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WO2025247924A1 - ANTI-IFN-α2 MONOCLONAL ANTIBODIES - Google Patents

ANTI-IFN-α2 MONOCLONAL ANTIBODIES

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Publication number
WO2025247924A1
WO2025247924A1 PCT/EP2025/064682 EP2025064682W WO2025247924A1 WO 2025247924 A1 WO2025247924 A1 WO 2025247924A1 EP 2025064682 W EP2025064682 W EP 2025064682W WO 2025247924 A1 WO2025247924 A1 WO 2025247924A1
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WO
WIPO (PCT)
Prior art keywords
seq
set forth
domain
amino acid
ifn
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2025/064682
Other languages
French (fr)
Inventor
Matthieu MAHEVAS
Guy Gorochov
Jean-Laurent Casanova
Pascal CHAPPERT
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Centre National de la Recherche Scientifique CNRS
Assistance Publique Hopitaux de Paris APHP
Institut National de la Sante et de la Recherche Medicale INSERM
Universite Paris Est Creteil Val de Marne
Sorbonne Universite
Fondation Imagine
Universite Paris Cite
Universite de Marne la Vallee
Rockefeller University
Original Assignee
Centre National de la Recherche Scientifique CNRS
Assistance Publique Hopitaux de Paris APHP
Institut National de la Sante et de la Recherche Medicale INSERM
Universite Paris Est Creteil Val de Marne
Sorbonne Universite
Fondation Imagine
Universite Paris Cite
Universite de Marne la Vallee
Rockefeller University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Centre National de la Recherche Scientifique CNRS, Assistance Publique Hopitaux de Paris APHP, Institut National de la Sante et de la Recherche Medicale INSERM, Universite Paris Est Creteil Val de Marne, Sorbonne Universite, Fondation Imagine, Universite Paris Cite, Universite de Marne la Vallee, Rockefeller University filed Critical Centre National de la Recherche Scientifique CNRS
Publication of WO2025247924A1 publication Critical patent/WO2025247924A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • 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
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/249—Interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/715—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
    • C07K14/7156—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons for interferons [IFN]
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Definitions

  • Type I interferons are a group of cytokines that play a crucial role in antiviral immunity. They are produced by various cells in response to viral infections and induce the expression of genes that inhibit viral replication and activate immune cells. Type I IFNs also modulate the adaptive immune response and regulate inflammation. Recently, it has been discovered that some individuals have autoantibodies that target type I IFNs, either neutralizing their activity or blocking their binding to their receptors.
  • the present invention relates to anti-IFN- ⁇ 2 monoclonal antibodies.
  • DETAILED DESCRIPTION OF THE INVENTION Main definitions:
  • the terms “polypeptide”, “peptide”, and “protein” are used interchangeably herein to refer to polymers of amino acids of any length. The terms also encompass an amino acid polymer that has been modified; for example, disulfide bond formation, glycosylation, lipidation, phosphorylation, or conjugation with a labeling component.
  • polynucleotide refers to a polymeric form of nucleotides of any length, including deoxyribonucleotides or ribonucleotides, or analogs thereof.
  • a polynucleotide may comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs, and may be interrupted by non-nucleotide components. If present, modifications to the nucleotide structure may be imparted before or after assembly of the polymer.
  • the term polynucleotide, as used herein, refers interchangeably to double- and single-stranded molecules. Unless otherwise specified or required, any embodiment of the invention described herein that is a polynucleotide encompasses both the double-stranded form and each of two complementary single-stranded forms known or predicted to make up the double-stranded form.
  • the term "encoding" refers to the inherent property of specific sequences of nucleotides in a polynucleotide, such as, for example, a gene, a cDNA, or an mRNA, to serve as templates for synthesis of other polymers and macromolecules in biological processes having either a defined sequence of nucleotides (e.g., rRNA, tRNA and mRNA) or a defined sequence of amino acids and the biological properties resulting therefrom.
  • a gene, cDNA, or RNA encodes a protein if transcription and translation of mRNA corresponding to that gene produces the protein in a cell or other biological system.
  • coding strand the nucleotide sequence of which is identical to the mRNA sequence and is usually provided in sequence listings
  • non-coding strand used as the template for transcription of a gene or cDNA
  • encoding the protein or other product of that gene or cDNA can be referred to as encoding the protein or other product of that gene or cDNA.
  • a "nucleotide sequence encoding an amino acid sequence” includes all nucleotide sequences that are degenerate versions of each other and that encode the same amino acid sequence.
  • the comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm, as described below.
  • the percent identity between two amino acid sequences can be determined using the Needleman and Wunsch algorithm (Needleman, Saul B. & Wunsch, Christian D. (1970). "A general method applicable to the search for similarities in the amino acid sequence of two proteins". Journal of Molecular Biology.48 (3): 443–53.).
  • the percent identity between two nucleotide or amino acid sequences may also be determined using for example algorithms such as EMBOSS Needle (pair wise alignment; available at www.ebi.ac.uk).
  • EMBOSS Needle may be used with a BLOSUM62 matrix, a “gap open penalty” of 10, a “gap extend penalty” of 0.5, a false “end gap penalty”, an “end gap open penalty” of 10 and an “end gap extend penalty” of 0.5.
  • the “percent identity” is a function of the number of matching positions divided by the number of positions compared and multiplied by 100. For instance, if 6 out of 10 sequence positions are identical between the two compared sequences after alignment, then the identity is 60%.
  • a first amino acid sequence having at least 70% of identity with a second amino acid sequence means that the first sequence has 70; 71; 72; 73; 74; 75; 76; 77; 78; 79; 80; 81; 82; 83; 84; 85; 86; 87; 88; 89; 90; 91; 92; 93; 94; 95; 96; 97; 98; 99 or 100% of identity with the second amino acid sequence.
  • type I interferon or “type I IFN” has its general meaning in the art and refers to members of the type I interferon family of molecules that are ligands for IFNAR- 1 (i.e., members of the type I interferon family of molecules that are capable of binding IFNAR- 1).
  • types of type I interferon ligands are interferon alpha 1, 2a, 2b, 4, 5, 6, 7, 8, 10, 14, 16, 17, 21, interferon beta and interferon omega. All type I IFNs bind to a specific cell surface receptor complex known as the IFN- ⁇ receptor (IFNAR) that consists of IFNAR1 and IFNAR2 chains.
  • IFNAR IFN- ⁇ receptor
  • IFNAR1 has its general meaning in the art and refers to the interferon- ⁇ / ⁇ receptor 1, which is a protein encoded by the IFNAR1 gene in humans and forms part of the type I interferon receptor complex. IFNAR1 is expressed on most cell types and binds to various subtypes of IFN- ⁇ and IFN- ⁇ , triggering signal transduction pathways that mediate antiviral, immunomodulatory, and antiproliferative effects.
  • the amino acid sequence of human IFNAR1 is represented by SEQ ID NO:1.
  • IFNAR2 is expressed on most cell types and binds to various subtypes of IFN- ⁇ and IFN- ⁇ , enhancing the affinity and specificity of IFNAR1 for these ligands.
  • the amino acid sequence of human IFNAR2 is represented by SEQ ID NO:2.
  • Native IFN- ⁇ consists of more than 23 closely related protein subtypes encoded by distinct genes with a high degree of structural homology (Weissmann and Weber, Prog. Nucl. Acid. Res. Mol. Biol., 33: 251, 1986; Roberts et al., J. Interferon Cytokine Res.18: 805-816, 1998).
  • the human IFN- ⁇ subtypes are at least IFN- ⁇ A (IFN- ⁇ 2), IFN- ⁇ B2 (IFN- ⁇ 8), IFN- ⁇ C (IFN- ⁇ 10), IFN- ⁇ D (IFN- ⁇ 1), IFN- ⁇ F (IFN- ⁇ 21), IFN- ⁇ G (IFN- ⁇ 5), and IFN- ⁇ H (IFN- ⁇ 14), IFN- ⁇ I with P34H substitution (IFN- ⁇ 17), IFN- ⁇ J1 (IFN- ⁇ 7), IFN- ⁇ K (IFN- ⁇ 6), IFN- ⁇ 4b (IFN- ⁇ 4), and IFN- ⁇ WA (IFN- ⁇ 6).
  • the amino acid sequence for IFN- ⁇ 2 is represented by SEQ ID NO:3.
  • Helix A is defined by the amino acid residues S8 to M21 in SEQ ID NO:3
  • the “Helix B” is defined by the amino acid residues H52 to F67 in SEQ ID NO:3
  • the “Helix C” is defined by the amino acid residues D77 to C98 in SEQ ID NO, 3.
  • IFN- ⁇ exhibits about 75% sequence homology with IFN- ⁇ , and contains two conserved disulfide bonds that are necessary for full biological activity.
  • the amino acid sequence for IFN- ⁇ 1 is represented by SEQ ID NO:4.
  • SEQ ID NO:4 >sp
  • OS Homo sapiens
  • antibody or "immunoglobulin” has the same meaning, and will be used equally in the present invention.
  • antibody refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain an antigen binding site that immunospecifically binds an antigen.
  • antibody encompasses not only whole antibody molecules, but also antibody fragments as well as variants (including derivatives) of antibodies and antibody fragments.
  • two heavy chains are linked to each other by disulfide bonds and each heavy chain is linked to a light chain by a disulfide bond. There are two types of light chain, lambda (1) and kappa (k).
  • the light chain includes two domains, a variable domain (VL) and a constant domain (CL).
  • the heavy chain includes four ( ⁇ , ⁇ , ⁇ ) to five ( ⁇ , ⁇ ) domains, a variable domain (VH) and three to four constant domains (CH1, CH2, CH3 and CH4 collectively referred to as CH).
  • the variable regions of both light (VL) and heavy (VH) chains determine binding recognition and specificity to the antigen.
  • the constant region domains of the light (CL) and heavy (CH) chains confer important biological properties such as antibody chain association, secretion, trans-placental mobility, complement binding, and binding to Fc receptors (FcR).
  • the Fv fragment is the N-terminal part of the Fab fragment of an immunoglobulin and consists of the variable portions of one light chain and one heavy chain.
  • the specificity of the antibody resides in the structural complementarity between the antibody combining site and the antigenic determinant.
  • Antibody combining sites are made up of residues that are primarily from the hypervariable or complementarity determining regions (CDRs). Occasionally, residues from nonhypervariable or framework regions (FR) can participate to the antibody binding site or influence the overall domain structure and hence the combining site.
  • CDRs refer to amino acid sequences which together define the binding affinity and specificity of the natural Fv region of a native immunoglobulin binding site.
  • the light and heavy chains of an immunoglobulin each have three CDRs, designated L-CDR1, L-CDR2, L-CDR3 and H- CDR1, H-CDR2, H-CDR3, respectively.
  • An antigen-binding site therefore, typically includes six CDRs, comprising the CDR set from each of a heavy and a light chain V region.
  • Framework Regions refer to amino acid sequences interposed between CDRs.
  • the amino acid residues in the variable domain, complementarity determining regions (CDRs) and framework regions (FR) of the antibody or the antigen-binding fragment of the present invention are identified using the Immunogenetics (IMGT) database (http://imgt.cines.fr). Lefranc et al. (2003) Dev Comp Immunol. 27(1):55-77.
  • the IMGT database was developed using sequence information for immunoglobulins (IgGs), T-cell receptors (TcR) and Major Histocompatibility Complex (MHC) molecules and unifies numbering across antibody lambda and kappa light chains, heavy chains and T-cell receptor chains and avoids the use of insertion codes for all but uncommonly long insertions.
  • IgGs immunoglobulins
  • TcR T-cell receptors
  • MHC Major Histocompatibility Complex
  • IMGT also takes into account and combines the definition of the framework (FR) and complementarity determining regions (CDR) from Kabat et al., the characterization of the hypervariable loops from Chothia et al., as well as structural data from X-ray diffraction studies.
  • FR framework
  • CDR complementarity determining regions
  • the terms “monoclonal antibody”, “monoclonal Ab”, “monoclonal antibody composition”, “mAb”, or the like, as used herein refer to a preparation of antibody molecules of single molecular composition.
  • a monoclonal antibody is obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprised in the population are identical except for possible naturally occurring mutations that may be present in minor amounts.
  • a monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope.
  • the term “chimeric antibody” refers to an antibody which comprises a VH domain and a VL domain of a non-human antibody, and a CH domain and a CL domain of a human antibody.
  • the term “humanized antibody” refers to an antibody having variable region framework and constant regions from a human antibody but retains the CDRs of a previous non-human antibody. In some embodiments, a humanized antibody contains minimal sequence derived from non-human immunoglobulin.
  • humanized antibodies and antibody fragments thereof may be human immunoglobulins (recipient antibody or antibody fragment) in which residues from a complementary-determining region (CDR) of the recipient are replaced by residues from a CDR of non-human species (donor antibody) such as mouse, rat or rabbit having the desired specificity, affinity, and capacity.
  • CDR complementary-determining region
  • donor antibody non-human species
  • human antibody is intended to include antibodies having variable and constant regions derived from human immunoglobulin sequences.
  • the human antibodies of the present invention may include amino acid residues not encoded by human immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo).
  • the term "human antibody”, as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.
  • the term “PMAB19” refers to the human monoclonal antibody having the VH sequence as set forth in SEQ ID NO:5 and the VL sequence as set forth in SEQ ID NO:9.
  • the VH region sequence details are depicted in Table 1 and the VL VH region sequence details are depicted in Table 2.
  • VH region sequence details are depicted in Table 3 and the VL VH region sequence details are depicted in Table 4.
  • H-CDR region sequences are depicted in Table 5 and the L-CDR sequences are depicted in Table 6.
  • H-CDR region sequences are depicted in Table 7 and the L-CDR sequences are depicted in Table 8.
  • H-CDR region sequences are depicted in Table 9 and the L-CDR sequences are depicted in Table 10.
  • H-CDR region sequences are depicted in Table 11 and the L-CDR sequences are depicted in Table 12.
  • an epitope presented on an antigen while having relatively little detectable reactivity with other target molecules.
  • Specificity can be relatively determined by binding or competitive binding assays, using, e.g., using, e.g., bio-layer interferometry (BLI) performed on Octet BLI instruments. Specificity can be exhibited by, e.g., an about 10:1, about 20:1, about 50:1, about 100:1, 10.000:1 or greater ratio of affinity/avidity in binding to the specific antigen versus nonspecific binding to other irrelevant molecules.
  • affinity means the strength of the binding of an antibody to a target molecule (e.g. an epitope). The affinity of a binding protein is given by the dissociation constant Kd.
  • Kd is defined as [Ab] x [Ag] / [Ab-Ag], where [Ab-Ag] is the molar concentration of the antibody-antigen complex, [Ab] is the molar concentration of the unbound antibody and [Ag] is the molar concentration of the unbound antigen.
  • the affinity constant Ka is defined by 1/Kd.
  • binding refers to a direct association between two molecules, due to, for example, covalent, electrostatic, hydrophobic, and ionic and/or hydrogen-bond interactions, including interactions such as salt bridges and water bridges.
  • binding'' in the context of the binding of an antibody to a predetermined target molecule (e.g.
  • an antigen or epitope typically is a binding with an affinity corresponding to a KD of about 10 -7 M or less, such as about 10 -8 M or less, such as about 10 -9 M or less, about 10- 10 M or less, or about 10 -11 M or even less.
  • the term “epitope” refers to a specific arrangement of amino acids located on a protein or proteins to which an antibody binds. Epitopes often consist of a chemically active surface grouping of molecules such as amino acids or sugar side chains, and have specific three- dimensional structural characteristics as well as specific charge characteristics.
  • Epitopes can be linear or conformational, i.e., involving two or more sequences of amino acids in various regions of the antigen that may not necessarily be contiguous.
  • antibody fragment refers to at least one portion of an intact antibody, preferably the antigen binding region or variable region of the intact antibody, that retains the ability to specifically interact with (e.g., by binding, steric hindrance, stabilizing/destabilizing, spatial distribution) an epitope of an antigen.
  • antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, Fv fragments, single chain antibody molecules, in particular scFv antibody fragments, disulfide-linked Fvs (sdFv), a Fd fragment consisting of the VH and CHI domains, linear antibodies, single domain antibodies such as, for example, sdAb (either VL or VH), camelid VHH domains, multi-specific antibodies formed from antibody fragments such as, for example, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region, and an isolated CDR or other epitope binding fragments of an antibody.
  • An antigen binding fragment can also be incorporated into single domain antibodies, maxibodies, minibodies, nanobodies, intrabodies, diabodies, triabodies, tetrabodies, v-NAR and bis-scFv (see, e.g., Hollinger and Hudson, Nature Biotechnology 23:1126-1136, 2005).
  • Antigen binding fragments can also be grafted into scaffolds based on polypeptides such as a fibronectin type III (see U.S. Patent No.: 6,703,199, which describes fibronectin polypeptide minibodies).
  • Papain digestion of antibodies produces two identical antigen-binding fragments, called "Fab" fragments, and a residual "Fc" fragment, a designation reflecting the ability to crystallize readily.
  • Fab or F(ab') 2 fragments may be produced by protease digestion of the isolated antibodies, according to conventional techniques. It will be appreciated that immunoreactive fragments can be modified using known methods, for example to slow clearance in vivo and obtain a more desirable pharmacokinetic profile the fragment may be modified with polyethylene glycol (PEG). Methods for coupling and site-specifically conjugating PEG to a Fab' fragment are described in, for example, Leong et al., Cytokines 16 (3): 106-119 (2001) and Delgado et al., Br. J. Cancer 573 (2): 175- 182 (1996), the disclosures of which are incorporated herein by reference.
  • PEG polyethylene glycol
  • Fc region is used to define the C-terminal region of an immunoglobulin heavy chain, including native sequence Fc region and variant Fc regions.
  • the human IgG heavy chain Fc region is generally defined as comprising the amino acid residue from position C226 or from P230 to the carboxyl-terminus of the IgG antibody. The numbering of residues in the Fc region is that of the EU index of Kabat.
  • the C-terminal lysine (residue K447) of the Fc region may be removed, for example, during production or purification of the antibody.
  • composition of antibodies of the invention may comprise antibody populations with all K447 residues removed, antibody populations with no K447 residues removed, and antibody populations having a mixture of antibodies with and without the K447 residue.
  • cross-competes refers to monoclonal antibodies which share the ability to bind to a specific region of an antigen.
  • the monoclonal antibody that “cross-competes” has the ability to interfere with the binding of another monoclonal antibody for the antigen in a standard competitive binding assay.
  • Such a monoclonal antibody may, according to non-limiting theory, bind to the same or a related or nearby (e.g., a structurally similar or spatially proximal) epitope as the antibody with which it competes.
  • Cross-competition is present if antibody A reduces binding of antibody B at least by 60%, specifically at least by 70% and more specifically at least by 80% and vice versa in comparison to the positive control which lacks one of said antibodies.
  • competition may be assessed in different assay set-ups.
  • One suitable assay involves the use of the biolayer interferometry (BLI) technology (e.g., by using the Octet BLI instrument (Sartorius, Göttingen, Germany)), which can measure the extent of interactions using surface plasmon resonance technology.
  • BLI biolayer interferometry
  • Another assay for measuring cross-competition uses an ELISA- based approach.
  • a high throughput process for "binning" antibodies based upon their cross-competition is described in International Patent Application No. WO2003/48731.
  • isolated antibody refers to the antibody that has been identified and separated and/or recovered from a component of its natural environment.
  • the antibody will be purified (1) to greater than 95% by weight of antibody as determined by the Lowry method, and most preferably more than 99% by weight, (2) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator, or (3) to homogeneity by SDS-PAGE under reducing or nonreducing conditions using Coomassie blue or, preferably, silver stain.
  • Isolated antibody includes the antibody in situ within recombinant cells since at least one component of the antibody's natural environment will not be present. Ordinarily, however, isolated antibody will be prepared by at least one purification step.
  • neutralizing antibody refers to an antibody molecule which is able to eliminate or significantly reduce an effector function of a target antigen to which it binds.
  • a “neutralizing anti-IFN- ⁇ antibody” refers to a antibody that is capable of eliminating or significantly reducing an effector function, such as receptor binding and/or elicitation of a cellular response, of IFN- ⁇ polypeptides.
  • the ability to neutralize the elicitation of a cellular response by IFN- ⁇ is typically tested by the neutralizing assay described in the EXAMPLE.
  • the term “significant reduction” means at least about 60%, or at least about 70%, preferably at least about 75%, more preferably at least about 80%, even more preferably at least about 85%, still more preferably at least about 90%, still more preferably at least about 95%, most preferably at least about 99% reduction of an effector function of the target antigen (e.g. IFN- ⁇ or IFN- ⁇ ), such as receptor (e.g. IFNAR2) binding and/or elicitation of a cellular response.
  • the target antigen e.g. IFN- ⁇ or IFN- ⁇
  • receptor e.g. IFNAR2
  • the “neutralizing” antibodies as defined herein will be capable of neutralizing at least about 60%, or at least about 70%, preferably at least about 75%, more preferably at least about 80%, even more preferably at least about 85%, still more preferably at least about 90%, still more preferably at least about 95%, most preferably at least about 99% of the activity of IFN ⁇ polypeptides.
  • the term "patient” or "patient in need thereof" is intended for a human or non-human mammal.
  • the patient is a human infant.
  • the patient is a human child.
  • the patient is a human adult.
  • treatment refers to both prophylactic or preventive treatment as well as curative or disease modifying treatment, including treatment of patient at risk of contracting the disease or suspected to have contracted the disease as well as patients who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse.
  • the treatment may be administered to a patient having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a patient beyond that expected in the absence of such treatment.
  • therapeutic regimen is meant the pattern of treatment of an illness, e.g., the pattern of dosing used during therapy.
  • a therapeutic regimen may include an induction regimen and a maintenance regimen.
  • the phrase “induction regimen” or “induction period” refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the initial treatment of a disease.
  • the general goal of an induction regimen is to provide a high level of drug to a patient during the initial period of a treatment regimen.
  • An induction regimen may employ (in part or in whole) a "loading regimen", which may include administering a greater dose of the drug than a physician would employ during a maintenance regimen, administering a drug more frequently than a physician would administer the drug during a maintenance regimen, or both.
  • maintenance regimen refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the maintenance of a patient during treatment of an illness, e.g., to keep the patient in remission for long periods of time (months or years).
  • a maintenance regimen may employ continuous therapy (e.g., administering a drug at a regular interval, e.g., weekly, monthly, yearly, etc.) or intermittent therapy (e.g., interrupted treatment, intermittent treatment, treatment at relapse, or treatment upon achievement of a particular predetermined criteria [e.g., pain, disease manifestation, etc.]).
  • the term “pharmaceutical composition” refers to a composition described herein, or pharmaceutically acceptable salts thereof, with other agents such as carriers and/or excipients.
  • the pharmaceutical compositions as provided herewith typically include a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical-Sciences, Sixteenth Edition, E. W.
  • the term “Therapeutically effective amount” refers to the level or amount of an antibody or antigen-binding fragment thereof as described herein that is aimed at, without causing significant negative or adverse side effects to the target, (1) delaying or preventing the onset of a disease, disorder, or condition; (2) slowing down or stopping the progression, aggravation, or deterioration of one or more symptoms of the disease, disorder, or condition; (3) bringing about ameliorations of the symptoms of the disease, disorder, or condition; (4) reducing the severity or incidence of the disease, disorder, or condition; or (5) curing the disease, disorder, or condition.
  • a therapeutically effective amount may be administered prior to the onset of the disease, disorder, or condition, for a prophylactic or preventive action. Alternatively or additionally, the therapeutically effective amount may be administered after initiation of the disease, disorder, or condition, for a therapeutic action.
  • Antibodies of the present invention The present invention relates to a monoclonal antibody or an antigen-binding fragment thereof that binds to IFN- ⁇ polypeptides and that blocks the binding of said polypeptides to IFNAR1. In some embodiments, the monoclonal antibody or the antigen-binding fragment of the present invention binds to IFN- ⁇ 2. In some embodiments, the monoclonal antibody or the antigen-binding fragment of the present invention does not bind to IFN- ⁇ 1.
