks at a dose of about 0.1 mg / kg to 100 mg / kg. In one embodiment, the C2 inhibitor is administered once every 8 weeks at a dose of about 5 mg / kg to 60 mg / kg. In one embodiment, the C2 inhibitor is administered once every 8 weeks at the following doses:

[0164] About 0.1mg / kg, 0.5mg / kg, 2.5mg / kg, 5mg / kg, 7.5mg / kg, 10mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg , 45mg / kg, 50mg / kg, 55mg / kg, 60mg / kg, 65mg / kg, 70mg / kg, 75mg / kg, 80mg / kg, 85mg / kg, 90mg / kg, 95mg / kg, or 100mg / kg.

[0165] In one embodiment, the C2 inhibitor is administered once every 8 weeks at a dose of about 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg or 80 mg / kg. In one embodiment, the C2 inhibitor is administered once every 8 weeks at a dose of about 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg or 60 mg / kg. In one embodiment, the C2 inhibitor is administered once every 8 weeks at a dose of about 5 mg / kg. In one embodiment, the C2 inhibitor is administered once every 8 weeks at a dose of about 10 mg / kg. In one embodiment, the C2 inhibitor is administered once every 8 weeks at a dose of about 15 mg / kg. In one embodiment, the C2 inhibitor is administered once every 8 weeks at a dose of about 30 mg / kg. In one embodiment, the C2 inhibitor is administered once every 8 weeks at a dose of about 60 mg / kg.

[0166] In one embodiment, the C2 inhibitor is administered once every 8 weeks at a dose of 0.1 mg / kg to 100 mg / kg. In one embodiment, the C2 inhibitor is administered once every 8 weeks at a dose of 5 mg / kg to 60 mg / kg. In one embodiment, the C2 inhibitor is administered once every 8 weeks at the following doses:

[0167] 0.1mg / kg, 0.5mg / kg, 2.5mg / kg, 5mg / kg, 7.5mg / kg, 10mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg , 45mg / kg, 50mg / kg, 55mg / kg, 60mg / kg, 65mg / kg, 70mg / kg, 75mg / kg, 80mg / kg, 85mg / kg, 90mg / kg, 95mg / kg, or 100mg / kg.

[0168] In one embodiment, the C2 inhibitor is administered once every 8 weeks at a dose of 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg. In one embodiment, the C2 inhibitor is administered once every 8 weeks at a dose of 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, or 60 mg / kg.

[0169] In one embodiment, the C2 inhibitor is administered once every 8 weeks at a fixed dose of about 500 mg to 1500 mg. In one embodiment, the C2 inhibitor is administered once every 8 weeks at a fixed dose of about 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, or 1500 mg.

[0170] In one embodiment, the C2 inhibitor is administered once every 8 weeks at a fixed dose of 500 mg to 1500 mg. In one embodiment, the C2 inhibitor is administered once every 8 weeks at a fixed dose of 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, or 1500 mg.

[0171] In one embodiment, the C2 inhibitor is administered intravenously at a dose of 10 mg / kg once per week or every 2 weeks. In one embodiment, the C2 inhibitor is administered intravenously at a dose of 30 mg / kg once per week or every 2 weeks. In one embodiment, the C2 inhibitor is administered intravenously at a dose of 60 mg / kg once per week or every 2 weeks. In one embodiment, the C2 inhibitor is administered intravenously at a dose of 15 mg / kg once per week or every 2 weeks. In one embodiment, the C2 inhibitor is administered intravenously at a dose of 5 mg / kg once per week, every 2 weeks, or every 4 weeks.

[0172] In one embodiment, the C2 inhibitor is administered according to a loading regimen that reduces the level of free C2 in the subject's blood to or below a threshold level.

[0173] In one embodiment, the method further comprises a maintenance regimen following the loading regimen, wherein the maintenance regimen comprises administering the C2 inhibitor according to a regimen that maintains the level of free C2 in the subject's blood at or below a threshold level.

[0174] In one embodiment, the threshold level is about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7 or 0.8 μg / mL. In one embodiment, the threshold level is about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20% of the baseline level of free C2 in the subject. In one embodiment, the threshold level is 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7 or 0.8 μg / mL. In one embodiment, the threshold level is 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20% of the baseline level of free C2 in the subject. As used herein, "baseline level of free C2" refers to the level or concentration of circulating (serum or plasma) C2 in a subject prior to the first administration of a C2 inhibitor (e.g., ARGX-117). C2 levels can be measured using any suitable technique. See, e.g., Tange CE et al., Clin Chem Lab Med 2018; 56(9): 1498-1506.

[0175] In one embodiment, the loading regimen is a single initial dose followed by one or more subsequent doses. In one embodiment, each of the one or more subsequent doses is an amount lower than the single initial dose. In one embodiment, each of the one or more subsequent doses is an amount greater than the single initial dose. In one embodiment, each of the one or more subsequent doses is equal to the amount of the single initial dose.

[0176] In one embodiment, a single initial dose is followed by 1, 2, 3, 4, 5, or 6 subsequent doses. In one embodiment, subsequent doses are administered weekly or every 2 weeks. In one embodiment, a single initial dose is followed by 1, 2, 3, 4, 5, or 6 subsequent doses administered once a week. In one embodiment, a single initial dose is followed by 1, 2, 3, 4, 5, or 6 subsequent doses administered once every 2 weeks. In one embodiment, a single initial dose is followed by 4 subsequent doses administered once a week.

[0177] In one embodiment, the first subsequent dose is administered one week after the single initial dose. In one embodiment, the first subsequent dose is administered 10 days after the single initial dose. In one embodiment, the first subsequent dose is administered two weeks after the single initial dose.

[0178] In one embodiment, a single initial dose is a dose of about 0.1 mg / kg to 100 mg / kg. In one embodiment, a single initial dose is a dose of about 10 mg / kg to 60 mg / kg. In one embodiment, a single initial dose is a dose of:

[0179] About 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 7.5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 55 mg / kg, 60 mg / kg, 65 mg / kg, 70 mg / kg, 75 mg / kg, 80 mg / kg, 85 mg / kg, 90 mg / kg, 95 mg / kg, or 100 mg / kg. In one embodiment, a single initial dose is a dose of about 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg or 80 mg / kg. In one embodiment, a single initial dose is a dose of about 10 mg / kg, 15 mg / kg, 30 mg / kg or 60 mg / kg. In one embodiment, a single initial dose is a dose of about 15 mg / kg. In one embodiment, a single initial dose is a dose of about 30 mg / kg. In one embodiment, a single initial dose is a dose of about 60 mg / kg.

[0180] In one embodiment, the single initial dose is a dose of 0.1 mg / kg to 100 mg / kg. In one embodiment, the single initial dose is a dose of 10 mg / kg to 60 mg / kg. In one embodiment, the single initial dose is a dose of:

[0181] 0.1mg / kg, 0.5mg / kg, 2.5mg / kg, 5mg / kg, 7.5mg / kg, 10mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg , 45mg / kg, 50mg / kg, 55mg / kg, 60mg / kg, 65mg / kg, 70mg / kg, 75mg / kg, 80mg / kg, 85mg / kg, 90mg / kg, 95mg / kg, or 100mg / kg.

[0182] In one embodiment, a single initial dose is a dose of 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg. In one embodiment, a single initial dose is a dose of 10 mg / kg, 15 mg / kg, 30 mg / kg, or 60 mg / kg.

[0183] In one embodiment, a single initial dose is a fixed dose of about 500 mg to 1500 mg. In one embodiment, a single initial dose is a fixed dose of about 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg or 1500 mg.

[0184] In one embodiment, the single initial dose is a fixed dose of 500 mg to 1500 mg. In one embodiment, the single initial dose is a fixed dose of 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg or 1500 mg.

[0185] In one embodiment, each subsequent dose is a dose of about 0.1 mg / kg to 100 mg / kg. In one embodiment, each subsequent dose is a dose of about 5 mg / kg to 60 mg / kg. In one embodiment, each subsequent dose is a dose of:

[0186] About 0.1mg / kg, 0.5mg / kg, 2.5mg / kg, 5mg / kg, 7.5mg / kg, 10mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg , 45mg / kg, 50mg / kg, 55mg / kg, 60mg / kg, 65mg / kg, 70mg / kg, 75mg / kg, 80mg / kg, 85mg / kg, 90mg / kg, 95mg / kg, or 100mg / kg.

[0187] In one embodiment, the subsequent dose is each about 0.1mg / kg, 0.5mg / kg, 2.5mg / kg, 5mg / kg, 10mg / kg, 15mg / kg, 30mg / kg, 60mg / kg or 80mg / kg. In one embodiment, the subsequent dose is each about 5mg / kg, 10mg / kg, 15mg / kg, 30mg / kg or 60mg / kg. In one embodiment, the subsequent dose is each about 5mg / kg. In one embodiment, the subsequent dose is each about 10mg / kg. In one embodiment, the subsequent dose is each about 30mg / kg.

[0188] In one embodiment, each subsequent dose is a dose of 0.1 mg / kg to 100 mg / kg. In one embodiment, each subsequent dose is a dose of 5 mg / kg to 60 mg / kg. In one embodiment, each subsequent dose is a dose of:

[0189] 0.1mg / kg, 0.5mg / kg, 2.5mg / kg, 5mg / kg, 7.5mg / kg, 10mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg , 45mg / kg, 50mg / kg, 55mg / kg, 60mg / kg, 65mg / kg, 70mg / kg, 75mg / kg, 80mg / kg, 85mg / kg, 90mg / kg, 95mg / kg, or 100mg / kg.

[0190] In one embodiment, each subsequent dose is a dose of 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg. In one embodiment, each subsequent dose is a dose of 5 mg / kg, 10 mg / kg, 30 mg / kg, or 60 mg / kg.

[0191] In one embodiment, each subsequent dose is a fixed dose of about 500 mg to 1500 mg. In one embodiment, each subsequent dose is a fixed dose of about 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg or 1500 mg.

[0192] In one embodiment, each subsequent dose is a fixed dose of 500 mg to 1500 mg. In one embodiment, each subsequent dose is a fixed dose of 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg or 1500 mg.

[0193] In one embodiment, the single initial dose is a dose of 0.1 mg / kg and subsequent doses are each a dose of 0.1 mg / kg to 100 mg / kg. In one embodiment, the single initial dose is a dose of 0.1 mg / kg and subsequent doses are each a dose of 5 mg / kg to 60 mg / kg. In one embodiment, the single initial dose is a dose of 0.1 mg / kg and subsequent doses are each a dose of:

[0194] 0.1mg / kg, 0.5mg / kg, 2.5mg / kg, 5mg / kg, 7.5mg / kg, 10mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg , 45mg / kg, 50mg / kg, 55mg / kg, 60mg / kg, 65mg / kg, 70mg / kg, 75mg / kg, 80mg / kg, 85mg / kg, 90mg / kg, 95mg / kg, or 100mg / kg.

[0195] In one embodiment, a single initial dose is a dose of 0.1 mg / kg and subsequent doses are each a dose of 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg. In one embodiment, a single initial dose is a dose of 0.1 mg / kg and subsequent doses are each a dose of 5 mg / kg, 15 mg / kg, 10 mg / kg, 30 mg / kg, or 60 mg / kg.

[0196] In one embodiment, a single initial dose is a dose of 0.1 mg / kg and subsequent doses are each a fixed dose of 500 mg to 1500 mg. In one embodiment, a single initial dose is a dose of 0.1 mg / kg and subsequent doses are each a fixed dose of 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, or 1500 mg.

[0197] In one embodiment, the single initial dose is a dose of 0.5 mg / kg and the subsequent doses are each a dose of 0.1 mg / kg to 100 mg / kg. In one embodiment, the single initial dose is a dose of 0.5 mg / kg and the subsequent doses are each a dose of 5 mg / kg to 60 mg / kg. In one embodiment, the single initial dose is a dose of 0.5 mg / kg and the subsequent doses are each a dose of:

[0198] 0.1mg / kg, 0.5mg / kg, 2.5mg / kg, 5mg / kg, 7.5mg / kg, 10mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg , 45mg / kg, 50mg / kg, 55mg / kg, 60mg / kg, 65mg / kg, 70mg / kg, 75mg / kg, 80mg / kg, 85mg / kg, 90mg / kg, 95mg / kg, or 100mg / kg.

