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WO2025166169A1 - Compositions, doses et méthodes de traitement de maladies et de troubles à médiation par c1s - Google Patents

Compositions, doses et méthodes de traitement de maladies et de troubles à médiation par c1s

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Publication number
WO2025166169A1
WO2025166169A1 PCT/US2025/014040 US2025014040W WO2025166169A1 WO 2025166169 A1 WO2025166169 A1 WO 2025166169A1 US 2025014040 W US2025014040 W US 2025014040W WO 2025166169 A1 WO2025166169 A1 WO 2025166169A1
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WIPO (PCT)
Prior art keywords
antibody
seq
dose
administered
antigen
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Pending
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PCT/US2025/014040
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English (en)
Inventor
Simrat RANDHAWA
Sankalp GOKHALE
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Dianthus Therapeutics Opco Inc
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Dianthus Therapeutics Opco Inc
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Publication of WO2025166169A1 publication Critical patent/WO2025166169A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • Embodiments provided herein related to compositions, doses, and methods for the treatment of Cis mediated diseases and disorders.
  • the complement system is a well-known effector mechanism of the innate immune response, providing not only protection against pathogens and other harmful agents but also recovery from injury. Complement activation due to autoantibodies and alloantibodies can lead to damage to normal cells or rejection of transplanted tissue.
  • the complement pathway comprises a number of proteins that typically exist in the body in inactive form.
  • the classical complement pathway is triggered by activation of the first component of complement, referred to as the Cl complex, which consists of Clq, Clr, and Cis proteins.
  • the Cis component a diisopropyl fluorophosphate (DFP)-sensitive serine protease
  • DFP diisopropyl fluorophosphate
  • the classical complement pathway appears to play a role in many diseases and disorders.
  • sutimlimab TNT009
  • EnJaymo® is an antibody that inhibits Cis for treatment of hemolysis in adults with cold agglutinin disease.
  • sutimlimab binds to both the active form of Cis, and the inactive zymogen proCis, and due to the lack of specificity of sutimlimab for either form of Cis, a very high dose must be administered to overcome circulating levels of proCis, and may limit the clinical use of sutimlimab. Therefore, there is a need in the art for compounds that treat a complement classical pathway-mediated disease or disorder with specificity for active forms of the complement proteins and pharmaceutically acceptable formulations to safely and effectively store and administer these compounds in a therapeutic setting.
  • the embodiments provided for herein satisfy these needs as well as others.
  • compositions and doses for treating Cis mediated disorders, kits, and administration methods thereof are disclosed herein. Embodiments disclosed herein are incorporated by reference into this section.
  • a method of treating a Cls-mediated disease or disorder in a subject in need thereof comprising administering a first dose of an antibody, or a fragment thereof, wherein the first dose is about 1 mg/kg to about 60 mg/kg; or about 60 mg to about 7200 mg; administering one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, wherein the one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, is about 60 mg to about 7200 mg, and wherein the antibody, or the antigenbinding fragment thereof, comprises: a heavy chain variable region comprising a HCDR1 of SEQ ID NO: 61, a HCDR2 of SEQ ID NO: 62, and a HCDR3 of SEQ ID NO: 78; and a light chain variable region comprising a LCDR1 of SEQ ID NO: 64, a LCDR2 of SEQ ID NO: 65, and a LCDR3 of SEQ ID NO: 79.
  • a method of treating a Cls-mediated disease or disorder in a subject in need thereof comprising administering a first dose of an antibody, or a fragment thereof, wherein the first dose is about 1 mg/kg to about 60 mg/kg; or about 60 mg to about 7200 mg; administering one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, wherein the one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, is about 60 mg to about 7200 mg, wherein the first dose is administered by intravenous or subcutaneous administration, wherein the one or more subsequent dose is administered by subcutaneous administration, and wherein the antibody, or the antigen-binding fragment thereof, comprises: a heavy chain variable region comprising a HCDR1 of SEQ ID NO: 61, a HCDR2 of SEQ ID NO: 62, and a HCDR3 of SEQ ID NO: 78; and a light chain variable region comprising a LCDR1 of SEQ ID
  • a method of treating a Cls-mediated disease or disorder in a subject in need thereof comprising administering a first dose of an antibody, or a fragment thereof, wherein the first dose is selected from: about 1 mg/kg, about 3 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 30 mg/kg, about 50 mg/kg, or about 60 mg/kg; or about 300 mg, or about 600 mg; administering one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, wherein the one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, is about 300 mg, or about 600 mg, wherein the first dose is administered by intravenous or subcutaneous administration, wherein the one or more subsequent dose is administered by subcutaneous administration, and wherein the antibody, or the antigenbinding fragment thereof, comprises: a heavy chain variable region comprising a HCDR1 of SEQ ID NO: 61, a HCDR2 of SEQ ID
  • a method of treating a Cls-mediated disease or disorder in a subject in need thereof comprising administering intravenously a first dose of an antibody, or a fragment thereof, in a dose of about 15 mg/kg to about 20 mg/kg; and administering subcutaneously a one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, in a dose of about 300 mg to about 600 mg, wherein the one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, is administered every two weeks following administration of the first dose, and wherein the antibody, or the antigen-binding fragment thereof, comprises: a heavy chain variable region comprising a HCDR1 of SEQ ID NO: 61, a HCDR2 of SEQ ID NO: 62, and a HCDR3 of SEQ ID NO: 78; and a light chain variable region comprising a LCDR1 of SEQ ID NO: 64, a LCDR2 of SEQ ID NO: 65, and
  • a method of treating a Myasthenia Gravis (MG) in a subject in need thereof comprising administering intravenously a first dose of an antibody, or a fragment thereof, in a dose of about 15 mg/kg to about 20 mg/kg; and administering subcutaneously a one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, in a dose of about 300 mg to about 600 mg, wherein the one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, is administered every two weeks following administration of the first dose, and wherein the antibody, or the antigen-binding fragment thereof, comprises: a heavy chain variable region comprising a HCDR1 of SEQ ID NO: 61, a HCDR2 of SEQ ID NO: 62, and a HCDR3 of SEQ ID NO: 78; and a light chain variable region comprising a LCDR1 of SEQ ID NO: 64, a LCDR2 of SEQ ID NO:
  • a method of treating a Multifocal Motor Neuropathy (MMN) in a subject in need thereof comprising administering intravenously a first dose of an antibody, or a fragment thereof, in a dose of about 1 mg/kg to about 60 mg/kg; and administering subcutaneously a one or more subsequent dose of the antibody, or the antigenbinding fragment thereof, in a dose of about 60 mg to about 7200 mg, wherein the one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, is administered every two weeks following administration of the first dose, and wherein the antibody, or the antigenbinding fragment thereof, comprises: a heavy chain variable region comprising a HCDR1 of SEQ ID NO: 61, a HCDR2 of SEQ ID NO: 62, and a HCDR3 of SEQ ID NO: 78; and a light chain variable region comprising a LCDR1 of SEQ ID NO: 64, a LCDR2 of SEQ ID NO:
  • a method of treating a Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) in a subject in need thereof comprising administering intravenously a first dose of an antibody, or a fragment thereof, in a dose of about 1 mg/kg to about 60 mg/kg; and administering a one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, in a dose of about 60 mg to about 8300 mg, wherein the one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, is administered every two weeks following administration of the first dose, and wherein the antibody, or the antigen-binding fragment thereof, comprises: a heavy chain variable region comprising a HCDR1 of SEQ ID NO: 61, a HCDR2 of SEQ ID NO: 62, and a HCDR3 of SEQ ID NO: 78; and a light chain variable region comprising a LCDR1 of SEQ ID NO: 64, a LCDR2 of
  • FIG. 1 illustrates preliminary mean MAB39 intravenous and subcutaneous single dose concentration-time profiles (log-linear scale).
  • FIG. 2 illustrates preliminary mean MAB39 subcutaneous multiple dose concentrationtime profiles (log-linear scale).
  • FIG. 3 shows mean CH50 inhibition over time (linear scale) from part A single ascending dose of MAB39 intravenous groups (pharmacodynamic population).
  • FIG. 4 shows mean CH50 inhibition over time (linear scale) from part A single ascending dose of MAB39 subcutaneous groups (pharmacodynamic population).
  • FIG. 5 depicts mean CH50 inhibition over time (linear scale) from part B multiple ascending dose of MAB39 groups (pharmacodynamic population).
  • FIG. 6 shows mean complement system classical pathway inhibition over time (linear scale) from part A single ascending dose of MAB39 intravenous groups (pharmacodynamic population).
  • FIG. 7 illustrates mean complement system classical pathway inhibition over time (linear scale) from part A single ascending dose of MAB39 subcutaneous groups (pharmacodynamic population).
  • FIG. 8 shows mean complement system classical pathway inhibition over time (linear scale) from part B multiple ascending dose of MAB39 groups.
  • FIG. 9 depicts mean MAB39 concentration-time profile simulations.
  • FIG. 10 depicts simulations of mean CH50 percent inhibition.
  • FIG. 11 is a bar graph showing that MAB9 prevents conduction velocity impairment in CIDP sera samples.
  • FIG. 12 is a graph showing PK/PD of MAB39 in NHP following a 20 mg/kg single acute dose (SAD) by subcutaneous (SC) administration.
  • binding proteins e.g., antibodies, or fragments, thereof, that selectively bind to Cis and have low binding to the zymogen proCis.
  • the antibodies inhibit activation of the classical complement pathway and can be used in methods to treat complement mediated disorders, such as, but not limited to those provided for herein.
  • the selectivity for Cis over proCis can be used to reduce or prevent target mediated clearance of the therapeutic antibody, thus requiring lower doses and frequency of administration of the antibody.
  • compositions of antibodies that bind and modulate the activity of Cis are also provided herein.
  • the antibodies can be used, for example, to treat Cis mediated disorders.
  • variable region of the binding molecules e.g., antibodies
  • the amino acid sequence of a variable region of the binding molecules set forth herein can determine the CDR sequences therein by these or any other conventions used to define CDR, such as, for example, IMGT, Kabat, Chothia, or Contact using web-based tools are available for determining the CDRs in such variable regions based on any known convention.
  • Such tools include those found at www. aby si s . org/ aby si s/ sequence_input/key_annotati on/key_annotati on . cgi and at www.novoprolabs.com/tools/cdr.
  • the term “about” means that the numerical value is approximate and small variations would not significantly affect the practice of the disclosed embodiments. Where a numerical limitation is used, unless indicated otherwise by the context, “about” means the numerical value can vary by ⁇ 10% and remain within the scope of the disclosed embodiments. Additionally, where a phrase recites “about x to y”, the term “about” modifies both x and y and can be used interchangeably with the phrase “about x to about y” unless context dictates differently.
  • the terms “comprising” (and any form of comprising, such as “comprise”, “comprises” and “comprised”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”), or “containing” (and any form of containing, such as “contains” and “contain”), are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.
  • any step or composition that uses the transitional phrase of “comprise” or “comprising” can also be said to describe the same with the transitional phase of “consisting of’ or “consists of.”
  • the singular forms “a” or “an” or “the” include plural references unless the context clearly dictates otherwise.
  • reference to “comprising a therapeutic agent” includes one or a plurality of such therapeutic agents.
  • the term “or” refers to a single element of stated alternative elements, unless the context clearly indicates otherwise.
  • the phrase “A or B” refers to A alone or B alone.
  • the phrase “A, B, or a combination thereof’ refers to A alone, B alone, or a combination of A and B.
  • a and B refers to A, B, or a combination of both A and B.
  • a and B refers to a combination of A and B.
  • a “disease” in an animal is a state of health wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal’s health continues to deteriorate.
  • a “disorder” in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal’s state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal’s state of health.
  • parenteral administration of a composition includes, e.g., subcutaneous (s.c.), intravenous (i.v.), intramuscular (i.m.), or intraci sternal injection, intrathecal, or infusion techniques.
  • terapéutica as used herein means a treatment and/or prophylaxis.
  • a therapeutic effect is obtained by suppression, remission, or eradication of a disease state.
  • range format is merely for convenience and brevity and should not be construed as an inflexible limitation. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3, to 6 etc., as well as the individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range. Unless otherwise explicitly stated to the contrary, a range that is disclosed also includes the endpoints of the range.
  • composition means a product which results from the mixing or combining of more than one element or ingredient.
  • the term “pharmaceutical composition” refers to a medicinal or pharmaceutical formulation that contains an active ingredient as well as one or more excipients and diluents to enable the active ingredient suitable for the method of administration.
  • carrier encompasses carriers, excipients, and diluents, meaning a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material involved in carrying or transporting a pharmaceutical, cosmetic or other agent across a tissue layer.
  • pharmaceutically acceptable is employed herein to refer to those agents of interest/compounds, salts, compositions, pharmaceutical dosage forms, etc., which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and/or other mammals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutical acceptable means approved by a regulatory agency of the federal or a state government, or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for the use in animals (e.g., mammals), and more particularly, in humans.
  • the term “pharmaceutically acceptable carrier” refers to an excipient or diluent in a pharmaceutical composition.
  • the pharmaceutically acceptable carrier must be compatible with the other ingredients of the formulation and not deleterious to the recipient.
  • the nature of the carrier differs with the mode of administration. For example, for intravenous administration, an aqueous solution carrier is generally used; for oral administration, a solid carrier is generally used.
  • stable a “stable composition” or a “stable pharmaceutical composition” refers to a composition or pharmaceutical composition that maintains one or more of the characteristics of the composition within a defined margin when subject to various stressors such as, but not limited to, heat, agitation, light, temperature, humidity, repeated freeze thaw cycles, and extended storage.
  • Such characteristics include, but are not limited to, pH, presence of aggregates, functional titer, or concentration of protein excipient.
  • the defined margins for pH, presence of aggregates, functional titer, or concentration of protein excipient are as provided for herein.
  • antibody refers to any form of antibody that exhibits the desired biological activity. Thus, it is used in the broadest sense and specifically covers, but is not limited to, monoclonal antibodies (including full length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), humanized, fully human antibodies, chimeric antibodies and camelized single domain antibodies.
  • An antibody consists of four polypeptide chains; two heavy chains (CHI and CH2) and two light chains (CLI and CL2) connected by disulfide bonds.
  • Each chain is a series of domains: Light chains consist of one variable domain (VL) and one constant domain (CL), while heavy chains contain one variable domain (VH) and three to four constant domains (CHI, CH2, CH3, CH4).
  • VL variable domain
  • CL constant domain
  • CHI constant domain
  • CH2, CH3, CH4 constant domains
  • antibody fragment or “antigen binding fragment” refers to antigen binding fragments of antibodies, i.e., antibody fragments that retain the ability to bind specifically to the antigen bound by the full-length antibody, e.g. fragments that retain one or more CDR regions.
  • antibody binding fragments include, but are not limited to, Fab, Fab', F(ab')2, and Fv fragments; diabodies; linear antibodies; single-chain antibody molecules, e.g., sc-Fv; nanobodies and multispecific antibodies formed from antibody fragments.
  • a “Fab fragment” is comprised of one light chain and the CHI and variable regions of one heavy chain.
  • the heavy chain of a Fab molecule cannot form a disulfide bond with another heavy chain molecule.
  • An “Fc” region contains two heavy chain fragments comprising the CHI and CH2 domains of an antibody.
  • the two heavy chain fragments are held together by two or more disulfide bonds and by hydrophobic interactions of the CH3 domains.
  • the term “fused” or “linked” when used in reference to a protein having different domains or heterologous sequences means that the protein domains are part of the same peptide chain that are connected to one another with either peptide bonds or other covalent bonding.
  • the domains or section can be linked or fused directly to one another or another domain or peptide sequence can be between the two domains or sequences and such sequences would still be considered to be fused or linked to one another.
  • the various domains or proteins provided for herein are linked or fused directly to one another or a linker sequences, such as a glycine/serine, glycine/alanine linker or other types of peptide linkers generally known to link the two domains together.
  • a linker sequences such as a glycine/serine, glycine/alanine linker or other types of peptide linkers generally known to link the two domains together.
  • Two peptide sequences are linked directly if they are directly connected to one another or indirectly if there is a linker or other structure that links the two regions.
  • a linker can be directly linked to two different peptide sequences or domains.
  • a “Fab 1 fragment” contains one light chain and a portion or fragment of one heavy chain that contains the VH domain and the CHI domain and also the region between the CHI and CH2 domains, such that an interchain disulfide bond can be formed between the two heavy chains of two Fab' fragments to form a F(ab') 2 molecule.
  • a “F(ab')2 fragment” contains two light chains and two heavy chains containing a portion of the constant region between the CHI and CH2 domains, such that an interchain disulfide bond is formed between the two heavy chains.
  • a F(ab') 2 fragment thus is composed of two Fab' fragments that are held together by a disulfide bond between the two heavy chains.
  • the “Fv region” comprises the variable regions from both the heavy and light chains, but lacks the constant regions.
  • single-chain Fv or “scFv” antibody refers to antibody fragments comprising the VH and VL domains of an antibody, wherein these domains are present in a single polypeptide chain.
  • the Fv polypeptide further comprises a polypeptide linker between the VH and VL domains which enables the scFv to form the desired structure for antigen binding.
  • scFv see Pluckthun (1994) THE PHARMACOLOGY OF MONOCLONAL ANTIBODIES, vol. 113, Rosenburg and Moore eds. Springer-Verlag, New York, pp. 269-315. See also, International Patent Application Publication No. WO 88/01649 and U.S. Pat. Nos. 4,946, 778 and 5,260,203.
  • a “domain antibody” is an immunologically functional immunoglobulin fragment containing only the variable region of a heavy chain or the variable region of a light chain. In some instances, two or more VH regions are covalently joined with a peptide linker to create a bivalent domain antibody. The two VH regions of a bivalent domain antibody may target the same or different antigens.
  • a “bivalent antibody” comprises two antigen binding sites. In some instances, the two binding sites have the same antigen specificities. However, bivalent antibodies may be bispecific (see below).
  • a “single-domain antibody” is an immunologically functional immunoglobulin fragment containing only the variable region of a heavy chain or the variable region of a light chain. In some instances, two or more VH regions are covalently joined with a peptide linker to create a bivalent domain antibody.
  • antibody molecules can be monospecific (e.g., monovalent or bivalent), bispecific (e.g., bivalent, trivalent, tetraval ent, pentavalent, or hexavalent), trispecific (e.g., trivalent, tetraval ent, pentavalent, hexavalent), or with higher orders of specificity (e.g., tetraspecific) and/or higher orders of valency beyond hexavalency.
  • An antibody molecule can comprise a functional fragment of a light chain variable region and a functional fragment of a heavy chain variable region, or heavy and light chains may be fused together into a single polypeptide.
  • monoclonal antibodies herein also include camelized single domain antibodies. See, e.g., Muyldermans et al. (2001) Trends Biochem. Sci. 26:230; Reichmann et al. (1999) J. Immunol. Methods 231 :25; WO 94/04678; WO 94/25591; U.S. Pat. No. 6,005,079).
  • the present invention provides single domain antibodies comprising two VH domains with modifications such that single domain antibodies are formed.
  • diabodies refers to small antibody fragments with two antigenbinding sites, which fragments comprise a heavy chain variable domain (VH) connected to a light chain variable domain (VL) in the same polypeptide chain (VH-VL or VL-VH).
  • VH heavy chain variable domain
  • VL light chain variable domain
  • VH-VL or VL-VH the domains are forced to pair with the complementary domains of another chain and create two antigen-binding sites.
  • Diabodies are described more fully in, e.g, EP 404,097; WO 93/11161; and Holliger et al. (1993) Proc. Natl. Acad. Sci. USA 90: 6444-6448.
  • Holliger and Hudson (2005) Nat. Biotechnol. 23 : 1126-1136 For a review of engineered antibody variants generally see Holliger and Hudson (2005) Nat. Biotechnol. 23 : 1126-1136.
  • a variant antibody or antigen binding fragment of the antibodies provided herein retain at least 10% of its Cis binding activity (when compared to a parental antibody that is modified) when that activity is expressed on a molar basis.
  • a variant antibody (or antigen fragment thereof), or antigen binding fragment of an antibody provided herein retains at least 20%, 50%, 70%, 80%, 90%, 95% or 100% or more of the Cis binding affinity as the parental antibody.
  • an antibody or antigen binding fragment of the invention can include conservative or non-conservative amino acid substitutions, which can also be referred to as “conservative variants” or “function conserved variants” of the antibody, that do not substantially alter its biologic activity.
  • isolated antibody refers to the purification status of a binding compound and in such context means the molecule is substantially free of other biological molecules such as nucleic acids, proteins, lipids, carbohydrates, or other material such as cellular debris and growth media. Generally, the term “isolated” is not intended to refer to a complete absence of such material or to an absence of water, buffers, or salts, unless they are present in amounts that substantially interfere with experimental or therapeutic use of the binding compound as described herein.
  • the term “monoclonal antibody”, as used herein, refers to population of substantially homogeneous antibodies, z.e., the antibody molecules comprising the population are identical in amino acid sequence except for possible naturally occurring mutations and/or post-translational modifications that may be present in minor amounts.
  • conventional (polyclonal) antibody preparations typically include a multitude of different antibodies having different amino acid sequences in their variable domains, particularly their CDRs, that are often specific for different epitopes.
  • the modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.
  • the monoclonal antibodies to be used in accordance with the present invention may be made by the hybridoma method first described by Kohler et al. (1975) Nature 256: 495, or may be made by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567).
  • the “monoclonal antibodies” may also be isolated from phage antibody libraries using the techniques described in Clackson et al. (1991) Nature 352: 624-628 and Marks et al. (1991) J. Mol. Biol. 222: 581-597, for example. See also Presta (2005) J. Allergy Clin. Immunol. 116:731.
  • a “chimeric antibody” is an antibody having the variable domain from a first antibody and constant domain from a second antibody, where the first and second antibodies are from different species.
  • the variable domains are obtained from an antibody from an experimental animal (the “parental antibody”), such as a rodent, and the constant domain sequences are obtained from human antibodies, so that the resulting chimeric antibody will be less likely to elicit an adverse immune response in a human subject than the parental (e.g., rodent) antibody.
  • humanized antibody refers to forms of antibodies that contain sequences from both human and non-human e.g., murine, rat) antibodies.
  • the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non- human immunoglobulin, and all or substantially all of the framework (FR) regions are those of a human immunoglobulin sequence.
  • the humanized antibody may optionally comprise at least a portion of a human immunoglobulin constant region (Fc).
  • Fully human antibody refers to an antibody that comprises human immunoglobulin protein sequences only.
  • a fully human antibody may contain murine carbohydrate chains if produced in a mouse, in a mouse cell, or in a hybridoma derived from a mouse cell.
  • mouse antibody refers to an antibody that comprises mouse immunoglobulin sequences only.
  • a fully human antibody may contain rat carbohydrate chains if produced in a rat, in a rat cell, or in a hybridoma derived from a rat cell.
  • rat antibody refers to an antibody that comprises rat immunoglobulin sequences only.
  • the basic antibody structural unit comprises a tetramer.
  • Each tetramer includes two identical pairs of polypeptide chains, each pair having one “light” (about 25 kDa) and one “heavy” chain (about 50-70 kDa).
  • the amino-terminal portion of each chain includes a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition.
  • the carboxy-terminal portion of the heavy chain may define a constant region primarily responsible for effector function.
  • human light chains are classified as kappa and lambda light chains.
  • human heavy chains are typically classified as mu, delta, gamma, alpha, or epsilon, and define the antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively.
  • the variable and constant regions are joined by a “J” region of about 12 or more amino acids, with the heavy chain also including a “D” region of about 10 more amino acids. See generally, Fundamental Immunology Ch. 7 (Paul, W ., ed., 2nd ed. Raven Press, N.Y. (1989).
  • variable regions of each light/heavy chain pair form the antibody binding site.
  • an intact antibody has two binding sites.
  • the two binding sites are, in general, not the same.
  • the variable domains of both the heavy and light chains comprise three hypervariable regions, also called complementarity determining regions (CDRs), located within relatively conserved framework regions (FR).
  • CDRs complementarity determining regions
  • FR framework regions
  • the CDRs are usually aligned by the framework regions, enabling binding to a specific epitope.