  • the monoclonal antibody or the antigen-binding fragment of the present invention binds to IFN- ⁇ 2 with a KD lower than 1 ⁇ 10 -7 M.
  • the binding can be measured and the KD calculated using any method known in the art, for example, the method as described in the EXAMPLE.
  • the monoclonal antibody or the antigen-binding fragment of the present invention binds to at least IFN- ⁇ 1, IFN- ⁇ 2, IFN- ⁇ 4, IFN- ⁇ 5, IFN- ⁇ 8, IFN- ⁇ 10, and IFN- ⁇ 21 with a KD lower than 1 ⁇ 10 -7 M.
  • the monoclonal antibody or the antigen-binding fragment of the present invention is a neutralizing antibody.
  • the monoclonal antibody or the antigen- binding fragment of the present invention blocks the binding of IFN- ⁇ 2 to IFNAR1.
  • the ability of an antibody of the present invention to block the binding of IFN- ⁇ 2 to receptor is defined as the property or capacity of a certain concentration of the antibody to reduce or eliminate the binding of IFN- ⁇ 2 to IFNAR1 in a competition binding assay, as compared to the effect of an equivalent concentration of irrelevant control antibody on IFN- ⁇ 2 binding to IFNAR1 in the assay.
  • the blocking antibody of the present invention reduces the binding of IFN- ⁇ 2 to IFNAR1 by at least about 50%, or at least about 55%, or at least about 60%, or at least about 65%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 99%, as compared to the irrelevant control antibody.
  • the ability of the antibody of the present invention to block the binding of IFN- ⁇ 2 to IFNAR1 can be determined by a routine competition assay such as that described in Kamat, Vishal, and Ashique Rafique.
  • the blocking anti-IFN- ⁇ antibodies of the present invention will block the IFNAR1-binding of IFN- ⁇ 2.
  • the monoclonal antibody or the antigen-binding fragment of the present invention blocks IFN- ⁇ 2 signaling with an IC50 of about 10ng/mL or lower.
  • the monoclonal antibody or the antigen-binding fragment of the present invention binds to IFN- ⁇ 2 with a KD of about 1 ⁇ 10 -7 M or less and blocks IFN- ⁇ 2 signaling with an IC50 of about 10ng/mL or lower. In some embodiments, the monoclonal antibody or the antigen-binding fragment of the present invention binds to Helix B and Helix C of IFN- ⁇ 2.
  • the monoclonal antibody or the antigen-binding fragment of the present invention binds to a conformational epitope IFN- ⁇ 2 that comprises i) one or more amino acid residues in the Helix B selected from the group consisting of P54, H57, E58, Q61, F64, N65, and S68 in SEQ ID NO:3 and ii) one or more amino acid residues in the Helix D selected from the group consisting of Y85, T86, Y89, Q90, L92, N93, E96, A97, V99, I100, and Q101 in SEQ ID NO:3.
  • the monoclonal antibody or the antigen-binding fragment of the present invention binds to IFN- ⁇ 2 at the same epitope as for PMAB19, PMAB06, PMAB09, PMAB12, and PMAB34 antibodies.
  • the monoclonal antibody or the antigen-binding fragment of the present invention binds to IFN- ⁇ 2 at the same epitope as for PMAB09 or PMAB34 antibody.
  • the monoclonal antibody or the antigen-binding fragment of the present invention cross-competes for binding to IFN- ⁇ 2 with the monoclonal antibody PMAB19.
  • the monoclonal antibody or the antigen-binding fragment of the present invention cross-competes for binding to IFN- ⁇ 2 with the monoclonal antibody comprising a VH domain having the H-CDR1 as set forth in SEQ ID NO:6, the H-CDR2 as set forth in SEQ ID NO: 7 and the H-CDR3 as set forth in SEQ ID NO:8 and a VL domain having the L-CDR1 as set forth in SEQ ID NO:10, the L-CDR2 as set forth in SEQ ID NO:11 and the L-CDR3 as set forth in SEQ ID NO:12.
  • the monoclonal antibody or the antigen-binding fragment of the present invention cross-competes for binding to IFN- ⁇ 2 with the monoclonal antibody PMAB06.
  • the monoclonal antibody or the antigen-binding fragment of the present invention cross-competes for binding to IFN- ⁇ 2 with the monoclonal antibody comprising a VH domain having the H-CDR1 as set forth in SEQ ID NO:14, the H-CDR2 as set forth in SEQ ID NO: 15 and the H-CDR3 as set forth in SEQ ID NO:16 and a VL domain having the L-CDR1 as set forth in SEQ ID NO:18, the L-CDR2 as set forth in SEQ ID NO:19 and the L-CDR3 as set forth in SEQ ID NO:20.
  • the monoclonal antibody or the antigen-binding fragment of the present invention cross-competes for binding to IFN- ⁇ 2 with the monoclonal antibody PMAB09.
  • the monoclonal antibody or the antigen-binding fragment of the present invention cross-competes for binding to IFN- ⁇ 2 with the monoclonal antibody comprising a VH domain having the H-CDR1 as set forth in SEQ ID NO:22, the H-CDR2 as set forth in SEQ ID NO:23 and the H-CDR3 as set forth in SEQ ID NO:24 and a VL domain having the L-CDR1 as set forth in SEQ ID NO:26, the L-CDR2 as set forth in SEQ ID NO:27 and the L-CDR3 as set forth in SEQ ID NO:28.
  • the monoclonal antibody or the antigen-binding fragment of the present invention cross-competes for binding to IFN- ⁇ 2 with the monoclonal antibody PMAB12.
  • the monoclonal antibody or the antigen-binding fragment of the present invention cross-competes for binding to IFN- ⁇ 2 with the monoclonal antibody comprising a VH domain having the H-CDR1 as set forth in SEQ ID NO:30, the H-CDR2 as set forth in SEQ ID NO:31 and the H-CDR3 as set forth in SEQ ID NO:32 and a VL domain having the L-CDR1 as set forth in SEQ ID NO:34, the L-CDR2 as set forth in SEQ ID NO:35 and the L-CDR3 as set forth in SEQ ID NO:36.
  • the monoclonal antibody or the antigen-binding fragment of the present invention cross-competes for binding to IFN- ⁇ 2 with the monoclonal antibody PMAB34.
  • the monoclonal antibody or the antigen-binding fragment of the present invention cross-competes for binding to IFN- ⁇ 2 with the monoclonal antibody comprising a VH domain having the H-CDR1 as set forth in SEQ ID NO:38, the H-CDR2 as set forth in SEQ ID NO:39 and the H-CDR3 as set forth in SEQ ID NO:40 and a VL domain having the L-CDR1 as set forth in SEQ ID NO:42, the L-CDR2 as set forth in SEQ ID NO:43 and the L-CDR3 as set forth in SEQ ID NO:44.
  • the monoclonal antibody or the antigen-binding fragment of the present invention binds to Helix A and Helix C of IFN- ⁇ 2. In some embodiments, the monoclonal antibody or the antigen-binding fragment of the present invention binds to a conformational epitope IFN- ⁇ 2 that comprises i) one or more amino acid residues in the Helix A selected from the group consisting of D2, Q5, T6, H7, L9, G10, R12, and R13 in SEQ ID NO:3 and ii) one or more amino acid residues in the Helix C selected from the group consisting of D82, Y85, T86, E87, Y89, Q90, Q91, N93, and D94 in SEQ ID NO:3.
  • amino acid residues D2, Q5, and R12 are recognized mostly by light chain, and amino acid residues H7, G1, R13, D82, Y85, T86, E87, Y89, Q90, Q91, N93, and D94 are recognized mostly by heavy chain, whereas amino acid residues T6 and Q90 are recognized by both chains.
  • the monoclonal antibody or the antigen-binding fragment of the present invention cross-competes for binding to IFN- ⁇ 2 with the monoclonal antibody GMAB03.
  • the monoclonal antibody or the antigen-binding fragment of the present invention cross-competes for binding to IFN- ⁇ 2 with the monoclonal antibody comprising a VH domain having the H-CDR1 as set forth in SEQ ID NO:46, the H-CDR2 as set forth in SEQ ID NO:47 and the H-CDR3 as set forth in SEQ ID NO:48 and a VL domain having the L-CDR1 as set forth in SEQ ID NO:50, the L-CDR2 as set forth in SEQ ID NO:51 and the L-CDR3 as set forth in SEQ ID NO:52.
  • antibodies and antigen-binding fragments include, without limitation, a whole antibody, a single chain antibody, a dimeric single chain antibody, a Fv, a scFv, a Fab, a Fab', a Fab'-SH, a F(ab)’2, a Fd, a defucosylated antibody, a bispecific antibody, a diabody, a triabody, a tetrabody, a unibody, or a domain antibody.
  • the antibody is a full-length antibody.
  • the full-length antibody is an IgG1 antibody.
  • the full-length antibody is an IgG3 antibody.
  • the full-length antibody is an IgG4 antibody.
  • the monoclonal antibody or the antigen-binding fragment of the present invention is a chimeric antibody, a humanized antibody or a human antibody.
  • PMAB19 antibodies In some embodiments, the monoclonal antibody or the antigen-binding fragment of the present invention comprises a VH domain having the H-CDR1 as set forth in SEQ ID NO:6, the H- CDR2 as set forth in SEQ ID NO: 7 and the H-CDR3 as set forth in SEQ ID NO:8.
  • the monoclonal antibody or the antigen-binding fragment of the present invention comprises a VL domain having the L-CDR1 as set forth in SEQ ID NO:10, the L- CDR2 as set forth in SEQ ID NO:11 and the L-CDR3 as set forth in SEQ ID NO:12.
  • the monoclonal antibody or the antigen-binding fragment of the present invention comprises a VH domain having the H-CDR1 as set forth in SEQ ID NO:6, the H- CDR2 as set forth in SEQ ID NO: 7 and the H-CDR3 as set forth in SEQ ID NO:8, and a VL domain having the L-CDR1 as set forth in SEQ ID NO:10, the L-CDR2 as set forth in SEQ ID NO:11 and the L-CDR3 as set forth in SEQ ID NO:12.
  • the antibody or the antigen-binding fragment of the present invention comprises a VH domain having an amino acid sequence having at least 70% of identity with the amino acid sequence as set forth in SEQ ID NO:5 and a VL domain having an amino acid sequence having at least 70% of identity with the amino acid sequence as set forth in SEQ ID NO:9.
  • the antibody or the antigen-binding fragment of the present invention comprises a VH domain having the amino acid as set forth in SEQ ID NO:5 and a VL domain having the amino acid sequence as set forth in SEQ ID NO:9.
  • the monoclonal antibody or the antigen-binding fragment of the present invention comprises a VH domain having the H-CDR1 as set forth in SEQ ID NO:14, the H- CDR2 as set forth in SEQ ID NO: 15 and the H-CDR3 as set forth in SEQ ID NO:16.
  • the monoclonal antibody or the antigen-binding fragment of the present invention comprises a VL domain having the L-CDR1 as set forth in SEQ ID NO:18, the L- CDR2 as set forth in SEQ ID NO:19 and the L-CDR3 as set forth in SEQ ID NO:20.
  • the monoclonal antibody or the antigen-binding fragment of the present invention comprises a VH domain having the H-CDR1 as set forth in SEQ ID NO:14, the H- CDR2 as set forth in SEQ ID NO: 15 and the H-CDR3 as set forth in SEQ ID NO:16, and a VL domain having the L-CDR1 as set forth in SEQ ID NO:18, the L-CDR2 as set forth in SEQ ID NO:19 and the L-CDR3 as set forth in SEQ ID NO:20.
  • the antibody or the antigen-binding fragment of the present invention comprises a VH domain having an amino acid sequence having at least 70% of identity with the amino acid sequence as set forth in SEQ ID NO:13 and a VL domain having an amino acid sequence having at least 70% of identity with the amino acid sequence as set forth in SEQ ID NO:17.
  • the antibody or the antigen-binding fragment of the present invention comprises a VH domain having the amino acid as set forth in SEQ ID NO:13 and a VL domain having the amino acid sequence as set forth in SEQ ID NO:17.
  • the monoclonal antibody or the antigen-binding fragment of the present invention comprises a VH domain having the H-CDR1 as set forth in SEQ ID NO:22, the H- CDR2 as set forth in SEQ ID NO:23 and the H-CDR3 as set forth in SEQ ID NO:24.
  • the monoclonal antibody or the antigen-binding fragment of the present invention comprises a VL domain having the L-CDR1 as set forth in SEQ ID NO:26, the L- CDR2 as set forth in SEQ ID NO:27 and the L-CDR3 as set forth in SEQ ID NO:28.
  • the monoclonal antibody or the antigen-binding fragment of the present invention comprises a VH domain having the H-CDR1 as set forth in SEQ ID NO:22, the H- CDR2 as set forth in SEQ ID NO:23 and the H-CDR3 as set forth in SEQ ID NO:24 and a VL domain having the L-CDR1 as set forth in SEQ ID NO:26, the L-CDR2 as set forth in SEQ ID NO:27 and the L-CDR3 as set forth in SEQ ID NO:28.
  • the antibody or the antigen-binding fragment of the present invention comprises a VH domain having an amino acid sequence having at least 70% of identity with the amino acid sequence as set forth in SEQ ID NO:21 and a VL domain having an amino acid sequence having at least 70% of identity with the amino acid sequence as set forth in SEQ ID NO:25.
  • the antibody or the antigen-binding fragment of the present invention comprises a VH domain having the amino acid as set forth in SEQ ID NO:21 and a VL domain having the amino acid sequence as set forth in SEQ ID NO:25.
  • the monoclonal antibody or the antigen-binding fragment of the present invention comprises a VH domain having the H-CDR1 as set forth in SEQ ID NO:30, the H- CDR2 as set forth in SEQ ID NO:31 and the H-CDR3 as set forth in SEQ ID NO:32.
  • the monoclonal antibody or the antigen-binding fragment of the present invention comprises a VL domain having the L-CDR1 as set forth in SEQ ID NO:34, the L- CDR2 as set forth in SEQ ID NO:35 and the L-CDR3 as set forth in SEQ ID NO:36.
  • the monoclonal antibody or the antigen-binding fragment of the present invention comprises a VH domain having the H-CDR1 as set forth in SEQ ID NO:30, the H- CDR2 as set forth in SEQ ID NO:31 and the H-CDR3 as set forth in SEQ ID NO:32 and a VL domain having the L-CDR1 as set forth in SEQ ID NO:34, the L-CDR2 as set forth in SEQ ID NO:35 and the L-CDR3 as set forth in SEQ ID NO:36.
  • the antibody or the antigen-binding fragment of the present invention comprises a VH domain having an amino acid sequence having at least 70% of identity with the amino acid sequence as set forth in SEQ ID NO:29 and a VL domain having an amino acid sequence having at least 70% of identity with the amino acid sequence as set forth in SEQ ID NO:33.
  • the antibody or the antigen-binding fragment of the present invention comprises a VH domain having the amino acid as set forth in SEQ ID NO:29 and a VL domain having the amino acid sequence as set forth in SEQ ID NO:33.
  • the monoclonal antibody or the antigen-binding fragment of the present invention comprises a VH domain having the H-CDR1 as set forth in SEQ ID NO:38, the H- CDR2 as set forth in SEQ ID NO:39 and the H-CDR3 as set forth in SEQ ID NO:40.
  • the monoclonal antibody or the antigen-binding fragment of the present invention comprises a VL domain having the L-CDR1 as set forth in SEQ ID NO:42, the L- CDR2 as set forth in SEQ ID NO:43 and the L-CDR3 as set forth in SEQ ID NO:44.
  • the monoclonal antibody or the antigen-binding fragment of the present invention comprises a VH domain having the H-CDR1 as set forth in SEQ ID NO:38, the H- CDR2 as set forth in SEQ ID NO:39 and the H-CDR3 as set forth in SEQ ID NO:40 and a VL domain having the L-CDR1 as set forth in SEQ ID NO:42, the L-CDR2 as set forth in SEQ ID NO:43 and the L-CDR3 as set forth in SEQ ID NO:44.
  • the antibody or the antigen-binding fragment of the present invention comprises a VH domain having an amino acid sequence having at least 70% of identity with the amino acid sequence as set forth in SEQ ID NO:37 and a VL domain having an amino acid sequence having at least 70% of identity with the amino acid sequence as set forth in SEQ ID NO:41.
  • the antibody or the antigen-binding fragment of the present invention comprises a VH domain having the amino acid as set forth in SEQ ID NO:37 and a VL domain having the amino acid sequence as set forth in SEQ ID NO:41.
  • the monoclonal antibody or the antigen-binding fragment of the present invention comprises a VH domain having the H-CDR1 as set forth in SEQ ID NO:46, the H- CDR2 as set forth in SEQ ID NO:47 and the H-CDR3 as set forth in SEQ ID NO:48.
  • the monoclonal antibody or the antigen-binding fragment of the present invention comprises a VL domain having the L-CDR1 as set forth in SEQ ID NO:50, the L- CDR2 as set forth in SEQ ID NO:51 and the L-CDR3 as set forth in SEQ ID NO:52.
  • the monoclonal antibody or the antigen-binding fragment of the present invention comprises a VH domain having the H-CDR1 as set forth in SEQ ID NO:46, the H- CDR2 as set forth in SEQ ID NO:47 and the H-CDR3 as set forth in SEQ ID NO:48 and a VL domain having the L-CDR1 as set forth in SEQ ID NO:50, the L-CDR2 as set forth in SEQ ID NO:51 and the L-CDR3 as set forth in SEQ ID NO:52.
  • the antibody or the antigen-binding fragment of the present invention comprises a VH domain having an amino acid sequence having at least 70% of identity with the amino acid sequence as set forth in SEQ ID NO:45 and a VL domain having an amino acid sequence having at least 70% of identity with the amino acid sequence as set forth in SEQ ID NO:49.
  • the antibody or the antigen-binding fragment of the present invention comprises a VH domain having the amino acid as set forth in SEQ ID NO:55 and a VL domain having the amino acid sequence as set forth in SEQ ID NO:49.
  • the VH sequence and/or the VL sequence of the antibody of the present invention comprises conservative sequence modifications.
  • conservative sequence modifications refers to amino acid modifications that do not significantly affect or alter the biologic function of the protein containing the amino acid sequence. Such conservative modifications include amino acid substitutions, additions and deletions. Modifications can be introduced into a protein by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis. A “conservative substitution” is one in which an amino acid is substituted for another amino acid that has similar properties, such that one skilled in the art of peptide chemistry would expect the secondary structure and hydropathic nature of the polypeptide to be substantially unchanged.
  • Amino acid substitutions are generally therefore based on the relative similarity of the amino acid side-chain substituents, for example, their hydrophobicity, hydrophilicity, charge, size, and the like.
  • Exemplary substitutions that take various of the foregoing characteristics into consideration are well known to those of skill in the art and include: arginine and lysine; glutamate and aspartate; serine and threonine; glutamine and asparagine; and valine, leucine and isoleucine.
  • Amino acid substitutions may further be made on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity and/or the amphipathic nature of the residues.
  • negatively charged amino acids include aspartic acid and glutamic acid; positively charged amino acids include lysine and arginine; and amino acids with uncharged polar head groups having similar hydrophilicity values include leucine, isoleucine and valine; glycine and alanine; asparagine and glutamine; and serine, threonine, phenylalanine and tyrosine.
  • amino acids that may represent conservative changes include: (1) ala, pro, gly, glu, asp, gln, asn, ser, thr; (2) cys, ser, tyr, thr; (3) val, ile, leu, met, ala, phe; (4) lys, arg, his; and (5) phe, tyr, trp, his.
  • Other families of amino acid residues having similar side chains have been defined in the art.
  • amino acids with basic side chains e.g., lysine, arginine, histidine
  • acidic side chains e.g., aspartic acid, glutamic acid
  • uncharged polar side chains e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan
  • nonpolar side chains e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine
  • beta-branched side chains e.g., threonine, valine, isoleucine
  • aromatic side chains e.g., tyrosine, phenylalanine, tryptophan, histidine
  • one or more amino acid residues within an antibody of the present invention can be replaced with other amino acid residues from the same side chain family and the altered antibody can be tested for binding to the sialylated glycoproteins.
  • the antibody (preferably the monoclonal antibody) of the present invention does not comprise a Fc region that mediates antibody-dependent cell-mediated cytotoxicity and thus does not comprise an Fc portion that induces antibody dependent cellular cytotoxicity (ADCC).
  • the antibody (preferably the monoclonal antibody) of the present invention does not comprise an Fc region that induces CDC or antibody- dependent phagocytosis.
  • the antibody (preferably the monoclonal antibody) of the present invention does not comprise an Fc domain capable of substantially binding to a Fc ⁇ RIIIA (CD16) polypeptide.
  • the antibody (preferably the monoclonal antibody) of the present invention lacks an Fc domain (e.g., lacks a CH2 and/or CH3 domain) or comprises an Fc domain of IgG2 or IgG4 isotype.
  • the antibody (preferably the monoclonal antibody) of the present invention comprises an Fc domain (e.g. of IgG1) with an altered glycosylation profile, resulting in the absence of ADCC activity of the antibody.
  • the antibody (preferably the monoclonal antibody) of the present invention consists of or comprises a Fab, Fab', Fab'-SH, F(ab') 2 , Fv, a diabody, single-chain antibody fragment, or a multispecific antibody comprising multiple different antibody fragments.
  • the antibody (preferably the monoclonal antibody) of the present invention is not linked to a toxic moiety.
  • one or more amino acids selected from amino acid residues can be replaced with a different amino acid residue such that the antibody has altered C2q binding and/or reduced or abolished complement dependent cytotoxicity (CDC). This approach is described in further detail in U.S. Patent Nos. 6,194,551 by ldusogie et al.
  • the antibody or the antigen-binding fragment of the present invention is produced by any technique known in the art, such as, without limitation, any chemical, biological, genetic or enzymatic technique, either alone or in combination.
  • any technique known in the art such as, without limitation, any chemical, biological, genetic or enzymatic technique, either alone or in combination.
  • knowing the amino acid sequence of the desired sequence one skilled in the art can readily produce said antibodies, by standard techniques for production of polypeptides. For instance, they can be synthesized using well-known solid phase method, preferably using a commercially available peptide synthesis apparatus (such as that made by Applied Biosystems, Foster City, California) and following the manufacturer’s instructions.
  • antibodies of the present invention can be synthesized by recombinant DNA techniques well-known in the art.
  • antibodies can be obtained as DNA expression products after incorporation of DNA sequences encoding the antibodies into expression vectors and introduction of such vectors into suitable eukaryotic or prokaryotic hosts that will express the desired antibodies, from which they can be later isolated using well-known techniques.
  • vectors and host cells A further object of the invention relates to a polynucleotide encoding the antibody or the antigen-binding fragment of the present invention. More particularly the polynucleotide encodes a heavy chain and/or a light chain of the antibody or the antigen-binding fragment of the present invention.
  • said polynucleotide is a DNA or RNA molecule, which may be included in any suitable vector, such as a plasmid, cosmid, episome, artificial chromosome, phage or a viral vector.
  • a further object of the invention relates to a vector comprising the polynucleotide of the invention.
  • Such vectors may comprise regulatory elements, such as a promoter, enhancer, terminator and the like, to cause or direct expression of said antibody upon administration to a subject.
  • the terms “vector”, “cloning vector” and “expression vector” mean the vehicle by which a DNA or RNA sequence (e.g., a foreign gene) can be introduced into a host cell, so as to transform the host and promote expression (e.g., transcription and translation) of the introduced sequence.
  • promote expression e.g., transcription and translation
  • promoter/regulatory sequence refers to a polynucleotide sequence (such as, for example, a DNA sequence) recognized by the synthetic machinery of the cell, or introduced synthetic machinery, required to initiate the specific transcription of a polynucleotide sequence, thereby allowing the expression of a gene product operably linked to the promoter/regulatory sequence.