[0199] In one embodiment, a single initial dose is a dose of 0.5 mg / kg and subsequent doses are each a dose of 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg. In one embodiment, a single initial dose is a dose of 0.5 mg / kg and subsequent doses are each a dose of 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, or 60 mg / kg.

[0200] In one embodiment, a single initial dose is a dose of 0.5 mg / kg and subsequent doses are each a fixed dose of 500 mg to 1500 mg. In one embodiment, a single initial dose is a dose of 0.5 mg / kg and subsequent doses are each a fixed dose of 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg or 1500 mg.

[0201] In one embodiment, the single initial dose is a dose of 2.5 mg / kg and subsequent doses are each a dose of 0.1 mg / kg to 100 mg / kg. In one embodiment, the single initial dose is a dose of 2.5 mg / kg and subsequent doses are each a dose of 5 mg / kg to 60 mg / kg. In one embodiment, the single initial dose is a dose of 2.5 mg / kg and subsequent doses are each the following doses:

[0202] 0.1mg / kg, 0.5mg / kg, 2.5mg / kg, 5mg / kg, 7.5mg / kg, 10mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg , 45mg / kg, 50mg / kg, 55mg / kg, 60mg / kg, 65mg / kg, 70mg / kg, 75mg / kg, 80mg / kg, 85mg / kg, 90mg / kg, 95mg / kg, or 100mg / kg.

[0203] In one embodiment, a single initial dose is a dose of 2.5 mg / kg and subsequent doses are each a dose of 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg. In one embodiment, a single initial dose is a dose of 2.5 mg / kg and subsequent doses are each a dose of 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, or 60 mg / kg.

[0204] In one embodiment, a single initial dose is a dose of 2.5 mg / kg and subsequent doses are each a fixed dose of 500 mg to 1500 mg. In one embodiment, a single initial dose is a dose of 2.5 mg / kg and subsequent doses are each a fixed dose of 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg or 1500 mg.

[0205] In one embodiment, the single initial dose is a dose of 10 mg / kg and the subsequent doses are each a dose of 0.1 mg / kg to 100 mg / kg. In one embodiment, the single initial dose is a dose of 10 mg / kg and the subsequent doses are each a dose of 5 mg / kg to 60 mg / kg. In one embodiment, the single initial dose is a dose of 10 mg / kg and the subsequent doses are each the following doses:

[0206] 0.1mg / kg, 0.5mg / kg, 2.5mg / kg, 5mg / kg, 7.5mg / kg, 10mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg , 45mg / kg, 50mg / kg, 55mg / kg, 60mg / kg, 65mg / kg, 70mg / kg, 75mg / kg, 80mg / kg, 85mg / kg, 90mg / kg, 95mg / kg, or 100mg / kg.

[0207] In one embodiment, a single initial dose is a dose of 10 mg / kg and subsequent doses are each a dose of 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg. In one embodiment, a single initial dose is a dose of 10 mg / kg and subsequent doses are each a dose of 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, or 60 mg / kg.

[0208] In one embodiment, a single initial dose is a dose of 10 mg / kg and subsequent doses are each a fixed dose of 500 mg to 1500 mg. In one embodiment, a single initial dose is a dose of 10 mg / kg and subsequent doses are each a fixed dose of 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, or 1500 mg.

[0209] In one embodiment, the single initial dose is a dose of 15 mg / kg and the subsequent doses are each a dose of 0.1 mg / kg to 100 mg / kg. In one embodiment, the single initial dose is a dose of 15 mg / kg and the subsequent doses are each a dose of 5 mg / kg to 60 mg / kg. In one embodiment, the single initial dose is a dose of 15 mg / kg and the subsequent doses are each the following doses:

[0210] 0.1mg / kg, 0.5mg / kg, 2.5mg / kg, 5mg / kg, 7.5mg / kg, 10mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg , 45mg / kg, 50mg / kg, 55mg / kg, 60mg / kg, 65mg / kg, 70mg / kg, 75mg / kg, 80mg / kg, 85mg / kg, 90mg / kg, 95mg / kg, or 100mg / kg.

[0211] In one embodiment, a single initial dose is a dose of 15 mg / kg and subsequent doses are each a dose of 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg or 80 mg / kg. In one embodiment, a single initial dose is a dose of 15 mg / kg and subsequent doses are each a dose of 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg or 60 mg / kg. In one embodiment, a single initial dose is a dose of 15 mg / kg and subsequent doses are each a dose of 5 mg / kg.

[0212] In one embodiment, a single initial dose is a dose of 15 mg / kg and subsequent doses are each a fixed dose of 500 mg to 1500 mg. In one embodiment, a single initial dose is a dose of 15 mg / kg and subsequent doses are each a fixed dose of 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg or 1500 mg.

[0213] In one embodiment, the single initial dose is a dose of 30 mg / kg and the subsequent doses are each a dose of 0.1 mg / kg to 100 mg / kg. In one embodiment, the single initial dose is a dose of 30 mg / kg and the subsequent doses are each a dose of 5 mg / kg to 60 mg / kg. In one embodiment, the single initial dose is a dose of 30 mg / kg and the subsequent doses are each the following doses:

[0214] 0.1mg / kg, 0.5mg / kg, 2.5mg / kg, 5mg / kg, 7.5mg / kg, 10mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg , 45mg / kg, 50mg / kg, 55mg / kg, 60mg / kg, 65mg / kg, 70mg / kg, 75mg / kg, 80mg / kg, 85mg / kg, 90mg / kg, 95mg / kg, or 100mg / kg.

[0215] In one embodiment, a single initial dose is a dose of 30 mg / kg and subsequent doses are each a dose of 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg or 80 mg / kg. In one embodiment, a single initial dose is a dose of 30 mg / kg and subsequent doses are each a dose of 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg or 60 mg / kg. In one embodiment, a single initial dose is a dose of 30 mg / kg and subsequent doses are each a dose of 10 mg / kg.

[0216] In one embodiment, a single initial dose is a dose of 30 mg / kg and subsequent doses are each a fixed dose of 500 mg to 1500 mg. In one embodiment, a single initial dose is a dose of 30 mg / kg and subsequent doses are each a fixed dose of 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, or 1500 mg.

[0217] In one embodiment, the single initial dose is a dose of 60 mg / kg and the subsequent doses are each a dose of 0.1 mg / kg to 100 mg / kg. In one embodiment, the single initial dose is a dose of 60 mg / kg and the subsequent doses are each a dose of 5 mg / kg to 60 mg / kg. In one embodiment, the single initial dose is a dose of 60 mg / kg and the subsequent doses are each the following doses:

[0218] 0.1mg / kg, 0.5mg / kg, 2.5mg / kg, 5mg / kg, 7.5mg / kg, 10mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg , 45mg / kg, 50mg / kg, 55mg / kg, 60mg / kg, 65mg / kg, 70mg / kg, 75mg / kg, 80mg / kg, 85mg / kg, 90mg / kg, 95mg / kg, or 100mg / kg.

[0219] In one embodiment, a single initial dose is a dose of 60 mg / kg and subsequent doses are each a dose of 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg or 80 mg / kg. In one embodiment, a single initial dose is a dose of 60 mg / kg and subsequent doses are each a dose of 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg or 60 mg / kg. In one embodiment, a single initial dose is a dose of 60 mg / kg and subsequent doses are each a dose of 30 mg / kg.

[0220] In one embodiment, a single initial dose is a dose of 60 mg / kg and subsequent doses are each a fixed dose of 500 mg to 1500 mg. In one embodiment, a single initial dose is a dose of 60 mg / kg and subsequent doses are each a fixed dose of 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, or 1500 mg.

[0221] In one embodiment, the single initial dose is a dose of 80 mg / kg and the subsequent doses are each a dose of 0.1 mg / kg to 100 mg / kg. In one embodiment, the single initial dose is a dose of 80 mg / kg and the subsequent doses are each a dose of 5 mg / kg to 60 mg / kg. In one embodiment, the single initial dose is a dose of 80 mg / kg and the subsequent doses are each the following doses:

[0222] 0.1mg / kg, 0.5mg / kg, 2.5mg / kg, 5mg / kg, 7.5mg / kg, 10mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg , 45mg / kg, 50mg / kg, 55mg / kg, 60mg / kg, 65mg / kg, 70mg / kg, 75mg / kg, 80mg / kg, 85mg / kg, 90mg / kg, 95mg / kg, or 100mg / kg.

[0223] In one embodiment, a single initial dose is a dose of 80 mg / kg and subsequent doses are each a dose of 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg. In one embodiment, a single initial dose is a dose of 80 mg / kg and subsequent doses are each a dose of 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, or 60 mg / kg.

[0224] In one embodiment, a single initial dose is a dose of 80 mg / kg and subsequent doses are each a fixed dose of 500 mg to 1500 mg. In one embodiment, a single initial dose is a dose of 80 mg / kg and subsequent doses are each a fixed dose of 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, or 1500 mg.

[0225] In one embodiment, the single initial dose is a fixed dose of 1200 mg and subsequent doses are each a dose of 0.1 mg / kg to 100 mg / kg. In one embodiment, the single initial dose is a fixed dose of 1200 mg and subsequent doses are each a dose of 5 mg / kg to 60 mg / kg. In one embodiment, the single initial dose is a fixed dose of 1200 mg and subsequent doses are each a dose of:

[0226] 0.1mg / kg, 0.5mg / kg, 2.5mg / kg, 5mg / kg, 7.5mg / kg, 10mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg , 45mg / kg, 50mg / kg, 55mg / kg, 60mg / kg, 65mg / kg, 70mg / kg, 75mg / kg, 80mg / kg, 85mg / kg, 90mg / kg, 95mg / kg, or 100mg / kg.

[0227] In one embodiment, a single initial dose is a fixed dose of 1200 mg and subsequent doses are each a dose of 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg. In one embodiment, a single initial dose is a fixed dose of 1200 mg and subsequent doses are each a dose of 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, or 60 mg / kg.

[0228] In one embodiment, the single initial dose is a fixed dose of 1200 mg and subsequent doses are each a fixed dose of 500 mg to 1500 mg. In one embodiment, the single initial dose is a fixed dose of 1200 mg and subsequent doses are each a fixed dose of 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, or 1500 mg.

[0229] In one embodiment, a single initial dose is 30 mg / kg and subsequent doses are each 10 mg / kg. In one embodiment, a single initial dose is 60 mg / kg and subsequent doses are each 30 mg / kg. In one embodiment, a single initial dose is 15 mg / kg and subsequent doses are each 5 mg / kg.

[0230] In one embodiment, the loading regimen is administered intravenously or subcutaneously. In one embodiment, the loading regimen is administered intravenously. In one embodiment, the loading regimen is administered subcutaneously. In one embodiment, a single initial dose is administered intravenously and subsequent doses are administered subcutaneously. In one embodiment, a single initial dose is administered subcutaneously and subsequent doses are administered intravenously. In one embodiment, both the single initial dose and subsequent doses are administered intravenously. In one embodiment, both the single initial dose and subsequent doses are administered subcutaneously.

[0231] In one embodiment, the loading regimen reduces the level of free C2 to a threshold level or below a threshold level in about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 days. In one embodiment, the loading regimen reduces the level of free C2 to a threshold level or below a threshold level in 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 days. In one embodiment, the loading regimen reduces the level of free C2 to a threshold level or below a threshold level in about 1, 2, 3, 4, 5, 6, 7 or 8 weeks. In one embodiment, the loading regimen reduces the level of free C2 to a threshold level or below a threshold level in 1, 2, 3, 4, 5, 6, 7 or 8 weeks.