  • both light and heavy chains variable domains comprise FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4.
  • hypervariable region refers to the amino acid residues of an antibody that are responsible for antigen-binding.
  • the hypervariable region comprises amino acid residues from a “complementarity determining region” or “CDR” (i.e. residues 24-34 (CDRL1), 50-56 (CDRL2) and 89-97 (CDRL3) in the light chain variable domain and residues 31-35 (CDRH1), 50-65 (CDRH2) and 95-102 (CDRH3) in the heavy chain variable domain; Kabat etal. (1991) Sequences of Proteins of Immunological Interest, 5th Ed.
  • CDR complementarity determining region
  • CDR residues refers to those variable domain residues other than the hypervariable region residues defined herein as CDR residues.
  • CDRs provide the majority of contact residues for the binding of the antibody to the antigen or epitope.
  • CDRs of interest can be derived from donor antibody variable heavy and light chain sequences, and include analogs of the naturally occurring CDRs, which analogs also share or retain the same antigen binding specificity and/or neutralizing ability as the donor antibody from which they were derived.
  • telomere binding refers to antibody binding to a predetermined antigen at a much higher affinity than for another antigen(s) (e.g. selectively binds the active form of complement component Cis as compared to inactive Cis, which can also be referred to as proCis zymogen).
  • the antibody binds the predetermined antigen with a dissociation constant (KD) of 10' 7 M or less, and such Kois at least two-fold less than its KD for binding to a non-specific antigen (e.g., BSA, casein, or another non-specific polypeptide).
  • KD dissociation constant
  • an antibody recognizing Cis and “an antibody specific for Cis” are used interchangeably herein with the term “an antibody which binds immunospecifically to Cis.”
  • the antibody binds specifically or preferentially to Cis, such as the active form of Cis over other proteins, such as, but not limited to, the inactive form of Cis (proCis).
  • the degree of specificity necessary for an anti-Cls antibody may depend on the intended use of the antibody, and at any rate is defined by its suitability for use for an intended purpose.
  • the antibody, or binding compound derived from the antigen-binding site of an antibody, of the contemplated method binds to its antigen (active form of Cis), with an affinity that is at least two-fold greater, at least ten times greater, at least 20-times greater, or at least 100- times greater than the affinity with any other antigen, including, but not limited to inactive Cis.
  • the term “homolog” means protein sequences having between 40% and 100% sequence identity to a reference sequence. Percent identity between two peptide chains can be determined by pair wise alignment using the default settings of the AlignX module of Vector NTI v.9.0.0 (Invitrogen Corp., Carlsbad, Calif.) or other suitable alignment software, such as BLAST.
  • the antibody, or antigen binding fragment thereof has, at least 50, 60, 70, 80, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% homology or identity to a sequence described herein. In some embodiments, the antibody has conservative substitutions as compared to a sequence described herein.
  • variants of the proteins and peptides provided herein are provided.
  • a variant comprises a substitution, deletions, or insertion.
  • the variant comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., 1-10) substitutions.
  • the substitutions can be conservative substitutions.
  • the substitution is non-conservative.
  • the variant comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., 1-10) deletions.
  • the variant comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., 1-10) insertions.
  • the substitutions, deletions, or insertions are present in the CDRs provided for herein. In some embodiments, the substitutions, deletions, or insertions are not present in the CDRs provided for herein.
  • epitope is meant to refer to that portion of any molecule capable of being recognized by and bound by an antibody at one or more of the Ab’s antigen binding regions.
  • Epitopes usually consist of chemically active surface groupings of molecules such as amino acids or sugar side chains and have specific three-dimensional structural characteristics as well as specific charge characteristics.
  • “Expression vector” refers to a vector comprising a recombinant polynucleotide comprising expression control sequences operatively linked to a nucleotide sequence to be expressed.
  • An expression vector comprises sufficient cis-acting elements for expression; other elements for expression can be supplied by the host cell or in an in vitro expression system.
  • Expression vectors include all those known in the art, such as cosmids, plasmids (e.g., naked or contained in liposomes) and viruses (e.g., Sendai viruses, lentiviruses, retroviruses, adenoviruses, and adeno- associated viruses) that incorporate the recombinant polynucleotide.
  • the antibody is a monoclonal antibody which binds to Cis.
  • the sequence of active Cis is as follows (SEQ ID NO: 258):
  • MWCIVLFSLLAWVYA (SEQ ID NO: 259); and residues 16-688 (SEQ ID NO: 260) constitute the mature protein EPTMYGEILSPNYPQAYPSEVEKSWDIEVPEGYGIHLYFTHLDIELSENCAYDSVQI ISGDTEEG RLCGQRSSNNPHSPIVEEFQVPYNKLQVI FKSDFSNEERFTGFAAYYVATDINECTDFVDVPCSH FCNNFIGGYFCSCPPEYFLHDDMKNCGVNCSGDVFTALIGEIASPNYPKPYPENSRCEYQIRLEK GFQVWTLRREDFDVEAADSAGNCLDSLVFVAGDRQFGPYCGHGFPGPLNIETKSNALDI I FQTD LTGQKKGWKLRYHGDPMPCPKEDTPNSVWEPAKAKYVFRDWQITCLDGFEWEGRVGATSFYST CQSNGKWSNSKLKCQPVDCGIPES IENGKVEDPESTLFGSVIRYTCEEPYYY
  • inactive Cis The difference between inactive Cis and active Cis is that inactive proCis is cleaved at the peptide bond between R437 and 1438 and undergoes a conformational change. The two fragments generated by this cleavage remain associated by a disulfide bond.
  • proCis is a single chain 86,000 Da protein that is the native form of Cis proteins (e.g. serine protease).
  • Cis is a subunit of the Cl complex which is the first complement component in the cascade referred to as the classical pathway of complement.
  • ProCis is an inactive zymogen until Cl is activated.
  • Cl complex binds to and is activated by antigenantibody complexes (immune complexes) yielding Clr enzyme.
  • Clr enzyme in the Cl complex activates proCis generating Cis enzyme.
  • Cl complex is a non-covalent calcium-dependent complex of one Clq, two Clr and two Cis molecules.
  • Clq binds through two or more of its six arms to the Fc domains of IgG or IgM. The binding of multiple arms to immune complexes causes the two Clr proteins in the complex (protease zymogens) to activate producing two proteases that cleave and activate the two proCis in the complex (Morikis, D. and Lambris, J.D. (2005)). This activation of proCis is caused by cleavage into the two chain Cis enzyme with 58,000 and 28,000 dalton fragments.
  • antibodies e.g. an anti-Cls antibody
  • the antibody is a recombinant antibody that binds to Cis.
  • the antibody binds to the active form of Cis.
  • the antibody binds to active form preferentially over the inactive form of Cis.
  • the antibody binds to the active form with an affinity that is at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, or 200% higher as compared to its affinity for the inactive form of C 1 s.
  • the Cis protein is a human Cis protein, such as the active form of Cis.
  • the antibody does not specifically bind to the inactive form of the Cis protein.
  • the term “recombinant antibody” refers to an antibody that is not naturally occurring. In some embodiments, the term “recombinant antibody” refers to an antibody that is not isolated from a human subject. In some embodiments, the antibody binds with at least 100X more affinity to the active form of Cis as compared to proCis.
  • an antibody, or antigen binding fragment thereof comprises any CDR sequence provided herein. In some embodiments, an antibody, or antigen binding fragment thereof comprises any heavy chain variable polypeptide provided herein. In some embodiments, an antibody, or antigen binding fragment thereof comprises any light chain variable polypeptide provided herein. In some embodiments, an antibody, or antigen binding fragment thereof comprises any heavy chain polypeptide provided herein. In some embodiments, an antibody, or antigen binding fragment thereof comprises any light chain polypeptide provided herein. In some embodiments, an antibody, or antigen binding fragment thereof comprises any combination of CDR sequences as provided for any one MAB1-MAB61 below.
  • an antibody, or antigen binding fragment thereof comprises any combination of a heavy chain variable polypeptide and a light chain variable polypeptide as provided for any one MAB1-MAB61 below. In some embodiments, an antibody, or antigen binding fragment thereof comprises any combination of a heavy chain polypeptide and a light chain polypeptide as provided for any one MAB1-MAB61 below.
  • an antibody, or antigen binding fragment thereof is provided, wherein the antibody or antibody fragment comprises a peptide selected from the following table, which illustrate the CDRs based on Kabat numbering.
  • the CDRs in the above-identified table can also be referred to according to Chothia CDRs or IMGT CDRs. These are illustrated in the following tables for the different antibodies.
  • the antibody comprises CDRs as provided in WO2014/066744, WO20 14/071206, WO2016/164358, WO2018/071676, W02023/250507, or WO2023/245048, each of which is hereby incorporated by reference in its entirety.
  • the antibody comprises CDRs as provided below:
  • the antibody comprises a heavy chain variable region (VH) polypeptide having one of the following sequences, or a variant thereof:
  • the antibody comprises a heavy chain variable region (VH) polypeptide as provided in WO2014/066744, WO2014/071206, WO2016/164358,
  • the antibody comprises a heavy chain variable region (VH) polypeptide as provided below:
  • an antibody, or an antigen-binding fragment thereof comprises a heavy chain variable region having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to any one of SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, or 430.
  • an antibody, or an antigen-binding fragment thereof comprises a heavy chain variable region having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to any one of SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, or 430, provided that the heavy chain variable region comprises HCDR1, HCDR2, and HCDR3
  • the antibody comprises a light chain variable region (VL) polypeptide having one of the following sequences, or a variant thereof:
  • the antibody comprises a light chain variable region (VL) polypeptide as provided in WO2014/066744, WO2014/071206, WO2016/164358,
  • the antibody comprises a light chain variable region (VL) polypeptide as provided below:
  • an antibody, or an antigen-binding fragment thereof comprises a light chain variable region having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to any one of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, or 431.
  • an antibody, or an antigen-binding fragment thereof comprises a light chain variable region having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to any one of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, or 431, provided that the light chain variable region comprises LCDR1, LCDR2, and LCDR3 of any one of MAB1-MAB61.
  • the antibody comprises a heavy chain as set forth below, which includes the heavy chain variable region and the constant domain: [0095] In some embodiments, the antibody comprises a heavy chain polypeptide as provided in WO20 14/066744, WO2014/071206, WO2016/164358, WO2018/071676, W02023/250507, or WO2023/245048, each of which is hereby incorporated by reference in its entirety. In some embodiments, the antibody comprises a heavy chain polypeptide as provided below:
  • an antibody, or an antigen-binding fragment thereof comprises a heavy chain having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to any one of SEQ ID NOs: 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189,
  • the antibody comprises a light chain as set forth below, which includes the light chain variable region and a constant domain, such as the human kappa constant domain:
  • the antibody comprises a light chain polypeptide as provided in
  • the antibody comprises a light chain polypeptide as provided below:
  • an antibody, or an antigen-binding fragment thereof comprises a light chain having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to any one of SEQ ID NOs: 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, or 433.
  • the antibody comprises a Fc domain.
  • the Fc domain can be linked to the heavy or light chain of the antibody.
  • the Fc domain comprises a mutation to extend the half-life of the antibody.
  • the Fc domain comprises a mutation such as those described in U.S. Patent No. 7,670,600, which is hereby incorporated by reference in its entirety.
  • the constant region comprises a mutation at position at amino acid residue 428 relative to a wild-type human IgG constant domain, numbered according to the EU numbering index of Kabat.
  • an antibody comprising a mutation that corresponds to residue 428 can have an increased half-life compared to the half-life of an IgG having the wild-type human IgG constant domain.
  • the mutation is a substitution of the native residue with a threonine, leucine, phenylalanine or serine.
  • the antibody further comprises one or more amino acid substitutions relative to the corresponding wild-type human IgG constant domain at one or more of amino acid residues 251-256, 285-290, 308-314, 385-389, and 429-436, numbered according to the Kabat EU numbering index. The specific mutations or substitutions at these positions are described in U.S. Patent No. 7,670,600, which is hereby incorporated by reference in its entirety.
  • the Fc region is a variant Fc region comprising amino acid substitutions at positions 428 and 434, wherein the amino acid substitutions are a leucine that is not the wild-type amino acid at position 428 and a serine that is not the wild-type amino acid at position 434, wherein the polypeptide is an antibody and wherein numbering is according to the EU Index in Kabat et al.
  • the Fc region comprises a S228P, L235E, M428L, or N434S substitution.
  • the Fc region comprises a M428L substitution. In some embodiments, the Fc region comprises a N434S substitution. In some embodiments, the Fc region comprises a M428L and a N434S substitution. In some embodiments, the Fc region comprises a M252Y, S254T, and/or T256E substitution.
  • the antibody comprises a constant region as set forth below with or without the mutations provided for in the list below:
  • the antibody comprises a constant region as provided herein, wherein the C-terminal lysine (K) amino acid has been deleted.
  • the antibody comprises a constant region as set follows: >IgG4 S228P L235E LS-trunc
  • the antibody such as the light chain, comprises a kappa constant region, such as the human constant domain, which can comprise a sequence of:
  • RTVAAPSVFI FPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC human kappa constant domain, SEQ ID NO: 265.
  • purified refers to an antibody that is substantially free of other material that associates with the molecule in its natural environment.
  • a purified protein is substantially free of the cellular material or other proteins from the cell or tissue from which it is derived.
  • the term refers to preparations where the isolated protein is sufficiently pure to be analyzed, or at least 70% to 80% (w/w) pure, at least 80%-90% (w/w) pure, 90-95% pure; and, at least 95%, 96%, 97%, 98%, 99%, or 100% (w/w) pure.
  • the antibody is purified.
  • a pharmaceutical composition comprising an antibody or antigen-binding fragment thereof as provided for herein.
  • the antibody, or antigen binding fragment thereof, or other proteins provided herein are admixed with a pharmaceutically acceptable carrier or excipient. See, e.g., Remington's Pharmaceutical Sciences and U.S. Pharmacopeia: National Formulary, Mack Publishing Company, Easton, PA (1984).
  • Formulations of therapeutic or the antibodies provided herein may be prepared by mixing with acceptable carriers, excipients, or stabilizers in the form of, e.g., lyophilized powders, slurries, aqueous solutions or suspensions (see, e.g., Hardman, el al. (2001) Goodman and Gilman ’s The Pharmacological Basis of Therapeutics, McGraw-Hill, New York, NY; Gennaro (2000) Remington: The Science and Practice of Pharmacy, Lippincott, Williams, and Wilkins, New York, NY; Avis, el al. (eds.) (1993) Pharmaceutical Dosage Forms: Parenteral Medications, Marcel Dekker, NY; Lieberman, et al.
  • the antibodies are diluted to an appropriate concentration in a sodium acetate solution pH 5-6, and NaCl or sucrose is added for tonicity. Additional agents, such as polysorbate 20 or polysorbate 80, may be added to enhance stability.
  • Toxicity and therapeutic efficacy of the antibody compositions, administered alone or in combination with another agent can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LDso (the dose lethal to 50% of the population) and the EDso (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index (LDso/ EDso).
  • antibodies exhibiting high therapeutic indices are desirable.
  • the data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in human.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the EDso with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration.
  • a composition is administered to a subject in accordance with the Physicians' Desk Reference 2003 (Thomson Healthcare; 57th edition (November 1, 2002)).
  • the mode of administration can vary. Suitable routes of administration include oral, rectal, transmucosal, intestinal, parenteral; intramuscular, subcutaneous, intradermal, intramedullary, intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, intraocular, inhalation, insufflation, topical, cutaneous, transdermal, or intra-arterial.
  • the composition is an injectable pharmaceutical composition.
  • the composition is formulated for intravenous or subcutaneous injection.
  • the composition is formulated for intravenous injection.
  • the composition is formulated for subcutaneous injection.
  • the antibody, or antigen binding fragment thereof can be administered by an invasive route such as by injection.
  • the antibodies or antigen binding fragment thereof, or pharmaceutical composition thereof is administered intravenously, subcutaneously, intramuscularly, intraarterially, intra-articularly (e.g. in arthritis joints), intratumorally, or by inhalation, aerosol delivery.
  • Administration by non-invasive routes e.g., orally; for example, in a pill, capsule or tablet) is also within the scope of the present embodiments.
  • the anti-Cls antibody, or antigen binding fragment thereof is administered in combination with at least one additional therapeutic agent, such as, but not limited to any therapeutic used to treat the disorders provided for herein.
  • the antibody is administered in combination with another treatment for the disorders provided for herein.
  • compositions can be administered with medical devices known in the art.
  • a pharmaceutical composition of the invention can be administered by injection with a hypodermic needle, including, e.g., a prefilled syringe or autoinjector.
  • the liposomes will be targeted to and taken up selectively by the afflicted tissue.
  • the administration regimen depends on several factors, including the serum or tissue turnover rate of the therapeutic antibody, the level of symptoms, the immunogenicity of the therapeutic antibody, and the accessibility of the target cells in the biological matrix.
  • the administration regimen delivers sufficient therapeutic antibody to effect improvement in the target disease state, while simultaneously minimizing undesired side effects.
  • the amount of biologic delivered depends in part on the particular therapeutic antibody and the severity of the condition being treated. Guidance in selecting appropriate doses of therapeutic antibodies is available (see, e.g., Wawrzynczak (1996) Antibody Therapy, Bios Scientific Pub.
  • Determination of the appropriate dose can be made by the clinician, e.g., using parameters or factors known or suspected in the art to affect treatment. Generally, the dose begins with an amount somewhat less than the optimum dose and it is increased by small increments thereafter until the desired or optimum effect is achieved relative to any negative side effects.
  • Important diagnostic measures include those of symptoms of, e.g., the inflammation or level of inflammatory cytokines produced. In general, it is desirable that a biologic that will be used is derived from the same species as the animal targeted for treatment, thereby minimizing any immune response to the reagent. In the case of human subjects, for example, chimeric, humanized and fully human antibodies may be desirable.
  • Polypeptides, antibodies, or antigen binding fragments thereof provided for herein may be provided by continuous infusion, or by doses administered, e.g., daily, 1-7 times per week, weekly, bi-weekly, every three weeks, monthly, bimonthly, or quarterly.
  • a total weekly dose is generally at least 0.05 pg/kg body weight, more generally at least 0.2 pg/kg, 0.5 pg/kg, 1 pg/kg, 10 pg/kg, 100 pg/kg, 0.25 mg/kg, 1.0 mg/kg, 2.0 mg/kg, 5.0 mg/kg, 10 mg/kg, 25 mg/kg, 50 mg/kg or more (see, e.g., Yang, et al.
  • Doses may also be provided to achieve a pre-determined target concentration of the antibody in the subj ect’ s serum, such as 0.1, 0.3, 1, 3, 10, 30, 100, 300, 400, 500, 600 pg/ml or more.
  • a fully human antibody is administered subcutaneously or intravenously, on a weekly, biweekly, “every 4 weeks,” monthly, bimonthly, or quarterly basis at 10, 20, 50, 80, 100, 200, 300, 400, 500, 600, 1000 or 2500 mg/subject.
  • the polypeptide, the antibody, or the antigen-binding fragment thereof is administered at a dose of about 1 mg/kg to about 60 mg/kg. In some embodiments, the polypeptide, the antibody, or the antigen-binding fragment thereof, is administered at a dose of about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg, about 25 mg/kg, about 26 mg/kg, about 27 mg/kg, about 28 mg/kg, about 29 mg/kg, about 30 mg/kg
  • the polypeptide, the antibody, or the antigen-binding fragment thereof is administered at a dose of 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 11 mg/kg, 12 mg/kg, 13 mg/kg, 14 mg/kg, 15 mg/kg, 16 mg/kg, 17 mg/kg, 18 mg/kg, 19 mg/kg, 20 mg/kg, 21 mg/kg, 22 mg/kg, 23 mg/kg, 24 mg/kg, 25 mg/kg, 26 mg/kg, 27 mg/kg, 28 mg/kg, 29 mg/kg, 30 mg/kg, 31 mg/kg, 32 mg/kg, 33 mg/kg, 34 mg/kg, 35 mg/kg, 36 mg/kg, 37 mg/kg, 38 mg/kg, 39 mg/kg, 40 mg/kg, 41 mg/kg, 42 mg/kg, 43 mg/kg, 44 mg/kg, 45
  • the polypeptide, the antibody, or the antigen-binding fragment thereof is administered at a dose of about 60 mg to about 7200 mg. In some embodiments, the polypeptide, the antibody, or the antigen-binding fragment thereof, is administered at a dose of about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg,
  • the polypeptide, the antibody, or the antigen-binding fragment thereof is administered at a dose of 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg,
  • the polypeptide, the antibody, or the antigen-binding fragment thereof is administered at a first dose. In some embodiments, the polypeptide, the antibody, or the antigen-binding fragment thereof, is administered at a one or more subsequent dose. In some embodiments, the polypeptide, the antibody, or the antigen-binding fragment thereof, is administered at a first dose and/or one or more subsequent dose. In some embodiments, the polypeptide, the antibody, or the antigen-binding fragment thereof, is administered at a first dose and one or more subsequent dose.
  • the first dose is about 1 mg/kg to about 60 mg/kg. In some embodiments, the first dose is about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg, about 25 mg/kg, about 26 mg/kg, about 27 mg/kg, about 28 mg/kg, about 29 mg/kg, about 30 mg/kg, about 31 mg/kg, about 32 mg/kg, about 33 mg/kg, about 34 mg/kg, about 35 mg/kg, about 36 mg/kg, about 37 mg/kg
  • the first dose is 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 11 mg/kg, 12 mg/kg, 13 mg/kg, 14 mg/kg, 15 mg/kg, 16 mg/kg, 17 mg/kg, 18 mg/kg, 19 mg/kg, 20 mg/kg, 21 mg/kg, 22 mg/kg, 23 mg/kg, 24 mg/kg,
  • the first dose is about 60 mg to about 7200 mg. In some embodiments, the first dose is about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540
  • the first dose is 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg, 700 mg, 710 mg
  • the one or more subsequent dose is about 1 mg/kg to about 60 mg/kg. In some embodiments, the one or more subsequent dose is about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg, about 25 mg/kg, about 26 mg/kg, about 27 mg/kg, about 28 mg/kg, about 29 mg/kg, about 30 mg/kg, about 31 mg/kg, about 32 mg/kg, about 33 mg/kg, about 34 mg/kg, about 35 mg/kg, about 36 mg/kg
  • the one or more subsequent dose is 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 11 mg/kg, 12 mg/kg, 13 mg/kg, 14 mg/kg, 15 mg/kg, 16 mg/kg, 17 mg/kg, 18 mg/kg, 19 mg/kg, 20 mg/kg, 21 mg/kg, 22 mg/kg,
  • the one or more subsequent dose is about 60 mg to about 7200 mg. In some embodiments, the one or more subsequent dose is about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about
  • the one or more subsequent dose is 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg,
  • the polypeptide, the antibody, or the antigen-binding fragment thereof is administered at a first dose of about 1 mg/kg to about 60 mg/kg and one or more subsequent dose of about 1 mg/kg to about 60 mg/kg.
  • the polypeptide, the antibody, or the antigen-binding fragment thereof is administered at a first dose of about 60 mg to about 7200 mg and one or more subsequent dose of about 1 mg/kg to about 60 mg/kg.
  • the polypeptide, the antibody, or the antigen-binding fragment thereof is administered at a first dose of about 1 mg/kg to about 60 mg/kg and one or more subsequent dose of about 60 mg to about 7200 mg.