  • this sequence may be the core promoter sequence and in other instances, this sequence may also include an enhancer sequence and other regulatory elements which are required for expression of the gene product.
  • the promoter/regulatory sequence may, for example, be one which expresses the gene product in a tissue specific manner.
  • the term "operably linked” or “transcriptional control” refers to functional linkage between a regulatory sequence and a heterologous polynucleotide sequence resulting in expression of the latter. For example, a first polynucleotide sequence is operably linked with a second polynucleotide sequence when the first polynucleotide sequence is placed in a functional relationship with the second polynucleotide sequence.
  • a promoter is operably linked to a coding sequence if the promoter affects the transcription or expression of the coding sequence.
  • Operably linked DNA sequences can be contiguous with each other and, e.g., where necessary to join two protein coding regions, are in the same reading frame.
  • promoters and enhancers used in the expression vector for animal cell include early promoter and enhancer of SV40, LTR promoter and enhancer of Moloney mouse leukemia virus, promoter and enhancer of immunoglobulin H chain and the like. Any expression vector for animal cell can be used, so long as a gene encoding the human antibody C region can be inserted and expressed.
  • Suitable vectors include pAGE107, pAGE103, pHSG274, pKCR, pSG1 beta d2-4 and the like.
  • Other examples of plasmids include replicating plasmids comprising an origin of replication, or integrative plasmids, such as for instance pUC, pcDNA, pBR, and the like.
  • Other examples of viral vector include adenoviral, retroviral, herpes virus and AAV vectors. Such recombinant viruses may be produced by techniques known in the art, such as by transfecting packaging cells or by transient transfection with helper plasmids or viruses.
  • Typical examples of virus packaging cells include PA317 cells, PsiCRIP cells, GPenv+ cells, 293 cells, etc.
  • a further object of the present invention relates to a host cell which has been transfected, infected or transformed by the nucleic acid and/or the vector according to the present invention.
  • the term “transformation” means the introduction of a “foreign” (i.e., extrinsic or extracellular) gene, DNA or RNA sequence to a host cell, so that the host cell will express the introduced gene or sequence to produce a desired substance, typically a protein or enzyme coded by the introduced gene or sequence.
  • a host cell that receives and expresses introduced DNA or RNA bas been "transformed”.
  • expression system means a host cell and compatible vector under suitable conditions, e.g., for the expression of a protein coded for by foreign DNA carried by the vector and introduced to the host cell.
  • the nucleic acids of the invention may be used to produce the antibody or the antigen-binding fragment of the present invention in a suitable expression system.
  • Common expression systems include E. coli host cells and plasmid vectors, insect host cells and Baculovirus vectors, and mammalian host cells and vectors.
  • Other examples of host cells include, without limitation, prokaryotic cells (such as bacteria) and eukaryotic cells (such as yeast cells, mammalian cells, insect cells, plant cells, etc.).
  • E.coli Escherreocoli
  • Kluyveromyces or Saccharomyces yeasts mammalian cell lines (e.g., Vero cells, CHO cells, 3T3 cells, COS cells, etc.) as well as primary or established mammalian cell cultures (e.g., produced from lymphoblasts, fibroblasts, embryonic cells, epithelial cells, nervous cells, adipocytes, etc.).
  • mammalian cell lines e.g., Vero cells, CHO cells, 3T3 cells, COS cells, etc.
  • primary or established mammalian cell cultures e.g., produced from lymphoblasts, fibroblasts, embryonic cells, epithelial cells, nervous cells, adipocytes, etc.
  • Examples also include mouse SP2/0-Ag14 cell (ATCC CRL1581), mouse P3X63-Ag8.653 cell (ATCC CRL1580), CHO cell in which a dihydrofolate reductase gene (hereinafter referred to as "DHFR gene") is defective (Urlaub G et al; 1980), rat YB2/3HL.P2.G11.16Ag.20 cell (ATCC CRL1662, hereinafter referred to as "YB2/0 cell”), and the like.
  • DHFR gene dihydrofolate reductase gene
  • the present invention also relates to a method of producing a recombinant host cell expressing an antibody according to the present invention, said method comprising the steps of: (i) introducing in vitro or ex vivo a recombinant nucleic acid or a vector as described above into a competent host cell, (ii) culturing in vitro or ex vivo the recombinant host cell obtained and (iii), optionally, selecting the cells which express and/or secrete said antibody.
  • recombinant host cells can be used for the production of antibodies of the present invention.
  • the present invention also relates to a method of producing the antibody of the present invention, said method comprising the steps of: (i) culturing in vitro or ex vivo the recombinant host cell of the present invention and (ii), and isolating the produced antibody in the culture medium.
  • Antibodies of the present invention are suitably separated from the culture medium by conventional immunoglobulin purification procedures such as, for example, protein A- Sepharose, hydroxylapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography. Methods of treatment: Accordingly, a further object of the present invention relates to the antibody or the antigen- binding fragment of the present invention for use as a drug.
  • the present invention relates a method of therapy in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the antibody or the antigen-binding fragment of the present invention.
  • the antibody or the antigen-binding fragment of the present invention is particularly for the treatment of an autoimmune inflammatory disease.
  • the autoimmune inflammatory disease is selected from the group consisting of arthritis, rheumatoid arthritis, acute arthritis, chronic rheumatoid arthritis, gouty arthritis, acute gouty arthritis, chronic inflammatory arthritis, degenerative arthritis, infectious arthritis, Lyme arthritis, proliferative arthritis, psoriatic arthritis, vertebral arthritis, and juvenile-onset rheumatoid arthritis, osteoarthritis, arthritis chronica progrediente, arthritis deformans, polyarthritis chronica primaria, reactive arthritis, and ankylosing spondylitis), inflammatory hyperproliferative skin diseases, psoriasis such as plaque psoriasis, gutatte psoriasis, pustular psoriasis, and psoriasis of the nails, dermatitis including contact dermatitis, chronic contact dermatitis, allergic dermatitis, allergic contact dermatitis, dermatitis herpetiformis, and atopic
  • the antibody or the antigen-binding fragment of the present invention is particularly suitable for the treatment of a type 1 interferonopathy.
  • type I interferonopathy has its general meaning in the art and refers to a subgroup of autoinflammatory diseases caused by mutations in genes associated with proteasome degradation or cytoplasmic RNA- and DNA-sensing pathways.
  • interferonopathy first appeared in 2003, when some authors identified phenotypic overlaps between Aicardi–Goutieres syndrome (AGS) encephalopathy, viral congenital infections, and some autoimmune diseases such as systemic lupus erythematosus (SLE), postulating a common pathological feature as an upregulation of interferon (IFN) ⁇ activity (Crow, Yanick J. "Type I interferonopathies: a novel set of inborn errors of immunity.” Annals of the New York Academy of Sciences 1238.1 (2011): 91-98).
  • AGS Aicardi–Goutieres syndrome
  • SLE systemic lupus erythematosus
  • the term includes Aicardi-Goutines syndrome (AGS), STING-associated vasculopathy with onset in infancy (SAVI), and chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome.
  • AGS Aicardi-Goutines syndrome
  • SAVI STING-associated vasculopathy with onset in infancy
  • chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome Patients with type I interferonopathy shared several clinical characteristics, including bilateral calcifications of the basal ganglia, chilblain-like rashes, and liver dysfunction.
  • Each subtype includes disease- specific severe complications, such as early-onset encephalopathy associated with AGS and pulmonary hypertension observed in patients diagnosed with STING-associated vasculopathy with onset in infancy.
  • composition of the invention is a pharmaceutical composition and further comprises a pharmaceutically acceptable carrier.
  • compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene- block polymers, polyethylene glycol and wool fat.
  • ion exchangers alumina, aluminum stearate, lecithin
  • serum proteins such as human serum albumin
  • buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial g
  • compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • the used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • Sterile injectable forms of the compositions of this invention may be aqueous or an oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • a non-toxic parenterally acceptable diluent or solvent for example as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono-or diglycerides.
  • Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include, e.g., lactose.
  • the active ingredient is combined with emulsifying and suspending agents.
  • certain sweetening, flavoring or coloring agents may also be added.
  • the compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • Such materials include cocoa butter, beeswax and polyethylene glycols.
  • compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • the compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2- octyldodecanol, benzyl alcohol and water.
  • Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Patches may also be used.
  • the compositions of this invention may also be administered by nasal aerosol or inhalation.
  • compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • an antibody present in a pharmaceutical composition of this invention can be supplied at a concentration of 10 mg/mL in either 100 mg (10 mL) or 500 mg (50 mL) single-use vials.
  • the product is formulated for IV administration in 9.0 mg/mL sodium chloride, 7.35 mg/mL sodium citrate dihydrate, 0.7 mg/mL polysorbate 80, and Sterile Water for Injection. The pH is adjusted to 6.5.
  • An exemplary suitable dosage range for an antibody in a pharmaceutical composition of this invention may between about 1 mg/m 2 and 500 mg/m 2 .
  • schedules are exemplary and that an optimal schedule and regimen can be adapted taking into account the affinity and tolerability of the particular antibody in the pharmaceutical composition that must be determined in clinical trials.
  • a pharmaceutical composition of the invention for injection e.g., intramuscular, i.v.
  • the antibodies of the present invention are also particularly of interest for diagnostic purposes.
  • the antibodies of the present invention are suitable for determining presence of IFN- ⁇ in a sample.
  • a further object of the present invention relates to a method for detecting the presence of a IFN- ⁇ polypeptide in a sample comprising contacting the sample with one or more antibodies of the present invention under conditions that allow an immunocomplex of IFN- ⁇ polypeptide and the antibodies to form wherein detection of the immunocomplex indicates the presence of a IFN- ⁇ polypeptide in the sample.
  • the method of the present invention is particularly suitable for diagnostic purposes.
  • the method of the present invention is particularly suitable for determining whether a subject has or is at risk of having an autoimmune inflammatory disease and more particularly a type 1 interferonopathy.
  • high levels of IFN- ⁇ polypeptides indicate that the subject has or is at risk of having an autoimmune inflammatory disease and more particularly a type 1 interferonopathy.
  • the term “high” refers to a measure that is significantly greater than normal, greater than a standard, such as a predetermined reference value or a subgroup measure, or that is relatively greater than another subgroup measure.
  • high levels of IFN- ⁇ polypeptides refers to a level of IFN- ⁇ polypeptides that is greater than a normal level.
  • a normal may be determined according to any method available to one skilled in the art.
  • a high level of IFN- ⁇ polypeptides may also refer to a level equal to or greater than a predetermined reference value, such as a predetermined cutoff.
  • a high level of IFN- ⁇ polypeptides may also refer to a level of IFN- ⁇ polypeptides wherein a high IFN- ⁇ polypeptides subgroup has relatively greater levels of IFN- ⁇ polypeptides than another subgroup.
  • two distinct patient subgroups can be created by dividing samples around a mathematically determined point, such as, without limitation, a median, thus creating a subgroup whose measure is high (i.e., higher than the median) and another subgroup whose measure is low.
  • a “high level” may comprise a range of levels that is very high and a range of levels that is “moderately high”, where moderately high is a level that is greater than normal but less than “very high”.
  • the method of the present invention is also particularly suitable for determining whether a subject is at risk of having a viral infection. More particular, the method of the present invention for determining whether a subject suffering from a viral infection is at risk of progressing to a severe viral disease.
  • the method of the present invention for determining whether a subject suffering from a viral disease is at risk of progressing to an acute respiratory distress syndrome.
  • the viral infection is caused by a virus selected from the group consisting of influenza virus (e.g., Influenza virus A, Influenza virus B), respiratory syncytial virus, adenovirus, metapneumovirus, cytomegalovirus, parainfluenza virus (e.g., hPIV-1, hPIV-2, hPIV-3, hPIV-4), rhinovirus, coxsackie virus, echo virus, herpes simplex virus, coronavirus (SARS-coronavirus such as SARS-Cov1 or SARS-Cov2), and smallpox.
  • influenza virus e.g., Influenza virus A, Influenza virus B
  • respiratory syncytial virus e.g., adenovirus, metapneumovirus, cytomegalovirus, parainfluenza virus (e.g., h
  • the viral lung infection may be due to a member of the Pneumoviridae, Paramyxoviridae and/or Coronaviridae families are in particular selected from the group consisting of upper and lower respiratory tract infections due to: human respiratory syncytial virus (hRSV), type A and type B, human metapneumovirus (hMPV) type A and type B; parainfluenza virus type 3 (PIV-3), measles virus, endemic human coronaviruses (HCoV-229E, -NL63, -OC43, and -HKU1), severe acute respiratory syndrome (SARS) and Middle-East respiratory syndrome (MERS) coronaviruses.
  • hRSV human respiratory syncytial virus
  • hMPV human metapneumovirus
  • PIV-3 parainfluenza virus type 3
  • measles virus endemic human coronaviruses
  • HoV-229E endemic human coronaviruses
  • SARS severe acute
  • the method of the present invention is suitable for the treatment of Severe Acute Respiratory Syndrome (SARS). More particularly, the method of the present invention is suitable for patients suffering from COVID19.
  • low levels of IFN- ⁇ polypeptides indicate that the subject is at risk of having a viral infection and/or to progress to a severe form of the viral disease.
  • the term “low” refers to a level that is less than normal, or less than a standard, such as a predetermined reference value or a subgroup measure that is relatively less than another subgroup level.
  • a low level of IFN- ⁇ polypeptides means a level of IFN- ⁇ polypeptides that is less than a normal level in a particular set of samples of patients.
  • a normal level of IFN- ⁇ polypeptides measure may be determined according to any method available to one skilled in the art.
  • a low level of IFN- ⁇ polypeptides may also mean a level that is less than a predetermined reference value, such as a predetermined cutoff.
  • a low level of IFN- ⁇ polypeptides may also mean a level wherein a low level IFN- ⁇ polypeptides subgroup is relatively lower than another subgroup.
  • two distinct patient subgroups can be created by dividing samples around a mathematically determined point, such as, without limitation, a median, thus creating a group whose measure is low (i.e., less than the median) with respect to another group whose measurement is high (i.e., greater than the median).
  • a mathematically determined point such as, without limitation, a median
  • the term "sample” includes any solid or fluid sample, liable to contain one or more IFN- ⁇ polypeptides.
  • the sample is selected from the group consisting of ascites; urine; saliva; sweat; milk; synovial fluid; peritoneal fluid; amniotic fluid; percerebrospinal fluid; lymph fluid; lung embolism; cerebrospinal fluid; and pericardial fluid.
  • the sample is a faeces samples.
  • the sample is a urine sample.
  • the sample is a saliva sample.
  • the sample is a blood sample.
  • blood sample means any blood sample derived from the subject.
  • the blood sample is a serum or plasma sample. Assays and conditions for the detection of immunocomplexes are known to those of skill in the art.
  • Such assays include, for example, competition assays, direct reaction assays sandwich- type assays and immunoassays (e.g. ELISA).
  • the assays may be quantitative or qualitative.
  • the detecting step can comprise performing an ELISA assay, performing a lateral flow immunoassay, performing an agglutination assay, analyzing the sample in an analytical rotor, or analyzing the sample with an electrochemical, optical, or opto-electronic sensor.
  • any of a number of variations of the sandwich assay technique may be used to perform an immunoassay.
  • a first antibody of the present invention is immobilized on a solid surface and the sample to be tested is brought into contact with the immobilized antibody for a time and under conditions allowing formation of the immunocomplex.
  • a second antibody of the present invention that is labelled with a detectable moiety is added and incubated under conditions allowing the formation of a ternary complex between any immunocomplex and the labelled antibody. Any unbound material is washed away, and the presence of polypeptide in the sample is determined by observation/detection of the signal directly or indirectly produced by the detectable moiety.
  • Detection may be either qualitative or quantitative.
  • Methods for labelling biological molecules such as antibodies are well-known in the art (see, for example, "Affinity Techniques. Enzyme Purification: Part B", Methods in EnzymoL, 1974, Vol. 34, W.B. Jakoby and M. Wilneck (Eds.), Academic Press: New York, NY; and M. Wilchek and E.A. Bayer, Anal. Biochem., 1988, 171 : 1-32).
  • the most commonly used detectable moieties in immunoassays are enzymes and fluorophores.
  • an enzyme such as horseradish perodixase, glucose oxidase, beta-galactosidase, alkaline phosphatase, and the like, is conjugated to the second antibody, generally by means of glutaraldehyde or periodate.
  • the substrates to be used with the specific enzymes are generally chosen for the production of a detectable color change, upon hydrolysis of the corresponding enzyme.
  • the second antibody is chemically coupled to a fluorescent moiety without alteration of its binding capacity.
  • the fluorescent signal generated by the fluorescent moiety is detected, and optionally quantified.
  • the second antibody may be labelled with a radioisotope, a chemiluminescent moiety, or a bio luminescent moiety.
  • the assay utilizes a solid phase or substrate to which the antibody of the present invention is directly or indirectly attached. Accordingly in some embodiments, the antibody of the present invention is attached to or immobilized on a substrate, such as a solid or semi-solid support.
  • the attachment can be covalent or non-covalent, and can be facilitated by a moiety associated with the protein that enables covalent or non-covalent binding, such as a moiety that has a high affinity to a component attached to the carrier, support or surface.
  • the substrate is a bead, such as a colloidal particle (e.g., a colloidal nanoparticle made from gold, silver, platinum, copper, metal composites, other soft metals, core-shell structure particles, or hollow gold nanospheres) or other type of particle (e.g., a magnetic bead or a particle or nanoparticle comprising silica, latex, polystyrene, polycarbonate, polyacrylate, or PVDF).
  • a colloidal particle e.g., a colloidal nanoparticle made from gold, silver, platinum, copper, metal composites, other soft metals, core-shell structure particles, or hollow gold nanospheres
  • other type of particle e.g., a magnetic bead or a particle or nano
  • Such particles can comprise a label (e.g., a colorimetric, chemiluminescent, or fluorescent label) and can be useful for visualizing the location of the proteins during immunoassays.
  • the substrate is a dot blot or a flow path in a lateral flow immunoassay device.
  • the antibody of the present invention can be attached or immobilized on a porous membrane, such as a PVDF membrane (e.g., an ImmobilonTM membrane), a nitrocellulose membrane, polyethylene membrane, nylon membrane, or a similar type of membrane.
  • the substrate is a flow path in an analytical rotor.
  • the substrate is a tube or a well, such as a well in a plate (e.g., a microtiter plate) suitable for use in an ELISA assay.
  • a plate e.g., a microtiter plate
  • Such substrates can comprise glass, cellulose-based materials, thermoplastic polymers, such as polyethylene, polypropylene, or polyester, sintered structures composed of particulate materials (e.g., glass or various thermoplastic polymers), or cast membrane film composed of nitrocellulose, nylon, polysulfone, or the like.
  • a substrate can be sintered, fine particles of polyethylene, commonly known as porous polyethylene, for example, 0.2-15 micron porous polyethylene from Chromex Corporation (Albuquerque, N. Mex.).
  • the antibodies of the present invention are particularly suitable for assessing the neutralizing activity of anti- autoantibodies detected in a subject.
  • anti-IFN- ⁇ autoantibodies refers to the antibodies which are produced by the immune system of the subject and that are directed against the subject's IFN- ⁇ polypeptides own polypeptides.
  • the presence of said auto-antibodies is associated with the risk for the subject to have a viral infection and/or to progress to a severe form of a viral disease.
  • the presence of said auto-antibodies is associated with the risk of COVID19.
  • the presence of said auto-antibodies is associated with the risk to progress to an acute respiratory distress syndrome in patients suffering from a lung viral infections, especially from a SARS-COV2 infection.
  • the presence of autoantibodies having substantially the same or higher neutralizing activity than the antibodies of the present inventio indicate that the subject is at risk of having a viral infection and/or to progress to a severe form of the viral disease.
  • a further object of the present invention relates to a method for determining whether a subject is at risk of having a viral infection and/or at risk to progress to a sever from a viral disease comprising i) detecting the presence of one or more IFN- ⁇ autoantibodies in a sample obtained from the subject, ii) determining the neutralizing activity of said autoantibodies, iii) comparing the neutralizing activity of said autoantibodies with the neutralizing activity of an antibody of the present invention and iv) concluding that the patient the subject is at risk of having a viral infection and/or to progress to a severe form of the viral disease wherein the neutralizing activity of the autoantibodies substantially the same or higher than the neutralizing activity of the antibody of the present invention.
  • a further object of the present invention relates to a kit or device comprising at least one antibody of the present invention (immobilized or not on a solid support as described above).
  • the kit can include a second antibody of the present invention which produces a detectable signal.
  • the antibody of the present invention is conjugated with a detectable label.
  • Suitable detectable labels include, for example, a radioisotope, a fluorescent label, a chemiluminescent label, an enzyme label, a bio luminescent label or colloidal gold.
  • the detectable label can be a radioisotope that is detected by autoradiography.
  • Isotopes that are particularly useful for the purpose of the present invention are 3 H, 125 I, 131 I, 35 S and 14 C.
  • the antibody of the present invention can also be labeled with a fluorescent compound.
  • the presence of a fluorescently-labeled antibody of the present invention is determined by exposing the immuno conjugate to light of the proper wavelength and detecting the resultant fluorescence.
  • Fluorescent labeling compounds include fluorescein isothiocyanate, rhodamine, phycoerytherin, phycocyanin, allophycocyanin, o-phthaldehyde and fluorescamine and Alexa Fluor dyes.
  • the antibody of the present invention can be detectably labeled by coupling said antibody to a chemiluminescent compound.
  • the presence of the chemiluminescent-tagged immuno conjugate is determined by detecting the presence of luminescence that arises during the course of a chemical reaction.
  • chemiluminescent labeling compounds include luminol, isoluminol, an aromatic acridinium ester, an imidazole, an acridinium salt and an oxalate ester.
  • a bio luminescent compound can be used to label the antibody of the present invention. Bioluminescence is a type of chemiluminescence found in biological systems in which a catalytic protein increases the efficiency of the chemiluminescent reaction.
  • Bioluminescent compounds that are useful for labeling include luciferin, luciferase and aequorin.
  • the presence of the fusion protein can be detected with any means well known in the art such as a microscope or microscope or automated analysis system.
  • the enzyme moiety reacts with the substrate to produce a chemical moiety which can be detected, for example, by spectrophotometric, fluorometric or visual means.
  • polyspecific immunoconjugates examples include ⁇ -galactosidase, glucose oxidase, peroxidase (e.g. horseradish perodixase) and alkaline phosphatase.
  • ⁇ -galactosidase glucose oxidase
  • peroxidase e.g. horseradish perodixase
  • alkaline phosphatase alkaline phosphatase.
  • suitable labels which can be employed in accordance with the present invention.
  • the binding of marker moieties to anti-the antibody of the present invention is accomplished using standard techniques known to the art. Typical methodology in this regard is described by Kennedy et al., Clin. Chim. Acta 70: 1, 1976; Schurs et al., Clin. Chim. Acta 81 : 1, 1977; Shih et al., Int'U.
  • kits include but are not limited to ELISA assay kits, and kits comprising test strips and dipsticks.
  • the kits described herein further comprise reference values of the levels of the protein or infectious particles. The reference values are typically average levels in samples from a population of healthy individuals.
  • the kits described herein further comprise at least one sample collection container for sample collection. Collection devices and container include but are not limited to syringes, lancets, BD VACUTAINER® blood collection tubes.
  • the kits described herein further comprise instructions for using the kit and interpretation of results.
  • FIGURES EXAMPLE: Methods Study participants PBMCs from an early time point post-infection ( ⁇ 2 weeks) were collected from 7 patients who experienced a severe COVID-19 disease requiring oxygen (WHO score ⁇ 5) and who were documented as having detectable in vitro neutralizing activity in their sera against 10ng/ml of IFN- ⁇ 2. Patients were recruited through the international COVID Human Genetic Effort consortium. Interferon neutralization assay The in vitro blocking activity of anti–IFN- ⁇ 2 and anti–IFN- ⁇ 1 auto-Abs – polyclonal patient sera, single-memory B cell culture supernatants or re-expressed monoclonal antibodies - was determined using a reporter luciferase activity.