[0232] In one embodiment, the maintenance regimen is a dose of about 0.1 to 100 mg / kg administered once per week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, or every 8 weeks. In one embodiment, the maintenance regimen is a dose of 0.1 to 100 mg / kg administered once per week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, or every 8 weeks.

[0233] In one embodiment, the maintenance regimen is a dosage of about 0.1 to 100 mg / kg administered once a week. In one embodiment, the maintenance regimen is a dosage of about 0.1 to 100 mg / kg administered once every 2 weeks. In one embodiment, the maintenance regimen is a dosage of about 0.1 to 100 mg / kg administered once every 3 weeks. In one embodiment, the maintenance regimen is a dosage of about 0.1 to 100 mg / kg administered once every 4 weeks. In one embodiment, the maintenance regimen is a dosage of about 0.1 to 100 mg / kg administered once every 5 weeks. In one embodiment, the maintenance regimen is a dosage of about 0.1 to 100 mg / kg administered once every 6 weeks. In one embodiment, the maintenance regimen is a dosage of about 0.1 to 100 mg / kg administered once every 7 weeks. In one embodiment, the maintenance regimen is a dosage of about 0.1 to 100 mg / kg administered once every 8 weeks.

[0234] In one embodiment, the maintenance regimen is a dose of 0.1 to 100 mg / kg administered once a week. In one embodiment, the maintenance regimen is a dose of 0.1 to 100 mg / kg administered once every 2 weeks. In one embodiment, the maintenance regimen is a dose of 0.1 to 100 mg / kg administered once every 3 weeks. In one embodiment, the maintenance regimen is a dose of 0.1 to 100 mg / kg administered once every 4 weeks. In one embodiment, the maintenance regimen is a dose of 0.1 to 100 mg / kg administered once every 5 weeks. In one embodiment, the maintenance regimen is a dose of 0.1 to 100 mg / kg administered once every 6 weeks. In one embodiment, the maintenance regimen is a dose of 0.1 to 100 mg / kg administered once every 7 weeks. In one embodiment, the maintenance regimen is a dose of 0.1 to 100 mg / kg administered once every 8 weeks.

[0235] In one embodiment, the maintenance regimen is a dosage of about 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg applied once a week. In one embodiment, the maintenance regimen is a dosage of about 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg applied once every 2 weeks. In one embodiment, the maintenance regimen is a dosage of about 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg applied once every 3 weeks. In one embodiment, the maintenance regimen is a dosage of about 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg administered once every 4 weeks. In one embodiment, the maintenance regimen is a dosage of about 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg administered once every 5 weeks. In one embodiment, the maintenance regimen is a dosage of about 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg administered once every 6 weeks. In one embodiment, the maintenance regimen is a dosage of about 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg administered once every 7 weeks. In one embodiment, the maintenance regimen is a dosage of about 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg administered once every 8 weeks.

[0236] In one embodiment, the maintenance regimen is a dosage of 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg administered once a week. In one embodiment, the maintenance regimen is a dosage of 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg administered once every 2 weeks. In one embodiment, the maintenance regimen is a dosage of 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg administered once every 3 weeks. In one embodiment, the maintenance regimen is a dosage of 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg administered once every 4 weeks. In one embodiment, the maintenance regimen is a dosage of 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg administered once every 5 weeks. In one embodiment, the maintenance regimen is a dosage of 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg administered once every 6 weeks. In one embodiment, the maintenance regimen is a dosage of 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg administered once every 7 weeks. In one embodiment, the maintenance regimen is a dosage of 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg administered once every 8 weeks.

[0237] In one embodiment, the maintenance regimen is a dosage of about 5 mg / kg administered once every 4 weeks. In one embodiment, the maintenance regimen is a dosage of about 10 mg / kg administered once every 2 weeks. In one embodiment, the maintenance regimen is a dosage of about 30 mg / kg administered once every 2 weeks.

[0238] In one embodiment, the maintenance regimen is a fixed dose of about 500 mg to 1500 mg administered once per week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, every 7 weeks, or every 8 weeks. In one embodiment, the maintenance regimen is a fixed dose of about 1200 mg administered once per week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, every 7 weeks, or every 8 weeks.

[0239] In one embodiment, the maintenance regimen is a fixed dose of 500 mg to 1500 mg administered once per week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, every 7 weeks, or every 8 weeks. In one embodiment, the maintenance regimen is a fixed dose of 1200 mg administered once per week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, every 7 weeks, or every 8 weeks.

[0240] In one embodiment, the maintenance regimen is administered 1, 2, 3, 4, 5, 6, 7, or 8 weeks after the loading regimen. In one embodiment, the maintenance regimen is administered if the level of free C2 in the subject's blood is above a threshold level.

[0241] In one embodiment, the threshold level is about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1.0 μg / mL. In one embodiment, the threshold level is about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 59%. In one embodiment, the threshold level is 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1.0 μg / mL. In one embodiment, the threshold level is 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94% 5%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39% or 40%.

[0242] In one embodiment, the maintenance regimen is administered intravenously or subcutaneously. In one embodiment, the maintenance regimen is administered intravenously. In one embodiment, the maintenance regimen is administered subcutaneously.

[0243] In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 0.1mg / kg applied once a week. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 0.1mg / kg applied once every 2 weeks. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 0.1mg / kg applied once every 3 weeks. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 0.1mg / kg applied once every 4 weeks. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 0.1mg / kg applied once every 5 weeks. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 0.1mg / kg applied once every 6 weeks. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 0.1mg / kg applied once every 7 weeks. In one embodiment, the loading regimen is any of the loading regimens described herein and the maintenance regimen is a dose of 0.1 mg / kg administered once every 8 weeks.

[0244] In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 0.5mg / kg applied once a week. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 0.5mg / kg applied once every 2 weeks. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 0.5mg / kg applied once every 3 weeks. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 0.5mg / kg applied once every 4 weeks. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 0.5mg / kg applied once every 5 weeks. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 0.5mg / kg applied once every 6 weeks. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 0.5mg / kg applied once every 7 weeks. In one embodiment, the loading regimen is any of the loading regimens described herein and the maintenance regimen is a dose of 0.5 mg / kg administered once every 8 weeks.

[0245] In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 2.5mg / kg used once a week. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 2.5mg / kg used once every 2 weeks. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 2.5mg / kg used once every 3 weeks. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 2.5mg / kg used once every 4 weeks. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 2.5mg / kg used once every 5 weeks. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 2.5mg / kg used once every 6 weeks. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 2.5mg / kg used once every 7 weeks. In one embodiment, the loading regimen is any of the loading regimens described herein and the maintenance regimen is a dose of 2.5 mg / kg administered once every 8 weeks.

[0246] In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 5mg / kg used once a week. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 5mg / kg used once every 2 weeks. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 5mg / kg used once every 3 weeks. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 5mg / kg used once every 4 weeks. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 5mg / kg used once every 5 weeks. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 5mg / kg used once every 6 weeks. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 5mg / kg used once every 7 weeks. In one embodiment, the loading regimen is any of the loading regimens described herein and the maintenance regimen is a dose of 5 mg / kg administered once every 8 weeks.

[0247] In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 10mg / kg used once a week. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 10mg / kg used once every 2 weeks. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 10mg / kg used once every 3 weeks. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 10mg / kg used once every 4 weeks. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 10mg / kg used once every 5 weeks. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 10mg / kg used once every 6 weeks. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 10mg / kg used once every 7 weeks. In one embodiment, the loading regimen is any of the loading regimens described herein and the maintenance regimen is a dose of 10 mg / kg administered once every 8 weeks.

[0248] In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 15mg / kg used once a week. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 15mg / kg used once every 2 weeks. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 15mg / kg used once every 3 weeks. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 15mg / kg used once every 4 weeks. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 15mg / kg used once every 5 weeks. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 15mg / kg used once every 6 weeks. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 15mg / kg used once every 7 weeks. In one embodiment, the loading regimen is any of the loading regimens described herein and the maintenance regimen is a dose of 15 mg / kg administered once every 8 weeks.

[0249] In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 30mg / kg used once a week. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 30mg / kg used once every 2 weeks. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 30mg / kg used once every 3 weeks. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 30mg / kg used once every 4 weeks. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 30mg / kg used once every 5 weeks. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 30mg / kg used once every 6 weeks. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 30mg / kg used once every 7 weeks. In one embodiment, the loading regimen is any of the loading regimens described herein and the maintenance regimen is a dose of 30 mg / kg administered once every 8 weeks.

[0250] In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 60mg / kg used once a week. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 60mg / kg used once every 2 weeks. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 60mg / kg used once every 3 weeks. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 60mg / kg used once every 4 weeks. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 60mg / kg used once every 5 weeks. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 60mg / kg used once every 6 weeks. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 60mg / kg used once every 7 weeks. In one embodiment, the loading regimen is any of the loading regimens described herein and the maintenance regimen is a dose of 60 mg / kg administered once every 8 weeks.

[0251] In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 80mg / kg used once a week. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 80mg / kg used once every 2 weeks. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 80mg / kg used once every 3 weeks. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 80mg / kg used once every 4 weeks. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 80mg / kg used once every 5 weeks. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 80mg / kg used once every 6 weeks. In one embodiment, the load regimen is any one of the load regimens described herein, and the maintenance regimen is a dosage of 80mg / kg used once every 7 weeks. In one embodiment, the loading regimen is any of the loading regimens described herein and the maintenance regimen is a dose of 80 mg / kg administered once every 8 weeks.

[0252] In one embodiment, the loading regimen is any one of the loading regimens described herein, and the maintenance regimen is a fixed dose of 1200mg administered once a week. In one embodiment, the loading regimen is any one of the loading regimens described herein, and the maintenance regimen is a fixed dose of 1200mg administered once every 2 weeks. In one embodiment, the loading regimen is any one of the loading regimens described herein, and the maintenance regimen is a fixed dose of 1200mg administered once every 3 weeks. In one embodiment, the loading regimen is any one of the loading regimens described herein, and the maintenance regimen is a fixed dose of 1200mg administered once every 4 weeks. In one embodiment, the loading regimen is any one of the loading regimens described herein, and the maintenance regimen is a fixed dose of 1200mg administered once every 5 weeks. In one embodiment, the loading regimen is any one of the loading regimens described herein, and the maintenance regimen is a fixed dose of 1200mg administered once every 6 weeks. In one embodiment, the loading regimen is any one of the loading regimens described herein, and the maintenance regimen is a fixed dose of 1200mg administered once every 7 weeks. In one embodiment, the loading regimen is any of the loading regimens described herein and the maintenance regimen is a fixed dose of 1200 mg administered once every 8 weeks.

[0253] In one embodiment, the loading regimen is: a single initial dose of 0.1 mg / kg to 100 mg / kg; and four subsequent doses, each of which is 0.1 mg / kg to 100 mg / kg administered weekly or once every 2 weeks starting one week after the single initial dose; and the maintenance regimen is: a dose of 0.1 mg / kg to 100 mg / kg administered once every 2 weeks or once every 4 weeks.

[0254] In one embodiment, the loading regimen is: a single initial fixed dose of 500 mg to 1500 mg; and four subsequent doses, each of which is 500 mg to 1500 mg administered weekly or once every 2 weeks starting one week after the single initial dose; and the maintenance regimen is: a dose of 500 mg to 1500 mg administered once every 2 weeks or once every 4 weeks.

[0255] In one embodiment, the loading regimen is: a single initial dose of 60 mg / kg; and four subsequent doses, each of which is 30 mg / kg administered once weekly starting one week after the single initial dose; and the maintenance regimen is: a dose of 30 mg / kg administered once every two weeks.

[0256] In one embodiment, the loading regimen is: a single initial dose of 30 mg / kg; and four subsequent doses, each of 10 mg / kg administered once weekly starting one week after the single initial dose; and the maintenance regimen is: a dose of 10 mg / kg administered once every two weeks.

[0257] In one embodiment, the loading regimen is: a single initial dose of 15 mg / kg; and four subsequent doses, each of 5 mg / kg administered once weekly starting one week after the single initial dose; and the maintenance regimen is: a dose of 5 mg / kg administered once every four weeks.