  • the polypeptide, the antibody, or the antigen-binding fragment thereof is administered at a first dose of about 60 mg to about 7200 mg and one or more subsequent dose of about 60 mg to about 7200 mg.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of any one of MAB1- MAB61 is administered at a first dose of about 1 mg/kg to about 60 mg/kg; and a one or more subsequent dose of about 1 mg/kg to about 60 mg/kg.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of any one of MAB1-MAB61 is administered at a first dose of about 1 mg/kg to about 60 mg/kg; and a one or more subsequent dose of about 60 mg to about 7200 mg.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of any one of MAB1-MAB61 is administered at a first dose of about 60 mg to about 7200 mg; and a one or more subsequent dose of about 60 mg to about 7200 mg.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, comprising VL of any one of MAB1-MAB61 is administered at a first dose of about 1 mg/kg to about 60 mg/kg; and a one or more subsequent dose of about 1 mg/kg to about 60 mg/kg.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, comprising VL of any one of MAB1-MAB61 is administered at a first dose of about 1 mg/kg to about 60 mg/kg; and a one or more subsequent dose of about 60 mg to about 7200 mg.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, comprising VL of any one of MAB 1-MAB61 is administered at a first dose of about 60 mg to about 7200 mg; and a one or more subsequent dose of about 60 mg to about 7200 mg.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, comprising VH of any one of MAB1-MAB61 is administered at a first dose of about 1 mg/kg to about 60 mg/kg; and a one or more subsequent dose of about 1 mg/kg to about 60 mg/kg.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, comprising VH of any one of MAB1-MAB61 is administered at a first dose of about 1 mg/kg to about 60 mg/kg; and a one or more subsequent dose of about 60 mg to about 7200 mg.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, comprising VH of any one of MAB 1-MAB61 is administered at a first dose of about 60 mg to about 7200 mg; and a one or more subsequent dose of about 60 mg to about 7200 mg.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, comprising VL and VH of any one of MAB1-MAB61 is administered at a first dose of about 1 mg/kg to about 60 mg/kg; and a one or more subsequent dose of about 1 mg/kg to about 60 mg/kg.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, comprising VL and VH of any one of MAB1-MAB61 is administered at a first dose of about 1 mg/kg to about 60 mg/kg; and a one or more subsequent dose of about 60 mg to about 7200 mg.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, comprising VL and VH of any one of MAB1-MAB61 is administered at a first dose of about 60 mg to about 7200 mg; and a one or more subsequent dose of about 60 mg to about 7200 mg.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof comprising HCDR1 having the amino acid sequence of any one of SEQ ID NOs: 61, 82, 103, 124, 126, 128, 130, 144, 156, or 424; HCDR2 having the amino acid sequence of any one of SEQ ID NOs: 62, 83, 104, 125, 125, 127, 129, 131, 145, 157, or 425; HCDR3 having the amino acid sequence of any one of SEQ ID NOs: 63, 67, 69, 70, 72, 73, 74, 76, 78, 80, 84, 88, 90, 91, 93, 96, 98, 100, 105, 109, 111, 114, 116, 117, 120, 122, 132, 135, 136, 137, 138, 139, 140, 141, 142, 143, 146, 149
  • a polypeptide, an antibody, or an antigen-binding fragment thereof comprising HCDR1 having the amino acid sequence of any one of SEQ ID NOs: 61, 82, 103, 124, 126, 128, 130, 144, 156, or 424; HCDR2 having the amino acid sequence of any one of SEQ ID NOs: 62, 83, 104, 125, 125, 127, 129, 131, 145, 157, or 425; HCDR3 having the amino acid sequence of any one of SEQ ID NOs: 63, 67, 69, 70, 72, 73, 74, 76, 78, 80, 84, 88, 90, 91, 93, 96, 98, 100, 105, 109, 111, 114, 116, 117, 120, 122, 132, 135, 136, 137, 138, 139, 140, 141, 142, 143, 146, 149, 150,
  • a polypeptide, an antibody, or an antigen-binding fragment thereof comprising HCDR1 having the amino acid sequence of any one of SEQ ID NOs: 61, 82, 103, 124, 126, 128, 130, 144, 156, or 424; HCDR2 having the amino acid sequence of any one of SEQ ID NOs: 62, 83, 104, 125, 125, 127, 129, 131, 145, 157, or 425; HCDR3 having the amino acid sequence of any one of SEQ ID NOs: 63, 67, 69, 70, 72, 73, 74, 76, 78, 80, 84, 88, 90, 91, 93, 96, 98, 100, 105, 109, 111, 114, 116, 117, 120, 122, 132, 135, 136, 137, 138, 139, 140, 141, 142, 143, 146, 149, 150,
  • a polypeptide, an antibody, or an antigen-binding fragment thereof comprising HCDR1 having the amino acid sequence of SEQ ID NO: 61; HCDR2 having the amino acid sequence of SEQ ID NO: 62; HCDR3 having the amino acid sequence of SEQ ID NO: 78; LCDR1 having the amino acid sequence of SEQ ID NO: 64; LCDR2 having the amino acid sequence of SEQ ID NO: 65; and LCDR3 having the amino acid sequence of SEQ ID NO: 79 is administered at a first dose of about 1 mg/kg to about 60 mg/kg; and a one or more subsequent dose of about 1 mg/kg to about 60 mg/kg.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof comprising HCDR1 having the amino acid sequence of SEQ ID NO: 61; HCDR2 having the amino acid sequence of SEQ ID NO: 62; HCDR3 having the amino acid sequence of SEQ ID NO: 78; LCDR1 having the amino acid sequence of SEQ ID NO: 64; LCDR2 having the amino acid sequence of SEQ ID NO: 65; and LCDR3 having the amino acid sequence of SEQ ID NO: 79 is administered at a first dose of about 1 mg/kg to about 60 mg/kg; and a one or more subsequent dose of about 60 mg to about 7200 mg.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof comprising HCDR1 having the amino acid sequence of SEQ ID NO: 61; HCDR2 having the amino acid sequence of SEQ ID NO: 62; HCDR3 having the amino acid sequence of SEQ ID NO: 78; LCDR1 having the amino acid sequence of SEQ ID NO: 64; LCDR2 having the amino acid sequence of SEQ ID NO: 65; and LCDR3 having the amino acid sequence of SEQ ID NO: 79 is administered at a first dose of about 60 mg to about 7200 mg; and a one or more subsequent dose of about 60 mg to about 7200 mg.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof comprising HCDR1 having the amino acid sequence of SEQ ID NO: 424; HCDR2 having the amino acid sequence of SEQ ID NO: 425; HCDR3 having the amino acid sequence of SEQ ID NO: 426; LCDR1 having the amino acid sequence of SEQ ID NO: 427; LCDR2 having the amino acid sequence of SEQ ID NO: 428; and LCDR3 having the amino acid sequence of SEQ ID NO: 429 is administered at a first dose of about 1 mg/kg to about 60 mg/kg; and a one or more subsequent dose of about 1 mg/kg to about 60 mg/kg.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof comprising HCDR1 having the amino acid sequence of SEQ ID NO: 424; HCDR2 having the amino acid sequence of SEQ ID NO: 425; HCDR3 having the amino acid sequence of SEQ ID NO: 426; LCDR1 having the amino acid sequence of SEQ ID NO: 427; LCDR2 having the amino acid sequence of SEQ ID NO: 428; and LCDR3 having the amino acid sequence of SEQ ID NO: 429 is administered at a first dose of about 1 mg/kg to about 60 mg/kg; and a one or more subsequent dose of about 60 mg to about 7200 mg.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof comprising HCDR1 having the amino acid sequence of SEQ ID NO: 424; HCDR2 having the amino acid sequence of SEQ ID NO: 425; HCDR3 having the amino acid sequence of SEQ ID NO: 426; LCDR1 having the amino acid sequence of SEQ ID NO: 427; LCDR2 having the amino acid sequence of SEQ ID NO: 428; and LCDR3 having the amino acid sequence of SEQ ID NO: 429 is administered at a first dose of about 60 mg to about 7200 mg; and a one or more subsequent dose of about 60 mg to about 7200 mg.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof comprising VL having the amino acid sequence of any one of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, or 431; and VH having the amino acid sequence of any one of SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, or 430 is administered at a first dose of about 1 mg/kg to about
  • a polypeptide, an antibody, or an antigen-binding fragment thereof comprising VL having the amino acid sequence of any one of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, or 431; and VH having the amino acid sequence of any one of SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, or 430 is administered at a first dose of about 1 mg/kg to about 60 mg/kg
  • a polypeptide, an antibody, or an antigen-binding fragment thereof comprising VL having the amino acid sequence of any one of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, or 431; and VH having the amino acid sequence of any one of SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, or 430 is administered at a first dose of about 60 mg to about 7200 mg; and
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, comprising VL having the amino acid sequence of SEQ ID NO: 18; and VH having the amino acid sequence of SEQ ID NO: 17 is administered at a first dose of about 1 mg/kg to about 60 mg/kg; and a one or more subsequent dose of about 1 mg/kg to about 60 mg/kg.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, comprising VL having the amino acid sequence of SEQ ID NO: 18; and VH having the amino acid sequence of SEQ ID NO: 17 is administered at a first dose of about 1 mg/kg to about 60 mg/kg; and a one or more subsequent dose of about 60 mg to about 7200 mg.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, comprising VL having the amino acid sequence of SEQ ID NO: 18; and VH having the amino acid sequence of SEQ ID NO: 17 is administered at a first dose of about 60 mg to about 7200 mg; and a one or more subsequent dose of about 60 mg to about 7200 mg.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, comprising VL having the amino acid sequence of SEQ ID NO: 18; and VH having the amino acid sequence of SEQ ID NO: 342 is administered at a first dose of about 1 mg/kg to about 60 mg/kg; and a one or more subsequent dose of about 1 mg/kg to about 60 mg/kg.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, comprising VL having the amino acid sequence of SEQ ID NO: 18; and VH having the amino acid sequence of SEQ ID NO: 342 is administered at a first dose of about 1 mg/kg to about 60 mg/kg; and a one or more subsequent dose of about 60 mg to about 7200 mg.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, comprising VL having the amino acid sequence of SEQ ID NO: 18; and VH having the amino acid sequence of SEQ ID NO: 342 is administered at a first dose of about 60 mg to about 7200 mg; and a one or more subsequent dose of about 60 mg to about 7200 mg.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, comprising VL having the amino acid sequence of SEQ ID NO: 431; and VH having the amino acid sequence of SEQ ID NO: 430 is administered at a first dose of about 1 mg/kg to about 60 mg/kg; and a one or more subsequent dose of about 1 mg/kg to about 60 mg/kg.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, comprising VL having the amino acid sequence of SEQ ID NO: 431; and VH having the amino acid sequence of SEQ ID NO: 430 is administered at a first dose of about 1 mg/kg to about 60 mg/kg; and a one or more subsequent dose of about 60 mg to about 7200 mg.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, comprising VL having the amino acid sequence of SEQ ID NO: 431; and VH having the amino acid sequence of SEQ ID NO: 430 is administered at a first dose of about 60 mg to about 7200 mg; and a one or more subsequent dose of about 60 mg to about 7200 mg.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof comprising a light chain having the amino acid sequence of any one of SEQ ID NOs: 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, or 433; and a heavy chain having the amino acid sequence of any one of SEQ ID NOs: 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201,
  • 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, or 432 is administered at a first dose of about 60 mg to about 7200 mg; and a one or more subsequent dose of about 60 mg to about 7200 mg.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, comprising a light chain having the amino acid sequence of SEQ ID NO: 236; and a heavy chain having the amino acid sequence of any one of SEQ ID NOs: 184 is administered at a first dose of about 1 mg/kg to about 60 mg/kg; and a one or more subsequent dose of about 1 mg/kg to about 60 mg/kg.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, comprising a light chain having the amino acid sequence of SEQ ID NO: 236; and a heavy chain having the amino acid sequence of any one of SEQ ID NOs: 184 is administered at a first dose of about 1 mg/kg to about 60 mg/kg; and a one or more subsequent dose of about 60 mg to about 7200 mg.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, comprising a light chain having the amino acid sequence of SEQ ID NO: 236; and a heavy chain having the amino acid sequence of any one of SEQ ID NOs: 184 is administered at a first dose of about 60 mg to about 7200 mg; and a one or more subsequent dose of about 60 mg to about 7200 mg.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, comprising a light chain having the amino acid sequence of SEQ ID NO: 236; and a heavy chain having the amino acid sequence of any one of SEQ ID NOs: 380 is administered at a first dose of about 1 mg/kg to about 60 mg/kg; and a one or more subsequent dose of about 1 mg/kg to about 60 mg/kg.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, comprising a light chain having the amino acid sequence of SEQ ID NO: 236; and a heavy chain having the amino acid sequence of any one of SEQ ID NOs: 380 is administered at a first dose of about 1 mg/kg to about 60 mg/kg; and a one or more subsequent dose of about 60 mg to about 7200 mg.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, comprising a light chain having the amino acid sequence of SEQ ID NO: 236; and a heavy chain having the amino acid sequence of any one of SEQ ID NOs: 380 is administered at a first dose of about 60 mg to about 7200 mg; and a one or more subsequent dose of about 60 mg to about 7200 mg.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, comprising a light chain having the amino acid sequence of SEQ ID NO: 236; and a heavy chain having the amino acid sequence of any one of SEQ ID NOs: 381 is administered at a first dose of about 1 mg/kg to about 60 mg/kg; and a one or more subsequent dose of about 1 mg/kg to about 60 mg/kg.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, comprising a light chain having the amino acid sequence of SEQ ID NO: 236; and a heavy chain having the amino acid sequence of any one of SEQ ID NOs: 381 is administered at a first dose of about 1 mg/kg to about 60 mg/kg; and a one or more subsequent dose of about 60 mg to about 7200 mg.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, comprising a light chain having the amino acid sequence of SEQ ID NO: 236; and a heavy chain having the amino acid sequence of any one of SEQ ID NOs: 381 is administered at a first dose of about 60 mg to about 7200 mg; and a one or more subsequent dose of about 60 mg to about 7200 mg.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, comprising a light chain having the amino acid sequence of SEQ ID NO: 433; and a heavy chain having the amino acid sequence of any one of SEQ ID NOs: 432 is administered at a first dose of about 1 mg/kg to about 60 mg/kg; and a one or more subsequent dose of about 1 mg/kg to about 60 mg/kg.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, comprising a light chain having the amino acid sequence of SEQ ID NO: 433; and a heavy chain having the amino acid sequence of any one of SEQ ID NOs: 432 is administered at a first dose of about 1 mg/kg to about 60 mg/kg; and a one or more subsequent dose of about 60 mg to about 7200 mg.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, comprising a light chain having the amino acid sequence of SEQ ID NO: 433; and a heavy chain having the amino acid sequence of any one of SEQ ID NOs: 432 is administered at a first dose of about 60 mg to about 7200 mg; and a one or more subsequent dose of about 60 mg to about 7200 mg.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, comprising a light chain having the amino acid sequence of SEQ ID NO: 236; and a heavy chain having the amino acid sequence of any one of SEQ ID NOs: 185 is administered at a first dose of about 1 mg/kg to about 60 mg/kg; and a one or more subsequent dose of about 1 mg/kg to about 60 mg/kg.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, comprising a light chain having the amino acid sequence of SEQ ID NO: 236; and a heavy chain having the amino acid sequence of any one of SEQ ID NOs: 185 is administered at a first dose of about 1 mg/kg to about 60 mg/kg; and a one or more subsequent dose of about 60 mg to about 7200 mg.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof comprising a light chain having the amino acid sequence of SEQ ID NO: 236; and a heavy chain having the amino acid sequence of any one of SEQ ID NOs: 185 is administered at a first dose of about 60 mg to about 7200 mg; and a one or more subsequent dose of about 60 mg to about 7200 mg.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, such as those provided for herein is administered in a dose of about 3 g to about 5 g.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, such as those provided for herein is administered in a dose of about 3.0 g, about 3.1 g, about 3.2 g, about 3.3 g, about 3.4 g, about 3.5 g, about 3.6 g, about 3.7 g, about 3.8 g, about 3.9 g, about 4.0 g, about 4.1 g, about 4.2 g, about 4.3 g, about 4.4 g, about 4.5 g, about 4.6 g, about 4.7 g, about 4.8 g, about 4.9 g, or about 5.0 g.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, such as those provided for herein is administered in a dose of 3.0 g, 3.1 g, 3.2 g, 3.3 g, 3.4 g, 3.5 g, 3.6 g, 3.7 g, 3.8 g, 3.9 g, 4.0 g, 4.1 g, 4.2 g, 4.3 g, 4.4 g, 4.5 g, 4.6 g, 4.7 g, 4.8 g, 4.9 g, or 5.0 g.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, such as those provided for herein is administered in a first dose of about 3 g to about 5 g.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, such as those provided for herein is administered in a first dose of about 3.0 g, about 3.1 g, about 3.2 g, about 3.3 g, about 3.4 g, about 3.5 g, about 3.6 g, about 3.7 g, about 3.8 g, about 3.9 g, about 4.0 g, about
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, such as those provided for herein, is administered in a first dose of 3.0 g, 3.1 g,
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, such as those provided for herein is administered in a one or more subsequent dose of about 3 g to about 5 g.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, such as those provided for herein is administered in a one or more subsequent dose of about 3.0 g, about 3.1 g, about 3.2 g, about 3.3 g, about 3.4 g, about 3.5 g, about 3.6 g, about 3.7 g, about 3.8 g, about 3.9 g, about 4.0 g, about 4.1 g, about 4.2 g, about 4.3 g, about 4.4 g, about 4.5 g, about 4.6 g, about 4.7 g, about 4.8 g, about 4.9 g, or about 5.0 g.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, such as those provided for herein is administered in a one or more subsequent dose of 3.0 g, 3.1 g, 3.2 g, 3.3 g, 3.4 g, 3.5 g, 3.6 g, 3.7 g, 3.8 g, 3.9 g, 4.0 g, 4.1 g, 4.2 g, 4.3 g, 4.4 g, 4.5 g, 4.6 g, 4.7 g, 4.8 g, 4.9 g, or 5.0 g.
  • MAB1-MAB61 is administered in a dose of about 3 g to about 5 g. In some embodiments, MAB1-MAB61 is administered in a dose of about 3.0 g, about 3.1 g, about 3.2 g, about 3.3 g, about 3.4 g, about 3.5 g, about 3.6 g, about 3.7 g, about 3.8 g, about 3.9 g, about 4.0 g, about 4.1 g, about 4.2 g, about 4.3 g, about 4.4 g, about 4.5 g, about 4.6 g, about 4.7 g, about 4.8 g, about 4.9 g, or about 5.0 g.
  • MAB1-MAB61 is administered in a dose of 3.0 g, 3.1 g, 3.2 g, 3.3 g, 3.4 g, 3.5 g, 3.6 g, 3.7 g, 3.8 g, 3.9 g, 4.0 g, 4.1 g, 4.2 g, 4.3 g, 4.4 g, 4.5 g, 4.6 g, 4.7 g, 4.8 g, 4.9 g, or 5.0 g.
  • MAB9 is administered in a dose of about 3 g to about 5 g.
  • MAB9 is administered in a dose of about 3.0 g, about 3.1 g, about 3.2 g, about 3.3 g, about 3.4 g, about 3.5 g, about 3.6 g, about 3.7 g, about 3.8 g, about 3.9 g, about 4.0 g, about 4.1 g, about 4.2 g, about 4.3 g, about 4.4 g, about 4.5 g, about 4.6 g, about 4.7 g, about 4.8 g, about 4.9 g, or about 5.0 g.
  • MAB9 is administered in a dose of 3.0 g, 3.1 g, 3.2 g, 3.3 g, 3.4 g, 3.5 g, 3.6 g, 3.7 g, 3.8 g, 3.9 g, 4.0 g, 4.1 g, 4.2 g, 4.3 g, 4.4 g, 4.5 g, 4.6 g, 4.7 g, 4.8 g, 4.9 g, or 5.0 g.
  • MAB39 is administered in a dose of about 3 g to about 5 g.
  • MAB39 is administered in a dose of about 3.0 g, about 3.1 g, about 3.2 g, about 3.3 g, about 3.4 g, about 3.5 g, about 3.6 g, about 3.7 g, about 3.8 g, about 3.9 g, about 4.0 g, about 4.1 g, about 4.2 g, about 4.3 g, about 4.4 g, about 4.5 g, about 4.6 g, about 4.7 g, about 4.8 g, about 4.9 g, or about 5.0 g.
  • MAB39 is administered in a dose of 3.0 g, 3.1 g, 3.2 g, 3.3 g, 3.4 g, 3.5 g, 3.6 g, 3.7 g, 3.8 g, 3.9 g, 4.0 g, 4.1 g, 4.2 g, 4.3 g, 4.4 g, 4.5 g, 4.6 g, 4.7 g, 4.8 g, 4.9 g, or 5.0 g.
  • MAB1-MAB61 is administered in a first dose of about 3 g to about 5 g. In some embodiments, MAB1-MAB61 is administered in a first dose of about 3.0 g, about 3.1 g, about 3.2 g, about 3.3 g, about 3.4 g, about 3.5 g, about 3.6 g, about 3.7 g, about 3.8 g, about 3.9 g, about 4.0 g, about 4.1 g, about 4.2 g, about 4.3 g, about 4.4 g, about 4.5 g, about 4.6 g, about 4.7 g, about 4.8 g, about 4.9 g, or about 5.0 g.
  • MAB1-MAB61 is administered in a first dose of 3.0 g, 3.1 g, 3.2 g, 3.3 g, 3.4 g, 3.5 g, 3.6 g, 3.7 g, 3.8 g, 3.9 g, 4.0 g, 4.1 g, 4.2 g,
  • MAB9 is administered in a first dose of about 3 g to about 5 g.
  • MAB9 is administered in a first dose of about 3.0 g, about 3.1 g, about 3.2 g, about 3.3 g, about 3.4 g, about 3.5 g, about 3.6 g, about 3.7 g, about 3.8 g, about 3.9 g, about 4.0 g, about 4.1 g, about 4.2 g, about 4.3 g, about 4.4 g, about 4.5 g, about 4.6 g, about 4.7 g, about 4.8 g, about 4.9 g, or about 5.0 g.
  • MAB9 is administered in a first dose of 3.0 g, 3.1 g, 3.2 g, 3.3 g, 3.4 g, 3.5 g, 3.6 g, 3.7 g, 3.8 g, 3.9 g, 4.0 g, 4.1 g, 4.2 g, 4.3 g, 4.4 g, 4.5 g, 4.6 g, 4.7 g, 4.8 g, 4.9 g, or 5.0 g.
  • MAB39 is administered in a first dose of about 3 g to about 5 g. In some embodiments, MAB39 is administered in a first dose of about 3.0 g, about 3.1 g, about 3.2 g, about
  • MAB39 is administered in a first dose of 3.0 g, 3.1 g,
  • MAB1-MAB61 is administered in a one or more subsequent dose of about 3 g to about 5 g. In some embodiments, MAB1-MAB61 is administered in a one or more subsequent dose of about 3.0 g, about 3.1 g, about 3.2 g, about 3.3 g, about 3.4 g, about 3.5 g, about
  • MAB1-MAB61 is administered in a one or more subsequent dose of 3.0 g, 3.1 g,
  • MAB9 is administered in a one or more subsequent dose of about 3 g to about 5 g. In some embodiments, MAB9 is administered in a one or more subsequent dose of about 3.0 g, about 3.1 g, about 3.2 g, about 3.3 g, about 3.4 g, about 3.5 g, about
  • MAB9 is administered in a one or more subsequent dose of 3.0 g, 3.1 g, 3.2 g, 3.3 g, 3.4 g, 3.5 g, 3.6 g, 3.7 g, 3.8 g, 3.9 g, 4.0 g, 4.1 g, 4.2 g, 4.3 g, 4.4 g, 4.5 g, 4.6 g, 4.7 g, 4.8 g,
  • MAB39 is administered in a one or more subsequent dose of about 3 g to about 5 g. In some embodiments, MAB39 is administered in a one or more subsequent dose of about 3.0 g, about 3.1 g, about 3.2 g, about 3.3 g, about 3.4 g, about 3.5 g, about
  • MAB39 is administered in a one or more subsequent dose of 3.0 g, 3.1 g, 3.2 g, 3.3 g, 3.4 g, 3.5 g, 3.6 g, 3.7 g, 3.8 g, 3.9 g, 4.0 g, 4.1 g, 4.2 g, 4.3 g, 4.4 g, 4.5 g, 4.6 g, 4.7 g, 4.8 g,
  • the administration is an intravenous, a subcutaneous, an intramuscular, an intraarterial, an intra-articular, an intratumoral, and/or an inhalation administration.