  • HEK293T cells were transfected with a plasmid containing the firefly luciferase gene under the control of the human ISRE promoter in the pGL4.45 backbone and a plasmid constitutively expressing Renilla luciferase for normalization (pRL-SV40).
  • Cells were transfected in the presence of the X-tremeGENE9 transfection reagent (Sigma-Aldrich, reference number 6365779001) for 24 hours.
  • luciferase levels were measured with the Dual- Luciferase Reporter 1000 Assay System (Promega, reference number E1980) according to the manufacturer’s protocol.
  • Luminescence intensity was measured with a VICTOR-X Multilabel Plate Reader (PerkinElmer Life Sciences, USA). Firefly luciferase activity values were normalized against Renilla luciferase activity values. These values were then normalized against the median induction level for non-neutralizing samples and expressed as a percentage. Samples were considered neutralizing if luciferase induction, normalized against Renilla luciferase activity, was below 15% of the median values for controls tested the same day.
  • Proteins biotinylation and Tetramers preparation Recombinant human IFN- ⁇ 2 (Miltenyi, 130-108-984), rhIFN- ⁇ 1 (Sigma, SRP3061) and BSA proteins were biotinylated using EZ link NHS biotin (Thermofischer) according to the manufacturer instructions. Tetramer were made fresh prior to each staining by further incubating biotinylated proteins with fluorochrome-conjugated streptavidin at 4:1 molar ratio for 1 hour at 4°C.2.4 ng of free biotin was then added for 10 additional minutes before mixing of tetramers.
  • PBMCs were isolated from blood samples via standard density gradient centrifugation and used after cryopreservation at -150°C. Cells were thawed in RPMI-1640 (Gibco)-10% FBS (Gibco), washed twice and incubated with a mixture of rhIFN- ⁇ 2 and rhIFN- ⁇ 1 tetramers (equivalent to 200ng of each protein) in 100 ⁇ L of PBS (Gibco)-2% FBS during 40 min on ice. To exclude cells with nonspecific binding, a non-relevant tetramer was constructed using biotinylated bovine serum albumin and added to the mix.
  • Single-cell culture Single cell culture was performed as previously described 1 .
  • Single B cells were sorted in 96- well plates containing MS40L lo cells expressing CD40L (kind gift from G. Kelsoe, Luo et al., 2009).
  • ELISA Total IgG and rhIFN- ⁇ 2 and rhIFN- ⁇ 1-specific IgG from culture supernatants were measured using homemade ELISA.96 well ELISA plates (Thermo Fisher) were coated either with goat anti-human Ig (10 ⁇ g/ml, Invitrogen) in sodium carbonate during 1h at 37°C or with rhIFN- ⁇ 2 and rhIFN- ⁇ 1 proteins (5 ⁇ g/ml each) at 4°C overnight. After plate blocking, cell culture supernatants were added for 1hr, then ELISA were developed using HRP-goat anti-human IgG (1 ⁇ g/ml, Immunotech) and TMB substrate (Eurobio).
  • OD450 and OD620 were measured, and supernatants whose OD450-OD620 values were above 0.09 and over 10 times blank wells values were considered as positive.
  • Single-cell IgH sequencing and monoclonal antibody re-expression At the end of each single B cell culture, cell pellets were resuspended in 50 ⁇ l RLT Buffer (Qiagen) and stored at -80 °C. Clones whose culture had proven successful (IgG concentration ⁇ 1 ⁇ g/mL and positive in rhIFN- ⁇ 2 and rhIFN- ⁇ 1-specific ELISA at day 21-25) were selected and extracted using the NucleoSpin96 RNA extraction kit (Macherey-Nagel) according to the manufacturer’s instructions.
  • a reverse transcription step was then performed using the SuperScript IV enzyme (ThermoFisher) in a 14 ⁇ l final volume (42°C 10 min, 25°C 10 min, 50°C 60 min, 94°C 5 min) with 4 ⁇ l of RNA and random hexamers (Thermofisher scientific).
  • a PCR was further performed based on the protocol established by Tiller et al 2 .
  • cDNA 3.5 ⁇ l of cDNA was used as template and amplified in a total volume of 40 ⁇ l with a mix of forward L-VH, L-V ⁇ or L-V ⁇ primers and reverse C ⁇ , C ⁇ or C ⁇ primers for heavy chains, ⁇ and ⁇ light chains respectively using the HotStar® Taq DNA polymerase (Qiagen) and 50 cycles of PCR (94°C 30 s, 58°C 30 s, 72°C 60 s). PCR products were sequenced with the reverse primer CHG- D1 and read on ABI PRISM 3130XL genetic analyzer (Applied Biosystems). Sequence quality was verified using CodonCode Aligner software (CodonCode Corporation).
  • Reverse transcription and a first PCR was performed as described above (50 cycles) before a second 50-cycles PCR using 5’AgeI VH, V ⁇ or V ⁇ primer mix and reverse C ⁇ , C ⁇ or C ⁇ primers for heavy chains, ⁇ and ⁇ light chains respectively, before sequencing.
  • the cDNAs coding for the variable regions of the heavy and light chains were chemically synthesized with optimization for expression in CHO cells and subcloned in ProteoGenix’s proprietary mammalian cells expression vectors containing backbones for human IgG1 heavy chain constant region and human kappa/lambda light chain constant region.
  • ProteoGenix proprietary mammalian cells expression vectors containing backbones for human IgG1 heavy chain constant region and human kappa/lambda light chain constant region.
  • An endotoxin-free DNA preparation was done for each construction and vectors were further transfected in XtenCHO cells by XtenCHO transfection protocol, in a total volume of 3.5 ml. Culture medium was collected 8 days after transfection and purified using one-step affinity purification (Protein A).
  • Biosensors were equilibrated for 5 minutes in 1x PBS buffer with 0.1% BSA and 0,01% Tween 20 surfactant (PBS-BT) prior to measurement. Association was performed for 240s in PBS-BT with individual glycosylated Type I IFNs (Bio-Techne (11014-IF; 10984-IF; 10998-IF; 11017- IF; 11168-IF; 11079-IF; 11018-IF; 11016-IF; 11019-IF; 11156-IF; 11082-IF; 11159-IF); Sigma (H6041; SRP3061; IF014)) at 100nM followed by dissociation for 480s in PBS-BT.
  • PBS-BT Tween 20 surfactant
  • biosensor regeneration was performed by alternating 30s cycles of regeneration buffer (glycine HCl, 10 mM, pH 2.0) and 30s of PBS-BT for 3 cycles. Traces were reference sensor (unloaded sensor) and reference well (additional association cycle in the absence of ligand) subtracted and curve fitting was performed using a local 1:1 binding model in the HT Data analysis software 11.1 (ForteBio). For each tested antibody in epitope binning experiments, anti-Human Fc Capture (AHC) biosensors (18-5060) were first immersed in a solution of that re-expressed monoclonal antibody solution (5 ⁇ g/ml) at 25°C for 600 seconds.
  • AHC anti-Human Fc Capture
  • biosensor regeneration was performed by alternating 30s cycles of regeneration buffer (glycine HCl, 10 mM, pH 2.0) and 30s of PBS-BT for 3 cycles.
  • References 1. Crickx, E., Chappert, P., Sokal, A., Weller, S., Azzaoui, I., Vandenberghe, A., Bonnard, G., Rossi, G., Fadeev, T., Storck, S., et al. (2021).
  • Rituximab-resistant splenic memory B cells and newly engaged naive B cells fuel relapses in patients with immune thrombocytopenia. Sci. Transl. Med.13.10.1126/scitranslmed.abc3961. 2.
  • ITD identified tolerance defect
  • IFN- ⁇ 2-specific B cell response we first optimized a multiparametric flow cytometry allowing simultaneous sorting and phenotyping analysis of IFN- ⁇ 2-specific B cells.
  • Available markers including CD21, CD11c and CD71, allowed us to retrospectively identify major memory B cell (MBC) populations using index-sorting data (data not shown) and ex vivo culture of sorted IgG + IFN- ⁇ 2 tetramer + cells confirmed an overall purity above 90% (data not shown).
  • IFN- ⁇ 2 tetramer + IgG + B cells were rare, often representing only a few tens of cells per vial, especially in some ITD donors with low peripheral B cell counts.
  • IFN- ⁇ 2 IgG + B cells could even be detected in four out of six S-CoV or ITD patients with AAN-I-IFNs at 0.1ng/ml only and in all subgroups of ITD donors (data not shown), albeit only in one out of three SLE patient analyzed.
  • Some of these IFN- ⁇ 2 IgG + B cells were further single-cell sorted and monoclonal IgGs containing supernatants from these in vitro cultured cells were assayed for affinity using Biolayer Interferometry (BLI) against IFN- ⁇ 2 protein.
  • BBI Biolayer Interferometry
  • IFN- ⁇ 2-specific IgG + B Cells To ascertain whether these high-affinity IFN- ⁇ 2 IgG + circulating B cells originated from de novo recruitment of unmutated autoreactive naive B cells through the extrafollicular (EF) pathway or prior germinal center reactions, we next sequenced all IFN- ⁇ 2-specific cells previously characterized (data not shown) and performed additional single-cell VDJ sequencing on sorted IFN- ⁇ 2-specific IgG + cells from other donors.
  • EF extrafollicular
  • IgVH antibody heavy chains
  • IFN- ⁇ 2-specific IgG + B cells clones shared a strong bias towards VH1-8 and VH4-30 gene (data not shown), as well as more specific overrepresentation of VH1-69 and VH1-3 in S-CoV patients, when compared with published IgG memory B cell reference repertoires (29). Most importantly, the observed IFN- ⁇ 2-specific IgG repertoire in both groups of patients showed signs of clonal expansion yet remained highly diverse in all patients analyzed (data not shown). Overall, these results indicate that IFN- ⁇ 2-specific B cells in S- CoV patients are a pre-existing MBC population that has undergone extensive germinal center maturation prior to SARS-CoV-2 infection.
  • IFN- ⁇ 2 and IFN- ⁇ To unravel the structural basis of IFN- ⁇ and ⁇ recognition in S-CoV patients, we first expressed and validated 32 representative antibodies from 7 S-COV patients, including 3 Abs monospecific for IFN- ⁇ (see methods).
  • IFN- ⁇ 2/IFN- ⁇ cross-reactive antibodies belonged exclusively to Group I antibodies, while similar experiment performed with IFN- ⁇ show that IFN- ⁇ monoreactive mAbs clustered as a distinct epitope group (data not shown).
  • These 3 groups of Abs were represented in all donors (data not shown) and IFN- ⁇ 2 neutralizing antibodies were equally distributed between groups (data not shown), with intragroup differences in neutralization potency mostly related to off-rate of individual antibodies.
  • Crystal structures of AAN-I-INFs complexes with type I IFNs To better delineate the epitopes targeted by antibodies in these 3 groups, we made crystallization trials of various complexes with IFN- ⁇ 2.
  • Helices A, E and a short helix in the connection between helices A and B form one side of the molecule, which is recognized by the receptor IFNAR2 subunit, while the central B, C and D helices form the opposite face, recognized by IFNAR1, to make a “sandwich” like signaling complex at the cell surface ( M. R. Walter, The Role of Structure in the Biology of Interferon Signaling. Front. Immunol. 11, 606489 (2020) ;C. Thomas, I. Moraga, D. Levin, P. O. Krutzik, Y. Podoplelova, A. Trejo, C. Lee, G. Yarden, S. E. Vleck, J. S. Glenn, G.
  • the epitope of PMAB19 lies at the opposite side of IFN- ⁇ 2 compared to Group I mAbs, encompassing residues on helices B and C, as previously described for Sifalimumab (PDB 4YPG)( (V. Oganesyan, L. Peng, R. M. Woods, H. Wu, W. F. Dall’Acqua, Structural Insights into the Neutralization Properties of the Fully Human, Anti-interferon Monoclonal Antibody Sifalimumab. J Biol Chem 290, 14979–14985 (2015)), and clashing with the SD2 and SD3 domains of IFNAR1.
  • AI-based structural predictions of the isolated mAbs in complex with IFN ⁇ reveals four unique classes of AAN-I-IFNs
  • AI artificial intelligence
  • AlphaFold 3 (ABRAMSON, Josh, ADLER, Jonas, DUNGER, Jack, et al. Accurate structure prediction of biomolecular interactions with AlphaFold 3. Nature, 2024, p. 1-3.), which predicts antibody/antigen complexes with higher confidence than previous AlphaFold versions, allowed us to extend the above observations to most of the sequenced anti-IFN- ⁇ 2 mAbs in our dataset, including mAbs from ITD patients.
  • IFN- ⁇ monoreactive mAbs isolated from the spleen of an AAB organ donor, were also found in a Class IV-like binding group, slightly shifted towards Class I binding sites compared to IFN- ⁇ 2 Class IV, with residues on Helix A and F of IFN- ⁇ (data not shown).
  • Class I mAbs appeared to dominate the anti-IFN- ⁇ 2 response in both S-CoV and ITD patients (Figure S6B), while Class IV antibodies were rare in S-CoV patients and were not observed in ITD patients. These frequencies, however, must be taken with caution as IGHV usage (e.g. IGHV3-23), targeted epitopes (e.g.
  • the K31M mutation, also unique to IFN- ⁇ 1 doesn’t impair binding as much, as seen for the one Class II mAbs tested with predicted binding at that site (PMAB08).
  • IFNAR human Interferon alpha/beta receptor
  • Tested monoclonal antibodies were loaded as saturating antibody (1st, row) on AHC biosensors and data shows row and column- normalized values of maximal binding measured by biolayer interferometry for each competing Ab (2nd, column)) after an association step with IFN- ⁇ 2.
  • KD values (M) as measured by biolayer interferometry at a ligand concentration of 100nM.
  • mAbs with no detectable binding are listed with KD >1.00E -7 while mAbs who did not display any significant dissociation from ligand over the time frame of the measurements are listed with KD >1.00E -12 .
  • Table C Neutralization potency against IFN- ⁇ 2 and IFN- ⁇ 1: Antibodies listed in column 1 (mAb_ID) represent all identified IFN- ⁇ 2 or IFN- ⁇ 1 binders and were tested for in vitro blocking activity of anti–IFN- ⁇ 2 and anti–IFN- ⁇ 1 signalling at a 1ng/ml final concentration of each cytokine. Data represent calculated IC50 values (ng/ml).

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Abstract

The invention relates to novel monoclonal antibodies that bind to human interferon-alpha 2 (IFN-α2), one subtype of type I interferons that play important roles in innate and adaptive immunity. Some of the antibodies are capable of neutralizing the biological activity of both IFN-α2. The antibodies can be used for the treatment of various diseases and conditions that are associated with excessive or dysregulated production of type I interferons, such as autoimmune diseases, inflammatory diseases. The antibodies can also be used for the diagnosis of these diseases and conditions by detecting the presence or level of IFN-α2 in biological samples. The invention further provides methods of producing the antibodies, nucleic acids encoding the antibodies, and pharmaceutical compositions comprising the antibodies.

Description

ANTI-IFN-α2 MONOCLONAL ANTIBODIES FIELD OF THE INVENTION: The present invention is in the field of medicine, in particular immunology. BACKGROUND OF THE INVENTION: Type I interferons (IFNs) are a group of cytokines that play a crucial role in antiviral immunity. They are produced by various cells in response to viral infections and induce the expression of genes that inhibit viral replication and activate immune cells. Type I IFNs also modulate the adaptive immune response and regulate inflammation. Recently, it has been discovered that some individuals have autoantibodies that target type I IFNs, either neutralizing their activity or blocking their binding to their receptors. These autoantibodies impair the antiviral defense and increase the susceptibility to severe viral diseases, such as influenza, herpes simplex virus, hepatitis C virus, and COVID-19. The prevalence and origin of these autoantibodies are not fully understood, but they seem to be more common in older people and in certain ethnic groups. Some studies suggest that they may arise from genetic mutations, environmental factors, or chronic viral infections. The detection and characterization of these autoantibodies are important for the diagnosis and treatment of patients with impaired antiviral immunity. Moreover, the characterization of these autoantibodies may provide new opportunities to develop antibodies having therapeutic value for patients with various diseases that involve type I IFN dysregulation. SUMMARY OF THE INVENTION: The present invention is defined by the claims. In particular, the present invention relates to anti-IFN-α2 monoclonal antibodies. DETAILED DESCRIPTION OF THE INVENTION: Main definitions: As used herein, the terms “polypeptide”, “peptide”, and “protein” are used interchangeably herein to refer to polymers of amino acids of any length. The terms also encompass an amino acid polymer that has been modified; for example, disulfide bond formation, glycosylation, lipidation, phosphorylation, or conjugation with a labeling component. As used herein, the term “polynucleotide” refers to a polymeric form of nucleotides of any length, including deoxyribonucleotides or ribonucleotides, or analogs thereof. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs, and may be interrupted by non-nucleotide components. If present, modifications to the nucleotide structure may be imparted before or after assembly of the polymer. The term polynucleotide, as used herein, refers interchangeably to double- and single-stranded molecules. Unless otherwise specified or required, any embodiment of the invention described herein that is a polynucleotide encompasses both the double-stranded form and each of two complementary single-stranded forms known or predicted to make up the double-stranded form. As used herein, the term "encoding" refers to the inherent property of specific sequences of nucleotides in a polynucleotide, such as, for example, a gene, a cDNA, or an mRNA, to serve as templates for synthesis of other polymers and macromolecules in biological processes having either a defined sequence of nucleotides (e.g., rRNA, tRNA and mRNA) or a defined sequence of amino acids and the biological properties resulting therefrom. Thus, a gene, cDNA, or RNA, encodes a protein if transcription and translation of mRNA corresponding to that gene produces the protein in a cell or other biological system. Both the coding strand, the nucleotide sequence of which is identical to the mRNA sequence and is usually provided in sequence listings, and the non-coding strand, used as the template for transcription of a gene or cDNA, can be referred to as encoding the protein or other product of that gene or cDNA. Unless otherwise specified, a "nucleotide sequence encoding an amino acid sequence" includes all nucleotide sequences that are degenerate versions of each other and that encode the same amino acid sequence. As used herein, the “percent identity” between the two sequences is a function of the number of identical positions shared by the sequences (i.e., % identity = number of identical positions/total number of positions x 100), taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences. The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm, as described below. The percent identity between two amino acid sequences can be determined using the Needleman and Wunsch algorithm (Needleman, Saul B. & Wunsch, Christian D. (1970). "A general method applicable to the search for similarities in the amino acid sequence of two proteins". Journal of Molecular Biology.48 (3): 443–53.). The percent identity between two nucleotide or amino acid sequences may also be determined using for example algorithms such as EMBOSS Needle (pair wise alignment; available at www.ebi.ac.uk). For example, EMBOSS Needle may be used with a BLOSUM62 matrix, a “gap open penalty” of 10, a “gap extend penalty” of 0.5, a false “end gap penalty”, an “end gap open penalty” of 10 and an “end gap extend penalty” of 0.5. In general, the “percent identity” is a function of the number of matching positions divided by the number of positions compared and multiplied by 100. For instance, if 6 out of 10 sequence positions are identical between the two compared sequences after alignment, then the identity is 60%. The % identity is typically determined over the whole length of the query sequence on which the analysis is performed. Two molecules having the same primary amino acid sequence or polynucleotide sequence are identical irrespective of any chemical and/or biological modification. According to the present invention, a first amino acid sequence having at least 70% of identity with a second amino acid sequence means that the first sequence has 70; 71; 72; 73; 74; 75; 76; 77; 78; 79; 80; 81; 82; 83; 84; 85; 86; 87; 88; 89; 90; 91; 92; 93; 94; 95; 96; 97; 98; 99 or 100% of identity with the second amino acid sequence. As used herein, the term “type I interferon” or “type I IFN” has its general meaning in the art and refers to members of the type I interferon family of molecules that are ligands for IFNAR- 1 (i.e., members of the type I interferon family of molecules that are capable of binding IFNAR- 1). Examples of type I interferon ligands are interferon alpha 1, 2a, 2b, 4, 5, 6, 7, 8, 10, 14, 16, 17, 21, interferon beta and interferon omega. All type I IFNs bind to a specific cell surface receptor complex known as the IFN-α receptor (IFNAR) that consists of IFNAR1 and IFNAR2 chains. As used herein, the term “IFNAR1” has its general meaning in the art and refers to the interferon-α/β receptor 1, which is a protein encoded by the IFNAR1 gene in humans and forms part of the type I interferon receptor complex. IFNAR1 is expressed on most cell types and binds to various subtypes of IFN-α and IFN-β, triggering signal transduction pathways that mediate antiviral, immunomodulatory, and antiproliferative effects. The amino acid sequence of human IFNAR1 is represented by SEQ ID NO:1. SEQ ID NO:1 >sp|P17181|INAR1_HUMAN Interferon alpha/beta receptor 1 OS=Homo sapiens OX=9606 GN=IFNAR1 PE=1 SV=3 MMVVLLGATTLVLVAVAPWVLSAAAGGKNLKSPQKVEVDIIDDNFILRWNRSDESVGNVT FSFDYQKTGMDNWIKLSGCQNITSTKCNFSSLKLNVYEEIKLRIRAEKENTSSWYEVDSF TPFRKAQIGPPEVHLEAEDKAIVIHISPGTKDSVMWALDGLSFTYSLVIWKNSSGVEERI ENIYSRHKIYKLSPETTYCLKVKAALLTSWKIGVYSPVHCIKTTVENELPPPENIEVSVQ NQNYVLKWDYTYANMTFQVQWLHAFLKRNPGNHLYKWKQIPDCENVKTTQCVFPQNVFQK GIYLLRVQASDGNNTSFWSEEIKFDTEIQAFLLPPVFNIRSLSDSFHIYIGAPKQSGNTP VIQDYPLIYEIIFWENTSNAERKIIEKKTDVTVPNLKPLTVYCVKARAHTMDEKLNKSSV FSDAVCEKTKPGNTSKIWLIVGICIALFALPFVIYAAKVFLRCINYVFFPSLKPSSSIDE YFSEQPLKNLLLSTSEEQIEKCFIIENISTIATVEETNQTDEDHKKYSSQTSQDSGNYSN EDESESKTSEELQQDFV As used herein, the term “IFNAR2” has its general meaning in the art and refers to the interferon-α/β receptor 2, which is a protein encoded by the IFNAR2 gene in humans and forms part of the type I interferon receptor complex. IFNAR2 is expressed on most cell types and binds to various subtypes of IFN-α and IFN-β, enhancing the affinity and specificity of IFNAR1 for these ligands. The amino acid sequence of human IFNAR2 is represented by SEQ ID NO:2. SEQ ID NO:2 >sp|P48551|INAR2_HUMAN Interferon alpha/beta receptor 2 OS=Homo sapiens OX=9606 GN=IFNAR2 PE=1 SV=1 MLLSQNAFIFRSLNLVLMVYISLVFGISYDSPDYTDESCTFKISLRNFRSILSWELKNHS IVPTHYTLLYTIMSKPEDLKVVKNCANTTRSFCDLTDEWRSTHEAYVTVLEGFSGNTTLF SCSHNFWLAIDMSFEPPEFEIVGFTNHINVMVKFPSIVEEELQFDLSLVIEEQSEGIVKK HKPEIKGNMSGNFTYIIDKLIPNTNYCVSVYLEHSDEQAVIKSPLKCTLLPPGQESESAE SAKIGGIITVFLIALVLTSTIVTLKWIGYICLRNSLPKVLNFHNFLAWPFPNLPPLEAMD MVEVIYINRKKKVWDYNYDDESDSDTEAAPRTSGGGYTMHGLTVRPLGQASATSTESQLI DPESEEEPDLPEVDVELPTMPKDSPQQLELLSGPCERRKSPLQDPFPEEDYSSTEGSGGR ITFNVDLNSVFLRVLDDEDSDDLEAPLMLSSHLEEMVDPEDPDNVQSNHLLASGEGTQPT FPSPSSEGLWSEDAPSDQSDTSESDVDLGDGYIMR As used herein, the term “interferon-α” or “IFN-α” refers to all native subtypes of human alpha interferons. Native IFN-α consists of more than 23 closely related protein subtypes encoded by distinct genes with a high degree of structural homology (Weissmann and Weber, Prog. Nucl. Acid. Res. Mol. Biol., 33: 251, 1986; Roberts et al., J. Interferon Cytokine Res.18: 805-816, 1998). The human IFN-α subtypes are at least IFN-αA (IFN-α2), IFN-αB2 (IFN-α8), IFN-αC (IFN-α10), IFN-αD (IFN-α1), IFN-αF (IFN-α21), IFN-αG (IFN-α5), and IFN-αH (IFN-α14), IFN-αI with P34H substitution (IFN-α17), IFN-αJ1 (IFN-α7), IFN-αK (IFN-α6), IFN-α4b (IFN-α4), and IFN-αWA (IFN-α6). The amino acid sequence for IFN-α2 is represented by SEQ ID NO:3. The “Helix A” is defined by the amino acid residues S8 to M21 in SEQ ID NO:3, the “Helix B” is defined by the amino acid residues H52 to F67 in SEQ ID NO:3 and the “Helix C” is defined by the amino acid residues D77 to C98 in SEQ ID NO, 3. SEQ ID NO:3 >sp|P01563|IFNA2_HUMAN Interferon alpha-2 OS=Homo sapiens OX=9606 GN=IFNA2 PE=1 SV=2 CDLPQTHSLGSRRTLMLLAQMRRISLFSCLKDRHDFGFPQEEFGNQFQKAETIPVLHEMIQQIFNLFST KDSSAAWDETLLDKFYTELYQQLNDLEACVIQGVGVTETPLMKEDSILAVRKYFQRITLYLKEKKYSPC AWEVVRAEIMRSFSLSTNLQESLRSKE As used herein, the term “interferon-ω” or “IFN-ω” refers to all native subtypes of human omega interferons. IFN-ω exhibits about 75% sequence homology with IFN-α, and contains two conserved disulfide bonds that are necessary for full biological activity. The amino acid sequence for IFN-ω1 is represented by SEQ ID NO:4. SEQ ID NO:4 >sp|P05000|IFNW1_HUMAN Interferon omega-1 OS=Homo sapiens OX=9606 GN=IFNW1 PE=1 SV=2 CDLPQNHGLLSRNTLVLLHQMRRISPFLCLKDRRDFRFPQEMVKGSQLQKAHVMSVLHEMLQQIFSLFH TERSSAAWNMTLLDQLHTGLHQQLQHLETCLLQVVGEGESAGAISSPALTLRRYFQGIRVYLKEKKYSD CAWEVVRMEIMKSLFLSTNMQERLRSKDRDLGSS As used herein the term "antibody" or "immunoglobulin" has the same meaning, and will be used equally in the present invention. The term "antibody" as used herein refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain an antigen binding site that immunospecifically binds an antigen. As such, the term antibody encompasses not only whole antibody molecules, but also antibody fragments as well as variants (including derivatives) of antibodies and antibody fragments. In natural antibodies, two heavy chains are linked to each other by disulfide bonds and each heavy chain is linked to a light chain by a disulfide bond. There are two types of light chain, lambda (1) and kappa (k). There are five main heavy chain classes (or isotypes) which determine the functional activity of an antibody molecule: IgM, IgD, IgG, IgA and IgE. Each chain contains distinct sequence domains. The light chain includes two domains, a variable domain (VL) and a constant domain (CL). The heavy chain includes four (α, δ, γ) to five (µ, ε) domains, a variable domain (VH) and three to four constant domains (CH1, CH2, CH3 and CH4 collectively referred to as CH). The variable regions of both light (VL) and heavy (VH) chains determine binding recognition and specificity to the antigen. The constant region domains of the light (CL) and heavy (CH) chains confer important biological properties such as antibody chain association, secretion, trans-placental mobility, complement binding, and binding to Fc receptors (FcR). The Fv fragment is the N-terminal part of the Fab fragment of an immunoglobulin and consists of the variable portions of one light chain and one heavy chain. The specificity of the antibody resides in the structural complementarity between the antibody combining site and the antigenic determinant. Antibody combining sites are made up of residues that are primarily from the hypervariable or complementarity determining regions (CDRs). Occasionally, residues from nonhypervariable or framework regions (FR) can participate to the antibody binding site or influence the overall domain structure and hence the combining site. CDRs refer to amino acid sequences which together define the binding affinity and specificity of the natural Fv region of a native immunoglobulin binding site. The light and heavy chains of an immunoglobulin each have three CDRs, designated L-CDR1, L-CDR2, L-CDR3 and H- CDR1, H-CDR2, H-CDR3, respectively. An antigen-binding site, therefore, typically includes six CDRs, comprising the CDR set from each of a heavy and a light chain V region. Framework Regions (FRs) refer to amino acid sequences interposed between CDRs. According to the present invention, the amino acid residues in the variable domain, complementarity determining regions (CDRs) and framework regions (FR) of the antibody or the antigen-binding fragment of the present invention are identified using the Immunogenetics (IMGT) database (http://imgt.cines.fr). Lefranc et al. (2003) Dev Comp Immunol. 