[0258] In one embodiment, the maintenance regimen starts 1 week after the last subsequent dose of the loading regimen. In one embodiment, the maintenance regimen starts 10 days after the last subsequent dose of the loading regimen. In one embodiment, the maintenance regimen starts 2 weeks after the last subsequent dose of the loading regimen. In one embodiment, the maintenance regimen starts 3 weeks after the last subsequent dose of the loading regimen. In one embodiment, the maintenance regimen starts 4 weeks after the last subsequent dose of the loading regimen.

[0259] In one embodiment, the loading regimen is administered intravenously and the maintenance regimen is administered subcutaneously. In one embodiment, the loading regimen is administered subcutaneously and the maintenance regimen is administered intravenously. In one embodiment, both the loading regimen and the maintenance regimen are administered intravenously. In one embodiment, both the loading regimen and the maintenance regimen are administered subcutaneously.

[0260] In one embodiment, the motor strength of the subject and / or the sensory symptoms of the subject are improved as compared to the motor strength of the subject and / or the sensory symptoms of the subject achieved with standard of care treatment using intravenous immunoglobulin (IVIg). Sensory symptoms include paresthesia (burning or tingling sensations usually felt in the hands, arms, legs, or feet, but can also occur in other parts of the body), hypoesthesia (impaired or reduced tactile sensibility), or a combination of the two.

[0261] In one embodiment, the subject exhibits a reduction in the level of free C2 in the subject's blood after administration of a C2 inhibitor, compared to a baseline level of free C2 in the subject's blood. In one embodiment, the level of free C2 in the subject's blood is reduced by at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% compared to a baseline level of free C2 in the subject's blood. Unexpectedly, a reduction in free C2 levels in a subject (at least an 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% reduction) compared to a baseline level of free C2 is sufficient to effectively treat a MMN patient, since the complement system is a cascading system that can be unbalanced in a MMN patient (an imbalance in the complement system or an overactivation of the complement system can lead to inflammation and subsequent tissue (e.g., motor nerve) damage in a MMN patient). It is generally not known how much free C2 levels can still be present in a subject, such that the complement system in a MMN patient returns to balance in response to treatment with a C2 inhibitor (e.g., ARGX-117), thereby effectively treating the MMN patient.

[0262] In one embodiment, the method further comprises administering to the subject an additional therapeutic agent. In one embodiment, the additional therapeutic agent is IVIg. In one embodiment, the additional therapeutic agent is rituximab, eculizumab, cyclophosphamide, or mycophenolate mofetil.

[0263] In one embodiment, IVIg is administered to the subject once every two weeks, once every three weeks, once every four weeks, or once every five weeks.

[0264] In one embodiment, the subject has a detectable baseline serum level of anti-ganglioside IgM antibodies. In one embodiment, the anti-ganglioside IgM antibodies are anti-GM1 antibodies. In one embodiment, the anti-ganglioside IgM antibodies are anti-GM2 antibodies.

[0265] In one embodiment, the subject exhibits a decrease in serum levels of a cytokine following administration of a C2 inhibitor, compared to the baseline serum level of the cytokine. In one embodiment, the cytokine is TNF-α, IFN-γ, IL-2, IL-6, IL-8, or IL-10.

[0266] In one embodiment, the subject has been previously treated with IVIg. In one embodiment, the subject has been previously stabilized with IVIg. In one embodiment, the subject is dependent on IVIg.

[0267] In one embodiment, the subject does not concurrently receive IVIg. In one embodiment, the subject does not require IVIg retreatment following administration of the C2 inhibitor. In one embodiment, administration of the C2 inhibitor prolongs the time to IVIg retreatment.

[0268] In one embodiment, the subject exhibits an improvement in modified Medical Research Council (mMRC) score following administration of a C2 inhibitor compared to the subject's baseline mMRC score. In one embodiment, the mMRC score is an mMRC-10 sum score or an mMRC-14 sum score.

[0269] In one embodiment, the subject shows an improvement in grip strength following administration of the C2 inhibitor as compared to the subject's baseline grip strength.

[0270] In one embodiment, the overall disability scale constructed with the subject's baseline MMN Rasch Compared with the scores, subjects showed Rating improved.

[0271] In one embodiment, the C2 inhibitor is administered subcutaneously, and the C2 inhibitor is administered together with a hyaluronidase. In one embodiment, the C2 inhibitor is administered subcutaneously, and the C2 inhibitor is co-formulated with a hyaluronidase. In one embodiment, the hyaluronidase is a recombinant human hyaluronidase PH20 (rHuPH20).

[0272] In one aspect, provided herein is a C2 inhibitor for use in treating multifocal motor neuropathy, wherein the treatment is performed according to a method disclosed herein.

[0273] In one aspect, provided herein is a C2 inhibitor for use in the preparation of a medicament for treating multifocal motor neuropathy, wherein the treatment is performed according to the methods disclosed herein.

[0274] Example

[0275] Example 1 - Study of the efficacy and safety of ARGX-117 in adults with multifocal motor neuropathy (MMN)

[0276] This example describes a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial to evaluate the safety and tolerability, efficacy, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of dosing regimens of ARGX-117, a therapeutic complement-inhibiting antibody targeting complement factor 2 (C2), in adults with multifocal motor neuropathy (MMN) (ARGX-117-2002).

[0277] Multifocal motor neuropathy (MMN) is a rare neuropathy characterized by progressive asymmetric weakness and atrophy without paresthesia. MMN is considered to be a chronic immune-mediated neuropathy driven by the classical complement pathway, which involves the presence of autoantibodies, such as anti-ganglioside GM1 (monosialyl tetrahexosyl ganglioside [anti-GM1]), anti-GM2 (and other gangliosides) immunoglobulin M (IgM) antibodies produced by a limited number of B cell clones. These antibodies activate the classical pathway of the complement system and subsequently produce membrane attack complex (MAC) deposition, leading to the destruction of Schwann cell-axon membrane connections, the displacement of ion channel aggregation, and the disturbance of membrane integrity at the (para) node region, thereby leading to demyelination and motor nerve conduction block.

[0278] Patients with MMN initially respond to standard of care intravenous immunoglobulin (IVIg); however, the disease will continue to progress despite this treatment.The purpose of the trial described in this example was to evaluate the safety and efficacy of ARGX-117 in treating patients with MMN who had been previously stabilized on IVIg.

[0279] A. Research Design

[0280] Overall Design

[0281] This is a Phase 2, randomized, stratified, double-blind, placebo-controlled, parallel-group, multicenter trial of ARGX-117 in adults with MMN. The total trial duration was at least 25 weeks for all participants. For both Cohort 1 and Cohort 2, the order and duration of the study periods were as follows:

[0282] Screening period: up to 28 days;

[0283] IVIg dependency period (IVDP) (if applicable): only participants with uncertain IVIg dependency at the end of the screening period will enter the IVDP;

[0284] IVIg monitoring period (IVMP): The length of the IVMP will depend on the participant’s IVIg dosing frequency;

[0285] Double-blinded treatment period (DBTP): 16 weeks.

[0286] Safety Follow-up Period: Participants who are not recruited into the long-term extension study (LTE) will enter a 15-month safety follow-up period after completing DBTP.

[0287] Enrollment in two treatment cohorts is planned, referred to as Cohort 1 and Cohort 2. Data collected from the first 9 participants who complete or prematurely terminate 16 weeks of DBTP in Cohort 1 will be evaluated by an independent data monitoring committee (IDMC). The IDMC will make a recommendation that will inform the decision to begin enrollment in Cohort 2 by the unblinded executive data review team (EDRT).

[0288] The diagnosis of MMN and IVIg dependence will be assessed by the MMN Confirmation Committee (MCC) during the screening period. Participants with uncertain IVIg dependence will enter the IVDP to evaluate the effects of delayed IVIg administration on grip strength (GS) and / or motor function. The IDMC will monitor the accumulated safety data throughout the trial.

[0289] Screening period

[0290] The screening period will be used to determine the eligibility of individuals to participate in the trial. The assessments will be performed as described in the schedule of activity (SoA), see Table 3.

[0291] The Screening Period will occur in up to 28 days and may be extended by an additional 14 days with written approval of the Medical Monitor, for a total of 42 days. Additional extensions of the Screening Period to coincide with a participant's subsequent IDV1 or IMV1 with their IVIg dosing schedule will not result in screening failure.

[0292] IVIg-dependent period (IVDP)

[0293] The IVDP will be used to determine IVIg dependence in participants with uncertain IVIg dependence based on the description outlined in the participant profile provided to the MCC during screening.

[0294] The IVDP will last up to 15 weeks (105 days), depending on the IVIg dosing frequency. Participants' IVIg administration will be delayed during the IVDP. Assessments will be performed at the time points described in the SoA, see Table 3.

[0295] Participants will receive IVIg following a delayed administration compared to the participant's stable IVIg regimen interval, as follows:

[0296] - Participants who received IVIg every 2 weeks will have the interval extended to 4 weeks;

[0297] - Participants who received IVIg every 3 weeks will have the interval extended to 6 weeks;

[0298] - Participants who received IVIg every 4 weeks will have the interval extended to 8 weeks; and

[0299] - Participants who received IVIg every 5 weeks will have the interval extended to 10 weeks.

[0300] Participants will be seen earlier than the scheduled visit during the IVDP if they demonstrate clinically significant worsening between scheduled visits of the IVDP. Clinically significant worsening is defined as a >30% decrease in GS in either hand observed for at least 2 consecutive days since the peak of the post-IVIg GS after IDV1 (based on a 3-day average calculation); and / or a decrease in the mMRC-10 sum score of at least 2 points from IDV1 to IDV2.

[0301] IVIg Monitoring Period (IVMP)

[0302] The IVMP will begin after participants complete the Screening Period and IVDP (if applicable) and will consist of multiple administration cycles of IVIg (see Table 3).

[0303] This period will establish baseline values ​​for all clinical endpoints assessed during the DBTP.

[0304] – Participants will receive IVIg at the frequency, duration, and dose described in their medical history.

[0305] -IVMP includes 3 cycles of IVIg treatment.

[0306] - The length of the IVMP will depend on the individual's IVIg dosing frequency, as follows:

[0307] ○ Every 2 weeks: 35 days

[0308] ○ Every 3 weeks: 49 days

[0309] ○ Every 4 weeks: 63 days

[0310] ○ For dosing every 5 weeks: 77 days.

[0311] The length of the IVMP may be greater if participants receive IVIg over the course of several days. Assessments will be performed at the time points described in Table 3.

[0312] Table 3: Timeline of activities during the IVIg-dependent and IVIg-monitoring phases until day 7

[0313]

[0314]

[0315] Table 3 (continued)

[0316]

[0317]

[0318] 9-HPT = nine-hole Peg Test; ANA = antinuclear antibodies; BMI = body mass index; CAP-PRI = Chronic Acquired Polyneuropathy Patient-Reported Index; C-SSRS = Columbia-suicide severity rating scale; DBTP = double-blind treatment period; dsDNA = double-stranded DNA; ECG = electrocardiogram; ENA = extractable nuclear antigen antibodies; EQ-5D-5L = Euro-Quality of Life 5 Dimensions 5Levels); FSH = follicle-stimulating hormone; FSS = fatigue severity scale; GM1 = monosialotetrahexosylganglioside; HRPQ = health-related productivity questionnaire; IDV = IVIg-dependent visit; IMP = investigational medicinal product; IMV = IVIg monitoring visit; INR = international normalized ratio; IVDP = IVIg-dependent period; IVMP = IVIg monitoring period; IVIg = intravenous immunoglobulin; MCC = MMN confirmation committee; MMN = multifocal motor neuropathy; A global disability scale constructed for MMN; mMRC = modified Medical Research Council; NAb = neutralizing antibodies; NfL = neurofilament light chain protein; PD = pharmacodynamics; PE = physical examination; PHQ-9 = patient health questionnaire 9 depression questionnaire; Q = per; SCN = screening period; SIB = suicidal ideation and behavior; SLE = systemic lupus erythematosus; SNP = single nucleotide polymorphism; TSQM = treatment satisfaction with medications 14-item questionnaire.