  • the administration is an intravenous administration.
  • the administration is a subcutaneous administration.
  • the administration is an intramuscular administration.
  • the administration is an intraarterial administration.
  • the administration is an intra-articular administration.
  • the administration is an intratumoral administration.
  • the administration is an inhalation administration.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, such as those provided herein is administered every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or more weeks.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, such as those provided herein is administered every week.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, such as those provided herein is administered every 2 weeks.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, such as those provided herein is administered every 3 weeks.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, such as those provided herein is administered every 4 weeks. In some embodiments, a polypeptide, an antibody, or an antigen-binding fragment thereof, such as those provided herein, is administered every 5 weeks. In some embodiments, a polypeptide, an antibody, or an antigen-binding fragment thereof, such as those provided herein, is administered every 6 weeks. In some embodiments, a polypeptide, an antibody, or an antigen-binding fragment thereof, such as those provided herein, is administered every 7 weeks. In some embodiments, a polypeptide, an antibody, or an antigenbinding fragment thereof, such as those provided herein, is administered every 8 weeks.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, such as those provided herein is administered every 9 weeks. In some embodiments, a polypeptide, an antibody, or an antigen-binding fragment thereof, such as those provided herein, is administered every 10 weeks. In some embodiments, a polypeptide, an antibody, or an antigen-binding fragment thereof, such as those provided herein, is administered every 11 weeks. In some embodiments, a polypeptide, an antibody, or an antigen-binding fragment thereof, such as those provided herein, is administered every 12 weeks. In some embodiments, a polypeptide, an antibody, or an antigenbinding fragment thereof, such as those provided herein, is administered every 13 weeks.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, such as those provided herein is administered every 14 weeks. In some embodiments, a polypeptide, an antibody, or an antigen-binding fragment thereof, such as those provided herein, is administered every 14 weeks. In some embodiments, a polypeptide, an antibody, or an antigen-binding fragment thereof, such as those provided herein, is administered every 16 weeks.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, such as those provided herein is administered in a first dose, and one or more subsequent dose.
  • the one or more subsequent dose is administered about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35,
  • the one or more subsequent dose is administered at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,
  • the one or more subsequent dose is administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,
  • the one or more subsequent dose is administered at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37,
  • the one or more subsequent dose is administered about every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, or more weeks after the first dose.
  • the one or more subsequent dose is administered at least every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, or more weeks after the first dose.
  • the one or more subsequent dose is administered every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, or more weeks after the first dose.
  • the one or more subsequent dose is administered about 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, or 50 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at least 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, or 50 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, or 50 weeks after the first dose.
  • the one or more subsequent dose is administered at 1 week after the first dose. In some embodiments, the one or more subsequent dose is administered at 2 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 3 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 4 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 5 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 6 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 7 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 8 weeks after the first dose.
  • the one or more subsequent dose is administered at 9 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 10 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 11 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 12 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 13 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 14 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 15 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 16 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 17 weeks after the first dose.
  • the one or more subsequent dose is administered at 18 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 19 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 20 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 21 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 22 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 23 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 24 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 25 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 26 weeks after the first dose.
  • the one or more subsequent dose is administered at 27 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 28 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 29 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 30 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 31 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 32 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 33 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 34 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 35 weeks after the first dose.
  • the one or more subsequent dose is administered at 36 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 37 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 38 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 39 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 40 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 41 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 42 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 43 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 44 weeks after the first dose.
  • the one or more subsequent dose is administered at 45 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 46 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 47 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 48 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 49 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 50 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 51 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 52 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 53 weeks after the first dose.
  • the one or more subsequent dose is administered at 54 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 55 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 56 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 57 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 58 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 59 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 60 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 61 weeks after the first dose.
  • the one or more subsequent dose is administered at 62 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 63 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 64 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 65 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 66 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 67 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 68 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 69 weeks after the first dose.
  • the one or more subsequent dose is administered at 70 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 71 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 72 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 73 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 74 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 75 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 76 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 77 weeks after the first dose.
  • the one or more subsequent dose is administered at 78 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 79 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 80 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 81 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 82 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 83 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 84 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 85 weeks after the first dose.
  • the one or more subsequent dose is administered at 86 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 87 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 88 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 89 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 90 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 91 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 92 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 93 weeks after the first dose.
  • the one or more subsequent dose is administered at 94 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 95 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 96 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 97 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 98 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 99 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 100 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 101 weeks after the first dose.
  • the one or more subsequent dose is administered at 102 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 103 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 104 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 105 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 106 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 107 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 108 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 109 weeks after the first dose.
  • the one or more subsequent dose is administered at 110 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 111 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 112 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 113 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 114 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 115 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 116 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 117 weeks after the first dose.
  • the one or more subsequent dose is administered at 118 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 119 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 120 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 121 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 122 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 123 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 124 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 125 weeks after the first dose.
  • the one or more subsequent dose is administered at 126 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 127 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 128 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 129 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 130 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 131 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 132 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 133 weeks after the first dose.
  • the one or more subsequent dose is administered at 134 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 135 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 136 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 137 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 138 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 139 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 140 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 141 weeks after the first dose.
  • the one or more subsequent dose is administered at 142 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 143 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 144 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 145 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 146 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 147 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 148 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 149 weeks after the first dose.
  • the one or more subsequent dose is administered at 150 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 151 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 152 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 153 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 154 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 155 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 156 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 157 weeks after the first dose.
  • the one or more subsequent dose is administered at 158 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 159 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 160 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 161 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 162 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 163 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 164 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 165 weeks after the first dose.
  • the one or more subsequent dose is administered at 166 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 167 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 168 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered at 169 weeks after the first dose. [0167] In some embodiments, the one or more subsequent dose is administered every 1 week after the first dose. In some embodiments, the one or more subsequent dose is administered every 2 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered every 3 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered every 4 weeks after the first dose.
  • the one or more subsequent dose is administered every 5 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered every 6 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered every 7 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered every 8 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered every 9 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered every 10 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered every 11 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered every 12 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered every 13 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered every 14 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered every 15 weeks after the first dose. In some embodiments, the one or more subsequent dose is administered every 16 weeks after the first dose.
  • the one or more subsequent dose is administered about 1, 2, 3, or 4 weeks after the previous dose. In some embodiments, the one or more subsequent dose is administered at least 1, 2, 3, or 4 weeks after the previous dose. In some embodiments, the one or more subsequent dose is administered 1, 2, 3, or 4 weeks after the previous dose. In some embodiments, the one or more subsequent dose is administered 1 week after the previous dose. In some embodiments, the one or more subsequent dose is administered 2 weeks after the previous dose. In some embodiments, the one or more subsequent dose is administered 3 weeks after the previous dose. In some embodiments, the one or more subsequent dose is administered 4 weeks after the previous dose.
  • the one or more subsequent dose is administered about every 1, 2, 3, or 4 weeks after the first dose for about 1-156 weeks. In some embodiments, the one or more subsequent dose is administered about every 1 week after the first dose for about 1-156 weeks. In some embodiments, the one or more subsequent dose is administered about every 2 weeks after the first dose for about 1-156 weeks. In some embodiments, the one or more subsequent dose is administered about every 3 weeks after the first dose for about 1-156 weeks. In some embodiments, the one or more subsequent dose is administered about every 4 weeks after the first dose for about 1-156 weeks.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof is administered in a total of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 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, or 84 doses.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, such as those provided for herein is administered in a total of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, such as those provided for herein, is administered in a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 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, or 84 doses, wherein each does is administered
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of any one of MAB1- MAB61 is administered at a first dose of about 1 mg/kg to about 60 mg/kg; and a one or more subsequent dose of about 1 mg/kg to about 60 mg/kg, and wherein the one or more subsequent dose is administered every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or more weeks.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of any one of MAB1- MAB61 is administered at a first dose of about 1 mg/kg to about 60 mg/kg; and a one or more subsequent dose of about 60 mg to about 7200 mg, and wherein the one or more subsequent dose is administered every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or more weeks.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of any one of MAB1-MAB61 is administered at a first dose of about 60 mg to about 7200 mg; and a one or more subsequent dose of about 60 mg to about 7200 mg, and wherein the one or more subsequent dose is administered every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or more weeks.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, comprising VL of any one of MAB1-MAB61 is administered at a first dose of about 1 mg/kg to about 60 mg/kg; and a one or more subsequent dose of about 1 mg/kg to about 60 mg/kg, and wherein the one or more subsequent dose is administered every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or more weeks.
  • a polypeptide, an antibody, or an antigenbinding fragment thereof, comprising VL of any one of MAB1-MAB61 is administered at a first dose of about 1 mg/kg to about 60 mg/kg; and a one or more subsequent dose of about 60 mg to about 7200 mg, and wherein the one or more subsequent dose is administered every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or more weeks.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, comprising VL of any one of MAB1-MAB61 is administered at a first dose of about 60 mg to about 7200 mg; and a one or more subsequent dose of about 60 mg to about 7200 mg, and wherein the one or more subsequent dose is administered every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or more weeks.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, comprising VH of any one of MAB1-MAB61 is administered at a first dose of about 1 mg/kg to about 60 mg/kg; and a one or more subsequent dose of about 1 mg/kg to about 60 mg/kg, and wherein the one or more subsequent dose is administered every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or more weeks.
  • a polypeptide, an antibody, or an antigenbinding fragment thereof, comprising VH of any one of MAB1-MAB61 is administered at a first dose of about 1 mg/kg to about 60 mg/kg; and a one or more subsequent dose of about 60 mg to about 7200 mg, and wherein the one or more subsequent dose is administered every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or more weeks.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, comprising VH of any one of MAB1-MAB61 is administered at a first dose of about 60 mg to about 7200 mg; and a one or more subsequent dose of about 60 mg to about 7200 mg, and wherein the one or more subsequent dose is administered every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or more weeks.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, comprising VL and VH of any one of MAB1-MAB61 is administered at a first dose of about 1 mg/kg to about 60 mg/kg; and a one or more subsequent dose of about 1 mg/kg to about 60 mg/kg, and wherein the one or more subsequent dose is administered every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or more weeks.
  • a polypeptide, an antibody, or an antigenbinding fragment thereof, comprising VL and VH of any one of MAB1-MAB61 is administered at a first dose of about 1 mg/kg to about 60 mg/kg; and a one or more subsequent dose of about 60 mg to about 7200 mg, and wherein the one or more subsequent dose is administered every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or more weeks.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, comprising VL and VH of any one of MAB1- MAB61 is administered at a first dose of about 60 mg to about 7200 mg; and a one or more subsequent dose of about 60 mg to about 7200 mg, and wherein the one or more subsequent dose is administered every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or more weeks.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, such as those provided for herein is administered by intravenous infusion.
  • the intravenous infusion is administered over about 30 minutes to about 90 minutes, over about 45 minutes to about 90 minutes, or over about 60 minutes to about 90 minutes.
  • the intravenous infusion is administered over about 30 minutes to about 90 minutes.
  • the intravenous infusion is administered over about 45 minutes to about 90 minutes.
  • the intravenous infusion is administered over about 60 minutes to about 90 minutes.
  • a dosage form in a container is provided.
  • the dosage form comprises a pharmaceutical composition such as those provided herein.
  • the container is a plastic vial or a glass vial.
  • a polypeptide, an antibody, or an antigen-binding fragment thereof, such as those provided for herein is administered as part of a pharmaceutical composition comprising the polypeptide, the antibody, or the antigen-binding fragment thereof, such as those provided for herein, and at least one pharmaceutically acceptable excipient.
  • Polypeptides, antibodies, antigen-binding fragments thereof, and pharmaceutical compositions may be administered with medical devices known in the art.
  • a pharmaceutical composition of the invention can be administered by injection with a hypodermic needle, including, e.g., a prefilled syringe or autoinjector.
  • kits comprising a pharmaceutical composition, such as those provided herein.
  • a pharmaceutical composition such as those provided herein.
  • the antibody or antigen binding fragment thereof or other proteins provided herein are admixed with a pharmaceutically acceptable carrier or excipient. See, e.g., Remington's Pharmaceutical Sciences and U.S. Pharmacopeia: National Formulary, Mack Publishing Company, Easton, PA (1984).
  • Polypeptides, antibodies, antigen-binding fragments thereof, and pharmaceutical compositions may be prepared by mixing with acceptable carriers, excipients, or stabilizers in the form of, e.g., lyophilized powders, slurries, aqueous solutions or suspensions (see, e.g., Hardman, el al. (2001) Goodman and Gilman ’s The Pharmacological Basis of Therapeutics, McGraw-Hill, New York, NY; Gennaro (2000) Remington: The Science and Practice of Pharmacy, Lippincott, Williams, and Wilkins, New York, NY; Avis, et al.
  • the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition can be administered by an invasive route such as by injection.
  • the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered intravenously, subcutaneously, intramuscularly, intraarterially, intra-articularly (e.g. in arthritis joints), or by inhalation, aerosol delivery.
  • Administration by non-invasive routes e.g., orally; for example, in a pill, capsule or tablet) is also within the scope of the present embodiments.
  • the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition may also be administered with a needleless hypodermic injection device; such as the devices disclosed in U.S. Patent Nos. 6,620,135; 6,096,002; 5,399,163; 5,383,851; 5,312,335; 5,064,413; 4,941,880; 4,790,824 or 4,596,556.
  • a needleless hypodermic injection device such as the devices disclosed in U.S. Patent Nos. 6,620,135; 6,096,002; 5,399,163; 5,383,851; 5,312,335; 5,064,413; 4,941,880; 4,790,824 or 4,596,556.
  • the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition may also be administered by infusion.
  • implants and modules form administering pharmaceutical compositions include: U.S. Patent No. 4,487,603, which discloses an implantable micro-infusion pump for dispensing medication at a controlled rate; U.S. Patent No. 4,447,233, which discloses a medication infusion pump for delivering medication at a precise infusion rate; U.S. Patent No. 4,447,224, which discloses a variable flow implantable infusion apparatus for continuous drug delivery; U.S. Patent. No. 4,439,196, which discloses an osmotic drug delivery system having multi-chamber compartments. Many other such implants, delivery systems, and modules are well known to those skilled in the art.
  • the liposomes will be targeted to and taken up selectively by the afflicted tissue.
  • the administration regimen depends on several factors, including the serum or tissue turnover rate of the therapeutic antibody, the level of symptoms, the immunogenicity of the therapeutic antibody, and the accessibility of the target cells in the biological matrix.
  • the administration regimen delivers sufficient therapeutic antibody to effect improvement in the target disease state, while simultaneously minimizing undesired side effects.
  • the amount of biologic delivered depends in part on the particular therapeutic antibody and the severity of the condition being treated. Guidance in selecting appropriate doses of therapeutic antibodies is available (see, e.g., Wawrzynczak (1996) Antibody Therapy, Bios Scientific Pub.
  • Determination of the appropriate dose is made by the clinician, e.g., using parameters or factors known or suspected in the art to affect treatment. Generally, the dose begins with an amount somewhat less than the optimum dose and it is increased by small increments thereafter until the desired or optimum effect is achieved relative to any negative side effects.
  • Important diagnostic measures include those of symptoms of, e.g., the inflammation or level of inflammatory cytokines produced.
  • a biologic that will be used is derived from the same species as the animal targeted for treatment, thereby minimizing any immune response to the reagent.
  • chimeric, humanized and fully human antibodies may be desirable.
  • the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition provided herein can be provided by continuous infusion, or by doses administered, e.g., daily, 1-7 times per week, weekly, bi-weekly, monthly, bimonthly, quarterly, semiannually, annually etc. Doses may be provided, e.g., intravenously, subcutaneously, topically, orally, nasally, rectally, intramuscular, intracerebrally, intraspinally, or by inhalation. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered for at least 1-52 weeks or longer.
  • the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered for at least 1-104 weeks or longer. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered for at least 1-156 weeks or longer. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g. infusion or subcutaneous injection) once. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g. infusion or subcutaneous injection) twice. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g.
  • the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g. infusion or subcutaneous injection) three times.
  • the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g. infusion or subcutaneous injection) four times.
  • the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g infusion or subcutaneous injection) five times.
  • the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g infusion or subcutaneous injection) six times.
  • the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g. infusion or subcutaneous injection) seven times.
  • the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g. infusion or subcutaneous injection) eight times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g. infusion or subcutaneous injection) nine times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g. infusion or subcutaneous injection) 10 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g. infusion or subcutaneous injection) 11 times.
  • the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g. infusion or subcutaneous injection) 12 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g. infusion or subcutaneous injection) 13 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g. infusion or subcutaneous injection) 14 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g. infusion or subcutaneous injection) 15 times.
  • the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g. infusion or subcutaneous injection) 16 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g. infusion or subcutaneous injection) 17 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g. infusion or subcutaneous injection) 18 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g. infusion or subcutaneous injection) 19 times.
  • the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g. infusion or subcutaneous injection) 20 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g. infusion or subcutaneous injection) 21 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g. infusion or subcutaneous injection) 22 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g. infusion or subcutaneous injection) 23 times.
  • the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g. infusion or subcutaneous injection) 24 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g. infusion or subcutaneous injection) 25 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 26 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 27 times.
  • the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 28 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 29 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 30 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 31 times.
  • the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 32 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 33 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 34 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 35 times.
  • the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 36 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 37 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 38 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 39 times.
  • the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 40 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 41 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 42 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 43 times.
  • the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 44 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 45 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 46 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 47 times.
  • the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 48 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 49 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 50 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 51 times.
  • the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 52 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 53 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 54 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 55 times.
  • the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 56 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 57 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 58 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 59 times.
  • the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 60 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 61 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 62 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 63 times.
  • the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 64 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 65 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 66 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 67 times.
  • the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 68 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 69 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 70 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 71 times.
  • the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 72 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 73 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 74 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 75 times.
  • the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 76 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 77 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 78 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 79 times.
  • the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 80 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 81 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 82 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 83 times.
  • the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 84 times.
  • the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered more than once it can be administered according to a schedule, such as the schedules provided for herein.
  • inhibitor or “treat” or “treatment” includes a postponement of development of the symptoms associated with a disorder and/or a reduction in the severity of the symptoms of such disorder.
  • the terms further include ameliorating existing uncontrolled or unwanted symptoms, preventing additional symptoms, and ameliorating or preventing the underlying causes of such symptoms.
  • the terms denote that a beneficial result has been conferred on a vertebrate subject with a disorder, disease or symptom, or with the potential to develop such a disorder, disease or symptom.
  • therapeutically effective amount refers to an amount of the antibody, or antigen binding fragment thereof, that, when administered alone or in combination with an additional therapeutic agent to a cell, tissue, or subject, is effective to cause a measurable improvement in one or more symptoms of a disease or condition or the progression of such disease or condition.
  • a therapeutically effective dose further refers to that amount of the binding compound sufficient to result in at least partial amelioration of symptoms, e.g., treatment, healing, prevention or amelioration of the relevant medical condition, or an increase in rate of treatment, healing, prevention or amelioration of such conditions.
  • a therapeutically effective dose refers to that ingredient alone.
  • a therapeutically effective dose refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously.
  • An effective amount of a therapeutic will result in an improvement of a diagnostic measure or parameter by at least 10%; usually by at least 20%; preferably at least about 30%; more preferably at least 40%, and most preferably by at least 50%.
  • An effective amount can also result in an improvement in a subjective measure in cases where subjective measures are used to assess disease severity.
  • an amount is a therapeutically effective amount if it is an amount that can be used to treat or ameliorate a condition as provided for herein.
  • Effective amount or “therapeutically effective amount” are used interchangeably herein, and refer to an amount of a compound, formulation, material, or composition, as described herein effective to achieve a particular biological result or provides a therapeutic or prophylactic benefit. Such results may include, but are not limited to an amount that when administered to a mammal, causes a detectable level of immune cell activation compared to the immune cell activation detected in the absence of the composition. The immune response can be readily assessed by a plethora of art-recognized methods.
  • the amount of the composition administered herein varies and can be readily determined based on a number of factors such as the disease or condition being treated, the age and health and physical condition of the mammal being treated, the severity of the disease, the particular compound being administered, and the like.
  • the term “individual” or “subject” or “patient” used interchangeably, means any organism, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, such as humans.
  • the subject is a human.
  • a subject can also be referred to as a patient.
  • the subject is a subject in need thereof.
  • a subject that is “in need thereof’ refers to a subject that has been identified as requiring treatment for the condition that is to be treated and is treated with the specific intent of treating such condition.
  • the conditions can be, for example, any of the conditions described herein.
  • methods of treating a subject with a Cis mediated disorder comprise administering a pharmaceutical composition comprising an antibody, or antigen binding fragment thereof, as provided herein.
  • the disorder is a Cis mediated disorder.
  • the antibodies, or antigen binding fragments thereof can be administered with other therapeutics. These can be administered simultaneously or sequentially.
  • the subject is a subject who has previously been treated with a different antibody than those provided herein.
  • the method provided herein comprise administering to a subject an antibody, or an antigen binding fragment thereof, that specifically binds to and inhibits Cis.
  • the antibody is as provided herein.
  • Kits are also provided which are useful for carrying out embodiments described herein.
  • the present kits comprise a first container containing or packaged in association with the abovedescribed antibodies.
  • the kit may also comprise another container containing or packaged in association solutions necessary or convenient for carrying out the embodiments.
  • the containers can be made of glass, plastic or foil and can be a vial, bottle, pouch, tube, bag, etc.
  • the kit may also contain written information, such as procedures for carrying out the embodiments or analytical information, such as the amount of reagent contained in the first container means.
  • the container may be in another container apparatus, e.g. a box or a bag, along with the written information.
  • antibodies that bind to a Cis protein are provided.
  • the antibody is isolated.
  • the antibody binds specifically.
  • the antibody binds to a Cis protein that is properly folded.
  • the antibody is specific for a specific Cis conformational state (open or closed).
  • the antibody binds to a Cis protein in a cell membrane.
  • the antibody binds to a Cis protein that is in a cell membrane in an intact cell.
  • the antibody inhibits or neutralizes the function of a Cis protein.
  • the term “neutralize” means that the activity or function of the protein is inhibited.
  • the inhibition can be complete or partial. In some embodiments, the activity or function of the protein is inhibited at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or 99%. The percent inhibition can be based upon the function or activity of the protein in the absence of the antibody. In some embodiments, the antibody inhibits the glucose transport facilitated by Cis. In some embodiments, the antibody inhibits the internalization of the Cis protein.
  • the antibody comprises a sequence as provided for herein or antigen binding fragment thereof.
  • the antibody comprises a heavy chain CDR or an antigen binding fragment thereof described herein.
  • the heavy chain may be one or more of the heavy chains described herein.
  • the antibody comprises a light chain, or an antigen binding fragment thereof as described herein.
  • methods of treating, inhibiting or ameliorating a Cls-associated pathology comprise administering a pharmaceutical composition described herein to a subject to treat, inhibit or ameliorate a Cls- associated pathology.
  • the pathology is as described herein.
  • the methods comprise administering a polypeptide, an antibody, an antigen-binding fragment thereof, or a pharmaceutical composition described herein to a susceptible subject or to one exhibiting a condition in which Cis is known to have caused the pathology observed.
  • Any active form of the antibody can be administered, including, but not limited to scFv, Fab and F(ab')2 fragments and other forms of antibodies provided for herein.
  • the present disclosure provides a method to treat an individual having a complement- mediated disease or disorder, the method comprising administering to the individual an anti-Cls antibody of any of the embodiments disclosed herein or a pharmaceutical composition thereof.
  • the individual is a mammal.
  • the individual is a human.
  • the administering is intravenous.
  • the administering is subcutaneous.
  • the administering results in an outcome selected from the group consisting of: (a) a reduction in complement activation; (b) an improvement in cognitive function; (c) a reduction in neuron loss; (d) a reduction in phospho-Tau levels in neurons; (e) a reduction in glial cell activation; (f) a reduction in lymphocyte infiltration; (g) a reduction in macrophage infiltration; (h) a reduction in antibody deposition, (i) a reduction in glial cell loss; (j) a reduction in oligodendrocyte loss; (k) a reduction in dendritic cell infiltration; (1) a reduction in neutrophil infiltration; (m) a reduction in red blood cell lysis; (n) a reduction in red blood cell phagocytosis; (o) a reduction in platelet phagocytosis; (p) a reduction in platelet lysis; (q) an improvement in transplant graft survival; (r) a reduction in macrophage mediated phag
  • a method of treating a subject with a Cis mediated disorder comprises administering to the subject a polypeptide, an antibody, an antigen-binding fragment thereof, or a pharmaceutical composition as provided for herein, thereby treating the Cis mediated disorder.