27(1):55-77. The IMGT database was developed using sequence information for immunoglobulins (IgGs), T-cell receptors (TcR) and Major Histocompatibility Complex (MHC) molecules and unifies numbering across antibody lambda and kappa light chains, heavy chains and T-cell receptor chains and avoids the use of insertion codes for all but uncommonly long insertions. IMGT also takes into account and combines the definition of the framework (FR) and complementarity determining regions (CDR) from Kabat et al., the characterization of the hypervariable loops from Chothia et al., as well as structural data from X-ray diffraction studies. As used herein, the terms "monoclonal antibody", "monoclonal Ab", "monoclonal antibody composition", "mAb", or the like, as used herein refer to a preparation of antibody molecules of single molecular composition. A monoclonal antibody is obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprised in the population are identical except for possible naturally occurring mutations that may be present in minor amounts. A monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope. As used herein, the term "chimeric antibody" refers to an antibody which comprises a VH domain and a VL domain of a non-human antibody, and a CH domain and a CL domain of a human antibody. As used herein, the term "humanized antibody" refers to an antibody having variable region framework and constant regions from a human antibody but retains the CDRs of a previous non-human antibody. In some embodiments, a humanized antibody contains minimal sequence derived from non-human immunoglobulin. For the most part, humanized antibodies and antibody fragments thereof may be human immunoglobulins (recipient antibody or antibody fragment) in which residues from a complementary-determining region (CDR) of the recipient are replaced by residues from a CDR of non-human species (donor antibody) such as mouse, rat or rabbit having the desired specificity, affinity, and capacity. As used herein the term "human antibody" is intended to include antibodies having variable and constant regions derived from human immunoglobulin sequences. The human antibodies of the present invention may include amino acid residues not encoded by human immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). However, the term "human antibody", as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences. As used herein, the term “PMAB19” refers to the human monoclonal antibody having the VH sequence as set forth in SEQ ID NO:5 and the VL sequence as set forth in SEQ ID NO:9. In particular, the VH region sequence details are depicted in Table 1 and the VL VH region sequence details are depicted in Table 2. SEQ ID NO:5 > Amino Acid Sequence: QVQLVQSGAEVKKPGASVKVSCKASGYDFSRFSIHWVRQAPGQRLEWMGWLITGNGDAKYSQKFQGRVTISRNIS ASTAYMEVTNLRSEDSAVYYCSRDPVAAGLWGQGTLVTVSS Table 1: Region Sequence Fragment SEQ ID NO : CDR-H1 GYDFSRFS 6 CDR-H2 LITGNGDA 7 CDR-H3 SRDPVAAGL 8 SEQ ID NO:9 > Amino Acid Sequence: EILLTQSPGTLSLSPGERATLSCRASQFVSSTYLAWYQHKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLT INGLEPEDFAVYYCQQYGSSPRTFGQGTKVEIK Table 2: Region Sequence Fragment SEQ ID NO : CDR-L1 QFVSSTY 10 CDR-L2 GA 11 CDR-L3 QQYGSSPRT 12 As used herein, the term “PMAB06” refers to the human monoclonal antibody having the VH sequence as set forth in SEQ ID NO:13 and the VL sequence as set forth in SEQ ID NO:17. In particular, the VH region sequence details are depicted in Table 3 and the VL VH region sequence details are depicted in Table 4. SEQ ID NO:13 > Amino Acid Sequence: EVQLVESGGGLVQPGGSLRLSCAASGFTFNNYAMAWVRQSPGKGLEWVSSVSGSGGNTYYADSVKGRFTISRDNS KHTLYLQMNSLRADDTAIYYCVKGAVVVVAAVRPFDYWGQGTLVTVSS Table 3 Region Sequence Fragment SEQ ID NO : CDR-H1 GFTFNNYA 14 CDR-H2 VSGSGGNT 15 CDR-H3 VKGAVVVVAAVRPFDY 16 SEQ ID NO: 17> Amino Acid Sequence: DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAVSSLQSGVPSRFSGSGSGTNYTLTI SSLQFEDFATYYCQQSYSTWYTFGQGTKLEIK Table 4 Region Sequence Fragment SEQ ID NO : CDR-L1 QSISSY 18 CDR-L2 AV 19 CDR-L3 QQSYSTWYT 20 As used herein, the term “PMAB09” refers to the human monoclonal antibody having the VH sequence as set forth in SEQ ID NO:21 and the VL sequence as set forth in SEQ ID NO:25. In particular, the H-CDR region sequences are depicted in Table 5 and the L-CDR sequences are depicted in Table 6. SEQ ID NO:21> Amino Acid Sequence: EVQLVQSGAEVKKPGESLKISCTGSGYTFARFWIGWVRQMPGKGLEWMGVIHPADSKTTYSPSFQGHVTMSADTS ISTAYLHWNTLKASDTARYYCHRGPILSGLWGQGTLVTVSS Table 5: Region Sequence Fragment SEQ ID NO : CDR-H1 GYTFARFW 22 CDR-H2 IHPADSKT 23 CDR-H3 HRGPILSGL 24 SEQ ID NO:25> Amino Acid Sequence: EIVLTQSPGTLSLSPGERATLSCRASQSVSSTYLAWYQQKPGQAPRLLIYGASSRATGIPDKFSGSGSGTDFTLT IYRLEPEDFAVYYCQQYGSSPYTFGQGTKLEIK Table 6: Region Sequence Fragment SEQ ID NO : CDR-L1 QSVSSTY 26 CDR-L2 GA 27 CDR-L3 QQYGSSPYT 28 As used herein, the term “PMAB12” refers to the human monoclonal antibody having the VH sequence as set forth in SEQ ID NO:29 and the VL sequence as set forth in SEQ ID NO:33. In particular, the H-CDR region sequences are depicted in Table 7 and the L-CDR sequences are depicted in Table 8. SEQ ID NO:29> Amino Acid Sequence: QVQLVQSGAEVKKPGASVKISCEASGYTFGNFAMHWVRQAPGQRPEWMGVINAGNVNTKYSQKFQGRVTITRDTF TSTAYMELTSLTSEDTAIYYCARGPVAAITWGQGTLVTVSS Table 7 Region Sequence Fragment SEQ ID NO : CDR-H1 GYTFGNFA 30 CDR-H2 INAGNVNT 31 CDR-H3 ARGPVAAIT 32 SEQ ID NO:33> Amino Acid Sequence: EIVLTQSPGTLSLSPGERATLSCRASQSVLSTYLAWYQQKPGQAPRLLIYGATSRATGIPDRFSGSGSGTDFTLI ISRLEPEDFAVYYCQQYGGSPWTFGQGTKVEIK Table 8 Region Sequence Fragment SEQ ID NO : CDR-L1 QSVLSTY 34 CDR-L2 GA 35 CDR-L3 QQYGGSPWT 36 As used herein, the term “PMAB34” refers to the human monoclonal antibody having the VH sequence as set forth in SEQ ID NO:37 and the VL sequence as set forth in SEQ ID NO:41. In particular, the H-CDR region sequences are depicted in Table 9 and the L-CDR sequences are depicted in Table 10. SEQ ID NO:37> Amino Acid Sequence: EVQLVQSGPEVKKPGEYLKISCKGSGYTFASFWIAWVRQTPGKGLQWMGMISPGDSNTRYSPSFQGQVTISADKS ISTAYLEWSSLKASDSAMYYCARGPVAAGYWGQGTLVIVSS Table 9: Region Sequence Fragment SEQ ID NO : CDR-H1 GYTFASFW 38 CDR-H2 ISPGDSNT 39 CDR-H3 ARGPVAAGY 40 SEQ ID NO:41> Amino Acid Sequence: EIVLTQSPGTLSLSPGERATLSCRASQSVSSTYLAWYQQKPGQAPRLLIYGASSRAAGIPDRFSGGGSGTDFTLS ISRLEPEDLAVYYCHQYGNSPPTFGGGTKVEIKRT Table 10: Region Sequence Fragment SEQ ID NO : CDR-L1 QSVSSTY 42 CDR-L2 GA 43 CDR-L3 HQYGNSPPT 44 As used herein, the term “GMAB03” refers to the human monoclonal antibody having the VH sequence as set forth in SEQ ID NO:45 and the VL sequence as set forth in SEQ ID NO:49. In particular, the H-CDR region sequences are depicted in Table 11 and the L-CDR sequences are depicted in Table 12. SEQ ID NO:45> Amino Acid Sequence: QVQLVQSGAEVKKPGSSVKVSCKASGFTFGTYSISWVRQAPGQGLEWMGRIIPTLGITNYEQKFQGRVTIIAEKS TTTVYMELSSLGVEDTAVYYCARDVGSSRKFDYWGQGTLVSVSS Table 11: Region Sequence Fragment SEQ ID NO : CDR-H1 GFTFGTYS 46 CDR-H2 IIPTLGIT 47 CDR-H3 ARDVGSSRKFDY 48 SEQ ID NO: 49> Amino Acid Sequence: DIQMTQSPSSLSASIGDRVTITCRASQTLSGALNWYQQKPGKAPKLLIYAASSLQTGVPSRFTGLESGTNYTLTI SSLQPEDFATYYCQQTYNTPRLSFGAGTRVEMK Table 12: Region Sequence Fragment SEQ ID NO : CDR-L1 QTLSGA 50 CDR-L2 AA 51 CDR-L3 QQTYNTPRLS 52 As used herein, the term “specificity” refers to the ability of an antibody to detectably bind target molecule (e.g. an epitope presented on an antigen) while having relatively little detectable reactivity with other target molecules. Specificity can be relatively determined by binding or competitive binding assays, using, e.g., using, e.g., bio-layer interferometry (BLI) performed on Octet BLI instruments. Specificity can be exhibited by, e.g., an about 10:1, about 20:1, about 50:1, about 100:1, 10.000:1 or greater ratio of affinity/avidity in binding to the specific antigen versus nonspecific binding to other irrelevant molecules. The term “affinity”, as used herein, means the strength of the binding of an antibody to a target molecule (e.g. an epitope). The affinity of a binding protein is given by the dissociation constant Kd. For an antibody said Kd is defined as [Ab] x [Ag] / [Ab-Ag], where [Ab-Ag] is the molar concentration of the antibody-antigen complex, [Ab] is the molar concentration of the unbound antibody and [Ag] is the molar concentration of the unbound antigen. The affinity constant Ka is defined by 1/Kd. Preferred methods for determining the affinity of a binding protein can be found in Harlow, et al., Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1988), Coligan et al., eds., Current Protocols in Immunology, Greene Publishing Assoc. and Wiley Interscience, N.Y., (1992, 1993), and Muller, Meth. Enzymol. 92:589-601 (1983), which references are entirely incorporated herein by reference. One preferred and standard method well known in the art for determining the affinity of binding protein is the use of bio-layer interferometry (BLI) performed on Octet BLI instruments. The term “binding” as used herein refers to a direct association between two molecules, due to, for example, covalent, electrostatic, hydrophobic, and ionic and/or hydrogen-bond interactions, including interactions such as salt bridges and water bridges. In particular, as used herein, the term "binding'' in the context of the binding of an antibody to a predetermined target molecule (e.g. an antigen or epitope) typically is a binding with an affinity corresponding to a KD of about 10-7 M or less, such as about 10-8 M or less, such as about 10-9 M or less, about 10- 10 M or less, or about 10-11 M or even less. As used herein, the term “epitope” refers to a specific arrangement of amino acids located on a protein or proteins to which an antibody binds. Epitopes often consist of a chemically active surface grouping of molecules such as amino acids or sugar side chains, and have specific three- dimensional structural characteristics as well as specific charge characteristics. Epitopes can be linear or conformational, i.e., involving two or more sequences of amino acids in various regions of the antigen that may not necessarily be contiguous. As used herein, the term "antibody fragment" refers to at least one portion of an intact antibody, preferably the antigen binding region or variable region of the intact antibody, that retains the ability to specifically interact with (e.g., by binding, steric hindrance, stabilizing/destabilizing, spatial distribution) an epitope of an antigen. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, Fv fragments, single chain antibody molecules, in particular scFv antibody fragments, disulfide-linked Fvs (sdFv), a Fd fragment consisting of the VH and CHI domains, linear antibodies, single domain antibodies such as, for example, sdAb (either VL or VH), camelid VHH domains, multi-specific antibodies formed from antibody fragments such as, for example, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region, and an isolated CDR or other epitope binding fragments of an antibody. An antigen binding fragment can also be incorporated into single domain antibodies, maxibodies, minibodies, nanobodies, intrabodies, diabodies, triabodies, tetrabodies, v-NAR and bis-scFv (see, e.g., Hollinger and Hudson, Nature Biotechnology 23:1126-1136, 2005). Antigen binding fragments can also be grafted into scaffolds based on polypeptides such as a fibronectin type III (see U.S. Patent No.: 6,703,199, which describes fibronectin polypeptide minibodies). Papain digestion of antibodies produces two identical antigen-binding fragments, called "Fab" fragments, and a residual "Fc" fragment, a designation reflecting the ability to crystallize readily. For instance, Fab or F(ab')2 fragments may be produced by protease digestion of the isolated antibodies, according to conventional techniques. It will be appreciated that immunoreactive fragments can be modified using known methods, for example to slow clearance in vivo and obtain a more desirable pharmacokinetic profile the fragment may be modified with polyethylene glycol (PEG). Methods for coupling and site-specifically conjugating PEG to a Fab' fragment are described in, for example, Leong et al., Cytokines 16 (3): 106-119 (2001) and Delgado et al., Br. J. Cancer 573 (2): 175- 182 (1996), the disclosures of which are incorporated herein by reference. As used herein, the term “Fc region” is used to define the C-terminal region of an immunoglobulin heavy chain, including native sequence Fc region and variant Fc regions. The human IgG heavy chain Fc region is generally defined as comprising the amino acid residue from position C226 or from P230 to the carboxyl-terminus of the IgG antibody. The numbering of residues in the Fc region is that of the EU index of Kabat. The C-terminal lysine (residue K447) of the Fc region may be removed, for example, during production or purification of the antibody. Accordingly, a composition of antibodies of the invention may comprise antibody populations with all K447 residues removed, antibody populations with no K447 residues removed, and antibody populations having a mixture of antibodies with and without the K447 residue. As used herein, the term “cross-competes” refers to monoclonal antibodies which share the ability to bind to a specific region of an antigen. In the present disclosure the monoclonal antibody that “cross-competes" has the ability to interfere with the binding of another monoclonal antibody for the antigen in a standard competitive binding assay. Such a monoclonal antibody may, according to non-limiting theory, bind to the same or a related or nearby (e.g., a structurally similar or spatially proximal) epitope as the antibody with which it competes. Cross-competition is present if antibody A reduces binding of antibody B at least by 60%, specifically at least by 70% and more specifically at least by 80% and vice versa in comparison to the positive control which lacks one of said antibodies. As the skilled artisan appreciates competition may be assessed in different assay set-ups. One suitable assay involves the use of the biolayer interferometry (BLI) technology (e.g., by using the Octet BLI instrument (Sartorius, Göttingen, Germany)), which can measure the extent of interactions using surface plasmon resonance technology. Another assay for measuring cross-competition uses an ELISA- based approach. Furthermore, a high throughput process for "binning" antibodies based upon their cross-competition is described in International Patent Application No. WO2003/48731. As used herein, the term “isolated antibody” refers to the antibody that has been identified and separated and/or recovered from a component of its natural environment. In some embodiments, the antibody will be purified (1) to greater than 95% by weight of antibody as determined by the Lowry method, and most preferably more than 99% by weight, (2) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator, or (3) to homogeneity by SDS-PAGE under reducing or nonreducing conditions using Coomassie blue or, preferably, silver stain. Isolated antibody includes the antibody in situ within recombinant cells since at least one component of the antibody's natural environment will not be present. Ordinarily, however, isolated antibody will be prepared by at least one purification step. As used herein, the term “neutralizing antibody” refers to an antibody molecule which is able to eliminate or significantly reduce an effector function of a target antigen to which it binds. Accordingly, a “neutralizing anti-IFN-α antibody” refers to a antibody that is capable of eliminating or significantly reducing an effector function, such as receptor binding and/or elicitation of a cellular response, of IFN-α polypeptides. For the purpose of the present invention, the ability to neutralize the elicitation of a cellular response by IFN-α is typically tested by the neutralizing assay described in the EXAMPLE. As used herein, the term “significant reduction” means at least about 60%, or at least about 70%, preferably at least about 75%, more preferably at least about 80%, even more preferably at least about 85%, still more preferably at least about 90%, still more preferably at least about 95%, most preferably at least about 99% reduction of an effector function of the target antigen (e.g. IFN-α or IFN-ω), such as receptor (e.g. IFNAR2) binding and/or elicitation of a cellular response. Preferably, the “neutralizing” antibodies as defined herein will be capable of neutralizing at least about 60%, or at least about 70%, preferably at least about 75%, more preferably at least about 80%, even more preferably at least about 85%, still more preferably at least about 90%, still more preferably at least about 95%, most preferably at least about 99% of the activity of IFNα polypeptides. As used herein, the term "patient" or "patient in need thereof", is intended for a human or non-human mammal. In some embodiments, the patient is a human infant. In some embodiments, the patient is a human child. In some embodiments, the patient is a human adult. As used herein, the term "treatment" or "treat" refer to both prophylactic or preventive treatment as well as curative or disease modifying treatment, including treatment of patient at risk of contracting the disease or suspected to have contracted the disease as well as patients who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse. The treatment may be administered to a patient having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a patient beyond that expected in the absence of such treatment. By "therapeutic regimen" is meant the pattern of treatment of an illness, e.g., the pattern of dosing used during therapy. A therapeutic regimen may include an induction regimen and a maintenance regimen. The phrase "induction regimen" or "induction period" refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the initial treatment of a disease. The general goal of an induction regimen is to provide a high level of drug to a patient during the initial period of a treatment regimen. An induction regimen may employ (in part or in whole) a "loading regimen", which may include administering a greater dose of the drug than a physician would employ during a maintenance regimen, administering a drug more frequently than a physician would administer the drug during a maintenance regimen, or both. The phrase "maintenance regimen" or "maintenance period" refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the maintenance of a patient during treatment of an illness, e.g., to keep the patient in remission for long periods of time (months or years). A maintenance regimen may employ continuous therapy (e.g., administering a drug at a regular interval, e.g., weekly, monthly, yearly, etc.) or intermittent therapy (e.g., interrupted treatment, intermittent treatment, treatment at relapse, or treatment upon achievement of a particular predetermined criteria [e.g., pain, disease manifestation, etc.]). As used herein, the term “pharmaceutical composition” refers to a composition described herein, or pharmaceutically acceptable salts thereof, with other agents such as carriers and/or excipients. The pharmaceutical compositions as provided herewith typically include a pharmaceutically acceptable carrier. As used herein, the term “pharmaceutically acceptable carrier” includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical-Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof. As used herein, the term “Therapeutically effective amount” refers to the level or amount of an antibody or antigen-binding fragment thereof as described herein that is aimed at, without causing significant negative or adverse side effects to the target, (1) delaying or preventing the onset of a disease, disorder, or condition; (2) slowing down or stopping the progression, aggravation, or deterioration of one or more symptoms of the disease, disorder, or condition; (3) bringing about ameliorations of the symptoms of the disease, disorder, or condition; (4) reducing the severity or incidence of the disease, disorder, or condition; or (5) curing the disease, disorder, or condition. A therapeutically effective amount may be administered prior to the onset of the disease, disorder, or condition, for a prophylactic or preventive action. Alternatively or additionally, the therapeutically effective amount may be administered after initiation of the disease, disorder, or condition, for a therapeutic action. Antibodies of the present invention: The present invention relates to a monoclonal antibody or an antigen-binding fragment thereof that binds to IFN-α polypeptides and that blocks the binding of said polypeptides to IFNAR1. In some embodiments, the monoclonal antibody or the antigen-binding fragment of the present invention binds to IFN-α2. In some embodiments, the monoclonal antibody or the antigen-binding fragment of the present invention does not bind to IFN-ω1. In some embodiments, the monoclonal antibody or the antigen-binding fragment of the present invention binds to IFN-α2 with a KD lower than 1×10-7 M. The binding can be measured and the KD calculated using any method known in the art, for example, the method as described in the EXAMPLE. In some embodiments, the monoclonal antibody or the antigen-binding fragment of the present invention binds to at least IFN-α1, IFN-α2, IFN-α4, IFN-α5, IFN-α8, IFN-α10, and IFN-α21 with a KD lower than 1×10-7 M. The binding can be measured and the KD calculated using any method known in the art, for example, the method as described in the EXAMPLE In some embodiments, the monoclonal antibody or the antigen-binding fragment of the present invention is a neutralizing antibody. In particular, the monoclonal antibody or the antigen- binding fragment of the present