[0319] a The screening period is 1 to 28 days before the IVIg monitoring period or the IVIg-dependent period. The planned visit time varies based on the participant's IVIg dosing regimen obtained from the participant's medical record (inclusion criterion 5.a) and whether an IVIg-dependent period is required. The screening period can be extended for an additional 14 days with written approval from the medical monitor, for a total of 42 days.

[0320] b The IVIg-dependent period (if applicable) occurred prior to the IVIg monitoring period for up to 15 weeks (105 days).

[0321] c The IVIg monitoring period occurred prior to trial day 1 and lasted up to 11 weeks.

[0322] d IDV1 will coincide with the participant's regularly scheduled IVIg administration.

[0323] e If a participant demonstrates clinically significant deterioration between scheduled visits of the IVDP, the participant will have a visit earlier than the scheduled visit. This visit will be considered IDV2.

[0324] f IMV1 will coincide with the participant's regularly scheduled IVIg administration and if the participant is enrolled in an IVDP, IMV1 will be the participant's next regularly scheduled IVIg visit after IDV2. If the participant is not enrolled in an IVDP, the visit window for IMV1 does not apply.

[0325] g Female participants will have a serum pregnancy test at screening. For females of childbearing potential, a urine pregnancy test will be performed at IMV1.

[0326] h For all female participants, FSH levels will be measured at Screening.

[0327] iPE will include, at a minimum, assessment of the skin, lymph nodes, and musculoskeletal extremities.

[0328] j Vital signs will include temperature, pulse rate, respiratory rate, and blood pressure. Weight, height, and BMI calculations will be performed at Screening. Weight will also be measured at IMV3 and used to calculate the dose for all IMP administrations.

[0329] k A 12-lead ECG will be performed in triplicate during Screening and at V1. A single 12-lead ECG will be performed at all other scheduled time points.

[0330] l The C-SSRS will be used to assess risk of suicidal ideation at screening. SIB risk monitoring will be based on question 9 of the PHQ-9 at all other scheduled time points.

[0331] m ANA testing will be performed at screening, and the titer and staining pattern will be reported; the potential presence of ENA autoantibodies (anti-dsDNA, anti-Smith, anti-phospholipids (anti-cardiolipin IgG and anti-beta-2-glycoprotein IgG), anti-Ro (anti-Ro52 and anti-Ro60), anti-La, and anti-U1RNP) will be evaluated from collected blood samples. The presence of ENA autoantibodies will be reported only if the ANA is ≥1:100.

[0332] n A detailed schedule for collecting blood samples for PD analysis is provided. Samples should be collected prior to administration of IVIg.

[0333] o Immunogenicity assessment will be performed prior to dosing of IVIg administration.

[0334] p Blood samples will be collected to evaluate the effects of C2 inhibition on C1q, C3, C4, and C5. Samples should be collected prior to administration of IVIg.

[0335] q Blood samples for SNP analysis will be collected at this time point.

[0336] r The sample must be collected prior to administration of IVIg.

[0337] s The research samples will be collected during the IVIg monitoring period (visiting IMV1 to IMV3). The samples should be collected before and after the administration of IVIg. The samples should be collected immediately after the end of IVIg administration, regardless of the duration of administration (after the last hour or last day). tIVIg will be administered at scheduled time points during the IVIg-dependent and IVIg-monitoring periods. IVIg may be administered over several days according to local standard of care. All IVIg administrations must occur within designated visit windows.

[0338] u Grip strength will be measured in situ at all trial visits and monitored daily beginning with the IVDP or IVMP.

[0339] v Adverse events and concomitant medications / procedures will be monitored continuously from receipt of the signed informed consent until the last trial-related activity. All available vaccination history should be recorded.

[0340] Double-blind treatment period

[0341] Administration of the investigational medicinal product (IMP) will begin at visit 1 (V1) and continue throughout the DBTP as described in the Schedule of Activities (SoA, Table 5). The DBTP will begin 7 days after the last IVIg administration of the IVMP (i.e., V1 will be 7 days after the last IVIg administration). Participants will be randomized to ARGX-117 or placebo at V1 of the DBTP in a 2:1 ratio or a 2:2:1:1 ratio, as discussed below. Randomization will be stratified based on individual IVIg dose frequency.

[0342] Two dosage regimens will be studied in this trial (see Table 4 below):

[0343] Group 1:

[0344] Dosage regimen 1

[0345] A single dose of 30 mg / kg ARGX-117 or placebo on Day 1, followed by 4 weekly doses of 10 mg / kg ARGX-117 or placebo on Days 8, 15, 22, and 29 (4 infusions total), and 10 mg / kg ARGX-117 or placebo every 2 weeks starting on Day 43 until the end of DBTP (5 infusions total). Participants will be randomized to ARGX-117 or placebo in a 2:1 ratio at V1 of the DBTP.

[0346] Cohort 2: - Three options are available for cohort 2 dosing regimens, 1 of which will be evaluated based on EDRT decisions. estimate:

[0347] Option 1 (Dosage Regimen 2)

[0348] A single dose of 60 mg / kg ARGX-117 or placebo on Day 1, followed by 4 weekly doses of 30 mg / kg ARGX-117 or placebo on Days 8, 15, 22, and 29 (4 infusions total), and 30 mg / kg ARGX-117 or placebo every 2 weeks starting on Day 43 until the end of DBTP (5 infusions total). Participants will be randomized to ARGX-117 or placebo in a 2:1 ratio at V1 of DBTP.

[0349] Option 2 (dosage regimen 3)

[0350] A single dose of 15 mg / kg ARGX-117 or placebo on Day 1, followed by 4 weekly doses of 5 mg / kg ARGX-117 or placebo on Days 8, 15, 22, and 29 (4 infusions total), and 5 mg / kg ARGX-117 or placebo every 4 weeks on Days 57 and 85 until the end of DBTP (2 infusions total), with placebo given every 4 weeks on Days 43, 71, and 99. Participants will be randomized in a 2:1 ratio to ARGX-117 or placebo at V1 of the DBTP.

[0351] Option 3 (dosage regimens 2 and 3)

[0352] Participants will be randomized in a 2:2:1:1 ratio to ARGX-117 (high dose / dose regimen 2), ARGX-117 (low dose / dose regimen 3), placebo (high dose / dose regimen 2), or placebo (low dose / dose regimen 3) at V1 of the DBTP.

[0353] The relationship between free C2 concentration and functional complement activity (CH50) after ARGX-117 administration suggests that small amounts of free C2 are able to trigger the complement cascade as reflected by CH50 activity. Therefore, different free C2 thresholds were selected, with the goal of a 99%, 98%, or 96% reduction in free C2 levels. Since the relationship between the PD effect of ARGX-117 and (the time to) clinical response in patients with MMN is currently unknown, in order to explore the dose / exposure response relationship of ARGX-117, the dose regimens selected in this study spanned a wide range of PD effects, from near-complete C2 and functional complement inhibition at the higher dose regimen (dose regimen 2) to 2 submaximal inhibition levels at the 2 lower dose regimens (dose regimen 1 and dose regimen 3).

[0354] • Dose regimen 1 targets a submaximal PD effect of ARGX-117: a free C2 threshold of 0.4 μg / mL was chosen, which predicted 98% inhibition of baseline free C2 concentration (20 μg / mL) while predicting a mean reduction in CH50 activity to approximately 35% of normal levels.

[0355] Dose regimen 2 (option 1; high dose) targets the maximal PD effect of ARGX-117: a free C2 threshold of 0.2 μg / mL, which is predicted to inhibit 99% of baseline free C2 concentration (20 μg / mL), while predicting a mean reduction in CH50 activity to approximately 15% of normal levels.

[0356] Dose regimen 3 (option 2; lower dose) targets a submaximal PD effect of ARGX-117: a free C2 threshold of 0.8 μg / mL, predicted to inhibit 96% of baseline free C2 concentration (20 μg / mL), with a predicted mean reduction in CH50 activity to approximately 70% of normal levels.

[0357] For both dosing regimens, the goal of ARGX-117's rapid PD effect translated into a clinical response was to avoid clinical worsening and subsequent IVIg retreatment. To achieve a rapid PD effect, a dosing regimen consisting of an induction or loading phase followed by a maintenance phase with less frequent dosing was selected. This concept of rapid and sustained reduction in complement activity achieved by an induction or loading dose and sustained by a maintenance dose also applies to eculizumab and ravulizumab, monoclonal antibodies targeting C5 approved for multiple indications.

[0358] Table 4: Study groups

[0359]

[0360] DBTP = double-blind treatment period; HD = high dose; LD = low dose; LLD = low low dose; IV = intravenous

[0361] a The dose level and / or administration frequency in Cohort 2 may be reduced based on emerging data from Cohort 1 reviewed by the IDMC and EDRT (this includes dose levels and / or frequencies lower than those evaluated in Cohort 1). Substantial changes to the clinical trial protocol will be submitted for review and approval by the Health Authority, EC / IRB according to local requirements.

[0362] Participants will be retreated with IVIg during DBTP if there is a clinically significant deterioration in muscle strength and / or motor function. Clinically significant deterioration is defined as a >30% decrease in grip strength (GS) in either hand (based on a 3-day average) and / or a decrease in the mMRC-10 sum score of at least 2 points observed on at least 2 consecutive days since randomization.

[0363] When IVIg retreatment is initiated, administration of IMP will not be suspended / stopped. Based on their clinical judgment, the investigator may choose not to retreat participants with IVIg in the event of a clinically significant exacerbation. All trial participants may request IVIg retreatment from the investigator at any time during the DBTP.

[0364]

[0365]

[0366]

[0367]

[0368]

[0369] Follow-up period

[0370] The safety follow-up period will characterize safety, PK, and PD during the elimination period of ARGX-117 and will include only participants who do not cross over to the LTE. The safety follow-up period will begin after DBTP and will be conducted over 15 months. Assessments will be conducted at the time points described in Table 6.

[0371] Table 6: Schedule of activities during the follow-up period

[0372]

[0373]

[0374] ANA = antinuclear antibodies; ECG = electrocardiogram; ENA = extractable nuclear antigen antibodies; EOT = end of trial; INR = international normalized ratio; SLE = systemic lupus erythematosus; FUV = follow-up visit; IVIg = intravenous immunoglobulin; W = week. Note: The follow-up period does not apply to participants who cross over to LTE. Note: FUV1 will be performed 4 weeks after the last follow-up visit in the double-blind treatment period.

[0375] a Female participants will undergo serum pregnancy tests at scheduled time points.

[0376] bPE will include, at a minimum, assessment of the skin, lymph nodes, and musculoskeletal extremities.

[0377] c Vital signs will include temperature, pulse rate, respiratory rate, and blood pressure.

[0378] d A 12-lead ECG will be performed.

[0379] e ANA testing will be performed at designated time points, and titers and staining patterns will be reported; the potential presence of ENA autoantibodies (anti-dsDNA, anti-Smith, anti-phospholipids (anti-cardiolipin IgG and anti-β-2-glycoprotein IgG), anti-Ro (anti-Ro52 and anti-Ro60), anti-La, and anti-U1RNP) will be evaluated from collected blood samples. The presence of ENA autoantibodies will be reported only if ANA ≥ 1:100. A detailed schedule for collecting blood samples for PK and PD analysis is provided.

[0380] f Adverse events and concomitant medications / procedures will be monitored continuously from receipt of the signed informed consent until the last trial-related activity. IVIg administered throughout the safety follow-up period will be monitored as a concomitant medication. All available vaccination history should be recorded as part of the participant's previous medication for vaccinations received previously or as a concomitant medication for vaccinations received during the trial.

[0381] End of trial limit

[0382] A participant was considered to have completed the trial if he / she completed the last visit of the DBTP period and was transferred to the last visit of the follow-up period described in the LTE or SoA (see Table 6).