  • the antibody or antigen-binding fragment thereof of any of the embodiments provided for herein or the pharmaceutical compositions of any of the embodiments provided for herein inhibit complement Cis activity in an individual having a complement-mediated disease or disorder.
  • the individual is a mammal.
  • the individual is a human.
  • the administering is intravenous.
  • the administering is subcutaneous.
  • the administering is intrathecal.
  • the administering results in an outcome selected from the group consisting of: (a) a reduction in complement activation; (b) an improvement in cognitive function; (c) a reduction in neuron loss; (d) a reduction in phospho-Tau levels in neurons; (e) a reduction in glial cell activation; (f) a reduction in lymphocyte infiltration; (g) a reduction in macrophage infiltration; (h) a reduction in antibody deposition, (i) a reduction in glial cell loss; (j) a reduction in oligodendrocyte loss; (k) a reduction in dendritic cell infiltration; (1) a reduction in neutrophil infiltration; (m) a reduction in red blood cell lysis; (n) a reduction in red blood cell phagocytosis; (o) a reduction in platelet phagocytosis; (p) a reduction in platelet lysis; (q) an improvement in transplant graft survival; (a) a reduction in complement
  • the reduction in glial cell activation comprises reduction in astrocyte activation or reduction in microglia activation.
  • the Cis mediated disorder is selected from the group including, but not limited to, hemolysis, Cold Agglutinin Disease, Immune Thrombocytopenia (ITP), Myasthenia Gravis, Glomerulopathies, Atypical Hemolytic uremic syndrome, antiphospholipid antibody syndrome, transplant rejection, Chronic inflammatory demyelinating polyneuropathy (CIDP), Multifocal motor neuropathy (MMN), Dermatomyositis, or Anti MAG neuropathy. In some embodiments, these conditions can be caused by stroke or due to spinal cord injury. In some embodiments, the Cis mediated disorder is hemolysis.
  • the Cis mediated disorder is Cold Agglutinin Disease. In some embodiments, the Cis mediated disorder is Immune Thrombocytopenia (ITP). In some embodiments, the Cis mediated disorder is Myasthenia Gravis. In some embodiments, the Cis mediated disorder is Glomerulopathies. In some embodiments, the Cis mediated disorder is Atypical Hemolytic uremic syndrome. In some embodiments, the Cis mediated disorder is antiphospholipid antibody syndrome. In some embodiments, the Cis mediated disorder is transplant rejection. In some embodiments, the Cis mediated disorder is Chronic inflammatory demyelinating polyneuropathy (CIDP). In some embodiments, the Cis mediated disorder is Multifocal motor neuropathy (MMN).
  • ITP Immune Thrombocytopenia
  • the Cis mediated disorder is Myasthenia Gravis.
  • the Cis mediated disorder is Glomerulopathies.
  • the Cis mediated disorder is Atypical Hemolytic uremic syndrome.
  • the Cis mediated disorder is Dermatomysositis. In some embodiments, the Cis mediated disorder is Anti MAG neuropathy. In some embodiments, the Cis mediated disorder is due to stroke. In some embodiments, the Cis mediated disorder is due to spinal cord injury.
  • a polypeptide, an antibody, an antigen-binding fragment thereof, or a pharmaceutical composition as provided for herein is for the use in the treatment of a complement-mediated disease or disorder.
  • the complement-mediated disorder is selected from the group including, but not limited to, hemolysis, Cold Agglutinin Disease, Immune Thrombocytopenia (ITP), Myasthenia Gravis, Glomerulopathies, Atypical Hemolytic uremic syndrome, antiphospholipid antibody syndrome, transplant rejection, Chronic inflammatory demyelinating polyneuropathy (CIDP), Multifocal motor neuropathy (MMN), Dermatomyositis, or Anti MAG neuropathy.
  • the Cis mediated disorder is hemolysis. In some embodiments, the Cis mediated disorder is Cold Agglutinin Disease. In some embodiments, the Cis mediated disorder is Immune Thrombocytopenia (ITP). In some embodiments, the Cis mediated disorder is Myasthenia Gravis. In some embodiments, the Cis mediated disorder is Glomerulopathies. In some embodiments, the Cis mediated disorder is Atypical Hemolytic uremic syndrome. In some embodiments, the Cis mediated disorder is antiphospholipid antibody syndrome. In some embodiments, the Cis mediated disorder is transplant rejection.
  • the Cis mediated disorder is Chronic inflammatory demyelinating polyneuropathy (CIDP). In some embodiments, the Cis mediated disorder is Multifocal motor neuropathy (MMN). In some embodiments, the Cis mediated disorder is Dermatomyositis. In some embodiments, the Cis mediated disorder is Anti MAG neuropathy. In some embodiments, the Cis mediated disorder is due to stroke. In some embodiments, the Cis mediated disorder is due to spinal cord injury.
  • CIDP chronic inflammatory demyelinating polyneuropathy
  • MNN Multifocal motor neuropathy
  • the Cis mediated disorder is Dermatomyositis.
  • the Cis mediated disorder is Anti MAG neuropathy.
  • the Cis mediated disorder is due to stroke. In some embodiments, the Cis mediated disorder is due to spinal cord injury.
  • the Cis mediated disorder is selected from the group including, but not limited to, hemolysis, Cold Agglutinin Disease, Immune Thrombocytopenia (ITP), Myasthenia Gravis, Glomerulopathies, Atypical Hemolytic uremic syndrome, antiphospholipid antibody syndrome, transplant rejection, Chronic inflammatory demyelinating polyneuropathy (CIDP), Multifocal motor neuropathy (MMN), Dermatomyositis, or Anti MAG neuropathy.
  • the Cis mediated disorder is hemolysis.
  • the Cis mediated disorder is Cold Agglutinin Disease.
  • the Cis mediated disorder is Immune Thrombocytopenia (ITP).
  • the Cis mediated disorder is Myasthenia Gravis. In some embodiments, the Cis mediated disorder is Glomerulopathies. In some embodiments, the Cis mediated disorder is Atypical Hemolytic uremic syndrome. In some embodiments, the Cis mediated disorder is antiphospholipid antibody syndrome. In some embodiments, the Cis mediated disorder is transplant rejection. In some embodiments, the Cis mediated disorder is Chronic inflammatory demyelinating polyneuropathy (CIDP). In some embodiments, the C 1 s mediated disorder is Multifocal motor neuropathy (MMN). In some embodiments, the Cis mediated disorder is Dermatomyositis. In some embodiments, the Cis mediated disorder is Anti MAG neuropathy. In some embodiments, the Cis mediated disorder is due to stroke. In some embodiments, the Cis mediated disorder is due to Spinal Cord Injury.
  • CIDP chronic inflammatory demyelinating polyneuropathy
  • MNN Multifocal motor neuropathy
  • the Cis mediated disorder is Dermato
  • an antibody, or antigen binding fragment thereof, or a pharmaceutical composition is provided for use as a medicament.
  • an antibody, or antigen binding fragment thereof is provided for use as a medicament.
  • a pharmaceutical composition is provided for use as a medicament.
  • the antibody, or antigen binding fragment thereof is an antibody or antigen binding fragment as provided for herein.
  • the pharmaceutical composition comprises an antibody or antigen binding fragment as provided for herein.
  • the pharmaceutical composition is as provided for herein.
  • the medicament is for use in treatment of a Cis mediated disease or disorder.
  • the complement-mediated disorder is, but not limited to, hemolysis, Cold Agglutinin Disease, Immune Thrombocytopenia (ITP), Myasthenia Gravis, Glomerulopathies, Atypical Hemolytic uremic syndrome, antiphospholipid antibody syndrome, transplant rejection, Chronic inflammatory demyelinating polyneuropathy (CIDP), Multifocal motor neuropathy (MMN), Dermatomyositis, or Anti MAG neuropathy.
  • the conditions can be due to stroke or due to spinal cord injury.
  • the Cis mediated disorder is hemolysis.
  • the Cis mediated disorder is Cold Agglutinin Disease. In some embodiments, the Cis mediated disorder is Immune Thrombocytopenia (ITP). In some embodiments, the Cis mediated disorder is Myasthenia Gravis. In some embodiments, the Cis mediated disorder is Glomerulopathies. In some embodiments, the Cis mediated disorder is Atypical Hemolytic uremic syndrome. In some embodiments, the Cis mediated disorder is antiphospholipid antibody syndrome. In some embodiments, the Cis mediated disorder is transplant rejection. In some embodiments, the Cis mediated disorder is Chronic inflammatory demyelinating polyneuropathy (CIDP). In some embodiments, the Cis mediated disorder is Multifocal motor neuropathy (MMN).
  • ITP Immune Thrombocytopenia
  • the Cis mediated disorder is Myasthenia Gravis.
  • the Cis mediated disorder is Glomerulopathies.
  • the Cis mediated disorder is Atypical Hemolytic uremic syndrome.
  • the Cis mediated disorder is Dermatomyositis. In some embodiments, the Cis mediated disorder is Anti MAG neuropathy. In some embodiments, the Cis mediated disorder is due to stroke. In some embodiments, the Cis mediated disorder is due to spinal cord injury.
  • a use of an antibody or antigen binding fragment as provided for herein or a pharmaceutical composition as provided for herein is provided.
  • the use is for the treatment of a C 1 s mediated disorder.
  • a use of an antibody or antigen binding fragment as provided for herein is provided, the use for the treatment of a Cis mediated disorder.
  • a use of a pharmaceutical composition comprising an antibody or antigen binging fragment as provided for herein is provided, the use for the treatment of a Cis mediated disorder.
  • the pharmaceutical composition is as provided for herein.
  • the antibody of any of the embodiments or pharmaceutical compositions thereof inhibit complement Cis activity in an individual having a complement-mediated disease or disorder.
  • the complement-mediated disorder is, but not limited to, hemolysis, Cold Agglutinin Disease, Immune Thrombocytopenia (ITP), Myasthenia Gravis, Glomerulopathies, Atypical Hemolytic uremic syndrome, antiphospholipid antibody syndrome, transplant rejection, Chronic inflammatory demyelinating polyneuropathy (CIDP), Multifocal motor neuropathy (MMN), Dermatomyositis, or Anti MAG neuropathy.
  • the conditions can be due to stroke, or due to spinal cord injury.
  • the Cis mediated disorder is hemolysis.
  • the Cis mediated disorder is Cold Agglutinin Disease.
  • the Cis mediated disorder is Immune Thrombocytopenia (ITP). In some embodiments, the Cis mediated disorder is Myasthenia Gravis. In some embodiments, the Cis mediated disorder is Glomerulopathies. In some embodiments, the Cis mediated disorder is Atypical Hemolytic uremic syndrome. In some embodiments, the Cis mediated disorder is antiphospholipid antibody syndrome. In some embodiments, the Cis mediated disorder is transplant rejection. In some embodiments, the Cis mediated disorder is Chronic inflammatory demyelinating polyneuropathy (CIDP). In some embodiments, the Cis mediated disorder is Multifocal motor neuropathy (MMN). In some embodiments, the Cis mediated disorder is Dermatomyositis. In some embodiments, the Cis mediated disorder is Anti MAG neuropathy. In some embodiments, the Cis mediated disorder is due to stroke. In some embodiments, the Cis mediated disorder is due to spinal cord injury.
  • ITP Immune Thrombocytopenia
  • the present disclosure provides use of an anti-Cls antibody of any of the embodiments or a pharmaceutical composition thereof in the manufacture of a medicament for inhibiting complement Cis activity.
  • the present disclosure provides use of an anti- Cls antibody of any of the embodiments or a pharmaceutical composition thereof in the manufacture of a medicament for inhibiting complement Cis activity in an individual having a complement-mediated disease or disorder.
  • the complement-mediated disorder is, but not limited to, hemolysis, Cold Agglutinin Disease, Immune Thrombocytopenia (ITP), Myasthenia Gravis, Glomerulopathies, Atypical Hemolytic uremic syndrome, antiphospholipid antibody syndrome, transplant rejection, Chronic inflammatory demyelinating polyneuropathy (CIDP), Multifocal motor neuropathy (MMN), Dermatomyositis, or Anti MAG neuropathy.
  • the conditions are caused by a stroke or due to spinal cord injury.
  • the present disclosure provides an anti-Cls antibody of any of the embodiments or a pharmaceutical composition thereof for use in medical therapy.
  • the present disclosure provides an anti-Cls antibody of any of the embodiments or a pharmaceutical composition thereof for treating an individual having a complement-mediated disease or disorder.
  • the complement-mediated disorder is, but not limited to, hemolysis, Cold Agglutinin Disease, Immune Thrombocytopenia (ITP), Myasthenia Gravis, Glomerulopathies, Atypical Hemolytic uremic syndrome, antiphospholipid antibody syndrome, transplant rejection, Chronic inflammatory demyelinating polyneuropathy (CIDP), Multifocal motor neuropathy (MMN), Dermatomyositis, or Anti MAG neuropathy.
  • the conditions are due to stroke or due to spinal cord injury.
  • the Cis mediated disorder is hemolysis.
  • the Cis mediated disorder is Cold Agglutinin Disease. In some embodiments, the Cis mediated disorder is Immune Thrombocytopenia (ITP). In some embodiments, the Cis mediated disorder is Myasthenia Gravis. In some embodiments, the Cis mediated disorder is Glomerulopathies. In some embodiments, the Cis mediated disorder is Atypical Hemolytic uremic syndrome. In some embodiments, the Cis mediated disorder is antiphospholipid antibody syndrome. In some embodiments, the Cis mediated disorder is transplant rejection. In some embodiments, the Cis mediated disorder is Chronic inflammatory demyelinating polyneuropathy (CIDP). In some embodiments, the Cis mediated disorder is Multifocal motor neuropathy (MMN).
  • ITP Immune Thrombocytopenia
  • the Cis mediated disorder is Myasthenia Gravis.
  • the Cis mediated disorder is Glomerulopathies.
  • the Cis mediated disorder is Atypical Hemolytic uremic syndrome.
  • the Cis mediated disorder is Dermatomyositis. In some embodiments, the Cis mediated disorder is Anti MAG neuropathy. In some embodiments, the Cis mediated disorder is due to stroke. In some embodiments, the Cis mediated disorder is due to Spinal Cord Injury.
  • the present disclosure provides an anti-Cls antibody of any of the embodiments or a pharmaceutical composition thereof for inhibiting complement Cis protein activity.
  • the present disclosure provides an anti-Cls antibody of any of the embodiments or a pharmaceutical composition thereof for inhibiting complement Cis protein activity in an individual having a complement-mediated disease or disorder.
  • the complement-mediated disorder is, but not limited to, hemolysis, Cold Agglutinin Disease, Immune Thrombocytopenia (ITP), Myasthenia Gravis, Glomerulopathies, Atypical Hemolytic uremic syndrome, antiphospholipid antibody syndrome, transplant rejection, Chronic inflammatory demyelinating polyneuropathy (CIDP), Multifocal motor neuropathy (MMN), Dermatomyositis, or Anti MAG neuropathy.
  • the conditions are caused by a stroke or spinal cord injury.
  • the Cis mediated disorder is hemolysis.
  • the Cis mediated disorder is Cold Agglutinin Disease.
  • the Cis mediated disorder is Immune Thrombocytopenia (ITP). In some embodiments, the Cis mediated disorder is Myasthenia Gravis. In some embodiments, the Cis mediated disorder is Glomerulopathies. In some embodiments, the Cis mediated disorder is Atypical Hemolytic uremic syndrome. In some embodiments, the Cis mediated disorder is antiphospholipid antibody syndrome. In some embodiments, the Cis mediated disorder is transplant rejection. In some embodiments, the Cis mediated disorder is Chronic inflammatory demyelinating polyneuropathy (CIDP). In some embodiments, the Cis mediated disorder is Multifocal motor neuropathy (MMN). In some embodiments, the Cis mediated disorder is Dermatomyositis. In some embodiments, the Cis mediated disorder is Anti MAG neuropathy. In some embodiments, the Cis mediated disorder is due to stroke. In some embodiments, the Cis mediated disorder is due to spinal cord injury.
  • ITP Immune Thrombocytopenia
  • the present disclosure provides a method to diagnose a complement-mediated disease or disorder in an individual, the method comprising: (a) determining the amount of a complement Cis protein in a biological sample obtained from the individual, wherein the step of determining comprises: (i) contacting the biological sample with an anti-Cls antibody of any of the embodiments; and (ii) quantitating binding of the antibody to complement Cis protein present in the sample; and (b) comparing the amount of the complement Cis protein to a normal control value that indicates the amount of complement Cis protein in a normal control individual, wherein a significant difference between the amount of Cis protein in the biological sample and the normal control value indicates that the individual has a complement-mediated disease or disorder.
  • the biological sample is selected from the group consisting of blood, serum, plasma, urine, saliva, cerebrospinal fluid, interstitial fluid, ocular fluid, synovial fluid, solid tissue sample, tissue culture sample, and cellular sample.
  • the present disclosure provides a method to monitor progression of a complement- mediated disease or disorder in an individual, the method comprising: (a) determining a first amount of complement a Cis protein in a biological sample obtained from the individual at a first time point; (b) determining a second amount of complement a Cis protein in a biological sample obtained from the individual at a second time point; and (c) comparing the second amount of complement Cis protein with the first amount of complement Cis protein.
  • the steps of determining comprise: (i) contacting the biological sample with an anti-Cls antibody of any of the embodiments; and (ii) quantitating binding of the antibody to complement Cis protein present in the sample.
  • the first time point is a time point before initiation of a treatment regimen
  • the second time point is a time point after initiation of a treatment regimen.
  • the biological sample is selected from the group consisting of blood, serum, plasma, urine, saliva, cerebrospinal fluid, interstitial fluid, ocular fluid, synovial fluid, solid tissue sample, tissue culture sample, and cellular sample.
  • the present disclosure provides an in vitro method to detect complement Cis protein in a biological sample obtained from an individual, the method comprising: (a) contacting the biological sample with an anti-Cls antibody of any of the embodiments; and (b) detecting binding of the antibody to complement Cis protein present in the sample.
  • the biological sample is selected from the group consisting of blood, serum, plasma, urine, saliva, cerebrospinal fluid, interstitial fluid, ocular fluid, synovial fluid, solid tissue sample, tissue culture sample, and cellular sample.
  • the method is quantitative.
  • the methods of the present disclosure provide that the individual is suspected of having a complement-mediated disease or disorder, has been diagnosed as having a complement-mediated disease or disorder, or has a genetic predisposition to developing a complement-mediated disease or disorder.
  • a method comprising treating a subject with a Cis mediated disorder, the method comprising administering to the subject the pharmaceutical composition described in any one of the embodiments described herein.
  • the Cis mediated disorder is hemolysis, Cold Agglutinin Disease, Immune Thrombocytopenia (ITP), Myasthenia Gravis, Glomerulopathies, Atypical Hemolytic uremic syndrome, antiphospholipid antibody syndrome, transplant rejection, chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN), dermatomyositis, anti MAG neuropathy, due to stroke, or due to spinal cord injury.
  • ITP Immune Thrombocytopenia
  • Glomerulopathies Atypical Hemolytic uremic syndrome, antiphospholipid antibody syndrome, transplant rejection, chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN), dermatomyositis, anti MAG neuropathy, due to stroke, or due to spinal cord injury.
  • the Cis mediated disorder is hemolysis. In some embodiments, the Cis mediated disorder is Cold Agglutinin Disease. In some embodiments, the Cis mediated disorder is Immune Thrombocytopenia (ITP). In some embodiments, the Cis mediated disorder is Myasthenia Gravis. In some embodiments, the Cis mediated disorder is Multifocal Motor Neuropathy (MMN). In some embodiments, the Cis mediated disorder is Chronic Inflammatory Demyelinating Polyneuropathy (CIDP). In some embodiments, the Cis mediated disorder is Glomerulopathies. In some embodiments, the Cis mediated disorder is Atypical Hemolytic uremic syndrome.
  • the Cis mediated disorder is antiphospholipid antibody syndrome. In some embodiments, the Cis mediated disorder is transplant rejection. In some embodiments, the Cis mediated disorder is chronic inflammatory demyelinating polyneuropathy (CIDP). In some embodiments, the Cis mediated disorder is multifocal motor neuropathy (MMN). In some embodiments, the Cis mediated disorder is dermatomyositis. In some embodiments, the Cis mediated disorder is anti MAG neuropathy. In some embodiments, the Cis mediated disorder is due to stroke. In some embodiments, the Cis mediated disorder is due to spinal cord injury.
  • CIDP chronic inflammatory demyelinating polyneuropathy
  • MNN multifocal motor neuropathy
  • the Cis mediated disorder is dermatomyositis.
  • the Cis mediated disorder is anti MAG neuropathy. In some embodiments, the Cis mediated disorder is due to stroke. In some embodiments, the Cis mediated disorder is due to spinal cord injury.
  • the present disclosure provides an in vitro method for inhibiting complement Cis activity in an organ or a tissue, the method comprising contacting the organ or the tissue with an anti-Cls antibody of any of the embodiments or a pharmaceutical composition thereof.
  • Treatment of individuals may comprise the administration of a therapeutically effective amount of the antibodies described herein.
  • the antibodies can be provided in a kit, such as those provided herein.
  • the antibodies can be used or administered alone or in admixture with another therapeutic, analgesic, or diagnostic agent, such as provided for herein.
  • another therapeutic, analgesic, or diagnostic agent such as provided for herein.
  • the dosage of administered agent will vary depending upon such factors as the patient's age, weight, height, sex, general medical condition, previous medical history, etc.
  • An antibody, capable treating a condition associated with Cis activity or use to treat a Cis related pathology is intended to be provided to subjects in an amount sufficient to affect a reduction, resolution, or amelioration in the Cis related symptom or pathology. Examples of such pathologies are provided for herein.
  • methods of treating a subject with a Cis mediated disorder comprise administering a pharmaceutical composition comprising an antibody, or antigen binding fragment thereof, as provided herein.
  • the disorder is as provided for herein.
  • the antibodies, or antigen binding fragments thereof can be administered with other therapeutics. These can be administered simultaneously or sequentially.
  • the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein, is administered to a subject in need thereof.
  • the administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein results in a change in a clinical activity score of the subject.
  • the change is a change from baseline.
  • the change is an improvement.
  • administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein results in a change in a clinical activity score selected from MG activity of daily living (MG-ADL) Scale Score, Quantitative Myasthenia Gravis (QMG) Scale score, Myasthenia Gravis Composite (MGC) Scale Score, Myasthenia Gravis Quality of Life 15-point (MG-QoL 15r) Scale Score, Multidimensional Fatigue Index (MFI) 20 Scale Score, or Myasthenia Gravis Post-Intervention Status (MG-PIS).
  • MG activity of daily living MG activity of daily living
  • QMG Quantitative Myasthenia Gravis
  • MCC Myasthenia Gravis Composite
  • MFI Multidimensional Fatigue Index
  • MFI Myasthenia Gravis Post-Intervention Status
  • the MG-ADL is an 8-point patient-reported questionnaire that focuses on relevant symptoms and functional performance of ADL in patients with MG, including unweighted items related to disability secondary to ocular (2 items), bulbar (3 items), respiratory (1 item), and gross motor or limb (2 items) impairment related to effects from MG.
  • the recall period for MG-ADL is the preceding 7 days, and patients must provide their responses without any outside input. In this functional status instrument, each response is graded between 0 (normal) to 3 (most severe) with a total MG-ADL score ranging from 0 to 24. A clinically meaningful improvement is reflected by a 2-point improvement in MG-ADL score.
  • the MG-ADL is a reliable and valid patient reported outcome measure used frequently in clinical trials as a primary or secondary measure of treatment response.