invention blocks the binding of IFN-α2 to IFNAR1. In particular, the ability of an antibody of the present invention to block the binding of IFN-α2 to receptor is defined as the property or capacity of a certain concentration of the antibody to reduce or eliminate the binding of IFN-α2 to IFNAR1 in a competition binding assay, as compared to the effect of an equivalent concentration of irrelevant control antibody on IFN-α2 binding to IFNAR1 in the assay. Preferably, the blocking antibody of the present invention reduces the binding of IFN-α2 to IFNAR1 by at least about 50%, or at least about 55%, or at least about 60%, or at least about 65%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 99%, as compared to the irrelevant control antibody. For the purpose of the present invention, the ability of the antibody of the present invention to block the binding of IFN-α2 to IFNAR1 can be determined by a routine competition assay such as that described in Kamat, Vishal, and Ashique Rafique. "Designing binding kinetic assay on the bio-layer interferometry (BLI) biosensor to characterize antibody-antigen interactions." Analytical biochemistry 536 (2017): 16-31. For example, the assay described in EXAMPLE could be used to determine the neutralizing activity of the antibody. In a particular, the blocking anti-IFN-α antibodies of the present invention will block the IFNAR1-binding of IFN-α2. In some embodiments, the monoclonal antibody or the antigen-binding fragment of the present invention blocks IFN-α2 signaling with an IC50 of about 10ng/mL or lower. In some embodiments, the monoclonal antibody or the antigen-binding fragment of the present invention binds to IFN-α2 with a KD of about 1×10-7 M or less and blocks IFN-α2 signaling with an IC50 of about 10ng/mL or lower. In some embodiments, the monoclonal antibody or the antigen-binding fragment of the present invention binds to Helix B and Helix C of IFN-α2. In some embodiments, the monoclonal antibody or the antigen-binding fragment of the present invention binds to a conformational epitope IFN-α2 that comprises i) one or more amino acid residues in the Helix B selected from the group consisting of P54, H57, E58, Q61, F64, N65, and S68 in SEQ ID NO:3 and ii) one or more amino acid residues in the Helix D selected from the group consisting of Y85, T86, Y89, Q90, L92, N93, E96, A97, V99, I100, and Q101 in SEQ ID NO:3. In this embodiment, all amino acid residues are recognized mostly by the heavy chain, excepting amino acid residues E97 and V104 that are recognized by both chains and amino acid residues T98 and G105 that are recognized by the light chain. In some embodiments, the monoclonal antibody or the antigen-binding fragment of the present invention binds to IFN-α2 at the same epitope as for PMAB19, PMAB06, PMAB09, PMAB12, and PMAB34 antibodies. Preferably, the monoclonal antibody or the antigen-binding fragment of the present invention binds to IFN-α2 at the same epitope as for PMAB09 or PMAB34 antibody. In some embodiments, the monoclonal antibody or the antigen-binding fragment of the present invention cross-competes for binding to IFN-α2 with the monoclonal antibody PMAB19. In particular, the monoclonal antibody or the antigen-binding fragment of the present invention cross-competes for binding to IFN-α2 with the monoclonal antibody comprising a VH domain having the H-CDR1 as set forth in SEQ ID NO:6, the H-CDR2 as set forth in SEQ ID NO: 7 and the H-CDR3 as set forth in SEQ ID NO:8 and a VL domain having the L-CDR1 as set forth in SEQ ID NO:10, the L-CDR2 as set forth in SEQ ID NO:11 and the L-CDR3 as set forth in SEQ ID NO:12. In some embodiments, the monoclonal antibody or the antigen-binding fragment of the present invention cross-competes for binding to IFN-α2 with the monoclonal antibody PMAB06. In particular, the monoclonal antibody or the antigen-binding fragment of the present invention cross-competes for binding to IFN-α2 with the monoclonal antibody comprising a VH domain having the H-CDR1 as set forth in SEQ ID NO:14, the H-CDR2 as set forth in SEQ ID NO: 15 and the H-CDR3 as set forth in SEQ ID NO:16 and a VL domain having the L-CDR1 as set forth in SEQ ID NO:18, the L-CDR2 as set forth in SEQ ID NO:19 and the L-CDR3 as set forth in SEQ ID NO:20. In some embodiments, the monoclonal antibody or the antigen-binding fragment of the present invention cross-competes for binding to IFN-α2 with the monoclonal antibody PMAB09. In particular, the monoclonal antibody or the antigen-binding fragment of the present invention cross-competes for binding to IFN-α2 with the monoclonal antibody comprising a VH domain having the H-CDR1 as set forth in SEQ ID NO:22, the H-CDR2 as set forth in SEQ ID NO:23 and the H-CDR3 as set forth in SEQ ID NO:24 and a VL domain having the L-CDR1 as set forth in SEQ ID NO:26, the L-CDR2 as set forth in SEQ ID NO:27 and the L-CDR3 as set forth in SEQ ID NO:28. In some embodiments, the monoclonal antibody or the antigen-binding fragment of the present invention cross-competes for binding to IFN-α2 with the monoclonal antibody PMAB12. In particular, the monoclonal antibody or the antigen-binding fragment of the present invention cross-competes for binding to IFN-α2 with the monoclonal antibody comprising a VH domain having the H-CDR1 as set forth in SEQ ID NO:30, the H-CDR2 as set forth in SEQ ID NO:31 and the H-CDR3 as set forth in SEQ ID NO:32 and a VL domain having the L-CDR1 as set forth in SEQ ID NO:34, the L-CDR2 as set forth in SEQ ID NO:35 and the L-CDR3 as set forth in SEQ ID NO:36. In some embodiments, the monoclonal antibody or the antigen-binding fragment of the present invention cross-competes for binding to IFN-α2 with the monoclonal antibody PMAB34. In particular, the monoclonal antibody or the antigen-binding fragment of the present invention cross-competes for binding to IFN-α2 with the monoclonal antibody comprising a VH domain having the H-CDR1 as set forth in SEQ ID NO:38, the H-CDR2 as set forth in SEQ ID NO:39 and the H-CDR3 as set forth in SEQ ID NO:40 and a VL domain having the L-CDR1 as set forth in SEQ ID NO:42, the L-CDR2 as set forth in SEQ ID NO:43 and the L-CDR3 as set forth in SEQ ID NO:44. In some embodiments, the monoclonal antibody or the antigen-binding fragment of the present invention binds to Helix A and Helix C of IFN-α2. In some embodiments, the monoclonal antibody or the antigen-binding fragment of the present invention binds to a conformational epitope IFN-α2 that comprises i) one or more amino acid residues in the Helix A selected from the group consisting of D2, Q5, T6, H7, L9, G10, R12, and R13 in SEQ ID NO:3 and ii) one or more amino acid residues in the Helix C selected from the group consisting of D82, Y85, T86, E87, Y89, Q90, Q91, N93, and D94 in SEQ ID NO:3. In this embodiment, amino acid residues D2, Q5, and R12 are recognized mostly by light chain, and amino acid residues H7, G1, R13, D82, Y85, T86, E87, Y89, Q90, Q91, N93, and D94 are recognized mostly by heavy chain, whereas amino acid residues T6 and Q90 are recognized by both chains. In some embodiments, the monoclonal antibody or the antigen-binding fragment of the present invention cross-competes for binding to IFN-α2 with the monoclonal antibody GMAB03. In particular, the monoclonal antibody or the antigen-binding fragment of the present invention cross-competes for binding to IFN-α2 with the monoclonal antibody comprising a VH domain having the H-CDR1 as set forth in SEQ ID NO:46, the H-CDR2 as set forth in SEQ ID NO:47 and the H-CDR3 as set forth in SEQ ID NO:48 and a VL domain having the L-CDR1 as set forth in SEQ ID NO:50, the L-CDR2 as set forth in SEQ ID NO:51 and the L-CDR3 as set forth in SEQ ID NO:52. Examples of antibodies and antigen-binding fragments include, without limitation, a whole antibody, a single chain antibody, a dimeric single chain antibody, a Fv, a scFv, a Fab, a Fab', a Fab'-SH, a F(ab)’2, a Fd, a defucosylated antibody, a bispecific antibody, a diabody, a triabody, a tetrabody, a unibody, or a domain antibody. In some embodiments, the antibody is a full-length antibody. In some embodiments, the full-length antibody is an IgG1 antibody. In some embodiments, the full-length antibody is an IgG3 antibody. In some embodiments, the full-length antibody is an IgG4 antibody. In some embodiments, the monoclonal antibody or the antigen-binding fragment of the present invention is a chimeric antibody, a humanized antibody or a human antibody. PMAB19 antibodies: In some embodiments, the monoclonal antibody or the antigen-binding fragment of the present invention comprises a VH domain having the H-CDR1 as set forth in SEQ ID NO:6, the H- CDR2 as set forth in SEQ ID NO: 7 and the H-CDR3 as set forth in SEQ ID NO:8. In some embodiments, the monoclonal antibody or the antigen-binding fragment of the present invention comprises a VL domain having the L-CDR1 as set forth in SEQ ID NO:10, the L- CDR2 as set forth in SEQ ID NO:11 and the L-CDR3 as set forth in SEQ ID NO:12. In some embodiments, the monoclonal antibody or the antigen-binding fragment of the present invention comprises a VH domain having the H-CDR1 as set forth in SEQ ID NO:6, the H- CDR2 as set forth in SEQ ID NO: 7 and the H-CDR3 as set forth in SEQ ID NO:8, and a VL domain having the L-CDR1 as set forth in SEQ ID NO:10, the L-CDR2 as set forth in SEQ ID NO:11 and the L-CDR3 as set forth in SEQ ID NO:12. In some embodiments, the antibody or the antigen-binding fragment of the present invention comprises a VH domain having an amino acid sequence having at least 70% of identity with the amino acid sequence as set forth in SEQ ID NO:5 and a VL domain having an amino acid sequence having at least 70% of identity with the amino acid sequence as set forth in SEQ ID NO:9. In some embodiments, the antibody or the antigen-binding fragment of the present invention comprises a VH domain having the amino acid as set forth in SEQ ID NO:5 and a VL domain having the amino acid sequence as set forth in SEQ ID NO:9. PMAB06 antibodies: In some embodiments, the monoclonal antibody or the antigen-binding fragment of the present invention comprises a VH domain having the H-CDR1 as set forth in SEQ ID NO:14, the H- CDR2 as set forth in SEQ ID NO: 15 and the H-CDR3 as set forth in SEQ ID NO:16. In some embodiments, the monoclonal antibody or the antigen-binding fragment of the present invention comprises a VL domain having the L-CDR1 as set forth in SEQ ID NO:18, the L- CDR2 as set forth in SEQ ID NO:19 and the L-CDR3 as set forth in SEQ ID NO:20. In some embodiments, the monoclonal antibody or the antigen-binding fragment of the present invention comprises a VH domain having the H-CDR1 as set forth in SEQ ID NO:14, the H- CDR2 as set forth in SEQ ID NO: 15 and the H-CDR3 as set forth in SEQ ID NO:16, and a VL domain having the L-CDR1 as set forth in SEQ ID NO:18, the L-CDR2 as set forth in SEQ ID NO:19 and the L-CDR3 as set forth in SEQ ID NO:20. In some embodiments, the antibody or the antigen-binding fragment of the present invention comprises a VH domain having an amino acid sequence having at least 70% of identity with the amino acid sequence as set forth in SEQ ID NO:13 and a VL domain having an amino acid sequence having at least 70% of identity with the amino acid sequence as set forth in SEQ ID NO:17. In some embodiments, the antibody or the antigen-binding fragment of the present invention comprises a VH domain having the amino acid as set forth in SEQ ID NO:13 and a VL domain having the amino acid sequence as set forth in SEQ ID NO:17. PMAB09 antibodies: In some embodiments, the monoclonal antibody or the antigen-binding fragment of the present invention comprises a VH domain having the H-CDR1 as set forth in SEQ ID NO:22, the H- CDR2 as set forth in SEQ ID NO:23 and the H-CDR3 as set forth in SEQ ID NO:24. In some embodiments, the monoclonal antibody or the antigen-binding fragment of the present invention comprises a VL domain having the L-CDR1 as set forth in SEQ ID NO:26, the L- CDR2 as set forth in SEQ ID NO:27 and the L-CDR3 as set forth in SEQ ID NO:28. In some embodiments, the monoclonal antibody or the antigen-binding fragment of the present invention comprises a VH domain having the H-CDR1 as set forth in SEQ ID NO:22, the H- CDR2 as set forth in SEQ ID NO:23 and the H-CDR3 as set forth in SEQ ID NO:24 and a VL domain having the L-CDR1 as set forth in SEQ ID NO:26, the L-CDR2 as set forth in SEQ ID NO:27 and the L-CDR3 as set forth in SEQ ID NO:28. In some embodiments, the antibody or the antigen-binding fragment of the present invention comprises a VH domain having an amino acid sequence having at least 70% of identity with the amino acid sequence as set forth in SEQ ID NO:21 and a VL domain having an amino acid sequence having at least 70% of identity with the amino acid sequence as set forth in SEQ ID NO:25. In some embodiments, the antibody or the antigen-binding fragment of the present invention comprises a VH domain having the amino acid as set forth in SEQ ID NO:21 and a VL domain having the amino acid sequence as set forth in SEQ ID NO:25. PMAB12 antibodies: In some embodiments, the monoclonal antibody or the antigen-binding fragment of the present invention comprises a VH domain having the H-CDR1 as set forth in SEQ ID NO:30, the H- CDR2 as set forth in SEQ ID NO:31 and the H-CDR3 as set forth in SEQ ID NO:32. In some embodiments, the monoclonal antibody or the antigen-binding fragment of the present invention comprises a VL domain having the L-CDR1 as set forth in SEQ ID NO:34, the L- CDR2 as set forth in SEQ ID NO:35 and the L-CDR3 as set forth in SEQ ID NO:36. In some embodiments, the monoclonal antibody or the antigen-binding fragment of the present invention comprises a VH domain having the H-CDR1 as set forth in SEQ ID NO:30, the H- CDR2 as set forth in SEQ ID NO:31 and the H-CDR3 as set forth in SEQ ID NO:32 and a VL domain having the L-CDR1 as set forth in SEQ ID NO:34, the L-CDR2 as set forth in SEQ ID NO:35 and the L-CDR3 as set forth in SEQ ID NO:36. In some embodiments, the antibody or the antigen-binding fragment of the present invention comprises a VH domain having an amino acid sequence having at least 70% of identity with the amino acid sequence as set forth in SEQ ID NO:29 and a VL domain having an amino acid sequence having at least 70% of identity with the amino acid sequence as set forth in SEQ ID NO:33. In some embodiments, the antibody or the antigen-binding fragment of the present invention comprises a VH domain having the amino acid as set forth in SEQ ID NO:29 and a VL domain having the amino acid sequence as set forth in SEQ ID NO:33. PMAB34 antibodies: In some embodiments, the monoclonal antibody or the antigen-binding fragment of the present invention comprises a VH domain having the H-CDR1 as set forth in SEQ ID NO:38, the H- CDR2 as set forth in SEQ ID NO:39 and the H-CDR3 as set forth in SEQ ID NO:40. In some embodiments, the monoclonal antibody or the antigen-binding fragment of the present invention comprises a VL domain having the L-CDR1 as set forth in SEQ ID NO:42, the L- CDR2 as set forth in SEQ ID NO:43 and the L-CDR3 as set forth in SEQ ID NO:44. In some embodiments, the monoclonal antibody or the antigen-binding fragment of the present invention comprises a VH domain having the H-CDR1 as set forth in SEQ ID NO:38, the H- CDR2 as set forth in SEQ ID NO:39 and the H-CDR3 as set forth in SEQ ID NO:40 and a VL domain having the L-CDR1 as set forth in SEQ ID NO:42, the L-CDR2 as set forth in SEQ ID NO:43 and the L-CDR3 as set forth in SEQ ID NO:44. In some embodiments, the antibody or the antigen-binding fragment of the present invention comprises a VH domain having an amino acid sequence having at least 70% of identity with the amino acid sequence as set forth in SEQ ID NO:37 and a VL domain having an amino acid sequence having at least 70% of identity with the amino acid sequence as set forth in SEQ ID NO:41. In some embodiments, the antibody or the antigen-binding fragment of the present invention comprises a VH domain having the amino acid as set forth in SEQ ID NO:37 and a VL domain having the amino acid sequence as set forth in SEQ ID NO:41. GMAB03 antibodies: In some embodiments, the monoclonal antibody or the antigen-binding fragment of the present invention comprises a VH domain having the H-CDR1 as set forth in SEQ ID NO:46, the H- CDR2 as set forth in SEQ ID NO:47 and the H-CDR3 as set forth in SEQ ID NO:48. In some embodiments, the monoclonal antibody or the antigen-binding fragment of the present invention comprises a VL domain having the L-CDR1 as set forth in SEQ ID NO:50, the L- CDR2 as set forth in SEQ ID NO:51 and the L-CDR3 as set forth in SEQ ID NO:52. In some embodiments, the monoclonal antibody or the antigen-binding fragment of the present invention comprises a VH domain having the H-CDR1 as set forth in SEQ ID NO:46, the H- CDR2 as set forth in SEQ ID NO:47 and the H-CDR3 as set forth in SEQ ID NO:48 and a VL domain having the L-CDR1 as set forth in SEQ ID NO:50, the L-CDR2 as set forth in SEQ ID NO:51 and the L-CDR3 as set forth in SEQ ID NO:52. In some embodiments, the antibody or the antigen-binding fragment of the present invention comprises a VH domain having an amino acid sequence having at least 70% of identity with the amino acid sequence as set forth in SEQ ID NO:45 and a VL domain having an amino acid sequence having at least 70% of identity with the amino acid sequence as set forth in SEQ ID NO:49. In some embodiments, the antibody or the antigen-binding fragment of the present invention comprises a VH domain having the amino acid as set forth in SEQ ID NO:55 and a VL domain having the amino acid sequence as set forth in SEQ ID NO:49. In some embodiments, the VH sequence and/or the VL sequence of the antibody of the present invention comprises conservative sequence modifications. The term "conservative sequence modifications" refers to amino acid modifications that do not significantly affect or alter the biologic function of the protein containing the amino acid sequence. Such conservative modifications include amino acid substitutions, additions and deletions. Modifications can be introduced into a protein by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis. A “conservative substitution” is one in which an amino acid is substituted for another amino acid that has similar properties, such that one skilled in the art of peptide chemistry would expect the secondary structure and hydropathic nature of the polypeptide to be substantially unchanged. Amino acid substitutions are generally therefore based on the relative similarity of the amino acid side-chain substituents, for example, their hydrophobicity, hydrophilicity, charge, size, and the like. Exemplary substitutions that take various of the foregoing characteristics into consideration are well known to those of skill in the art and include: arginine and lysine; glutamate and aspartate; serine and threonine; glutamine and asparagine; and valine, leucine and isoleucine. Amino acid substitutions may further be made on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity and/or the amphipathic nature of the residues. For example, negatively charged amino acids include aspartic acid and glutamic acid; positively charged amino acids include lysine and arginine; and amino acids with uncharged polar head groups having similar hydrophilicity values include leucine, isoleucine and valine; glycine and alanine; asparagine and glutamine; and serine, threonine, phenylalanine and tyrosine. Other groups of amino acids that may represent conservative changes include: (1) ala, pro, gly, glu, asp, gln, asn, ser, thr; (2) cys, ser, tyr, thr; (3) val, ile, leu, met, ala, phe; (4) lys, arg, his; and (5) phe, tyr, trp, his. Other families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Thus, one or more amino acid residues within an antibody of the present invention can be replaced with other amino acid residues from the same side chain family and the altered antibody can be tested for binding to the sialylated glycoproteins. In some embodiments, the antibody (preferably the monoclonal antibody) of the present invention does not comprise a Fc region that mediates antibody-dependent cell-mediated cytotoxicity and thus does not comprise an Fc portion that induces antibody dependent cellular cytotoxicity (ADCC). In one embodiment, the antibody (preferably the monoclonal antibody) of the present invention does not comprise an Fc region that induces CDC or antibody- dependent phagocytosis. In some embodiments, the antibody (preferably the monoclonal antibody) of the present invention does not comprise an Fc domain capable of substantially binding to a FcγRIIIA (CD16) polypeptide. In some embodiments, the antibody (preferably the monoclonal antibody) of the present invention lacks an Fc domain (e.g., lacks a CH2 and/or CH3 domain) or comprises an Fc domain of IgG2 or IgG4 isotype. In some embodiments, the antibody (preferably the monoclonal antibody) of the present invention comprises an Fc domain (e.g. of IgG1) with an altered glycosylation profile, resulting in the absence of ADCC activity of the antibody. In some embodiments, the antibody (preferably the monoclonal antibody) of the present invention consists of or comprises a Fab, Fab', Fab'-SH, F(ab')2, Fv, a diabody, single-chain antibody fragment, or a multispecific antibody comprising multiple different antibody fragments. In some embodiments, the antibody (preferably the monoclonal antibody) of the present invention is not linked to a toxic moiety. In some embodiments, one or more amino acids selected from amino acid residues can be replaced with a different amino acid residue such that the antibody has altered C2q binding and/or reduced or abolished complement dependent cytotoxicity (CDC). This approach is described in further detail in U.S. Patent Nos. 6,194,551 by ldusogie et al. The antibody or the antigen-binding fragment of the present invention is produced by any technique known in the art, such as, without limitation, any chemical, biological, genetic or enzymatic technique, either alone or in combination. Typically, knowing the amino acid sequence of the desired sequence, one skilled in the art can readily produce said antibodies, by standard techniques for production of polypeptides. For instance, they can be synthesized using well-known solid phase method, preferably using a commercially available peptide synthesis apparatus (such as that made by Applied Biosystems, Foster City, California) and following the manufacturer’s instructions. Alternatively, antibodies of the present invention can be synthesized by recombinant DNA techniques well-known in the art. For example, antibodies can be obtained as DNA expression products after incorporation of DNA sequences encoding the antibodies into expression vectors and introduction of such vectors into suitable eukaryotic or prokaryotic hosts that will express the desired antibodies, from which they can be later isolated using well-known techniques. vectors and host cells: A further object of the invention relates to a polynucleotide encoding the antibody or the antigen-binding fragment of the present invention. More particularly the polynucleotide encodes a heavy chain and/or a light chain of the antibody or the antigen-binding fragment of the present invention. Typically, said polynucleotide is a DNA or RNA molecule, which may be included in any suitable vector, such as a plasmid, cosmid, episome, artificial chromosome, phage or a viral vector. So, a further object of the invention relates to a vector comprising the polynucleotide of the invention. Such vectors may comprise regulatory elements, such as a promoter, enhancer, terminator and the like, to cause or direct expression of said antibody upon administration to a subject. As used herein, the terms "vector", "cloning vector" and "expression vector" mean the vehicle by which a DNA or RNA sequence (e.g., a foreign gene) can be introduced into a host cell, so as to transform the host and promote expression (e.g., transcription and translation) of the introduced sequence. As used herein, the term “promoter/regulatory sequence” refers to a polynucleotide sequence (such as, for example, a DNA sequence) recognized by the synthetic machinery of the cell, or introduced synthetic machinery, required to initiate the specific transcription of a polynucleotide sequence, thereby allowing the expression of a gene product operably linked to the promoter/regulatory sequence. In some instances, this sequence may be the core promoter sequence and in other instances, this sequence may also include an enhancer sequence and other regulatory elements which are required for expression of the gene product. The promoter/regulatory sequence may, for example, be one which expresses the gene product