[0383] B. Research Group

[0384] Inclusion criteria

[0385] Participants were eligible for inclusion in the trial only if they met all of the following criteria:

[0386] 1. Ability to give signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and this protocol.

[0387] 2. The male / female must be at least 18 years old when signing the ICF.

[0388] 3. Probable MMN or definite MMN confirmed by the MCC at Screening according to the EFNS / PNS 2010 guidelines (see Clinical Criteria and Guidelines in Tables 7 to 10 below).

[0389] 4. Receiving a stable IVIg regimen prior to screening, and both of the following:

[0390] a. IVIg treatment intervals are 2 to 5 weeks, and

[0391] b. IVIg doses range from 0.4 to 2.0 g / kg body weight and are infused.

[0392] 5. Confirmation of IVIg treatment dependence by the MCC at screening or at IVIg monitoring visit 1 (IMV1) based on one of the following:

[0393] a. Recently initiated IVIg therapy (less than 3 months):

[0394] - Clinical improvement following IVIg initiation as documented in the participant's medical record.

[0395] b. Maintenance therapy (longer than 3 months) with IVIg based on one of the following:

[0396] - Clinical worsening following IVIg withdrawal, IVIg dose reduction, or IVIg delay in administration within the 12 months prior to screening (documented in the participant's medical record), or

[0397] -Clinical worsening following delayed administration of IVIg during IVDP.

[0398] 6. The first immunization with meningococcal and pneumococcal vaccines and a single Haemophilus influenzae type B vaccine must have been performed at least 14 days prior to IMP administration at V1 according to the local country-specific immunization schedule. A documented history of vaccination against Neisseria meningitidis, Haemophilus influenza type B, and streptococcus pneumonia will be allowed.

[0399] 7. Contraceptive measures for men and women should comply with local regulations on contraceptive methods for men and women participating in clinical research.

[0400] a. Male participants must agree not to donate sperm from the time they sign the ICF until 12 months after the last IMP administration.

[0401] b. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test at screening and a negative urine pregnancy test at baseline before IMP can be administered.

[0402] Table 7: Clinical criteria for MMN

[0403]

[0404] Source: Joint Task Force of the EFNS and the PNS, J Peripher NervSyst. 2010;15(4):295-301.

[0405] MMN=multifocal motor neuropathy; mMRC=modified Medical Research Council.

[0406] a Asymmetry = if the strength is mMRC>3, the difference is 1 mMRC grade, and if the strength is MRC≤3, the difference is 2 mMRC grades.

[0407] b Usually more than 6 months.

[0408] c Sensory signs and symptoms may develop during the course of MMN.

[0409] d At onset, major lower extremity involvement accounts for nearly 10% of cases.

[0410] e Slightly increased tendon reflexes, particularly in the affected arm, have been reported and do not exclude the diagnosis of MMN as long as criterion 8 is met.

[0411] f Twelfth nerve palsy has been reported.

[0412] Table 8: Electrophysiological criteria for conduction block (CB)

[0413]

[0414] Source: Joint Task Force of the EFNS and the PNS, J Peripher NervSyst. 2010;15(4):295-301.

[0415] CB = conduction block; CMAP = compound muscle action potential.

[0416] a Evidence for CB must be found at a site other than the common entrapment or compression syndrome.

[0417] Table 9: Supporting Standards

[0418] 1. Increased IgM anti-ganglioside GM1 antibodies 2. Laboratory: Increased CSF protein (<1g / L) 3. Magnetic resonance imaging shows increased T2-weighted imaging signal intensity associated with diffuse neural swelling of the brachial plexus 4. Objective clinical improvement after IVIg treatment

[0419] Source: Joint Task Force of the EFNS and the PNS, J Peripher NervSyst. 2010;15(4):295-301.

[0420] Table 10: Diagnostic categories used for MMN

[0421]

[0422]

[0423] Source: Joint Task Force of the EFNS and the PNS, J Peripher NervSyst. 2010;15(4):295-301.

[0424] Exclusion criteria

[0425] Participants were excluded from the trial if any of the following criteria applied:

[0426] 1. Any comorbid conditions that could interfere with outcome assessment (e.g., diabetic neuropathy, CIDP, inflammatory arthritis, or osteoarthritis affecting the hands).

[0427] 2. Clinical signs or symptoms indicative of a neuropathy other than MMN, such as motor neuron disease (eg, bulbar signs or brisk reflexes) or other inflammatory neuropathies (eg, sensory neuropathy).

[0428] 3. Severe mental disorders (e.g., major depression, psychosis, bipolar disorder), history of suicide attempt, or current suicidal ideation, which the investigator believes may pose an undue risk to the participants or may affect compliance with the trial protocol.

[0429] 4. Presence of clinically significant uncontrolled active or chronic bacterial, viral or fungal infection during screening and / or IVMP.

[0430] 5. Any other known autoimmune disease (e.g., SLE) that the investigator believes would interfere with the accurate assessment of clinical symptoms of MMN or place the participant at undue risk.

[0431] 6. History of malignancy, unless resolved by adequate treatment with no evidence of recurrence, for ≥3 years prior to first administration of IMP. Participants with the following carcinomas will be eligible:

[0432] a. Adequately treated basal cell carcinoma or squamous cell skin cancer;

[0433] b. Cervical cancer in situ;

[0434] c. Breast cancer in situ; or

[0435] d. Incidental histological findings of prostate cancer (TNM stage T1a or T1b).

[0436] 7. Clinical evidence of other major serious illness, recent major surgery, or any other condition that the investigator believes may confound the trial results or place the participants at undue risk.

[0437] 8. Previous / concomitant treatment:

[0438] a. Use of cyclophosphamide and / or rituximab and / or eculizumab and / or mycophenolate mofetil within 3 months before screening; and / or

[0439] b. Use of the investigational product within 3 months or 5 half-lives (whichever is longer) before the first dose of IMP.

[0440] 9. Positive serological test for active viral infection with any of the following conditions at screening:

[0441] a. Indication of acute or chronic infection with hepatitis B virus (HBV);

[0442] b. Hepatitis C virus (HCV) based on HCV antibody assay; or

[0443] c. Based on AIDS-defining condition or CD4 count < 200 cells / mm 3 Related test results for HIV.

[0444] 10. Current or past (i.e., within 12 months of screening) alcohol, drug, or substance abuse history.

[0445] 11. Known hypersensitivity to one of the components of the IMP or any of its excipients.

[0446] 12. Female participants with a positive serum or urine pregnancy test, lactating women, and those intending to become pregnant during the trial or within 15 months after the last dose of IMP.

[0447] 13. Total bilirubin ≥1.5×upper limit of normal of the central laboratory reference range, and ALT or AST ≥2×upper limit of normal, or any other clinically significant laboratory abnormalities.

[0448] 14. Estimated glomerular filtration rate calculated by the central laboratory using the 4-variable modified diet in renal disease equation ≤ 60 mL / min / 1.73 m 2 .

[0449] C. Research Evaluation and Operations

[0450] The activity timelines in Tables 3, 5 and 6 above outline the trial operations and their timing.

[0451] To calculate changes from baseline, the last value collected prior to the first dose of IMP will be used as the baseline.

[0452] Effectiveness evaluation

[0453] Preferably, efficacy assessment is performed prior to administration of IMP and IVIg and is performed in the following preferred order:

[0454] ·GS

[0455] mMRC-14 total score

[0456] Participant-reported outcome measures, including: EQ-5D-5L, CAP-PRI, PGIC, FSS, HRPQ and TSQM

[0457] 9-HPT.

[0458] If IVIg and IMP are administered on the same day, it is preferred that the IMP be administered before the IVIg. Re-treatment with IVIg Time

[0459] The criteria for retreatment with IVIg will be based on clinical worsening, which is defined as a decrease in GS of >30% (based on a 3-day average calculation) and / or a decrease in the mMRC-10 sum score of at least 2 points observed in either hand for at least 2 consecutive days compared to the day of randomization. Both GS and mMRC-10 sum score are standard and clinically relevant tools for measuring clinical efficacy in MMN clinical trials. By using these measurements as criteria for retreatment with IVIg, the time from retreatment is directly related to clinically meaningful outcomes. Both outcomes will be evaluated separately as secondary endpoints to support the results of the time from retreatment with IVIg endpoint. The corresponding threshold for worsening is set to represent a clinically significant decrease in disease activity.

[0460] The time when the participant reaches this threshold is considered the time of relapse. The date and time of retreatment with IVIg will be considered the time since retreatment with IVIg. Both the time of relapse and the time since retreatment with IVIg will be recorded.

[0461] During the DBTP period, all trial participants could request IVIg retreatment from the investigator at any time. If a participant did not meet the criteria for a clinically significant exacerbation but requested retreatment with IVIg, the investigator would contact the medical monitor.

[0462] mMRC-14 and mMRC-10 combined score

[0463] The mMRC total score evaluates motor strength / weakness of predefined muscle groups (upper and lower extremities). It is recommended that the mMRC total score of the participant be scored by the same assessor during the trial visits.

[0464] The scoring system for the mMRC sum scores and the muscle groups tested for each mMRC sum score are provided in Tables 11 and 12, respectively.

[0465] Table 11: Scoring of mMRC sum score

[0466]

[0467] Table 12: Muscle groups tested for each mMRC sum score

[0468]

[0469] Source: Leger et al. J Peripher Nerv Syst. 2019;24(1):56-63.

[0470] mMRC = modified Medical Research Council.

[0471] aEach muscle group is scored from 0 (paralysis) to 5 (normal strength). Higher values ​​indicate better muscle strength. The total score is based on the sum of both the left and right sides of the body.

[0472] grip strength

[0473] Grip strength will be measured daily using a Martin vigorimeter during the screening period, IVDP (if applicable), IVMP, and DBTP. Grip strength will be measured daily in a standardized manner during these periods.

[0474] Each daily grip strength measurement will consist of 3 repetitions of contraction at the participant's maximum effort. The duration of each contraction will be 3 seconds. It is recommended that each test begin with the participant gripping with the right hand, followed by the left hand. The test will be performed in the following recommended order: 3 repetitions are performed consecutively with the right hand, followed by 3 repetitions with the left hand. There will be a 30-second rest period between each of the 3 repetitions, and a 2-minute rest period between each hand.

[0475] Participants will perform all grip strength tests in a seated position: Participants will sit comfortably in a chair without armrests with their feet fully on the ground, their hips as far back as possible on the chair, and their hip and knee positions at approximately 90°. The shoulder of the tested limb will be adducted and neutrally rotated, the elbow flexed 90°, the forearm in a neutral position, and the wrist dorsiflexed 0° to 30°, and ulnar deviation 0° to 15°. Participants will be instructed to maintain their position during the grip strength test.

[0476] Measurements will be assessed and reported by the trial physician during the on-site trial visit. It is recommended that participants be assessed by the same assessor during the on-site visit. Participants will have their handgrip strength measured daily throughout the IVDP, IVMP, and DBTP. When performed by the participant, the time of day and results will be recorded electronically.

[0477] It is recommended that measurements be taken at a similar time of day for each assessment, preferably in the morning.

[0478] 3 daily measurements of GS from the left hand and 3 daily measurements of GS from the right hand will be recorded, and daily averages will be calculated for the left and right hands, respectively. A 3-day moving average will be generated based on the average of the averages obtained for each hand. The daily moving average will consist of Day -2, Day -1, and Day 0.

[0479] Rasch Overall Disability Scale (RODS)

[0480] The PRO instrument is a disease-specific PRO instrument that was specifically constructed to capture activity limitations in patients with MMN. It consists of 25 items, each scored as 0 (cannot perform), 1 (can perform but with difficulty), or 2 (can perform without difficulty), resulting in a total score of 0 to 50. The 25 items are provided in Table 13.

[0481] Table 13: 25-item Rasch-constructed global disability scale for MMN

[0482]

[0483]

[0484] Source: Vanhoute et al. J Peripher Nerv Syst. 2015;20(3):296-305.