  • the administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein results in a change from baseline in MG- ADL score over time or after 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, and/or 52 weeks of treatment.
  • the change from baseline of MG-ADL score is an improvement on the MG-ADL scale.
  • the change from baseline of MG-ADL score is a reduction in score on the MG-ADL scale. In some embodiments, the change from baseline of MG-ADL score is greater than or equal to 2 points on the MG-ADL scale. In some embodiments, the change from baseline of MG-ADL score is a 2 point reduction on the MG-ADL scale. In some embodiments, the change from baseline of MG-ADL score is greater than or equal to 2 points on the MG-ADL scale at 13 weeks following administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein.
  • the change from baseline of MG-ADL score is a 2 point reduction on the MG-ADL scale at 13 weeks following administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein. In some embodiments, the change from baseline of MG-ADL score is greater than or equal to 2 points on the MG-ADL scale at 52 weeks following administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein.
  • the change from baseline of MG-ADL score is a 2 point reduction on the MG-ADL scale at 52 weeks following administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein.
  • the QMG assessment consists of 13 items: ocular (2 items), facial (1 item), bulbar (2 items), gross motor (6 items), axial (1 item), and respiratory (1 item); each graded 0 to 3, with 3 being the most severe (28).
  • the total QMG score ranges from 0 to 39.
  • the QMG scoring system is an objective evaluation of treatment response for MG and is based on quantitative testing of sentinel muscle groups. A 3.5-point change in QMG score is considered a clinically meaningful change.
  • the MGF A task force has recommended that the QMG score be used in prospective studies of therapy for MG.
  • the administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein results in a change from baseline in QMG score over time or after 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, and/or 52 weeks of treatment.
  • the change from baseline of QMG score is an improvement on the QMG scale.
  • the change from baseline of QMG score is a reduction in score on the QMG scale.
  • the change from baseline of QMG score is greater than or equal to 3 points on the QMG scale. In some embodiments, the change from baseline QMG score is a 3 point reduction on the QMG scale. In some embodiments, the change from baseline of QMG score is greater than or equal to 3 points on the QMG scale at 13 weeks following administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein. In some embodiments, the change from baseline of QMG score is a 3 point reduction on the QMG scale at 13 weeks following administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein.
  • the change from baseline of QMG score is greater than or equal to 3 points on the QMG scale at 52 weeks following administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein. In some embodiments, the change from baseline of QMG score is a 3 point reduction on the QMG scale at 52 weeks following administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein.
  • the MGC is a validated assessment tool for measuring clinical status of patients with MG.
  • the range of total MGC score is 0 to 50 and a clinically meaningful improvement is reflected by a 3-point improvement in MGC score.
  • the MGC assesses 10 important functional areas most frequently affected by MG and the scales are weighted for clinical significance that incorporates patient-reported outcomes.
  • the administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein results in a change from baseline in MGC score over time or after 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, and/or 52 weeks of treatment.
  • the change from baseline of MGC score is an improvement on the MGC scale.
  • the change from baseline of MGC score is a reduction in score on the MGC scale.
  • the change from baseline of MGC score is a reduction in score on the MGC scale at 13 weeks following administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein. In some embodiments, the change from baseline of MGC score is a reduction in score on the MGC scale at 52 weeks following administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein.
  • the revised Myasthenia Gravis Qualify of Life 15-item scale (MG-QoL15r) is a health- related QoL evaluative instrument specific to patients with MG.
  • the MG-QoL15r was designed to provide information about patients’ perception of impairment and disability, determine the degree to which disease manifestations are tolerated, and to be administered and interpreted easily (31).
  • the MG-QoL15r will be completed by the participant. Higher scores indicate greater extent of and dissatisfaction with MG-related dysfunction.
  • the administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein results in a change from baseline in MG-QoL15r score over time or after 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, and/or 52 weeks of treatment.
  • the change from baseline of MG-QoL15r score is an improvement on the MG- QoL15r scale.
  • the change from baseline of MG-QoL15r score is a reduction in score on the MG-QoL15r scale. In some embodiments, the change from baseline of MG-QoL15r score is a reduction in score on the MG-QoL15r scale at 13 weeks following administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein. In some embodiments, the change from baseline of MG-QoL15r score is a reduction in score on the MG-QoL15r scale at 52 weeks following administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein.
  • the MFI-20 is a 20-item questionnaire that assesses 5 dimensions of fatigue: general fatigue, physical fatigue, reduced motivation, reduced activity, and mental fatigue (32). Participants are asked to score each item ranging from 1 to 5 to indicate their experience related to the statement over a period described as “lately”. Several positively phrased items are reverse- scored. Higher total scores on the MFI-20 correspond to worse fatigue.
  • the administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein results in a change from baseline in MFI-20 score over time or after 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, and/or 52 weeks of treatment.
  • the change from baseline of MFI-20 score is an improvement on the MFI-20 scale.
  • the change from baseline of MFI-20 score is a reduction in score on the MFI-20 scale.
  • the change from baseline of MFI-20 score is a reduction in score on the MFI-20 scale at 13 weeks following administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein. In some embodiments, the change from baseline of MFI-20 score is a reduction in score on the MFI-20 scale at 52 weeks following administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein.
  • the MG clinical state is assessed using a modified version of the MGFA-PIS. Change in status categories of improved, unchanged, or worse, as well as whether the participant reaches minimal manifestations (MM) are assessed and recorded at the time points indicated in the SOAs.
  • the administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein results in a change from baseline in MGFA-PIS score over time or after 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, and/or 52 weeks of treatment.
  • the change from baseline of MGFA-PIS score is an improvement on the MGFA- PIS scale.
  • the change from baseline of MGFA-PIS score is a reduction in score on the MGFA-PIS scale. In some embodiments, the change from baseline of MGFA-PIS score is a reduction in score on the MGFA-PIS scale at 13 weeks following administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein. In some embodiments, the change from baseline of MGFA-PIS score is a reduction in score on the MGFA-PIS scale at 52 weeks following administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein.
  • the administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein, results in the subject reaching Minimal Symptom Expression (MSE).
  • MSE Minimal Symptom Expression
  • the Minimal Symptom Expression (MSE) is defined as MG-ADL Scale score of 0 or 1.
  • the subject reaches Minimal Symptom Expression (MSE) at week 13, or week 52 following administration of the first dose.
  • the subject reaches Minimal Symptom Expression (MSE) at week 13 following administration of the first dose.
  • the subject reaches Minimal Symptom Expression (MSE) at week 52 following administration of the first dose.
  • administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein results in a change in a clinical activity score selected from Rasch-built Overall Disability Scale for Multifocal motor neuropathy (MMN-RODS), grip strength, or 9 hole peg test (9HPT).
  • MN-RODS Rasch-built Overall Disability Scale for Multifocal motor neuropathy
  • grip strength grip strength
  • 9HPT 9 hole peg test
  • the Rasch-built Overall Disability Scale for Multifocal motor neuropathy is a Rasch-built interval-weighted outcome measure constructed specifically to capture activity limitations in MMN patients.
  • the patient is administered the 25-item MMN-RODS questionnaire at various time points.
  • the 25-item MMN-RODS questionnaire records patient’s responses to a series of questions about tasks, where the responses are scored as follows: 0 (unable to perform); 1 (able to perform, but with difficulty); and 2 (able to perform without difficulty).
  • the administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein results in a change from baseline in MMN-RODS score over time or after 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, or 69 weeks of treatment.
  • the change from baseline of MMN-RODS score is an improvement on the MMN-RODS scale. In some embodiments, the change from baseline of MMN-RODS score is an increase in score on the MMN- RODS scale. In some embodiments, the change from baseline of I-RODS score is greater than or equal to 1 point on the MMN-RODS scale. In some embodiments, the change from baseline of MMN-RODS score is a 1, or more, point increase on the MMN-RODS scale.
  • the Nine-Hole Peg Test is used to measure finger dexterity in patients with various neurological diagnoses.
  • the test uses: a board (wood or plastic) with 9 holes (10 mm diameter, 15 mm depth) placed apart by 32 mm or 50 mm; a container for the pegs: square box (100 x 100 x 10 mm) apart from the board or a shallow round dish at the end of the board; 9 pegs (7 mm diameter, 32 mm length); and a stopwatch.
  • the patient is instructed to take the pegs from a container, one by one, and place them into the holes on the board, as quickly as possible, using only the hand being evaluated.
  • the evaluator should start the stopwatch as soon as the patient touches the first peg.
  • the evaluator should stop the stopwatch once the last peg is in the container.
  • the patient is scored on the number of seconds it takes for the patient to complete the test, or the number of pegs placed in 50 or 100 seconds that can be recorded (in this case, results are expressed as the number of pegs placed per second).
  • the administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein results in a change from baseline in 9HPT score over time or after 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, or 69 weeks of treatment.
  • the change from baseline in 9HPT score is an improvement on the 9HPT scale.
  • the change from baseline of 9HPT score is an increase in score on the 9HPT scale.
  • Grip strength assessments have been recommended to be used in clinical practice because they can be done with relatively simple tools and provide near instantenous results. Although it is a relatively objective tool that may be less susceptible to bias than other assessments, it is also limited in that muscle impairment is assessed solely in the hands.
  • a variety of tools are available to assess grip strength; two commonly used instruments are the Martin Vigorimeter and Jamar Dynamometer. With the Martin Vigorimeter, the patient squeezes a rubber ball that is connected to a manometer with rubber tubing. The patient’s grip strength is expressed in kilopascal (kPa), with a range of 0-160 kPa. With the Jamar Dynamometer, the patient squeezes the handle of a hand-held device inwards against increasing resistance. The patient’s grip strength is expressed in kg or lb, with a range of 0-90 kg or 0-200 lb.
  • the administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein results in a change from baseline in grip strength score over time or after 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
  • the change from baseline in grip strength score is an improvement in the grip strength score.
  • administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein results in a change in a clinical activity score selected from Inflammatory Neuropathy Cause and Treatment (INCAT) Disability Score, Inflammatory Rasch-build Overall Disability Score (I-RODS), or Medical Research Council Sum Score (MRC-16).
  • INCAT Inflammatory Neuropathy Cause and Treatment
  • I-RODS Inflammatory Rasch-build Overall Disability Score
  • MRC-16 Medical Research Council Sum Score
  • the INCAT was developed in 2001 and used for the first time in a clinical study comparing the efficacy and safety of intravenous immunoglobulin with oral prednisone in patients with CIDP.
  • the INCAT has subsequently been used in several CIDP clinical trials, although its use in day-to- day clinical practice is uncommon.
  • the INCAT comprises two parts, the arm score and the leg score. Based on a patient’s level of impairment in their arms and legs, each part is scored between 0 and 5 points, resulting in an INCAT total score between 0 and 10.
  • the arm disability score comprises scores of: 0 (no upper limb problems); 1 (symptoms, in one or both arms, not affecting the ability to perform any of the following functions: doing all zips and buttons; washing or brushing hair; using a knife and fork together; handling small coins); 2 (symptoms, in one arm or both arms, affecting but not preventing any of the previously mentioned functions); 3 (symptoms, in one arm or both arms, preventing one or two of the previously mentioned functions); 4 (symptoms, in one arm or both arms, preventing three or all of the functions listed, but some purposeful movements still possible); and 5 (inability to use either arm for any purposeful movement).
  • the leg disability score comprises scores of: 0 (walking not affected); 1 (walking affected, but walks independently outdoors); 2 (usually uses unilateral support (stick, single crutch, one arm) to walk outdoors); 3 (usually uses bilateral support (sticks, crutches, frame, two arms) to walk outdoors); 4 (usually uses wheelchair to travel outdoors, but able to stand and walk a few steps with help); and 5 (restricted to wheelchair, unable to stand and walk a few steps with help).
  • the administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein results in a change from baseline in INCAT score over time or after 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
  • the change from baseline of INCAT score is an improvement on the INCAT scale. In some embodiments, the change from baseline of INCAT score is a reduction in score on the INCAT scale. In some embodiments, the change from baseline of INCAT score is greater than or equal to 1 point on the INCAT scale. In some embodiments, the change from baseline of INCAT score is a 1, or more, point reduction on the INCAT scale.
  • I-RODS Inflammatory Rasch-built Overall Disability Scale
  • the administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein results in a change from baseline in I-RODS score over time or after 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37,
  • the change from baseline of I-RODS score is an improvement on the I-RODS scale. In some embodiments, the change from baseline of I-RODS score is an increase in score on the I-RODS scale. In some embodiments, the change from baseline of I-RODS score is greater than or equal to 1 point on the I-RODS scale. In some embodiments, the change from baseline of I-RODS score is a 1, or more, point increase on the I-RODS scale.
  • the Medical Research Council (MRC) system for testing and grading of muscle function aims to provide a standardized and objective way to assess muscle function. It was originally introduced in 1943 and has a long history of use in neurology, rehabilitation and general medicine examinations.
  • MRC grading system each tested muscle is assigned one of the following scores based on its function: 0 (paralysis); 1 (only a trace or flicker of muscle contraction); 2 (muscle movement is possible with gravity eliminated); 3 (muscle movement is possible against gravity); 4 (muscle strength is reduced, but movement against resistance is possible); and 5 (normal strength).
  • Assessments of muscles are done bilaterally, meaning that for each muscle tested, the same muscle on the opposite side of the body is also tested.
  • the MRC sum score is finally calculated by adding the score of each individually assessed muscle.
  • CIDP and Guillain-Barre Syndrome the following six muscle sets are commonly assessed: upper arm abductors; elbow flexors; wrist extensors; hip flexors; knee extensors; and foot dorsal flexors.
  • the administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein results in a change from baseline in MRC-16 score over time or after 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
  • the change from baseline of MRC-16 score is an improvement on the MRC-16 scale. In some embodiments, the change from baseline of MRC-16 score is an increase in score on the MRC-16 scale. In some embodiments, the change from baseline of MRC- 16 score is greater than or equal to 1 point on the MRC-16 scale. In some embodiments, the change from baseline of MRC-16 score is a 1, or more, point increase on the MRC-16 scale.
  • the administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein achieves a serum concentration of about 50 ug/mL to about 300 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of about 50 ug/mL to about 250 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of about 75 ug/mL to about 250 ug/mL.
  • the administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein achieves a serum concentration of about 75 ug/mL to about 250 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of about 125 ug/mL to about 250 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of about 87 ug/mL to about 149 ug/mL.
  • the administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein achieves a serum concentration of at least 50 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of at least 60 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of at least 65 ug/mL.
  • the administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein achieves a serum concentration of at least 70 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of at least 75.5 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of at least 80 ug/mL.
  • the administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein achieves a serum concentration of at least 87 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of at least 85 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of at least 90 ug/mL.
  • the administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein achieves a serum concentration of at least 95 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of at least 100 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of at least 105 ug/mL.
  • the administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein achieves a serum concentration of at least 110 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of at least 115 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of at least 120 ug/mL.
  • the administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein achieves a serum concentration of at least 125 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of at least 130 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of at least 140 ug/mL.
  • the administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein achieves a serum concentration of at least 149 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of at least 150 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of at least 160 ug/mL.
  • the administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein achieves a serum concentration of at least 170 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of at least 180 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of at least 190 ug/mL.
  • the administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein achieves a serum concentration of at least 200 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of at least 210 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of at least 220 ug/mL.
  • the administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein achieves a serum concentration of at least 230 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of at least 240 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of at least 250 ug/mL.
  • the administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein achieves a serum concentration of about 50 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of about 60 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of about 65 ug/mL.
  • the administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein achieves a serum concentration of about 70 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of about 75.5 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of about 80 ug/mL.
  • the administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein achieves a serum concentration of about 85 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of about 90 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of about 95 ug/mL.
  • the administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein achieves a serum concentration of about 100 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of about 105 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of about 110 ug/mL.
  • the administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein achieves a serum concentration of about 115 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of about 120 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of about 125 ug/mL.
  • the administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein achieves a serum concentration of about 130 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of about 131 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of about 135 ug/mL.
  • the administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein achieves a serum concentration of about 140 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of about 145 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of about 150 ug/mL.
  • the administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein achieves a serum concentration of about 155 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of about 160 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of about 165 ug/mL.
  • the administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein achieves a serum concentration of about 170 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of about 175 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of about 180 ug/mL.
  • the administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein achieves a serum concentration of about 185 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of about 190 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of about 195 ug/mL.
  • the administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein achieves a serum concentration of about 200 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of about 210 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of about 220 ug/mL.
  • the administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein achieves a serum concentration of about 230 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of about 240 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of about 250 ug/mL.
  • the administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein achieves a serum concentration of about 260 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of about 270 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of about 280 ug/mL.
  • the administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein achieves a serum concentration of about 290 ug/mL. In some embodiments, the administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves a serum concentration of about 300 ug/mL.
  • the administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein achieves inhibition of the complement pathway. In some embodiments, the administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least
  • the administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein achieves inhibition of the complement pathway. In some embodiments, the administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%,
  • the administration of the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition, such as those provided for herein achieves inhibition of the complement pathway. In some embodiments, the administration of the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition, such as those provided for herein, achieves 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%,
  • a method of treating a Cls-mediated disease or disorder in a subject in need thereof comprises administering a first dose of an antibody, or a fragment thereof, wherein the first dose is about 1 mg/kg to about 60 mg/kg; or about 60 mg to about 7200 mg; administering one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, wherein the one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, is about 60 mg to about 7200 mg, and wherein the antibody, or the antigenbinding fragment thereof, comprises a heavy chain variable region comprising a HCDR1 of SEQ ID NO: 61, a HCDR2 of SEQ ID NO: 62, and a HCDR3 of SEQ ID NO: 78; and a light chain variable region comprising a LCDR1 of SEQ ID NO: 64, a LCDR2 of SEQ ID NO: 65, and a LCDR3 of SEQ ID NO: 79.
  • a method of treating a Cls-mediated disease or disorder in a subject in need thereof comprises administering a first dose of an antibody, or a fragment thereof, wherein the first dose is about 1 mg/kg to about 60 mg/kg; or about 60 mg to about 7200 mg; administering one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, wherein the one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, is about 60 mg to about 7200 mg, wherein the first dose is administered by intravenous or subcutaneous administration, wherein the one or more subsequent dose is administered by subcutaneous administration, and wherein the antibody, or the antigen-binding fragment thereof, comprises a heavy chain variable region comprising a HCDR1 of SEQ ID NO: 61, a HCDR2 of SEQ ID NO: 62, and a HCDR3 of SEQ ID NO: 78; and a light chain variable region comprising a LCDR1 of SEQ ID NO: 64, a
  • a method of treating a Cls-mediated disease or disorder in a subject in need thereof comprises administering a first dose of an antibody, or a fragment thereof, wherein the first dose is selected from: about 1 mg/kg, about 3 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 30 mg/kg, about 50 mg/kg, or about 60 mg/kg; or about 300 mg, or about 600 mg; administering one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, wherein the one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, is about 300 mg, or about 600 mg, wherein the first dose is administered by intravenous or subcutaneous administration, wherein the one or more subsequent dose is administered by subcutaneous administration, and wherein the antibody, or the antigenbinding fragment thereof, comprises a heavy chain variable region comprising a HCDR1 of SEQ ID NO: 61, a HCDR2 of SEQ ID NO: 62, and
  • a method of treating a Cls-mediated disease or disorder in a subject in need thereof comprises administering intravenously a first dose of an antibody, or a fragment thereof, in a dose of about 15 mg/kg to about 20 mg/kg; and administering subcutaneously a one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, in a dose of about 300 mg to about 600 mg, wherein the one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, is administered every two weeks following administration of the first dose, and wherein the antibody, or the antigen-binding fragment thereof, comprises a heavy chain variable region comprising a HCDR1 of SEQ ID NO: 61, a HCDR2 of SEQ ID NO: 62, and a HCDR3 of SEQ ID NO: 78; and a light chain variable region comprising a LCDR1 of SEQ ID NO: 64, a LCDR2 of SEQ ID NO: 65, and a LCDR3 of
  • a method of treating a Cls-mediated disease or disorder in a subject in need thereof comprises administering a first dose of an antibody, or a fragment thereof, wherein the first dose is about 1 mg/kg to about 60 mg/kg; or about 60 mg to about 7200 mg; administering one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, wherein the one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, is about 60 mg to about 7200 mg, and wherein the antibody, or the antigenbinding fragment thereof, comprises a heavy chain variable region comprising a HCDR1 of SEQ ID NO: 61, a HCDR2 of SEQ ID NO: 62, and a HCDR3 of SEQ ID NO: 78; and a light chain variable region comprising a LCDR1 of SEQ ID NO: 64, a LCDR2 of SEQ ID NO: 65, and a LCDR3 of SEQ ID NO: 79.
  • a method of treating a Cls-mediated disease or disorder in a subject in need thereof comprises administering a first dose of an antibody, or a fragment thereof, wherein first dose is selected from: about 1 mg/kg, about 3 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 30 mg/kg, about 50 mg/kg, or about 60 mg/kg; or about 300 mg, or about 600 mg 1 mg/kg to about 60 mg/kg; or about 60 mg to about 7200 mg; administering one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, wherein the one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, is about 300 mg, or about 600 mg, wherein the one or more subsequent dose is administered by subcutaneous administration, and wherein the antibody, or the antigen-binding fragment thereof, comprises a heavy chain variable region comprising a HCDR1 of SEQ ID NO: 61, a HCDR2 of SEQ ID NO:
  • a method of treating a Cls-mediated disease or disorder in a subject in need thereof comprises administering intravenously a first dose of an antibody, or a fragment thereof, in a dose of about 15 mg/kg to about 20 mg/kg; and administering subcutaneously a one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, in a dose of about 300 mg to about 600 mg, wherein the one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, is administered every 1 week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, every 7 weeks, every 8 weeks, every 9 weeks, every 10 weeks, every 11 weeks, every 12 weeks, every 13 weeks, every 14 weeks, every 15 weeks, or every 16 weeks following administration of the first dose, and wherein the antibody, or the fragment thereof, is any antibody provided for herein.
  • a method of treating a Myasthenia Gravis (MG) in a subject in need thereof comprises administering a first dose of an antibody, or a fragment thereof, wherein the first dose is about 1 mg/kg to about 60 mg/kg; or about 60 mg to about 7200 mg; administering one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, wherein the one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, is about 60 mg to about 7200 mg, and wherein the antibody, or the antigenbinding fragment thereof, comprises a heavy chain variable region comprising a HCDR1 of SEQ ID NO: 61, a HCDR2 of SEQ ID NO: 62, and a HCDR3 of SEQ ID NO: 78; and a light chain variable region comprising a LCDR1 of SEQ ID NO: 64, a LCDR2 of SEQ ID NO: 65, and a LCDR3 of SEQ ID NO: 79.