in a tissue specific manner. As used herein, the term "operably linked" or "transcriptional control" refers to functional linkage between a regulatory sequence and a heterologous polynucleotide sequence resulting in expression of the latter. For example, a first polynucleotide sequence is operably linked with a second polynucleotide sequence when the first polynucleotide sequence is placed in a functional relationship with the second polynucleotide sequence. For instance, a promoter is operably linked to a coding sequence if the promoter affects the transcription or expression of the coding sequence. Operably linked DNA sequences can be contiguous with each other and, e.g., where necessary to join two protein coding regions, are in the same reading frame. Examples of promoters and enhancers used in the expression vector for animal cell include early promoter and enhancer of SV40, LTR promoter and enhancer of Moloney mouse leukemia virus, promoter and enhancer of immunoglobulin H chain and the like. Any expression vector for animal cell can be used, so long as a gene encoding the human antibody C region can be inserted and expressed. Examples of suitable vectors include pAGE107, pAGE103, pHSG274, pKCR, pSG1 beta d2-4 and the like. Other examples of plasmids include replicating plasmids comprising an origin of replication, or integrative plasmids, such as for instance pUC, pcDNA, pBR, and the like. Other examples of viral vector include adenoviral, retroviral, herpes virus and AAV vectors. Such recombinant viruses may be produced by techniques known in the art, such as by transfecting packaging cells or by transient transfection with helper plasmids or viruses. Typical examples of virus packaging cells include PA317 cells, PsiCRIP cells, GPenv+ cells, 293 cells, etc. Detailed protocols for producing such replication- defective recombinant viruses may be found for instance in WO 95/14785, WO 96/22378, US 5,882,877, US 6,013,516, US 4,861,719, US 5,278,056 and WO 94/19478. A further object of the present invention relates to a host cell which has been transfected, infected or transformed by the nucleic acid and/or the vector according to the present invention. As used herein, the term "transformation" means the introduction of a "foreign" (i.e., extrinsic or extracellular) gene, DNA or RNA sequence to a host cell, so that the host cell will express the introduced gene or sequence to produce a desired substance, typically a protein or enzyme coded by the introduced gene or sequence. A host cell that receives and expresses introduced DNA or RNA bas been "transformed". As used herein, the term "expression system" means a host cell and compatible vector under suitable conditions, e.g., for the expression of a protein coded for by foreign DNA carried by the vector and introduced to the host cell. The nucleic acids of the invention may be used to produce the antibody or the antigen-binding fragment of the present invention in a suitable expression system. Common expression systems include E. coli host cells and plasmid vectors, insect host cells and Baculovirus vectors, and mammalian host cells and vectors. Other examples of host cells include, without limitation, prokaryotic cells (such as bacteria) and eukaryotic cells (such as yeast cells, mammalian cells, insect cells, plant cells, etc.). Specific examples include E.coli, Kluyveromyces or Saccharomyces yeasts, mammalian cell lines (e.g., Vero cells, CHO cells, 3T3 cells, COS cells, etc.) as well as primary or established mammalian cell cultures (e.g., produced from lymphoblasts, fibroblasts, embryonic cells, epithelial cells, nervous cells, adipocytes, etc.). Examples also include mouse SP2/0-Ag14 cell (ATCC CRL1581), mouse P3X63-Ag8.653 cell (ATCC CRL1580), CHO cell in which a dihydrofolate reductase gene (hereinafter referred to as "DHFR gene") is defective (Urlaub G et al; 1980), rat YB2/3HL.P2.G11.16Ag.20 cell (ATCC CRL1662, hereinafter referred to as "YB2/0 cell"), and the like. The present invention also relates to a method of producing a recombinant host cell expressing an antibody according to the present invention, said method comprising the steps of: (i) introducing in vitro or ex vivo a recombinant nucleic acid or a vector as described above into a competent host cell, (ii) culturing in vitro or ex vivo the recombinant host cell obtained and (iii), optionally, selecting the cells which express and/or secrete said antibody. Such recombinant host cells can be used for the production of antibodies of the present invention. The present invention also relates to a method of producing the antibody of the present invention, said method comprising the steps of: (i) culturing in vitro or ex vivo the recombinant host cell of the present invention and (ii), and isolating the produced antibody in the culture medium. Antibodies of the present invention are suitably separated from the culture medium by conventional immunoglobulin purification procedures such as, for example, protein A- Sepharose, hydroxylapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography. Methods of treatment: Accordingly, a further object of the present invention relates to the antibody or the antigen- binding fragment of the present invention for use as a drug. More specifically, the present invention relates a method of therapy in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the antibody or the antigen-binding fragment of the present invention. In some embodiments, the antibody or the antigen-binding fragment of the present invention is particularly for the treatment of an autoimmune inflammatory disease. In some embodiments, the autoimmune inflammatory disease is selected from the group consisting of arthritis, rheumatoid arthritis, acute arthritis, chronic rheumatoid arthritis, gouty arthritis, acute gouty arthritis, chronic inflammatory arthritis, degenerative arthritis, infectious arthritis, Lyme arthritis, proliferative arthritis, psoriatic arthritis, vertebral arthritis, and juvenile-onset rheumatoid arthritis, osteoarthritis, arthritis chronica progrediente, arthritis deformans, polyarthritis chronica primaria, reactive arthritis, and ankylosing spondylitis), inflammatory hyperproliferative skin diseases, psoriasis such as plaque psoriasis, gutatte psoriasis, pustular psoriasis, and psoriasis of the nails, dermatitis including contact dermatitis, chronic contact dermatitis, allergic dermatitis, allergic contact dermatitis, dermatitis herpetiformis, and atopic dermatitis, x-linked hyper IgM syndrome, urticaria such as chronic allergic urticaria and chronic idiopathic urticaria, including chronic autoimmune urticaria, polymyositis/dermatomyositis, juvenile dermatomyositis, toxic epidermal necrolysis, scleroderma, systemic scleroderma, sclerosis, systemic sclerosis, multiple sclerosis (MS), spino-optical MS, primary progressive MS (PPMS), relapsing remitting MS (RRMS), progressive systemic sclerosis, atherosclerosis, arteriosclerosis, sclerosis disseminata, and ataxic sclerosis, inflammatory bowel disease (IBD), Crohn's disease, colitis, ulcerative colitis, colitis ulcerosa, microscopic colitis, collagenous colitis, colitis polyposa, necrotizing enterocolitis, transmural colitis, autoimmune inflammatory bowel disease, pyoderma gangrenosum, erythema nodosum, primary sclerosing cholangitis, episcleritis, respiratory distress syndrome, adult or acute respiratory distress syndrome (ARDS), meningitis, inflammation of all or part of the uvea, iritis, choroiditis, an autoimmune hematological disorder, rheumatoid spondylitis, sudden hearing loss, IgE-mediated diseases such as anaphylaxis and allergic and atopic rhinitis, encephalitis, Rasmussen's encephalitis, limbic and/or brainstem encephalitis, uveitis, anterior uveitis, acute anterior uveitis, granulomatous uveitis, nongranulomatous uveitis, phacoantigenic uveitis, posterior uveitis, autoimmune uveitis, glomerulonephritis (GN), idiopathic membranous GN or idiopathic membranous nephropathy, membrano- or membranous proliferative GN (MPGN), rapidly progressive GN, allergic conditions, autoimmune myocarditis, leukocyte adhesion deficiency, systemic lupus erythematosus (SLE) or systemic lupus erythematodes such as cutaneous SLE, subacute cutaneous lupus erythematosus, neonatal lupus syndrome (NLE), lupus erythematosus disseminatus, lupus (including nephritis, cerebritis, pediatric, non-renal, extra-renal, discoid, alopecia), juvenile onset (Type I) diabetes mellitus, including pediatric insulin-dependent diabetes mellitus (IDDM), adult onset diabetes mellitus (Type II diabetes), autoimmune diabetes, idiopathic diabetes insipidus, immune responses associated with acute and delayed hypersensitivity mediated by cytokines and T-lymphocytes, tuberculosis, sarcoidosis, granulomatosis, lymphomatoid granulomatosis, Wegener's granulomatosis, agranulocytosis, vasculitides, including vasculitis, large vessel vasculitis, polymyalgia rheumatica, giant cell (Takayasu's) arteritis, medium vessel vasculitis, Kawasaki's disease, polyarteritis nodosa, microscopic polyarteritis, CNS vasculitis, necrotizing, cutaneous, hypersensitivity vasculitis, systemic necrotizing vasculitis, and ANCA-associated vasculitis, such as Churg-Strauss vasculitis or syndrome (CSS), temporal arteritis, aplastic anemia, autoimmune aplastic anemia, Coombs positive anemia, Diamond Blackfan anemia, hemolytic anemia or immune hemolytic anemia including autoimmune hemolytic anemia (AIHA), pernicious anemia (anemia perniciosa), Addison's disease, pure red cell anemia or aplasia (PRCA), Factor VIII deficiency, hemophilia A, autoimmune neutropenia, pancytopenia, leukopenia, diseases involving leukocyte diapedesis, CNS inflammatory disorders, multiple organ injury syndrome such as those secondary to septicemia, trauma or hemorrhage, antigen-antibody complex-mediated diseases, anti-glomerular basement membrane disease, anti-phospholipid antibody syndrome, allergic neuritis, Bechet's or Behcet's disease, Castleman's syndrome, Goodpasture's syndrome, Reynaud's syndrome, Sjogren's syndrome, Stevens-Johnson syndrome, pemphigoid such as pemphigoid bullous and skin pemphigoid, pemphigus, optionally pemphigus vulgaris, pemphigus foliaceus, pemphigus mucus-membrane pemphigoid, pemphigus erythematosus, autoimmune polyendocrinopathies, Reiter's disease or syndrome, immune complex nephritis, antibody-mediated nephritis, neuromyelitis optica, polyneuropathies, chronic neuropathy, IgM polyneuropathies, IgM-mediated neuropathy, thrombocytopenia, thrombotic thrombocytopenic purpura (TTP), idiopathic thrombocytopenic purpura (ITP), autoimmune orchitis and oophoritis, primary hypothyroidism, hypoparathyroidism, autoimmune thyroiditis, Hashimoto's disease, chronic thyroiditis (Hashimoto's thyroiditis); subacute thyroiditis, autoimmune thyroid disease, idiopathic hypothyroidism, Grave's disease, polyglandular syndromes such as autoimmune polyglandular syndromes (or polyglandular endocrinopathy syndromes), paraneoplastic syndromes, including neurologic paraneoplastic syndromes such as Lambert-Eaton myasthenic syndrome or Eaton-Lambert syndrome, stiff-man or stiff-person syndrome, encephalomyelitis, allergic encephalomyelitis, experimental allergic encephalomyelitis (EAE), myasthenia gravis, thymoma-associated myasthenia gravis, cerebellar degeneration, neuromyotonia, opsoclonus or opsoclonus myoclonus syndrome (OMS), and sensory neuropathy, multifocal motor neuropathy, Sheehan's syndrome, autoimmune hepatitis, chronic hepatitis, lupoid hepatitis, giant cell hepatitis, chronic active hepatitis or autoimmune chronic active hepatitis, lymphoid interstitial pneumonitis, bronchiolitis obliterans (non-transplant) vs NSIP, Guillain-Barre syndrome, Berger's disease (IgA nephropathy), idiopathic IgA nephropathy, linear IgA dermatosis, primary biliary cirrhosis, pneumonocirrhosis, autoimmune enteropathy syndrome, Celiac disease, Coeliac disease, celiac sprue (gluten enteropathy), refractory sprue, idiopathic sprue, cryoglobulinemia, amylotrophic lateral sclerosis (ALS; Lou Gehrig's disease), coronary artery disease, autoimmune ear disease such as autoimmune inner ear disease (AGED), autoimmune hearing loss, opsoclonus myoclonus syndrome (OMS), polychondritis such as refractory or relapsed polychondritis, pulmonary alveolar proteinosis, amyloidosis, scleritis, a non-cancerous lymphocytosis, a primary lymphocytosis, which includes monoclonal B cell lymphocytosis, optionally benign monoclonal gammopathy or monoclonal garnmopathy of undetermined significance, MGUS, peripheral neuropathy, paraneoplastic syndrome, channelopathies such as epilepsy, migraine, arrhythmia, muscular disorders, deafness, blindness, periodic paralysis, and channelopathies of the CNS, autism, inflammatory myopathy, focal segmental glomerulosclerosis (FSGS), endocrine opthalmopathy, uveoretinitis, chorioretinitis, autoimmune hepatological disorder, fibromyalgia, multiple endocrine failure, Schmidt's syndrome, adrenalitis, gastric atrophy, presenile dementia, demyelinating diseases such as autoimmune demyelinating diseases, diabetic nephropathy, Dressler's syndrome, alopecia greata, CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyl), and telangiectasia), male and female autoimmune infertility, mixed connective tissue disease, Chagas' disease, rheumatic fever, recurrent abortion, farmer's lung, erythema multiforme, post-cardiotomy syndrome, Cushing's syndrome, bird-fancier's lung, allergic granulomatous angiitis, benign lymphocytic angiitis, Alport's syndrome, alveolitis such as allergic alveolitis and fibrosing alveolitis, interstitial lung disease, transfusion reaction, leprosy, malaria, leishmaniasis, kypanosomiasis, schistosomiasis, ascariasis, aspergillosis, Sampter's syndrome, Caplan's syndrome, dengue, endocarditis, endomyocardial fibrosis, diffuse interstitial pulmonary fibrosis, interstitial lung fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, endophthalmitis, erythema elevatum et diutinum, erythroblastosis fetalis, eosinophilic faciitis, Shulman's syndrome, Felty's syndrome, flariasis, cyclitis such as chronic cyclitis, heterochronic cyclitis, iridocyclitis, or Fuch's cyclitis, Henoch-Schonlein purpura, human immunodeficiency virus (HIV) infection, echovirus infection, cardiomyopathy, Alzheimer's disease, parvovirus infection, rubella virus infection, post-vaccination syndromes, congenital rubella infection, Epstein-Barr virus infection, mumps, Evan's syndrome, autoimmune gonadal failure, Sydenham's chorea, post-streptococcal nephritis, thromboangitis ubiterans, thyrotoxicosis, tabes dorsalis, chorioiditis, giant cell polymyalgia, endocrine ophthamopathy, chronic hypersensitivity pneumonitis, keratoconjunctivitis sicca, epidemic keratoconjunctivitis, idiopathic nephritic syndrome, minimal change nephropathy, benign familial and ischemia- reperfusion injury, retinal autoimmunity, joint inflammation, bronchitis, chronic obstructive airway disease, silicosis, aphthae, aphthous stomatitis, arteriosclerotic disorders, aspermiogenese, autoimmune hemolysis, Boeck's disease, cryoglobulinemia, Dupuytren's contracture, endophthalmia phacoanaphylactica, enteritis allergica, erythema nodosum leprosum, idiopathic facial paralysis, chronic fatigue syndrome, febris rheumatica, Hamman- Rich's disease, sensoneural hearing loss, haemoglobinuria paroxysmatica, hypogonadism, ileitis regionalis, leucopenia, mononucleosis infectiosa, traverse myelitis, primary idiopathic myxedema, nephrosis, ophthalmia symphatica, orchitis granulomatosa, pancreatitis (e.g. chronic pancreatitis), polyradiculitis acuta, pyoderma gangrenosum, Quervain's thyreoiditis, acquired splenic atrophy, infertility due to antispermatozoan antibodies, non-malignant thymoma, vitiligo, SCID and Epstein-Barr virus-associated diseases, acquired immune deficiency syndrome (AIDS), parasitic diseases such as Leishmania, toxic-shock syndrome, food poisoning, conditions involving infiltration of T cells, leukocyte-adhesion deficiency, immune responses associated with acute and delayed hypersensitivity mediated by cytokines and T-lymphocytes, diseases involving leukocyte diapedesis, multiple organ injury syndrome, antigen-antibody complex-mediated diseases, antiglomerular basement membrane disease, allergic neuritis, autoimmune polyendocrinopathies, oophoritis, primary myxedema, autoimmune atrophic gastritis, sympathetic ophthalmia, rheumatic diseases, mixed connective tissue disease, nephrotic syndrome, insulitis, polyendocrine failure, peripheral neuropathy, autoimmune polyglandular syndrome type I, adult-onset idiopathic hypoparathyroidism (AOIH), alopecia totalis, dilated cardiomyopathy, epidermolisis bullosa acquisita (EBA), hemochromatosis, myocarditis, nephrotic syndrome, primary sclerosing cholangitis, purulent or nonpurulent sinusitis, acute or chronic sinusitis, ethmoid, frontal, maxillary, or sphenoid sinusitis, an eosinophil-related disorder such as eosinophilia, pulmonary infiltration eosinophilia, eosinophilia-myalgia syndrome, Loffler's syndrome, chronic eosinophilic pneumonia, tropical pulmonary eosinophilia, bronchopneumonic aspergillosis, aspergilloma, or granulomas containing eosinophils, anaphylaxis, seronegative spondyloarthritides, polyendocrine autoimmune disease, sclerosing cholangitis, sclera, episclera, chronic mucocutaneous candidiasis, Bruton's syndrome, transient hypogammaglobulinemia of infancy, Wiskott-Aldrich syndrome, ataxia telangiectasia, autoimmune disorders associated with collagen disease, rheumatism, neurological disease, ischemic re-perfusion disorder, reduction in blood pressure response, vascular dysfunction, antgiectasis, tissue injury, cardiovascular ischemia, hyperalgesia, cerebral ischemia, and disease accompanying vascularization, allergic hypersensitivity disorders, glomerulonephritides, reperfusion injury, reperfusion injury of myocardial or other tissues, dermatoses with acute inflammatory components, acute purulent meningitis or other central nervous system inflammatory disorders, ocular and orbital inflammatory disorders, granulocyte transfusion-associated syndromes, cytokine-induced toxicity, acute serious inflammation, chronic intractable inflammation, pyelitis, pneumonocirrhosis, diabetic retinopathy, diabetic large-artery disorder, endarterial hyperplasia, peptic ulcer, valvulitis, and endometriosis. In some embodiments, the antibody or the antigen-binding fragment of the present invention is particularly suitable for the treatment of a type 1 interferonopathy. As used herein, the term “type I interferonopathy” has its general meaning in the art and refers to a subgroup of autoinflammatory diseases caused by mutations in genes associated with proteasome degradation or cytoplasmic RNA- and DNA-sensing pathways. The term “interferonopathy” first appeared in 2003, when some authors identified phenotypic overlaps between Aicardi–Goutieres syndrome (AGS) encephalopathy, viral congenital infections, and some autoimmune diseases such as systemic lupus erythematosus (SLE), postulating a common pathological feature as an upregulation of interferon (IFN) α activity (Crow, Yanick J. "Type I interferonopathies: a novel set of inborn errors of immunity." Annals of the New York Academy of Sciences 1238.1 (2011): 91-98). In particular, the term includes Aicardi-Goutières syndrome (AGS), STING-associated vasculopathy with onset in infancy (SAVI), and chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome. Patients with type I interferonopathy shared several clinical characteristics, including bilateral calcifications of the basal ganglia, chilblain-like rashes, and liver dysfunction. Each subtype includes disease- specific severe complications, such as early-onset encephalopathy associated with AGS and pulmonary hypertension observed in patients diagnosed with STING-associated vasculopathy with onset in infancy. Pharmaceutical A further object of the present invention relates to a composition comprising, consisting of or consisting essentially of the antibody or the antigen-binding fragment of the present invention. In some embodiments, the composition of the invention is a pharmaceutical composition and further comprises a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers that may be used in these compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene- block polymers, polyethylene glycol and wool fat. For use in administration to a patient, the composition will be formulated for administration to the patient. The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Sterile injectable forms of the compositions of this invention may be aqueous or an oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation. The compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include, e.g., lactose. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added. Alternatively, the compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols. The compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs. For topical applications, the compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2- octyldodecanol, benzyl alcohol and water. Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Patches may also be used. The compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents. For example, an antibody present in a pharmaceutical composition of this invention can be supplied at a concentration of 10 mg/mL in either 100 mg (10 mL) or 500 mg (50 mL) single-use vials. The product is formulated for IV administration in 9.0 mg/mL sodium chloride, 7.35 mg/mL sodium citrate dihydrate, 0.7 mg/mL polysorbate 80, and Sterile Water for Injection. The pH is adjusted to 6.5. An exemplary suitable dosage range for an antibody in a pharmaceutical composition of this invention may between about 1 mg/m2 and 500 mg/m2. However, it will be appreciated that these schedules are exemplary and that an optimal schedule and regimen can be adapted taking into account the affinity and tolerability of the particular antibody in the pharmaceutical composition that must be determined in clinical trials. A pharmaceutical composition of the invention for injection (e.g., intramuscular, i.v.) could be prepared to contain sterile buffered water (e.g., 1 ml for intramuscular), and between about 1 ng to about 100 mg, e.g., about 50 ng to about 30 mg or more preferably, about 5 mg to about 25 mg, of an antibody of the invention. Diagnostic methods: The antibodies of the present invention are also particularly of interest for diagnostic purposes. In particular, the antibodies of the present invention are suitable for determining presence of IFN-α in a sample. Accordingly a further object of the present invention relates to a method for detecting the presence of a IFN-α polypeptide in a sample comprising contacting the sample with one or more antibodies of the present invention under conditions that allow an immunocomplex of IFN-α polypeptide and the antibodies to form wherein detection of the immunocomplex indicates the presence of a IFN-α polypeptide in the sample. The method of the present invention is particularly suitable for diagnostic purposes. In particular, the method of the present invention is particularly suitable for determining whether a subject has or is at risk of having an autoimmune inflammatory disease and more particularly a type 1 interferonopathy. Typically high levels of IFN-α polypeptides indicate that the subject has or is at risk of having an autoimmune inflammatory disease and more particularly a type 1 interferonopathy. As used herein, the term “high” refers to a measure that is significantly greater than normal, greater than a standard, such as a predetermined reference value or a subgroup measure, or that is relatively greater than another subgroup measure. For example, high levels of IFN-α polypeptides refers to a level of IFN-α polypeptides that is greater than a normal level. A normal may be determined according to any method available to one skilled in the art. A high level of IFN-α polypeptides may also refer to a level equal to or greater than a predetermined reference value, such as a predetermined cutoff. A high level of IFN-α polypeptides may also refer to a level of IFN-α polypeptides wherein a high IFN-α polypeptides subgroup has relatively greater levels of IFN-α polypeptides than another subgroup. For example, without limitation, according to the present specification, two distinct patient subgroups can be created by dividing samples around a mathematically determined point, such as, without limitation, a median, thus creating a subgroup whose measure is high (i.e., higher than the median) and another subgroup whose measure is low. In some cases, a “high level” may comprise a range of levels that is very high and a range of levels that is “moderately high”, where moderately high is a level that is greater than normal but less than “very high”. The