[0485] 9-hole column test

[0486] The 9-HPT is a quantitative measure of upper limb (arm and hand) function. Both the dominant and non-dominant hands will be tested twice (2 consecutive trials of the dominant hand immediately followed by 2 consecutive trials of the non-dominant hand). All participants should be trained in assessing the 9-HPT before the start of the trial to rule out any training effects. It is recommended that the same assessor assess the participants during the site visit.

[0487] Europe's 5 dimensions and 5 levels of quality of life

[0488] Quality of life will be assessed by EQ-5D-5L, which allows responses to be recorded based on 5 severity levels. It is a standardized tool for health measurement used as clinical and economic evaluation. The descriptive system contains 5 dimensions: mobility, self-care, daily activities, pain / discomfort, and anxiety / depression. The scoring of each dimension includes 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. Participants will score their health status from 0 (the worst health status you can imagine) to 100 (the best health status you can imagine).

[0489] Chronic Acquired Polyneuropathy Patient Reported Index

[0490] In addition to general QOL, disease-specific QOL will be assessed by CAP-PRI. This tool includes the assessment of 15 items. Items are scored as 0 (not at all), 1 (a little bit), or 2 (a lot), resulting in a total score of 0 to 30.

[0491] Patient Global Impression of Change

[0492] The PGIC is a patient-reported outcome that was published by the National Institute of Mental Health (US) in 1976. The self-report measure PGIC reflects the patient's belief in the effectiveness of treatment. The PGIC is a 7-point scale that describes the patient's rating of overall improvement.

[0493] Fatigue Severity Scale

[0494] The FSS is a 9-item self-report questionnaire developed in 1989 and designed to differentiate fatigue from clinical depression, as the two share some of the same symptoms. The FSS consists of a short questionnaire that asks the participant to rate his or her own level of fatigue on 9 items on a scale of 1 to 7, depending on how much they felt the statement applied to them during the previous week. A low value means that the statement is not very appropriate, while a high value indicates agreement. Scoring is done by calculating the average response to the question (adding all the answers and dividing by 9).

[0495] Health-Related Productivity Questionnaire

[0496] The HRPQ was originally developed in patients with Parkinson's disease to provide data related to time missed from work or educational activities and reduced effectiveness during any attempted work. These criteria form an important part of work-related productivity and will be used to assess health-related and work-related productivity in this trial.

[0497] 14-item questionnaire for medications

[0498] The original version of the TSQM questionnaire (version 1.4) was developed in 2004 to measure patients' satisfaction with their medications using 4 scales (side effects, effectiveness, convenience, and overall satisfaction) and was used in this trial.

[0499] D. Pharmacokinetics

[0500] The concentration of ARGX-117 in serum will be determined using a validated enzyme-linked immunosorbent assay. The concentration will be calculated by interpolation from the calibration curve. Quality control samples will be analyzed throughout the trial. The measured concentration will be used to determine the between-run, overall precision and accuracy of the assay.

[0501] The serum PK parameters of ARGX-117 will be derived by non-compartmental analysis of the serum concentration-time profile using actual collection times. The PK parameters, definitions, and calculation methods are as follows:

[0502] AUC 0-t AUC from time zero to the last measured quantifiable concentration at time t calculated using the linear upper / log lower trapezoidal method

[0503] AUC 0-xh AUC from time zero to x hours after IMP administration calculated using the linear upper / log lower trapezoidal method

[0504] AUC ∞ The AUC from time zero to infinity is calculated as AUC 0-t +(C t / λ z ), where C t is the last observed quantifiable concentration, and λ z is the terminal elimination rate constant

[0505] C max Maximum observed serum concentration

[0506] C xh Concentration at x hours after administration

[0507] t max Time to reach Cmax

[0508] t 1 / 2 Apparent terminal half-life

[0509] V z ( / F) (Apparent) volume of distribution

[0510] C L ( / F) (Apparent) Total Clearance

[0511] Dose normalization parameters will be evaluated, including C max / dose and AUC / dose.

[0512] E. Pharmacodynamics

[0513] Blood samples will be collected as indicated in the assessment schedule to determine free C2 concentration, total C2 concentration, and functional complement activity (CH50). Visit 2 (Day 4), Visit 10 (Day 78), and Visit 13 (Day 102) are not mandatory and are considered optional. A minimum of 14 participants per cohort is targeted to attend the optional visits.

[0514] Blood will be collected according to professional laboratory standard procedures. Information about the equipment and further details about the sample collection procedures are documented in a separate laboratory manual.

[0515] These PD markers will be determined using assays validated for their intended use.

[0516] F.Genetics

[0517] Blood samples for DNA isolation will be collected from participants who have agreed to participate in the genetic analysis component of the trial. Participation is optional. Participants who do not wish to participate in genetic research may still participate in the trial.

[0518] DNA will be isolated from blood samples for single nucleotide polymorphism (SNP) analysis, including complement regulatory proteins. Samples will be collected according to the schedule described in the SoA.

[0519] G. Biomarkers

[0520] Blood samples will be collected to assess the effects of ARGX-117 treatment on complement cascade components. Biomarkers will include C1q, C3, C4, and C5. Samples will be collected according to the schedule described in the SoA.

[0521] H. Exploratory Endpoints

[0522] The following exploratory endpoints will be reported in the clinical trial report. Blood samples for cytokine measurements will be collected. At least the following cytokines will be assessed: TNF-α, IFN-γ, IL-2, IL-6, IL-8, and IL-10. Blood samples for biomarkers will be collected to assess the effects of ARGX-117 treatment on complement cascade components.

[0523] The following exploratory endpoints will be reported separately from the main clinical trial report. Blood samples will be collected to assess the effect of ARGX-117 on the neuronal injury marker NfL.

[0524] Blood samples will be collected to assess the effect of ARGX-117 treatment on autoantibody titers to gangliosides, including but not limited to anti-GM1 and anti-GM2.

[0525] Blood samples will also be collected for SNP analysis.

[0526] Research samples will also be collected; additional markers may be measured in samples that will be stored for future analysis.

[0527] After the trial is completed, the Sponsor may store the samples for up to 15 years. In addition, with the consent of the participant, the Sponsor or others (e.g., a university or other company) may use the samples for additional research to address any scientific questions related to ARGX-117, complement biology, MMN, or other diseases, development of related or new treatments, or research methods. In addition, blood samples may be used to validate methods for measuring ARGX-117, antibodies, and biomarkers.

[0528] I. Immunogenicity Assessment

[0529] Evaluation of anti-ARGX-117 antibodies

[0530] Blood samples will be collected at the time points specified in the activity schedule to evaluate serum levels of ADA against ARGX-117. These samples will be tested by the Sponsor or the Sponsor's designee.

[0531] Serum samples will be screened and confirmed for ADA against ARGX-117, and titers for confirmed positive samples will be reported. Additional analyses may be performed to further characterize the immunogenicity of ARGX-117.

[0532] Samples may be stored for up to 15 years after the last participant's final visit on the trial at a facility selected by the Sponsor (or in accordance with local regulations) to enable further analysis of the immune response to ARGX-117.

[0533] Anti-ARGX-117 neutralizing antibodies

[0534] Depending on the event schedule, neutralizing antibodies to ARGX-117 may be evaluated in serum samples collected and serum samples from all participants will be banked.

[0535] Samples will be stored for up to 15 years (or in accordance with local regulations) at a facility selected by the Sponsor for future use following the last participant's final visit on the trial to enable further analysis of the immune response to ARGX-117.

[0536] J. Purpose and End Point

[0537] Table 14: Objectives and End Points

[0538]

[0539]

[0540] a The threshold for retreatment with IVIg was defined as a clinical worsening in muscle strength of >30% (>30% decrease in GS observed in either hand (based on the average of 3 days) for at least 2 consecutive days compared with the day of randomization) and / or a worsening of at least 2 points based on the mMRC-10 sum score.

[0541] To determine the effectiveness of ARGX-117 compared with placebo in adult participants with MMN previously stabilized on IVIg, the median time to first retreatment with IVIg will be estimated by treatment group using the Kaplan-Meier product limit method and compared between treatment groups using the stratified log-rank test. Participants who discontinue the trial for any reason or complete the DBTP before retreatment with IVIg will be censored at the last visit on the contact date.

[0542] A sensitivity analysis of time to relapse, defined as the time until a participant met the clinical worsening threshold, will also be performed.

[0543] To correct for differences in trial duration, AUC-based endpoints were normalized to the mean AUC for each week (7 days).

[0544] For continuous endpoints, an ANCOVA model will be used, including factors for treatment and stratification variables and baseline (mMRC-10 score or GS) as covariates. For proportions, a stratified Cochran-Mantel-Haenszel test will be used, controlling for stratification variables.

[0545] Incorporation by Reference

[0546] All patent and non-patent literature references cited above are incorporated herein by reference in their entirety.

Claims

1. A method for treating multifocal motor neuropathy (MMN) in a subject in need thereof, the method comprising administering to the subject an effective amount of a complement component 2 (C2) inhibitor.

2. The method of claim 1, wherein the C2 inhibitor is administered at a dose of 0.1 mg / kg to 100 mg / kg.

3. The method of claim 1 or 2, wherein the C2 inhibitor is administered at a dose of 5 mg / kg to 60 mg / kg.

4. The method of any one of claims 1 to 3, wherein the C2 inhibitor is administered at a dose of 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg.

5. The method of any one of claims 1 to 4, wherein the C2 inhibitor is administered at a dose of 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, or 60 mg / kg.

6. The method of claim 1, wherein the C2 inhibitor is administered at a fixed dose of 500 mg to 1500 mg.

7. The method of claim 6, wherein the C2 inhibitor is administered at a fixed dose of 1200 mg.

8. The method of any one of claims 1 to 7, wherein the C2 inhibitor is administered intravenously.

9. The method of any one of claims 1 to 7, wherein the C2 inhibitor is administered subcutaneously.

10. The method of any one of claims 1 to 9, wherein the C2 inhibitor is administered once a week.

11. The method of any one of claims 1 to 9, wherein the C2 inhibitor is administered once every 2 weeks.

12. The method of any one of claims 1 to 9, wherein the C2 inhibitor is administered once every 4 weeks.

13. The method of any one of claims 1 to 9, wherein the C2 inhibitor is administered once every 8 weeks.

14. The method of any one of claims 1 to 9, wherein the C2 inhibitor is administered at a dose of 5 mg / kg once per week, every 2 weeks, or every 4 weeks.

15. The method of any one of claims 1 to 9, wherein the C2 inhibitor is administered at a dose of 10 mg / kg once per week, every 2 weeks, or every 4 weeks.

16. The method of any one of claims 1 to 9, wherein the C2 inhibitor is administered at a dose of 15 mg / kg once per week, every 2 weeks, or every 4 weeks.

17. The method of any one of claims 1 to 9, wherein the C2 inhibitor is administered at a dose of 30 mg / kg once per week, every 2 weeks, or every 4 weeks.

18. The method of any one of claims 1 to 9, wherein the C2 inhibitor is administered at a dose of 60 mg / kg once per week, every 2 weeks, or every 4 weeks.

19. The method of any one of claims 1 to 18, wherein the C2 inhibitor is administered according to a loading regimen that reduces the level of free C2 in the subject's blood to or below a threshold level.

20. The method of claim 19, further comprising a maintenance regimen following the loading regimen, wherein the maintenance regimen comprises administering the C2 inhibitor according to a regimen that maintains the level of free C2 in the subject's blood at or below the threshold level.

21. The method of claim 19 or 20, wherein the threshold level is 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7 or 0.8 μg / mL.

22. The method of claims 19 or 20, wherein the threshold level is 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20% of the subject's baseline level of free C2.

23. The method of any one of claims 19 to 22, wherein the loading regimen is a single initial dose followed by one or more subsequent doses.

24. The method of claim 23, wherein the one or more subsequent doses are each a lower amount than the single initial dose.

25. The method of claim 23 or 24, wherein the single initial dose is followed by 1, 2, 3, 4, 5 or 6 subsequent doses.

26. The method of any one of claims 23 to 25, wherein the subsequent doses are administered weekly or every 2 weeks.

27. The method of any one of claims 23 to 26, wherein the single initial dose is followed by 4 subsequent doses, and wherein the subsequent doses are administered once a week.