  • a method of treating a Myasthenia Gravis (MG) in a subject in need thereof comprises administering a first dose of an antibody, or a fragment thereof, wherein first dose is selected from: about 1 mg/kg, about 3 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 30 mg/kg, about 50 mg/kg, or about 60 mg/kg; or about 300 mg, or about 600 mg 1 mg/kg to about 60 mg/kg; or about 60 mg to about 7200 mg; administering one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, wherein the one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, is about 300 mg, or about 600 mg, wherein the one or more subsequent dose is administered by subcutaneous administration, and wherein the antibody, or the antigen-binding fragment thereof, comprises a heavy chain variable region comprising a HCDR1 of SEQ ID NO: 61, a HCDR2 of SEQ
  • a method of treating a Myasthenia Gravis (MG) in a subject in need thereof comprises administering intravenously a first dose of an antibody, or a fragment thereof, in a dose of about 15 mg/kg to about 20 mg/kg; and administering subcutaneously a one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, in a dose of about 300 mg to about 600 mg, wherein the one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, is administered every 1 week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, every 7 weeks, every 8 weeks, every 9 weeks, every 10 weeks, every 11 weeks, every 12 weeks, every 13 weeks, every 14 weeks, every 15 weeks, or every 16 weeks following administration of the first dose, and wherein the antibody, or the antigen-binding fragment thereof, comprises a heavy chain variable region comprising a HCDR1 of SEQ ID NO: 61, a HCDR2 of SEQ
  • a method of treating a Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) in a subject in need thereof comprises administering a first dose of an antibody, or a fragment thereof, wherein the first dose is about 1 mg/kg to about 60 mg/kg; or about 60 mg to about 7200 mg; administering one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, wherein the one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, is about 60 mg to about 7200 mg, and wherein the antibody, or the antigen-binding fragment thereof, comprises a heavy chain variable region comprising a HCDR1 of SEQ ID NO: 61, a HCDR2 of SEQ ID NO: 62, and a HCDR3 of SEQ ID NO: 78; and a light chain variable region comprising a LCDR1 of SEQ ID NO: 64, a LCDR2 of SEQ ID NO: 65, and a LCDR3 of SEQ ID
  • a method of treating a Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) in a subject in need thereof comprises administering a first dose of an antibody, or a fragment thereof, wherein first dose is selected from: about 1 mg/kg, about 3 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 30 mg/kg, about 50 mg/kg, or about 60 mg/kg; or about 300 mg, or about 600 mg 1 mg/kg to about 60 mg/kg; or about 60 mg to about 7200 mg; administering one or more subsequent dose of the antibody, or the antigenbinding fragment thereof, wherein the one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, is about 300 mg, or about 600 mg, wherein the one or more subsequent dose is administered by subcutaneous administration, and wherein the antibody, or the antigen-binding fragment thereof, comprises a heavy chain variable region comprising a HCDR1 of SEQ ID NO: 61, a
  • a method of treating a Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) in a subject in need thereof comprises administering intravenously a first dose of an antibody, or a fragment thereof, in a dose of about 50 mg/kg; and administering a one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, in a dose of about 100 mg to about 8300 mg, wherein the one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, is administered every 1 week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, every 7 weeks, every 8 weeks, every 9 weeks, every 10 weeks, every 11 weeks, every 12 weeks, every 13 weeks, every 14 weeks, every 15 weeks, or every 16 weeks following administration of the first dose, and wherein the antibody, or the antigen-binding fragment thereof, comprises a heavy chain variable region comprising a HCDR1 of SEQ ID NO: 61, a HCDR2 of SEQ ID
  • a method of treating a Multifocal Motor Neuropathy (MMN) in a subject in need thereof comprises administering a first dose of an antibody, or a fragment thereof, wherein the first dose is about 1 mg/kg to about 60 mg/kg; or about 60 mg to about 7200 mg; administering one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, wherein the one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, is about 60 mg to about 7200 mg, and wherein the antibody, or the antigenbinding fragment thereof, comprises a heavy chain variable region comprising a HCDR1 of SEQ ID NO: 61, a HCDR2 of SEQ ID NO: 62, and a HCDR3 of SEQ ID NO: 78; and a light chain variable region comprising a LCDR1 of SEQ ID NO: 64, a LCDR2 of SEQ ID NO: 65, and a LCDR3 of SEQ ID NO: 79.
  • MTN Multifocal Motor Neuropathy
  • a method of treating a Multifocal Motor Neuropathy (MMN) in a subject in need thereof comprises administering intravenously a first dose of an antibody, or a fragment thereof, in a dose of about 1 mg/kg to about 60 mg/kg; and administering subcutaneously a one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, in a dose of about 60 mg to about 7200 mg, wherein the one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, is administered every 1 week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, every 7 weeks, every 8 weeks, every 9 weeks, every 10 weeks, every 11 weeks, every 12 weeks, every 13 weeks, every 14 weeks, every 15 weeks, or every 16 weeks following administration of the first dose, and wherein the antibody, or the antigen-binding fragment thereof, comprises a heavy chain variable region comprising a HCDR1 of SEQ ID NO: 61, a HCDR2 of
  • the first dose and/or the one or more subsequent dose are administered using a syringe, a pre-filled syringe, an autoinjector, a large-volume injector, or a pump.
  • the injector is as provided for herein, such as in U.S. Patent No. 11779704, U.S. Patent No. 11654244, U.S. Patent No. 11612690, U.S. Patent No. 11607494, U.S. Patent No. 11602596, U.S. Patent No. 11541189, U.S. Patent No. 11534556, U.S. Patent No. 11524118, U.S. Patent No. 11458257, U.S.
  • Patent No. 11458254 U.S. Patent No. 11426529, U.S. Patent No. 11426524, U.S. Patent No. 11406768, U.S. Patent No. 11383044, U.S. Patent No. 11331437, U.S. Patent No. 11311681, U.S. Patent No. 11291771, U.S. Patent No. 11273265, U.S. Patent No. 11253653, U.S. Patent No. 11229748, U.S. Patent No. 11224697, U.S. Patent No. 11154654, U.S. Patent No. 11141536, U.S. Patent No. 11103647, U.S. Patent No. 11103646, U.S. Patent No.
  • Kits are also provided which are useful for carrying out embodiments described herein.
  • the present kits can comprise a first container containing or packaged in association with the abovedescribed antibodies.
  • the kit may also comprise another container containing or packaged in association solutions necessary or convenient for carrying out the embodiments.
  • the containers can be made of glass, plastic or foil and can be a vial, bottle, pouch, tube, bag, etc.
  • the kit may also contain written information, such as procedures for carrying out the embodiments or analytical information, such as the amount of reagent contained in the first container means.
  • the container may be in another container apparatus, e.g. a box or a bag, along with the written information.
  • antibodies that bind to a Cis protein are provided.
  • the antibodies are antibodies or antigen binding fragments as provided for herein.
  • the antibodies or antigen binding fragments comprise an amino acid sequence as provided for herein, or a variant thereof as provided for herein.
  • the antibody is isolated.
  • the antibody binds specifically to the active form of Cls.
  • the antibody inhibits or neutralizes the function of an active form of Cis protein.
  • the term “neutralize” means that the activity or function of the protein is inhibited. The inhibition can be complete or partial. In some embodiments, the activity or function of the protein is inhibited at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or 99%. The percent inhibition can be based upon the function or activity of the protein in the absence of the antibody. In some embodiments, the antibody inhibits the function facilitated by Cis.
  • a method of treating a Cls-mediated disease or disorder in a subject in need thereof comprising: administering a first dose of an antibody, or a fragment thereof, wherein the first dose is about 1 mg/kg to about 60 mg/kg; or about 60 mg to about 7200 mg; administering one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, wherein the one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, is about 60 mg to about 7200 mg, and wherein the antibody, or the antigen-binding fragment thereof, comprises: a heavy chain variable region comprising: a HCDR1 of SEQ ID NO: 61, a HCDR2 of SEQ ID NO: 62, and a HCDR3 of SEQ ID NO: 78; and a light chain variable region comprising: a LCDR1 of SEQ ID NO: 64, a LCDR2 of SEQ ID NO: 65, and a LCDR3 of SEQ ID NO: 79.
  • the antibody, or the antigen-binding fragment thereof comprises: the heavy chain variable region having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to SEQ ID NO: 342, provided that the heavy chain comprises a HCDR1 of SEQ ID NO: 61, a HCDR2 of SEQ ID NO: 62, and a HCDR3 of SEQ ID NO: 78; or the heavy chain variable region having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to SEQ ID NO: 17, provided that the heavy chain comprises a
  • the antibody, or the antigen-binding fragment thereof comprises the light chain variable region having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to SEQ ID NO: 18, provided that the light chain comprises a LCDR1 of SEQ ID NO: 64, a LCDR2 of SEQ ID NO: 65, and a LCDR3 of SEQ ID NO: 79.
  • the antibody, or the antigen-binding fragment thereof comprises: the heavy chain variable region having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to SEQ ID NO: 342, provided that the heavy chain variable region comprises a HCDR1 of SEQ ID NO: 61, a HCDR2 of SEQ ID NO: 62, and a HCDR3 of SEQ ID NO: 78, and the light chain variable region having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to SEQ ID NO: 18,
  • the antibody, or the antigen-binding fragment thereof comprises: the heavy chain variable region having an amino acid sequence of SEQ ID NO: 342, and the light chain variable region having an amino acid sequence of SEQ ID NO: 18; or the heavy chain variable region having an amino acid sequence of SEQ ID NO: 17, and the light chain variable region having an amino acid sequence of SEQ ID NO: 18.
  • the antibody, or the antigen-binding fragment thereof comprises: the heavy chain having an amino acid sequence of SEQ ID NO: 380; the heavy chain having an amino acid sequence of SEQ ID NO: 381; the heavy chain having an amino acid sequence of SEQ ID NO: 184; or the heavy chain having an amino acid sequence of SEQ ID NO: 185.
  • the antibody, or the antigen-binding fragment thereof comprises: the heavy chain having an amino acid sequence of SEQ ID NO: 380, and the light chain having an amino acid sequence of SEQ ID NO: 236; the heavy chain having an amino acid sequence of SEQ ID NO: 381, and the light chain having an amino acid sequence of SEQ ID NO: 236; the heavy chain having an amino acid sequence of SEQ ID NO: 184, and the light chain having an amino acid sequence of SEQ ID NO: 236; or the heavy chain having an amino acid sequence of SEQ ID NO: 185, and the light chain having an amino acid sequence of SEQ ID NO: 236.
  • the first dose is selected from: about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg, about 25 mg/kg, about 26 mg/kg, about 27 mg/kg, about 28 mg/kg, about 29 mg/kg, about 30 mg/kg, about 31 mg/kg, about 32 mg/kg, about 33 mg/kg, about 34 mg/kg, about 35 mg/kg, about 36 mg/kg, about 37 mg/kg, about 38 mg/kg, about 39 mg/kg, about 40 mg/kg,
  • the one or more subsequent dose is selected from: about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg,
  • the one or more subsequent dose is selected from: 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg,
  • intravenous administration comprises administering the antibody, or the antigen-binding fragment thereof, by intravenous infusion over 45 minutes to about 90 minutes, or over 60 minutes to about 90 minutes.
  • Cls-mediated disease or disorder is selected from Myasthenia Gravis, hemolysis, Cold Agglutinin Disease, Immune Thrombocytopenia (ITP), Glomerulopathies, Atypical Hemolytic uremic syndrome, antiphospholipid antibody syndrome, transplant rejection, chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN), dermatomyositis, anti-MAG neuropathy, due to stroke, or due to spinal cord injury.
  • ITP Immune Thrombocytopenia
  • Glomerulopathies Atypical Hemolytic uremic syndrome, antiphospholipid antibody syndrome, transplant rejection, chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN), dermatomyositis, anti-MAG neuropathy, due to stroke, or due to spinal cord injury.
  • MG-ADL Scale Score Quantitative Myasthenia Gravis (QMG) Scale score, Myasthenia Gravis Composite (MGC) Scale Score, Myasthenia Gravis Quality of Life 15-point (MG-QoL 15r) Scale Score, Multidimensional Fatigue Index (MFI) 20 Scale Score, or Myasthenia Gravis PostIntervention Status (MG-PIS).
  • QMG Quantitative Myasthenia Gravis
  • MCC Myasthenia Gravis Composite
  • MFI Multidimensional Fatigue Index
  • MSE Minimal Symptom Expression
  • MSE Minimal Symptom Expression
  • a method of treating a Cls-mediated disease or disorder in a subject in need thereof comprising: administering a first dose of an antibody, or a fragment thereof, wherein the first dose is about 1 mg/kg to about 60 mg/kg; or about 60 mg to about 7200 mg; administering one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, wherein the one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, is about 60 mg to about 7200 mg, wherein the first dose is administered by intravenous or subcutaneous administration, wherein the one or more subsequent dose is administered by subcutaneous administration, and wherein the antibody, or the antigen-binding fragment thereof, comprises: a heavy chain variable region comprising: a HCDR1 of SEQ ID NO: 61, a HCDR2 of SEQ ID NO: 62, and a HCDR3 of SEQ ID NO: 78; and a light chain variable region comprising: a LCDR1 of SEQ ID NO: 64, a LCDR
  • the antibody, or the antigen-binding fragment thereof comprises: the heavy chain variable region having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to SEQ ID NO: 342, provided that the heavy chain comprises a HCDR1 of SEQ ID NO: 61, a HCDR2 of SEQ ID NO: 62, and a HCDR3 of SEQ ID NO: 78; or the heavy chain variable region having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to SEQ ID NO: 17, provided that the heavy chain variable region having at least 70%, at least 75%
  • the antibody, or the antigen-binding fragment thereof comprises the light chain variable region having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to SEQ ID NO: 18, provided that the light chain comprises a LCDR1 of SEQ ID NO: 64, a LCDR2 of SEQ ID NO: 65, and a LCDR3 of SEQ ID NO: 79.
  • the antibody, or the antigen-binding fragment thereof comprises: the heavy chain variable region having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to SEQ ID NO: 342, provided that the heavy chain variable region comprises a HCDR1 of SEQ ID NO: 61, a HCDR2 of SEQ ID NO: 62, and a HCDR3 of SEQ ID NO: 78, and the light chain variable region having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to SEQ ID NO: 342, provided that the heavy chain variable region comprises a HCDR
  • any one of embodiments 63-70, wherein the antibody, or the antigen-binding fragment thereof, comprises: the heavy chain variable region having an amino acid sequence of SEQ ID NO: 342; or the heavy chain variable region having an amino acid sequence of SEQ ID NO: 17.
  • any one of embodiments 63-72, wherein the antibody, or the antigen-binding fragment thereof, comprises: the heavy chain variable region having an amino acid sequence of SEQ ID NO: 342, and the light chain variable region having an amino acid sequence of SEQ ID NO: 18; or the heavy chain variable region having an amino acid sequence of SEQ ID NO: 17, and the light chain variable region having an amino acid sequence of SEQ ID NO: 18.
  • any one of embodiments 63-73, wherein the antibody, or the antigen-binding fragment thereof, comprises: the heavy chain having an amino acid sequence of SEQ ID NO: 380; the heavy chain having an amino acid sequence of SEQ ID NO: 381; the heavy chain having an amino acid sequence of SEQ ID NO: 184; or the heavy chain having an amino acid sequence of SEQ ID NO: 185.
  • any one of embodiments 63-75, wherein the antibody, or the antigen-binding fragment thereof, comprises: the heavy chain having an amino acid sequence of SEQ ID NO: 380, and the light chain having an amino acid sequence of SEQ ID NO: 236; the heavy chain having an amino acid sequence of SEQ ID NO: 381, and the light chain having an amino acid sequence of SEQ ID NO: 236; the heavy chain having an amino acid sequence of SEQ ID NO: 184, and the light chain having an amino acid sequence of SEQ ID NO: 236; or the heavy chain having an amino acid sequence of SEQ ID NO: 185, and the light chain having an amino acid sequence of SEQ ID NO: 236.
  • the method of embodiment 63, wherein the first dose is selected from: about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg, about 25 mg/kg, about 26 mg/kg, about 27 mg/kg, about 28 mg/kg, about 29 mg/kg, about 30 mg/kg, about 31 mg/kg, about 32 mg/kg, about 33 mg/kg, about 34 mg/kg, about 35 mg/kg, about 36 mg/kg, about 37 mg/kg, about 38 mg/kg, about 39 mg/kg, about 40
  • the one or more subsequent dose is selected from: about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 5
  • the method of embodiment 83, wherein the first dose is about 1 mg/kg, about 3 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 30 mg/kg, about 50 mg/kg, or about 60 mg/kg.
  • any one of embodiments 94-96, wherein the intravenous administration comprises administering the antibody, or the antigen-binding fragment thereof, by intravenous infusion over 45 minutes to about 90 minutes, or over 60 minutes to about 90 minutes.
  • Cls-mediated disease or disorder is selected from Myasthenia Gravis, hemolysis, Cold Agglutinin Disease, Immune Thrombocytopenia (ITP), Glomerulopathies, Atypical Hemolytic uremic syndrome, antiphospholipid antibody syndrome, transplant rejection, chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN), dermatomyositis, anti-MAG neuropathy, due to stroke, or due to spinal cord injury.
  • ITP Immune Thrombocytopenia
  • Glomerulopathies Atypical Hemolytic uremic syndrome, antiphospholipid antibody syndrome, transplant rejection, chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN), dermatomyositis, anti-MAG neuropathy, due to stroke, or due to spinal cord injury.
  • MG-ADL Scale Score Quantitative Myasthenia Gravis (QMG) Scale score, Myasthenia Gravis Composite (MGC) Scale Score, Myasthenia Gravis Quality of Life 15-point (MG-QoL 15r) Scale Score, Multidimensional Fatigue Index (MFI) 20 Scale Score, or Myasthenia Gravis Post-Intervention Status (MG-PIS).
  • QMG Quantitative Myasthenia Gravis
  • MCC Myasthenia Gravis Composite
  • MFI Multidimensional Fatigue Index
  • MG-PIS Myasthenia Gravis Post-Intervention Status
  • MSE Minimal Symptom Expression
  • MSE Minimal Symptom Expression
  • MSE Minimal Symptom Expression
  • a method of treating a Cls-mediated disease or disorder in a subject in need thereof comprising: administering a first dose of an antibody, or a fragment thereof, wherein the first dose is selected from: about 1 mg/kg, about 3 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 30 mg/kg, about 50 mg/kg, or about 60 mg/kg; or about 300 mg, or about 600 mg; administering one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, wherein the one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, is about 300 mg, or about 600 mg, wherein the first dose is administered by intravenous or subcutaneous administration, wherein the one or more subsequent dose is administered by subcutaneous administration, and wherein the antibody, or the antigen-binding fragment thereof, comprises: a heavy chain variable region comprising: a HCDR1 of SEQ ID NO: 61, a HCDR2 of SEQ ID NO: 62, and a
  • the antibody, or the antigen-binding fragment thereof comprises: the heavy chain variable region having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to SEQ ID NO: 342, provided that the heavy chain comprises a HCDR1 of SEQ ID NO: 61, a HCDR2 of SEQ ID NO: 62, and a HCDR3 of SEQ ID NO: 78; or the heavy chain variable region having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to SEQ ID NO: 17, provided that the heavy chain
  • the antibody, or the antigen-binding fragment thereof comprises the light chain variable region having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to SEQ ID NO: 18, provided that the light chain comprises a LCDR1 of SEQ ID NO: 64, a LCDR2 of SEQ ID NO: 65, and a LCDR3 of SEQ ID NO: 79.
  • any one of embodiments 125-131, wherein the antibody, or the antigenbinding fragment thereof, comprises: the heavy chain variable region having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to SEQ ID NO: 342, provided that the heavy chain variable region comprises a HCDR1 of SEQ ID NO: 61, a HCDR2 of SEQ ID NO: 62, and a HCDR3 of SEQ ID NO: 78, and the light chain variable region having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to SEQ ID NO: 342, provided
  • the method of any one of embodiments 125-134, wherein the antibody, or the antigenbinding fragment thereof, comprises: the heavy chain variable region having an amino acid sequence of SEQ ID NO: 342, and the light chain variable region having an amino acid sequence of SEQ ID NO: 18; or the heavy chain variable region having an amino acid sequence of SEQ ID NO: 17, and the light chain variable region having an amino acid sequence of SEQ ID NO: 18.
  • any one of embodiments 125-135, wherein the antibody, or the antigenbinding fragment thereof, comprises: the heavy chain having an amino acid sequence of SEQ ID NO: 380; the heavy chain having an amino acid sequence of SEQ ID NO: 381; the heavy chain having an amino acid sequence of SEQ ID NO: 184; or the heavy chain having an amino acid sequence of SEQ ID NO: 185.
  • any one of embodiments 125-137, wherein the antibody, or the antigenbinding fragment thereof, comprises: the heavy chain having an amino acid sequence of SEQ ID NO: 380, and the light chain having an amino acid sequence of SEQ ID NO: 236; the heavy chain having an amino acid sequence of SEQ ID NO: 381, and the light chain having an amino acid sequence of SEQ ID NO: 236; the heavy chain having an amino acid sequence of SEQ ID NO: 184, and the light chain having an amino acid sequence of SEQ ID NO: 236; or the heavy chain having an amino acid sequence of SEQ ID NO: 185, and the light chain having an amino acid sequence of SEQ ID NO: 236.
  • the method of embodiment 125, wherein the first dose is about 1 mg/kg, about 3 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 30 mg/kg, about 50 mg/kg, or about 60 mg/kg.
  • any one of embodiments 125-150 comprising administering a total of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 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, or 84 doses to the subject.
  • intravenous administration comprises administering the antibody, or the antigen-binding fragment thereof, by intravenous infusion over 45 minutes to about 90 minutes, or over 60 minutes to about 90 minutes.
  • Cls-mediated disease or disorder is selected from Myasthenia Gravis, hemolysis, Cold Agglutinin Disease, Immune Thrombocytopenia (ITP), Glomerulopathies, Atypical Hemolytic uremic syndrome, antiphospholipid antibody syndrome, transplant rejection, chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN), dermatomyositis, anti-MAG neuropathy, due to stroke, or due to spinal cord injury.
  • CIDP chronic inflammatory demyelinating polyneuropathy
  • MN multifocal motor neuropathy
  • MN multifocal motor neuropathy
  • anti-MAG neuropathy due to stroke, or due to spinal cord injury.
  • MG-ADL Scale Score Quantitative Myasthenia Gravis (QMG) Scale score, Myasthenia Gravis Composite (MGC) Scale Score, Myasthenia Gravis Quality of Life 15-point (MG-QoL 15r) Scale Score, Multidimensional Fatigue Index (MFI) 20 Scale Score, or Myasthenia Gravis Post-Intervention Status (MG-PIS).
  • QMG Quantitative Myasthenia Gravis
  • MCC Myasthenia Gravis Composite
  • MFI Multidimensional Fatigue Index
  • MG-PIS Myasthenia Gravis Post-Intervention Status
  • MSE Minimal Symptom Expression
  • MSE Minimal Symptom Expression
  • a method of treating a Cls-mediated disease or disorder in a subject in need thereof comprising: administering intravenously a first dose of an antibody, or a fragment thereof, in a dose of about 15 mg/kg to about 20 mg/kg; and administering subcutaneously a one or more subsequent dose of the antibody, or the antigenbinding fragment thereof, in a dose of about 300 mg to about 600 mg, wherein the one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, is administered every two weeks following administration of the first dose, and wherein the antibody, or the antigen-binding fragment thereof, comprises: a heavy chain variable region comprising: a HCDR1 of SEQ ID NO: 61, a HCDR2 of SEQ ID NO: 62, and a HCDR3 of SEQ ID NO: 78; and a light chain variable region comprising: a LCDR1 of SEQ ID NO: 64, a LCDR2 of SEQ ID NO: 65, and a LCDR3 of SEQ ID
  • the antibody, or the antigen-binding fragment thereof comprises: the heavy chain variable region having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to SEQ ID NO: 342, provided that the heavy chain comprises a HCDR1 of SEQ ID NO: 61, a HCDR2 of SEQ ID NO: 62, and a HCDR3 of SEQ ID NO: 78; or the heavy chain variable region having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to SEQ ID NO: 17, provided that the heavy chain variable region having at least 70%, at least 75%
  • the antibody, or the antigen-binding fragment thereof comprises the light chain variable region having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to SEQ ID NO: 18, provided that the light chain comprises a LCDR1 of SEQ ID NO: 64, a LCDR2 of SEQ ID NO: 65, and a LCDR3 of SEQ ID NO: 79.
  • the antibody, or the antigenbinding fragment thereof comprises: the heavy chain variable region having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to SEQ ID NO: 342, provided that the heavy chain variable region comprises a HCDR1 of SEQ ID NO: 61, a HCDR2 of SEQ ID NO: 62, and a HCDR3 of SEQ ID NO: 78, and the light chain variable region having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to SEQ ID NO: 342, provided that the heavy chain variable region comprises a HCDR1
  • any one of embodiments 183-190, wherein the antibody, or the antigenbinding fragment thereof, comprises: the heavy chain variable region having an amino acid sequence of SEQ ID NO: 342; or the heavy chain variable region having an amino acid sequence of SEQ ID NO: 17.