28. The method of any one of claims 23 to 27, wherein a first subsequent dose is administered one week after the single initial dose.

29. The method of any one of claims 23 to 28, wherein the single initial dose is between 0.1 mg / kg and 100 mg / kg.

30. The method of any one of claims 23 to 28, wherein the single initial dose is 10 mg / kg to 60 mg / kg.

31. The method of claim 30, wherein the single initial dose is 15 mg / kg.

32. The method of claim 30, wherein the single initial dose is 30 mg / kg.

33. The method of claim 30, wherein the single initial dose is 60 mg / kg.

34. The method of any one of claims 23 to 28, wherein the single initial dose is a fixed dose of 500 mg to 1500 mg.

35. The method of claim 34, wherein the single initial dose is a fixed dose of 1200 mg.

36. The method of any one of claims 23 to 35, wherein each of the subsequent doses is between 0.1 mg / kg and 100 mg / kg.

37. The method of any one of claims 23 to 35, wherein each of the subsequent doses is between 5 mg / kg and 60 mg / kg.

38. The method of claim 37, wherein each of the subsequent doses is 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg.

39. The method of claim 38, wherein each of the subsequent doses is 5 mg / kg.

40. The method of claim 38, wherein each of the subsequent doses is 10 mg / kg.

41. The method of claim 38, wherein each of the subsequent doses is 30 mg / kg.

42. The method of any one of claims 23 to 35, wherein each of the subsequent doses is a fixed dose of 500 mg to 1500 mg.

43. The method of claim 42, wherein each of the subsequent doses is a fixed dose of 1200 mg.

44. The method of any one of claims 23 to 31, wherein the single initial dose is 15 mg / kg and the subsequent doses are each 5 mg / kg.

45. The method of any one of claims 23 to 31, wherein the single initial dose is 30 mg / kg and the subsequent doses are each 10 mg / kg.

46. ​​The method of any one of claims 23 to 31, wherein the single initial dose is 60 mg / kg and the subsequent doses are each 30 mg / kg.

47. The method of any one of claims 19 to 46, wherein the loading regimen is administered intravenously.

48. The method of any one of claims 19-46, wherein the loading regimen is administered subcutaneously.

49. The method of any one of claims 19 to 48, wherein the loading regimen reduces the level of free C2 to or below the threshold level within 1, 2, 3, 4, 5, 6, or 7 days.

50. The method of any one of claims 19-48, wherein the loading regimen reduces the level of free C2 to or below the threshold level within 1, 2, 3, 4, or 5 weeks.

51. The method of any one of claims 20 to 50, wherein the maintenance regimen is a dose of 0.1 to 100 mg / kg administered once per week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, every 7 weeks, or every 8 weeks.

52. The method of any one of claims 20 to 51, wherein the maintenance regimen is a dose of 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg administered once weekly.

53. The method of any one of claims 20 to 51, wherein the maintenance regimen is a dose of 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg administered once every 2 weeks.

54. The method of claim 53, wherein the maintenance regimen is a dose of 10 mg / kg administered once every 2 weeks.

55. The method of claim 53, wherein the maintenance regimen is a dose of 30 mg / kg administered once every 2 weeks.

56. The method of any one of claims 20 to 51, wherein the maintenance regimen is a dose of 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg administered once every 3 weeks.

57. The method of any one of claims 20 to 51, wherein the maintenance regimen is a dose of 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg administered once every 4 weeks.

58. The method of claim 57, wherein the maintenance regimen is a dose of 5 mg / kg administered once every 4 weeks.

59. The method of any one of claims 20 to 51, wherein the maintenance regimen is a dose of 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg administered once every 5 weeks.

60. The method of any one of claims 20 to 51, wherein the maintenance regimen is a dose of 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg administered once every 6 weeks.

61. The method of any one of claims 20 to 51, wherein the maintenance regimen is a dose of 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg administered once every 7 weeks.

62. The method of any one of claims 20 to 51, wherein the maintenance regimen is a dose of 0.1 mg / kg, 0.5 mg / kg, 2.5 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 30 mg / kg, 60 mg / kg, or 80 mg / kg administered once every 8 weeks.

63. The method of any one of claims 20 to 51, wherein the maintenance regimen is a dose of 500 mg to 1500 mg administered once per week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, every 7 weeks, or every 8 weeks.

64. The method of claim 63, wherein each of the subsequent doses is a fixed dose of 1200 mg.

65. The method of any one of claims 20-64, wherein the maintenance regimen is administered 1, 2, 3, 4, 5, 6, 7, or 8 weeks after the loading regimen.

66. The method of any one of claims 20 to 65, wherein the maintenance regimen is administered if the level of free C2 in the subject's blood is above a threshold level.

67. The method of any one of claims 20-66, wherein the maintenance regimen is administered intravenously.

68. The method of any one of claims 20-66, wherein the maintenance regimen is administered subcutaneously.

69. The method of claim 20, wherein: The load scheme is: A single initial dose of 15 mg / kg; and four subsequent doses, each of which is 5 mg / kg administered once weekly starting one week after the single initial dose; and The maintenance regimen is: A dose of 5 mg / kg was administered once every four weeks.

70. The method of claim 20, wherein: The load scheme is: A single initial dose of 30 mg / kg; and four subsequent doses, each of which is 10 mg / kg administered once weekly starting one week after the single initial dose; and The maintenance regimen is: A dose of 10 mg / kg was administered once every two weeks.

71. The method of claim 20, wherein: The load scheme is: A single initial dose of 60 mg / kg; and four subsequent doses, each of which is 30 mg / kg administered once weekly starting one week after the single initial dose; and The maintenance regimen is: A dose of 30 mg / kg was administered once every two weeks.

72. The method of any one of claims 69-71, wherein the maintenance regimen begins 1 week after the last subsequent dose of the loading regimen. E 73. The method of any one of claims 69-71, wherein said maintenance regimen is initiated 2 weeks after the last subsequent dose of said loading regimen.

74. The method of any one of claims 20-73, wherein the loading regimen is administered intravenously and the maintenance regimen is administered subcutaneously.

75. The method of any one of claims 20-73, wherein the loading regimen is administered subcutaneously and the maintenance regimen is administered intravenously.

76. The method of any one of claims 20-73, wherein the loading regimen and the maintenance regimen are both administered intravenously.

77. The method of any one of claims 20-73, wherein the loading regimen and the maintenance regimen are both administered subcutaneously.

78. The method of any of the preceding claims, wherein the subject's motor strength is improved as compared to the subject's motor strength and / or the subject's sensory symptoms achieved with standard of care treatment using intravenous immunoglobulin (IVIg).

79. The method of any of the preceding claims, wherein the subject exhibits a decrease in the level of free C2 in the subject's blood following administration of the C2 inhibitor compared to a baseline level of free C2 in the subject's blood.

80. The method of claim 79, wherein the level of free C2 in the subject's blood is reduced by at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% as compared to a baseline level of free C2 in the subject's blood.

81. The method of any of the preceding claims, further comprising administering to the subject an additional therapeutic agent.

82. The method of claim 81, wherein the additional therapeutic agent is IVIg.

83. The method of claim 81, wherein the additional therapeutic agent is rituximab, eculizumab, cyclophosphamide, or mycophenolate mofetil.

84. The method of claim 82, wherein the IVIg is administered to the subject once every two weeks, once every three weeks, once every four weeks, or once every five weeks.

85. The method of any of the preceding claims, wherein the subject has a detectable baseline serum level of anti-ganglioside IgM antibodies.

86. The method of any of the preceding claims, wherein the subject has been previously treated with IVIg.

87. The method of any of the preceding claims, wherein the subject has been previously stabilized on IVIg.

88. The method of any of the preceding claims, wherein the subject is dependent on IVIg.

89. The method of any one of claims 1-81, wherein the subject is not concurrently receiving IVIg.

90. The method of claim 89, wherein the subject does not require IVIg retreatment following administration of the C2 inhibitor.

91. The method of any one of claims 1 to 89, wherein administration of the C2 inhibitor prolongs time to retreatment with IVIg.

92. The method of any of the preceding claims, wherein the subject exhibits an improvement in a modified Medical Research Council (mMRC) score following administration of the C2 inhibitor compared to the subject's baseline mMRC score.

93. The method of claim 92, wherein the mMRC score is an mMRC-10 sum score or an mMRC-14 sum score.

94. The method of any of the preceding claims, wherein the subject demonstrates an improvement in grip strength following administration of the C2 inhibitor compared to the subject's baseline grip strength.

95. The method of any of the preceding claims, wherein the subject exhibits an improvement in MMN Rasch Constructed Global Disability Scale (MMN-RODS) score following administration of the C2 inhibitor compared to the subject's baseline MMN-RODS score.

96. The method of any of the preceding claims, wherein the C2 inhibitor is an antibody that specifically binds to C2.

97. The method of any of the preceding claims, wherein the C2 inhibitor is an antibody that specifically binds to C2b.

98. The method of claim 96 or claim 97, wherein the antibody comprises: a heavy chain variable region (VH) and / or a light chain variable region (VL); the heavy chain variable region (VH) comprises the CDRH1, CDRH2 and CDRH3 amino acid sequences of the VH amino acid sequence shown in SEQ ID NO:7 or a variant thereof, wherein the variant comprises 1 to 5 amino acid changes in any one of the CDRH1, CDRH2 or CDRH3 amino acid sequences; the light chain variable region (VL) comprises the CDRL1, CDRL2 and CDRL3 amino acid sequences of the VL amino acid sequence shown in SEQ ID NO:8 or a variant thereof, wherein the variant comprises 1 to 5 amino acid changes in any one of the CDRL1, CDRL2 or CDRL3 amino acid sequences.

99. The method of claim 96 or claim 97, wherein: (a) the VH comprises the following CDRH1, CDRH2 and CDRH3 amino acid sequences respectively: SEQ ID NO: 1 or a variant thereof containing 1 to 5 amino acid changes, SEQ ID NO: 2 or a variant thereof containing 1 to 5 amino acid changes, and SEQ ID NO:3 or a variant thereof containing 1 to 5 amino acid changes; and / or (b) the VL comprises the following CDRL1, CDRL2 and CDRL3 amino acid sequences, respectively: SEQ ID NO: 4 or a variant thereof containing 1 to 5 amino acid changes, SEQ ID NO: 5 or a variant thereof containing 1 to 5 amino acid changes, and SEQ ID NO: 6 or a variant thereof containing 1 to 5 amino acid changes.

100. The method of claim 99, wherein the antibody comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences set forth in SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively.

101. The method of any one of claims 96 to 100, wherein the antibody comprises: a VH comprising an amino acid sequence that is at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in SEQ ID NO:7; and / or a VL comprising an amino acid sequence that is at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in SEQ ID NO:

8.

102. The method of claim 96 or claim 97, wherein the antibody comprises a VH comprising the amino acid sequence shown in SEQ ID NO:7 and a VL comprising the amino acid sequence shown in SEQ ID NO:

8.

103. The method of any one of claims 96 to 102, wherein the antibody comprises: a heavy chain comprising an amino acid sequence that is at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in SEQ ID NO:9; and / or a light chain comprising an amino acid sequence that is at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in SEQ ID NO:

10.

104. The method of any one of claims 96 to 102, wherein the antibody comprises a heavy chain comprising the amino acid sequence shown in SEQ ID NO:9 and a light chain comprising the amino acid sequence shown in SEQ ID NO:

10.

105. A C2 inhibitor for use in treating multifocal motor neuropathy, wherein the treatment is performed according to a method according to any one of the preceding claims.

106. A C2 inhibitor for use in the preparation of a medicament for the treatment of multifocal motor neuropathy, wherein the treatment is performed according to the method of any one of the preceding claims.

107. Use of a C2 inhibitor for treating multifocal motor neuropathy, wherein the treatment is performed according to the method of any one of the preceding claims.

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