  • any one of embodiments 183-192, wherein the antibody, or the antigenbinding fragment thereof, comprises: the heavy chain variable region having an amino acid sequence of SEQ ID NO: 342, and the light chain variable region having an amino acid sequence of SEQ ID NO: 18; or the heavy chain variable region having an amino acid sequence of SEQ ID NO: 17, and the light chain variable region having an amino acid sequence of SEQ ID NO: 18.
  • any one of embodiments 183-193, wherein the antibody, or the antigenbinding fragment thereof, comprises: the heavy chain having an amino acid sequence of SEQ ID NO: 380; the heavy chain having an amino acid sequence of SEQ ID NO: 381; the heavy chain having an amino acid sequence of SEQ ID NO: 184; or the heavy chain having an amino acid sequence of SEQ ID NO: 185.
  • any one of embodiments 183-195, wherein the antibody, or the antigenbinding fragment thereof, comprises: the heavy chain having an amino acid sequence of SEQ ID NO: 380, and the light chain having an amino acid sequence of SEQ ID NO: 236; the heavy chain having an amino acid sequence of SEQ ID NO: 381, and the light chain having an amino acid sequence of SEQ ID NO: 236; the heavy chain having an amino acid sequence of SEQ ID NO: 184, and the light chain having an amino acid sequence of SEQ ID NO: 236; or the heavy chain having an amino acid sequence of SEQ ID NO: 185, and the light chain having an amino acid sequence of SEQ ID NO: 236.
  • Cls-mediated disease or disorder is selected from Myasthenia Gravis, hemolysis, Cold Agglutinin Disease, Immune Thrombocytopenia (ITP), Glomerulopathies, Atypical Hemolytic uremic syndrome, antiphospholipid antibody syndrome, transplant rejection, chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN), dermatomyositis, anti-MAG neuropathy, due to stroke, or due to spinal cord injury.
  • CIDP chronic inflammatory demyelinating polyneuropathy
  • MN multifocal motor neuropathy
  • MN multifocal motor neuropathy
  • anti-MAG neuropathy due to stroke, or due to spinal cord injury.
  • MG-ADL Scale Score Quantitative Myasthenia Gravis (QMG) Scale score, Myasthenia Gravis Composite (MGC) Scale Score, Myasthenia Gravis Quality of Life 15-point (MG-QoL 15r) Scale Score, Multidimensional Fatigue Index (MFI) 20 Scale Score, or Myasthenia Gravis Post-Intervention Status (MG-PIS).
  • QMG Quantitative Myasthenia Gravis
  • MCC Myasthenia Gravis Composite
  • MFI Multidimensional Fatigue Index
  • MSE Minimal Symptom Expression
  • MSE Minimal Symptom Expression
  • a method of treating a Myasthenia Gravis (MG) in a subject in need thereof comprising: administering intravenously a first dose of an antibody, or a fragment thereof, in a dose of about 15 mg/kg to about 20 mg/kg; and administering subcutaneously a one or more subsequent dose of the antibody, or the antigenbinding fragment thereof, in a dose of about 300 mg to about 600 mg, wherein the one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, is administered every two weeks following administration of the first dose, and wherein the antibody, or the antigen-binding fragment thereof, comprises: a heavy chain variable region comprising: a HCDR1 of SEQ ID NO: 61, a HCDR2 of SEQ ID NO: 62, and a HCDR3 of SEQ ID NO: 78; and a light chain variable region comprising: a LCDR1 of SEQ ID NO: 64, a LCDR2 of SEQ ID NO: 65, and a LCDR3 of S
  • the method of embodiment 221, wherein the antibody, or the antigen-binding fragment thereof, comprises: the heavy chain variable region having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to SEQ ID NO: 342, provided that the heavy chain comprises a HCDR1 of SEQ ID NO: 61, a HCDR2 of SEQ ID NO: 62, and a HCDR3 of SEQ ID NO: 78; or the heavy chain variable region having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to SEQ ID NO: 17, provided that the heavy chain
  • the antibody, or the antigen-binding fragment thereof comprises the light chain variable region having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to SEQ ID NO: 18, provided that the light chain comprises a LCDR1 of SEQ ID NO: 64, a LCDR2 of SEQ ID NO: 65, and a LCDR3 of SEQ ID NO: 79.
  • the antibody, or the antigenbinding fragment thereof comprises: the heavy chain variable region having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to SEQ ID NO: 342, provided that the heavy chain variable region comprises a HCDR1 of SEQ ID NO: 61, a HCDR2 of SEQ ID NO: 62, and a HCDR3 of SEQ ID NO: 78, and the light chain variable region having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to SEQ ID NO: 342, provided that the heavy chain variable region comprises a HCDR1
  • the method of any one of embodiments 221-230, wherein the antibody, or the antigenbinding fragment thereof, comprises: the heavy chain variable region having an amino acid sequence of SEQ ID NO: 342, and the light chain variable region having an amino acid sequence of SEQ ID NO: 18; or the heavy chain variable region having an amino acid sequence of SEQ ID NO: 17, and the light chain variable region having an amino acid sequence of SEQ ID NO: 18.
  • the method of any one of embodiments 221-231, wherein the antibody, or the antigenbinding fragment thereof, comprises: the heavy chain having an amino acid sequence of SEQ ID NO: 380; the heavy chain having an amino acid sequence of SEQ ID NO: 381; the heavy chain having an amino acid sequence of SEQ ID NO: 184; or the heavy chain having an amino acid sequence of SEQ ID NO: 185.
  • the method of any one of embodiments 221-233, wherein the antibody, or the antigenbinding fragment thereof, comprises: the heavy chain having an amino acid sequence of SEQ ID NO: 380, and the light chain having an amino acid sequence of SEQ ID NO: 236; the heavy chain having an amino acid sequence of SEQ ID NO: 381, and the light chain having an amino acid sequence of SEQ ID NO: 236; the heavy chain having an amino acid sequence of SEQ ID NO: 184, and the light chain having an amino acid sequence of SEQ ID NO: 236; or the heavy chain having an amino acid sequence of SEQ ID NO: 185, and the light chain having an amino acid sequence of SEQ ID NO: 236.
  • MG-ADL Scale Score Quantitative Myasthenia Gravis (QMG) Scale score, Myasthenia Gravis Composite (MGC) Scale Score, Myasthenia Gravis Quality of Life 15-point (MG-QoL 15r) Scale Score, Multidimensional Fatigue Index (MFI) 20 Scale Score, or Myasthenia Gravis Post-Intervention Status (MG-PIS).
  • QMG Quantitative Myasthenia Gravis
  • MCC Myasthenia Gravis Composite
  • MFI Multidimensional Fatigue Index
  • MSE Minimal Symptom Expression
  • MSE Minimal Symptom Expression
  • a method of treating a Multifocal Motor Neuropathy (MMN) in a subject in need thereof comprising: administering intravenously a first dose of an antibody, or a fragment thereof, in a dose of about 1 mg/kg to about 60 mg/kg; and administering subcutaneously a one or more subsequent dose of the antibody, or the antigenbinding fragment thereof, in a dose of about 60 mg to about 7200 mg, wherein the one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, is administered every two weeks following administration of the first dose, and wherein the antibody, or the antigen-binding fragment thereof, comprises: a heavy chain variable region comprising: a HCDR1 of SEQ ID NO: 61, a HCDR2 of SEQ ID NO: 62, and a HCDR3 of SEQ ID NO: 78; a light chain variable region comprising: a LCDR1 of SEQ ID NO: 64, a LCDR2 of SEQ ID NO: 65, and a LCDR3 of
  • the antibody, or the antigen-binding fragment thereof comprises: the heavy chain variable region having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to SEQ ID NO: 342, provided that the heavy chain comprises a HCDR1 of SEQ ID NO: 61, a HCDR2 of SEQ ID NO: 62, and a HCDR3 of SEQ ID NO: 78; or the heavy chain variable region having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to SEQ ID NO: 17, provided that the heavy chain variable region having at least 70%, at least 75%
  • the antibody, or the antigen-binding fragment thereof comprises the light chain variable region having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to SEQ ID NO: 18, provided that the light chain comprises a LCDR1 of SEQ ID NO: 64, a LCDR2 of SEQ ID NO: 65, and a LCDR3 of SEQ ID NO: 79.
  • any one of embodiments 259-265, wherein the antibody, or the antigenbinding fragment thereof, comprises: the heavy chain variable region having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to SEQ ID NO: 342, provided that the heavy chain variable region comprises a HCDR1 of SEQ ID NO: 61, a HCDR2 of SEQ ID NO: 62, and a HCDR3 of SEQ ID NO: 78, and the light chain variable region having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to SEQ ID NO: 342, provided
  • the method of any one of embodiments 259-266, wherein the antibody, or the antigenbinding fragment thereof, comprises: the heavy chain variable region having an amino acid sequence of SEQ ID NO: 342; or the heavy chain variable region having an amino acid sequence of SEQ ID NO: 17.
  • any one of embodiments 259-268, wherein the antibody, or the antigenbinding fragment thereof comprises: the heavy chain variable region having an amino acid sequence of SEQ ID NO: 342, and the light chain variable region having an amino acid sequence of SEQ ID NO: 18; or the heavy chain variable region having an amino acid sequence of SEQ ID NO: 17, and the light chain variable region having an amino acid sequence of SEQ ID NO: 18.
  • the method of any one of embodiments 259-270, wherein the antibody, or the antigenbinding fragment thereof, comprises the light chain having an amino acid sequence of SEQ ID NO: 236.
  • any one of embodiments 259-271, wherein the antibody, or the antigenbinding fragment thereof, comprises: the heavy chain having an amino acid sequence of SEQ ID NO: 380, and the light chain having an amino acid sequence of SEQ ID NO: 236; the heavy chain having an amino acid sequence of SEQ ID NO: 381, and the light chain having an amino acid sequence of SEQ ID NO: 236; the heavy chain having an amino acid sequence of SEQ ID NO: 184, and the light chain having an amino acid sequence of SEQ ID NO: 236; or the heavy chain having an amino acid sequence of SEQ ID NO: 185, and the light chain having an amino acid sequence of SEQ ID NO: 236.
  • the method of embodiment 259, wherein the first dose is selected from: about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg, about 25 mg/kg, about 26 mg/kg, about 27 mg/kg, about 28 mg/kg, about 29 mg/kg, about 30 mg/kg, about 31 mg/kg, about 32 mg/kg, about 33 mg/kg, about 34 mg/kg, about 35 mg/kg, about 36 mg/kg, about 37 mg/kg, about 38 mg/kg, about 39 mg/kg, about 40 mg
  • a method of treating a Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) in a subject in need thereof comprising: administering intravenously a first dose of an antibody, or a fragment thereof, in a dose of about 1 mg/kg to about 60 mg/kg; and administering a one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, in a dose of about 60 mg to about 8300 mg, wherein the one or more subsequent dose of the antibody, or the antigen-binding fragment thereof, is administered every two weeks following administration of the first dose, and wherein the antibody, or the antigen-binding fragment thereof, comprises: a heavy chain variable region comprising: a HCDR1 of SEQ ID NO: 61, a HCDR2 of SEQ ID NO: 62, and a HCDR3 of SEQ ID NO: 78; and a light chain variable region comprising: a LCDR1 of SEQ ID NO: 64, a LCDR2 of SEQ ID NO: 65, and
  • the method of embodiment 283, wherein the antibody, or the antigen-binding fragment thereof, comprises: the heavy chain variable region having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to SEQ ID NO: 342, provided that the heavy chain comprises a HCDR1 of SEQ ID NO: 61, a HCDR2 of SEQ ID NO: 62, and a HCDR3 of SEQ ID NO: 78; or the heavy chain variable region having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to SEQ ID NO: 17, provided that the heavy chain
  • the method of embodiment 283, wherein the antibody, or the antigen-binding fragment thereof, comprises the light chain variable region having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to SEQ ID NO: 18, provided that the light chain comprises a LCDR1 of SEQ ID NO: 64, a LCDR2 of SEQ ID NO: 65, and a LCDR3 of SEQ ID NO: 79.
  • the antibody, or the antigenbinding fragment thereof comprises: the heavy chain variable region having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to SEQ ID NO: 342, provided that the heavy chain variable region comprises a HCDR1 of SEQ ID NO: 61, a HCDR2 of SEQ ID NO: 62, and a HCDR3 of SEQ ID NO: 78, and the light chain variable region having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to SEQ ID NO: 342, provided that the heavy chain variable region comprises a HCDR1
  • the method of any one of embodiments 283-290, wherein the antibody, or the antigenbinding fragment thereof, comprises: the heavy chain variable region having an amino acid sequence of SEQ ID NO: 342; or the heavy chain variable region having an amino acid sequence of SEQ ID NO: 17.
  • the method of any one of embodiments 283-292, wherein the antibody, or the antigenbinding fragment thereof, comprises: the heavy chain variable region having an amino acid sequence of SEQ ID NO: 342, and the light chain variable region having an amino acid sequence of SEQ ID NO: 18; or the heavy chain variable region having an amino acid sequence of SEQ ID NO: 17, and the light chain variable region having an amino acid sequence of SEQ ID NO: 18.
  • the method of any one of embodiments 283-293, wherein the antibody, or the antigenbinding fragment thereof, comprises: the heavy chain having an amino acid sequence of SEQ ID NO: 380; the heavy chain having an amino acid sequence of SEQ ID NO: 381; the heavy chain having an amino acid sequence of SEQ ID NO: 184; or the heavy chain having an amino acid sequence of SEQ ID NO: 185.
  • the method of any one of embodiments 283-295, wherein the antibody, or the antigenbinding fragment thereof, comprises: the heavy chain having an amino acid sequence of SEQ ID NO: 380, and the light chain having an amino acid sequence of SEQ ID NO: 236; the heavy chain having an amino acid sequence of SEQ ID NO: 381, and the light chain having an amino acid sequence of SEQ ID NO: 236; the heavy chain having an amino acid sequence of SEQ ID NO: 184, and the light chain having an amino acid sequence of SEQ ID NO: 236; or the heavy chain having an amino acid sequence of SEQ ID NO: 185, and the light chain having an amino acid sequence of SEQ ID NO: 236.
  • the method of embodiment 283, wherein the first dose is selected from: about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg, about 25 mg/kg, about 26 mg/kg, about 27 mg/kg, about 28 mg/kg, about 29 mg/kg, about 30 mg/kg, about 31 mg/kg, about 32 mg/kg, about 33 mg/kg, about 34 mg/kg, about 35 mg/kg, about 36 mg/kg, about 37 mg/kg, about 38 mg/kg, about 39 mg/kg, about 40 mg
  • the method of embodiment 283, wherein the one or more subsequent dose is selected from: about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg
  • clinical activity score is selected from Inflammatory Neuropathy Cause and Treatment (INCAT) Disability Score, Inflammatory Rasch-build Overall Disability Score (I-RODS), or Medical Research Council Sum Score (MRC-16).
  • ICAT Inflammatory Neuropathy Cause and Treatment
  • I-RODS Inflammatory Rasch-build Overall Disability Score
  • MRC-16 Medical Research Council Sum Score
  • I-RODS Inflammatory Rasch-build Overall Disability Score
  • Example 1 A Phase 1, Placebo-Controlled, Single/Multiple Ascending Dose Study of MAB39 Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Following Intravenous and Subcutaneous Administration in Healthy Volunteers.
  • MAB39 Preclinical studies have demonstrated the ability of MAB39 to bind selectively to active Cis and inhibit the complement CP cascade following either IV or subcutaneous (SC) administration in cynomolgus monkeys.
  • SC subcutaneous
  • MAB39 is designed to selectively target the complement CP whilst leaving the alternative and lectin-activated defense pathways intact, with the aim of reducing the infection risk.
  • MAB39 also preserves the function of other Cl complex proteins such as Clq, which in addition to initiating CP complement activation also plays a role in the maintenance of homeostasis including synaptic pruning, clearance of apoptotic cells and cellular debris, and modulation of the adaptive immune system.
  • MAB39 may enable lower and less frequent dosing regimens, providing crucial differentiation advantages over existing Cis targeted therapies.
  • the study has two parts: Part A, the single ascending dose (SAD) portion, and Part B, the multiple ascending dose (MAD) portion.
  • SAD single ascending dose
  • MAD multiple ascending dose
  • Each study part consists of an 8-week core study phase (up to Day 57), a safety extension phase, and an optional PK extension phase for selected cohorts.
  • This interim CSR presents data from the first 7 cohorts (3 SAD IV cohorts, 2 SAD SC cohorts, and 2 MAD SC cohorts).
  • the study was conducted in a sequentially escalating order with lower dose levels evaluated first in the sequence.
  • the starting dose, dose increments, and dose range to be evaluated were based on available nonclinical data.
  • Part A the protocol identified nominal dose levels of IV1 (1 mg/kg), IV2 (3 mg/kg), IV3 (10 mg/kg), IV4 (30 mg/kg) and IV5 (60 mg/kg) for IV dosing, and SCI (300 mg) and SC2 (600 mg) for SC dosing. These nominal dosing levels could be changed depending on emerging data; the protocol specified that the IV2 (3 mg/kg) dosing level was optional and that the Sponsor could elect not to proceed to the higher dosing level cohorts and/or to add intermediate dose cohorts, as appropriate.
  • Part B the protocol identified nominal dose levels of 300 mg SC and 600 mg SC given every 2 weeks for a total of 3 doses.
  • Each SAD and MAD cohort was to enroll a target of 8 participants with 6 participants randomized to receive MAB39 and 2 participants randomized to receive placebo.
  • Study treatment for IV administration was to be infused through a peripheral IV line over a period of 60 ⁇ 10 minutes.
  • the infusion could be slowed or interrupted for participants experiencing infusion-related AEs.
  • Study treatment for SC administration was administered manually via SC injection in the abdomen (preferred site) or thigh (secondary site). Where multiple injections were required to be administered for a dose level, each injection was to be administered at a different site (e.g., for abdomen: right upper quadrant, left upper quadrant, right lower quadrant, left lower quadrant).
  • MAB39 was well tolerated. There were no serious adverse effects (SAEs) or deaths, no participant withdrew from the study due to AEs, and no dose limiting toxicities were reported.
  • AEs adverse effects
  • 3 participants in the MAD MAB39 groups had AEs which were of Grade 2 severity: 1 participant (16.7%) in the 300 mg SC group had 2 AEs of Grade 2 severity (injection site erythema and upper respiratory tract infection) both of which resolved, and 2 participants (33.3%) in the 600 mg SC group each had an AE of Grade 2 severity (urticaria which resolved and urinary tract infection which was listed as resolving/recovering at the data cut off). No placebo participants had AEs of Grade 2 severity.
  • Injection site reactions were reported in 2 participants (16.7%) in Part B (MAD), 1 in the 300 mg SC group and 1 in the 600 mg SC group; no placebo participants reported injection site reactions. All events resolved without treatment.
  • AUC0-7 Area under the concentration-time curve from time zero to 7 days post-dose
  • AUC 0 -t Area under the concentration versus time curve from time zero to the last measurable time point postdose
  • AUCo-inf Area under the concentration-time curve from time zero to infinity
  • CL/F Apparent clearance (SC only)
  • C ma x Maximum (or peak) serum concentration
  • CV Coefficient of variation
  • h Hour
  • N Number
  • NA Not applicable
  • NE Not estimable
  • PK Pharmacokinetic
  • SC Subcutaneous
  • SD Standard deviation
  • ti/2 Terminal elimination half life
  • T max time to maximum concentration
  • Vz Volume of distribution (IV only)
  • Vz/F Apparent volume of distribution (SC only).
  • Terminal phase parameters of CL, Vz and 11/2 were only reportable for the 1 mg/kg group and 1 participant in the 10 mg/kg dose groups as data were not yet mature enough for these values to be calculated for the remainder of the participants and the 30 mg/kg group.
  • MAB39 displayed a low clearance (range of 3.3 to 5.5 mL/h), low volume of distribution (range of 5872 to 12743 mL), and long tl/2 (range of ⁇ 37 to 82.3 days), for the 1 mg/kg and 10 mg/kg dose groups where estimates were possible. Additionally, based on the limited data taken together along with visual inspection of the concentration-time profiles (FIG. 1), there does not appear to be dose dependent PK for MAB39 within the range evaluated in this study.
  • MAB39 Consistent with IV data, following SC administration at 300 mg and 600 mg, MAB39 has low apparent clearance (mean CL/F of 8.7 and 7.4 mL/h, respectively), low apparent volume of distribution (mean Vz/F of 18414 and 14714 mL, respectively), and a long tl/2 (mean 58 to 60 days) following SC dosing. No dose dependency was evident in the PK of MAB39 at these SC doses.
  • the mean accumulation ratio (AR) values for the Day 29 doses based on Cmax were 2.6 and 2.8 for the 300 mg and 600 mg groups, respectively.
  • the AUCO-inf on Day 29 was not yet mature for the SC MAD groups as at the data cut off, however, AUCO-7 and AUCO-14 are reported for all groups and are presented in Table 3.
  • the mean AR values for the 300 mg and 600 mg Day 29 doses based on AUCO-14 were 2.7 and 3.0, respectively. These AR values indicate that MAB39 accumulates approximately 3 -fold following SC dosing given every 2 weeks for a total of 3 doses.
  • AUC0-7 Area under the concentration-time curve from time zero to 7 days post-dose
  • AUCo-14 Area under the concentration versus time curve from time zero to 14 days post-dose
  • AUCo- m f Area under the concentration-time curve from time zero to infinity
  • CL/F Apparent clearance
  • C ma x Maximum (or peak) serum concentration
  • CV Coefficient of variation
  • h Hour
  • N Number
  • NA Not applicable
  • NE Not estimable
  • PK Pharmacokinetic
  • SC Subcutaneous
  • SD Standard deviation
  • ti/2 Terminal elimination half life
  • Tmax time to maximum concentration
  • Vz/F Apparent volume of distribution .

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Abstract

L'invention concerne des compositions, des doses et des méthodes d'utilisation d'un anticorps, ou d'un fragment de liaison à l'antigène de celui-ci, pour le traitement de maladies ou de troubles à médiation par C1s.
PCT/US2025/014040 2024-02-02 2025-01-31 Compositions, doses et méthodes de traitement de maladies et de troubles à médiation par c1s Pending WO2025166169A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008054881A2 (fr) * 2006-06-07 2008-05-08 The Penn State Research Foundation Agents antibactériens et d'élimination de plasmides
US20210324100A1 (en) * 2017-11-01 2021-10-21 Juno Therapeutics, Inc. Chimeric antigen receptors specific for b-cell maturation antigen and encoding polynucleotides
US20220213201A1 (en) * 2019-08-14 2022-07-07 Pharmabcine Inc. Anti-tie2 antibody and use thereof
US20220380483A1 (en) * 2021-05-20 2022-12-01 Dianthus Therapeutics, Inc. Antibodies that bind to c1s and uses thereof
US20230312729A1 (en) * 2019-06-26 2023-10-05 Amunix Pharmaceuticals, Inc. Egfr antigen binding fragments and compositions comprising same
US20240166769A1 (en) * 2022-11-21 2024-05-23 Dianthus Therapeutics Opco, Inc. Antibodies that bind to c1s and uses thereof

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008054881A2 (fr) * 2006-06-07 2008-05-08 The Penn State Research Foundation Agents antibactériens et d'élimination de plasmides
US20210324100A1 (en) * 2017-11-01 2021-10-21 Juno Therapeutics, Inc. Chimeric antigen receptors specific for b-cell maturation antigen and encoding polynucleotides
US20230312729A1 (en) * 2019-06-26 2023-10-05 Amunix Pharmaceuticals, Inc. Egfr antigen binding fragments and compositions comprising same
US20220213201A1 (en) * 2019-08-14 2022-07-07 Pharmabcine Inc. Anti-tie2 antibody and use thereof
US20220380483A1 (en) * 2021-05-20 2022-12-01 Dianthus Therapeutics, Inc. Antibodies that bind to c1s and uses thereof
US20240166769A1 (en) * 2022-11-21 2024-05-23 Dianthus Therapeutics Opco, Inc. Antibodies that bind to c1s and uses thereof

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