method of the present invention is also particularly suitable for determining whether a subject is at risk of having a viral infection. More particular, the method of the present invention for determining whether a subject suffering from a viral infection is at risk of progressing to a severe viral disease. More particular, the method of the present invention for determining whether a subject suffering from a viral disease is at risk of progressing to an acute respiratory distress syndrome. In some embodiments, the viral infection is caused by a virus selected from the group consisting of influenza virus (e.g., Influenza virus A, Influenza virus B), respiratory syncytial virus, adenovirus, metapneumovirus, cytomegalovirus, parainfluenza virus (e.g., hPIV-1, hPIV-2, hPIV-3, hPIV-4), rhinovirus, coxsackie virus, echo virus, herpes simplex virus, coronavirus (SARS-coronavirus such as SARS-Cov1 or SARS-Cov2), and smallpox. In some embodiments, the viral lung infection may be due to a member of the Pneumoviridae, Paramyxoviridae and/or Coronaviridae families are in particular selected from the group consisting of upper and lower respiratory tract infections due to: human respiratory syncytial virus (hRSV), type A and type B, human metapneumovirus (hMPV) type A and type B; parainfluenza virus type 3 (PIV-3), measles virus, endemic human coronaviruses (HCoV-229E, -NL63, -OC43, and -HKU1), severe acute respiratory syndrome (SARS) and Middle-East respiratory syndrome (MERS) coronaviruses. In particular, the method of the present invention is suitable for the treatment of Severe Acute Respiratory Syndrome (SARS). More particularly, the method of the present invention is suitable for patients suffering from COVID19. Typically, low levels of IFN-α polypeptides indicate that the subject is at risk of having a viral infection and/or to progress to a severe form of the viral disease. As used herein, the term “low” refers to a level that is less than normal, or less than a standard, such as a predetermined reference value or a subgroup measure that is relatively less than another subgroup level. For example, a low level of IFN-α polypeptides means a level of IFN- α polypeptides that is less than a normal level in a particular set of samples of patients. A normal level of IFN-α polypeptides measure may be determined according to any method available to one skilled in the art. A low level of IFN-α polypeptides may also mean a level that is less than a predetermined reference value, such as a predetermined cutoff. A low level of IFN-α polypeptides may also mean a level wherein a low level IFN-α polypeptides subgroup is relatively lower than another subgroup. For example, without limitation, according to the present specification, two distinct patient subgroups can be created by dividing samples around a mathematically determined point, such as, without limitation, a median, thus creating a group whose measure is low (i.e., less than the median) with respect to another group whose measurement is high (i.e., greater than the median). As used herein, the term "sample" includes any solid or fluid sample, liable to contain one or more IFN-α polypeptides. In some embodiments, the sample is selected from the group consisting of ascites; urine; saliva; sweat; milk; synovial fluid; peritoneal fluid; amniotic fluid; percerebrospinal fluid; lymph fluid; lung embolism; cerebrospinal fluid; and pericardial fluid. In some embodiments, the sample is a faeces samples. In some embodiments, the sample is a urine sample. In some embodiments, the sample is a saliva sample. In some embodiments, the sample is a blood sample. As used herein the term “blood sample” means any blood sample derived from the subject. In some embodiments, the blood sample is a serum or plasma sample. Assays and conditions for the detection of immunocomplexes are known to those of skill in the art. Such assays include, for example, competition assays, direct reaction assays sandwich- type assays and immunoassays (e.g. ELISA). The assays may be quantitative or qualitative. There are a number of different conventional assays for detecting formation of an antibody-peptide complex comprising a protein of the present invention. For example, the detecting step can comprise performing an ELISA assay, performing a lateral flow immunoassay, performing an agglutination assay, analyzing the sample in an analytical rotor, or analyzing the sample with an electrochemical, optical, or opto-electronic sensor. These different assays are well-known to those skilled in the art. For example, any of a number of variations of the sandwich assay technique may be used to perform an immunoassay. Briefly, in a typical sandwich assay, a first antibody of the present invention is immobilized on a solid surface and the sample to be tested is brought into contact with the immobilized antibody for a time and under conditions allowing formation of the immunocomplex. Following incubation, a second antibody of the present invention that is labelled with a detectable moiety is added and incubated under conditions allowing the formation of a ternary complex between any immunocomplex and the labelled antibody. Any unbound material is washed away, and the presence of polypeptide in the sample is determined by observation/detection of the signal directly or indirectly produced by the detectable moiety. Detection may be either qualitative or quantitative. Methods for labelling biological molecules such as antibodies are well-known in the art (see, for example, "Affinity Techniques. Enzyme Purification: Part B", Methods in EnzymoL, 1974, Vol. 34, W.B. Jakoby and M. Wilneck (Eds.), Academic Press: New York, NY; and M. Wilchek and E.A. Bayer, Anal. Biochem., 1988, 171 : 1-32). The most commonly used detectable moieties in immunoassays are enzymes and fluorophores. In the case of an enzyme immunoassay (EIA or ELISA), an enzyme such as horseradish perodixase, glucose oxidase, beta-galactosidase, alkaline phosphatase, and the like, is conjugated to the second antibody, generally by means of glutaraldehyde or periodate. The substrates to be used with the specific enzymes are generally chosen for the production of a detectable color change, upon hydrolysis of the corresponding enzyme. In the case of immunofluorescence, the second antibody is chemically coupled to a fluorescent moiety without alteration of its binding capacity. After binding of the fiuorescently labeled antibody to the immunocomplex and removal of any unbound material, the fluorescent signal generated by the fluorescent moiety is detected, and optionally quantified. Alternatively, the second antibody may be labelled with a radioisotope, a chemiluminescent moiety, or a bio luminescent moiety. In some embodiments, the assay utilizes a solid phase or substrate to which the antibody of the present invention is directly or indirectly attached. Accordingly in some embodiments, the antibody of the present invention is attached to or immobilized on a substrate, such as a solid or semi-solid support. The attachment can be covalent or non-covalent, and can be facilitated by a moiety associated with the protein that enables covalent or non-covalent binding, such as a moiety that has a high affinity to a component attached to the carrier, support or surface. In some embodiments, the substrate is a bead, such as a colloidal particle (e.g., a colloidal nanoparticle made from gold, silver, platinum, copper, metal composites, other soft metals, core-shell structure particles, or hollow gold nanospheres) or other type of particle (e.g., a magnetic bead or a particle or nanoparticle comprising silica, latex, polystyrene, polycarbonate, polyacrylate, or PVDF). Such particles can comprise a label (e.g., a colorimetric, chemiluminescent, or fluorescent label) and can be useful for visualizing the location of the proteins during immunoassays. In some embodiments, the substrate is a dot blot or a flow path in a lateral flow immunoassay device. For example, the antibody of the present invention can be attached or immobilized on a porous membrane, such as a PVDF membrane (e.g., an Immobilon™ membrane), a nitrocellulose membrane, polyethylene membrane, nylon membrane, or a similar type of membrane. In some embodiments, the substrate is a flow path in an analytical rotor. In some embodiments, the substrate is a tube or a well, such as a well in a plate (e.g., a microtiter plate) suitable for use in an ELISA assay. Such substrates can comprise glass, cellulose-based materials, thermoplastic polymers, such as polyethylene, polypropylene, or polyester, sintered structures composed of particulate materials (e.g., glass or various thermoplastic polymers), or cast membrane film composed of nitrocellulose, nylon, polysulfone, or the like. A substrate can be sintered, fine particles of polyethylene, commonly known as porous polyethylene, for example, 0.2-15 micron porous polyethylene from Chromex Corporation (Albuquerque, N. Mex.). All of these substrate materials can be used in suitable shapes, such as films, sheets, or plates, or they may be coated onto or bonded or laminated to appropriate inert carriers, such as paper, glass, plastic films, or fabrics. Suitable methods for immobilizing peptides on solid phases include ionic, hydrophobic, covalent interactions and the like. In some embodiments, the antibodies of the present invention are particularly suitable for assessing the neutralizing activity of anti- autoantibodies detected in a subject. As used herein, the term “anti-IFN-α autoantibodies” refers to the antibodies which are produced by the immune system of the subject and that are directed against the subject's IFN-α polypeptides own polypeptides. The presence of said auto-antibodies is associated with the risk for the subject to have a viral infection and/or to progress to a severe form of a viral disease. In particular, the presence of said auto-antibodies is associated with the risk of COVID19. More particularly, the presence of said auto-antibodies is associated with the risk to progress to an acute respiratory distress syndrome in patients suffering from a lung viral infections, especially from a SARS-COV2 infection. Typically, the presence of autoantibodies having substantially the same or higher neutralizing activity than the antibodies of the present inventio indicate that the subject is at risk of having a viral infection and/or to progress to a severe form of the viral disease. Thus a further object of the present invention relates to a method for determining whether a subject is at risk of having a viral infection and/or at risk to progress to a sever from a viral disease comprising i) detecting the presence of one or more IFN-α autoantibodies in a sample obtained from the subject, ii) determining the neutralizing activity of said autoantibodies, iii) comparing the neutralizing activity of said autoantibodies with the neutralizing activity of an antibody of the present invention and iv) concluding that the patient the subject is at risk of having a viral infection and/or to progress to a severe form of the viral disease wherein the neutralizing activity of the autoantibodies substantially the same or higher than the neutralizing activity of the antibody of the present invention. A further object of the present invention relates to a kit or device comprising at least one antibody of the present invention (immobilized or not on a solid support as described above). In some embodiments, the kit can include a second antibody of the present invention which produces a detectable signal. In some embodiments, the antibody of the present invention is conjugated with a detectable label. Suitable detectable labels include, for example, a radioisotope, a fluorescent label, a chemiluminescent label, an enzyme label, a bio luminescent label or colloidal gold. Methods of making and detecting such detectably-labeled immunoconjugates are well-known to those of ordinary skill in the art, and are described in more detail below. For instance, the detectable label can be a radioisotope that is detected by autoradiography. Isotopes that are particularly useful for the purpose of the present invention are 3H, 125I, 131I, 35S and 14C. The antibody of the present invention can also be labeled with a fluorescent compound. The presence of a fluorescently-labeled antibody of the present invention is determined by exposing the immuno conjugate to light of the proper wavelength and detecting the resultant fluorescence. Fluorescent labeling compounds include fluorescein isothiocyanate, rhodamine, phycoerytherin, phycocyanin, allophycocyanin, o-phthaldehyde and fluorescamine and Alexa Fluor dyes. Alternatively, the antibody of the present invention can be detectably labeled by coupling said antibody to a chemiluminescent compound. The presence of the chemiluminescent-tagged immuno conjugate is determined by detecting the presence of luminescence that arises during the course of a chemical reaction. Examples of chemiluminescent labeling compounds include luminol, isoluminol, an aromatic acridinium ester, an imidazole, an acridinium salt and an oxalate ester. Similarly, a bio luminescent compound can be used to label the antibody of the present invention. Bioluminescence is a type of chemiluminescence found in biological systems in which a catalytic protein increases the efficiency of the chemiluminescent reaction. The presence of a bioluminescent protein is determined by detecting the presence of luminescence. Bioluminescent compounds that are useful for labeling include luciferin, luciferase and aequorin. Typically, when the antibody is conjugated to a fluorescent label as described above, the presence of the fusion protein can be detected with any means well known in the art such as a microscope or microscope or automated analysis system. Typically, when antibody is conjugated to an enzyme then, the enzyme moiety reacts with the substrate to produce a chemical moiety which can be detected, for example, by spectrophotometric, fluorometric or visual means. Examples of enzymes that can be used to detectably label polyspecific immunoconjugates include β-galactosidase, glucose oxidase, peroxidase (e.g. horseradish perodixase) and alkaline phosphatase. Those of skill in the art will know of other suitable labels which can be employed in accordance with the present invention. The binding of marker moieties to anti-the antibody of the present invention is accomplished using standard techniques known to the art. Typical methodology in this regard is described by Kennedy et al., Clin. Chim. Acta 70: 1, 1976; Schurs et al., Clin. Chim. Acta 81 : 1, 1977; Shih et al., Int'U. Cancer 46: 1101, 1990; Stein et al, Cancer Res. 50: 1330, 1990; and Coligan, supra. Moreover, the convenience and versatility of immunochemical detection can be enhanced by using antibodies of the present invention that have been conjugated with avidin, streptavidin, and biotin. {See, e.g., Wilchek et al. (eds.), "Avidin-Biotin Technology," Methods In Enzymology (Vol. 184) (Academic Press 1990); Bayer et al., "Immunochemical Applications of Avidin-Biotin Technology," in Methods In Molecular Biology (Vol.10) 149- 162 (Manson, ed., The Humana Press, Inc.1992).). Examples of kits include but are not limited to ELISA assay kits, and kits comprising test strips and dipsticks. In some embodiments, the kits described herein further comprise reference values of the levels of the protein or infectious particles. The reference values are typically average levels in samples from a population of healthy individuals. In some embodiments, the kits described herein further comprise at least one sample collection container for sample collection. Collection devices and container include but are not limited to syringes, lancets, BD VACUTAINER® blood collection tubes. In some embodiments, the kits described herein further comprise instructions for using the kit and interpretation of results. The invention will be further illustrated by the following figures and examples. However, these examples and figures should not be interpreted in any way as limiting the scope of the present invention. FIGURES: EXAMPLE: Methods Study participants PBMCs from an early time point post-infection (< 2 weeks) were collected from 7 patients who experienced a severe COVID-19 disease requiring oxygen (WHO score ≥ 5) and who were documented as having detectable in vitro neutralizing activity in their sera against 10ng/ml of IFN-α2. Patients were recruited through the international COVID Human Genetic Effort consortium. Interferon neutralization assay The in vitro blocking activity of anti–IFN-α2 and anti–IFN-ω1 auto-Abs – polyclonal patient sera, single-memory B cell culture supernatants or re-expressed monoclonal antibodies - was determined using a reporter luciferase activity. Briefly, HEK293T cells were transfected with a plasmid containing the firefly luciferase gene under the control of the human ISRE promoter in the pGL4.45 backbone and a plasmid constitutively expressing Renilla luciferase for normalization (pRL-SV40). Cells were transfected in the presence of the X-tremeGENE9 transfection reagent (Sigma-Aldrich, reference number 6365779001) for 24 hours. Cells in Dulbecco’s modified Eagle medium (DMEM; Thermo Fisher Scientific) supplemented with 2% fetal calf serum and 10% healthy control or patient serum/plasma (after inactivation at 56°C for 20 min) were either left unstimulated or were stimulated with IFN-α2 (Miltenyi Biotec, reference number 130-108-984) and IFN-ω1 (Merck, reference number SRP3061) at 10 ng/, 1 ng/ml and 100 pg/ml or IFN-β1 (Miltenyi Biotech, reference number 130-107-888) at 1 ng/ml for 16 hours at 37°C. Each sample was tested once for each cytokine and dose. Last, cells were lysed for 20 min at room temperature, and luciferase levels were measured with the Dual- Luciferase Reporter 1000 Assay System (Promega, reference number E1980) according to the manufacturer’s protocol. Luminescence intensity was measured with a VICTOR-X Multilabel Plate Reader (PerkinElmer Life Sciences, USA). Firefly luciferase activity values were normalized against Renilla luciferase activity values. These values were then normalized against the median induction level for non-neutralizing samples and expressed as a percentage. Samples were considered neutralizing if luciferase induction, normalized against Renilla luciferase activity, was below 15% of the median values for controls tested the same day. Proteins biotinylation and Tetramers preparation: Recombinant human IFN-α2 (Miltenyi, 130-108-984), rhIFN-ω1 (Sigma, SRP3061) and BSA proteins were biotinylated using EZ link NHS biotin (Thermofischer) according to the manufacturer instructions. Tetramer were made fresh prior to each staining by further incubating biotinylated proteins with fluorochrome-conjugated streptavidin at 4:1 molar ratio for 1 hour at 4°C.2.4 ng of free biotin was then added for 10 additional minutes before mixing of tetramers. Flow cytometry and cell sorting: PBMCs were isolated from blood samples via standard density gradient centrifugation and used after cryopreservation at -150°C. Cells were thawed in RPMI-1640 (Gibco)-10% FBS (Gibco), washed twice and incubated with a mixture of rhIFN-α2 and rhIFN-ω1 tetramers (equivalent to 200ng of each protein) in 100 µL of PBS (Gibco)-2% FBS during 40 min on ice. To exclude cells with nonspecific binding, a non-relevant tetramer was constructed using biotinylated bovine serum albumin and added to the mix. Cells were then washed and resuspended in the same conditions and the fluorochrome-conjugated antibody cocktail was added at pre-titrated concentrations (1:200 for CD14, 1:100 for CD19, CD38, CD3, and IgD, 1:50 for CD21, CD11c, CD27 and IgG) for 40 min at 4°C. Viable cells were identified using a LIVE/DEAD Fixable Aqua Dead Cell Stain Kit (Thermo Fisher Scientific, 1:30) incubated with conjugated antibodies. Samples were acquired on ARIA II SORP (BD Biosciences) or SONY MA900 cell sorters and IFNα2 and IFNϖ-specific IgG+ B cells were sorted in 96 plates using the ultra- purity mode. Data were analyzed using dedicated SONY or FlowJO softwares. Single-cell culture Single cell culture was performed as previously described 1. Single B cells were sorted in 96- well plates containing MS40Llo cells expressing CD40L (kind gift from G. Kelsoe, Luo et al., 2009). Cells were co-cultured at 37°C with 5% CO2 during 21 or 25 days in RPMI-1640 (Invitrogen) supplemented with 10% HyClone FBS (Thermo Scientific), 55 µM 2- mercaptoethanol, 10 mM HEPES, 1 mM sodium pyruvate, 100 units/mL penicillin, 100 µg/mL streptomycin, and MEM non-essential amino acids (all Invitrogen), with the addition of recombinant human BAFF (10 ng/ml), IL2 (50 ng/ml), IL4 (10 ng/ml), and IL21 (10 ng/ml; all Peprotech). Part of the supernatant was carefully removed at days 4, 8, 12, 15 and 18 and the same amount of fresh medium with cytokines was added to the cultures. After 25 days of single cell culture, supernatants were harvested and stored at -20°C. Cell pellets were placed on ice and gently washed with PBS (Gibco) before being resuspended in 50 µL of RLT buffer (Qiagen) supplemented with 1% β-mercaptoethanol and subsequently stored at -80°C until further processing. ELISA Total IgG and rhIFN-α2 and rhIFN-ω1-specific IgG from culture supernatants were measured using homemade ELISA.96 well ELISA plates (Thermo Fisher) were coated either with goat anti-human Ig (10 μg/ml, Invitrogen) in sodium carbonate during 1h at 37°C or with rhIFN-α2 and rhIFN-ω1 proteins (5 µg/ml each) at 4°C overnight. After plate blocking, cell culture supernatants were added for 1hr, then ELISA were developed using HRP-goat anti-human IgG (1 μg/ml, Immunotech) and TMB substrate (Eurobio). OD450 and OD620 were measured, and supernatants whose OD450-OD620 values were above 0.09 and over 10 times blank wells values were considered as positive. Single-cell IgH sequencing and monoclonal antibody re-expression At the end of each single B cell culture, cell pellets were resuspended in 50µl RLT Buffer (Qiagen) and stored at -80 °C. Clones whose culture had proven successful (IgG concentration ≥ 1 µg/mL and positive in rhIFN-α2 and rhIFN-ω1-specific ELISA at day 21-25) were selected and extracted using the NucleoSpin96 RNA extraction kit (Macherey-Nagel) according to the manufacturer’s instructions. A reverse transcription step was then performed using the SuperScript IV enzyme (ThermoFisher) in a 14 μl final volume (42°C 10 min, 25°C 10 min, 50°C 60 min, 94°C 5 min) with 4 µl of RNA and random hexamers (Thermofisher scientific). A PCR was further performed based on the protocol established by Tiller et al 2. Briefly, 3.5 μl of cDNA was used as template and amplified in a total volume of 40 μl with a mix of forward L-VH, L-Vλ or L-Vκ primers and reverse Cγ, Cλ or Cκ primers for heavy chains, λ and κ light chains respectively using the HotStar® Taq DNA polymerase (Qiagen) and 50 cycles of PCR (94°C 30 s, 58°C 30 s, 72°C 60 s). PCR products were sequenced with the reverse primer CHG- D1 and read on ABI PRISM 3130XL genetic analyzer (Applied Biosystems). Sequence quality was verified using CodonCode Aligner software (CodonCode Corporation). 5’ PCR1 Primer Mix : VH : *5′ L-VH 1 ACAGGTGCCCACTCCCAGGTGCAG *5′ L-VH 3 AAGGTGTCCAGTGTGARGTGCAG *5′ L-VH 4/6 CCCAGATGGGTCCTGTCCCAGGTGCAG *5′ L-VH 5 CAAGGAGTCTGTTCCGAGGTGCAG *5’L-VH 2 CCTTCATGGGTCTTGTCCCAGATCACC *5’ L-VH 6 CCATGGGGTGTCCTGTCACAGGTACAG *5’ L-VH 7 GCAACAGGTGCCCACTCCCAGGTGCAG Vκ : *5′ L Vκ 1/2 ATGAGGSTCCCYGCTCAGCTGCTGG *5′ L Vκ 3 CTCTTCCTCCTGCTACTCTGGCTCCCAG *5′ L Vκ 4 ATTTCTCTGTTGCTCTGGATCTCTG Vλ : *5′ L Vλ 1 GGTCCTGGGCCCAGTCTGTGCTG *5′ L Vλ 2 GGTCCTGGGCCCAGTCTGCCCTG *5′ L Vλ 3 GCTCTGTGACCTCCTATGAGCTG *5′ L Vλ 4/5 GGTCTCTCTCSCAGCYTGTGCTG *5′ L Vλ 6 GTTCTTGGGCCAATTTTATGCTG *5′ L Vλ 7 GGTCCAATTCYCAGGCTGTGGTG *5′ L Vλ 8 GAGTGGATTCTCAGACTGTGGTG 3’ PCR1 Primers: VH : *3′ Cγ (IgG) CH1 GGAAGGTGTGCACGCCGCTGGTC Vκ : *3′ Cκ 543 GTTTCTCGTAGTCTGCTTTGCTCA Vλ : *3′ Cλ CACCAGTGTGGCCTTGTTGGCTTG Additionally, for some patients and time points, some IgH and paired IgL sequences were obtained directly from single cell sorting in 4µL lysis buffer containing PBS (Gibco), DTT (ThermoFisher) and RNAsin (Promega). Reverse transcription and a first PCR was performed as described above (50 cycles) before a second 50-cycles PCR using 5’AgeI VH, Vλ or Vκ primer mix and reverse Cγ, Cλ or Cκ primers for heavy chains, λ and κ light chains respectively, before sequencing. 5’ PCR2 Primer Mix : VH : *5’AgeI VH1/5 CTGCAACCGGTGTACATTCCGAGGTGCAGCTGGTGCAG *5′ AgeI VH3 CTGCAACCGGTGTACATTCTGAGGTGCAGCTGGTGGAG *5′ AgeI VH4 CTGCAACCGGTGTACATTCCCAGGTGCAGCTGCAGGAG *5’ AgeI VH 6–1 CTGCAACCGGTGTACATTCCCAGGTACAGCTGCAGCAG *5’ AgeI VH2 CTGCAACCGGTGTACATTCCCAGATCACCTTGAAGGAG *5’ AgeI VH7 CTGCAACCGGTGTACATTCCCAGGTGCAGCTGGTCCAA *5′ Pan Vκ ATGACCCAGWCTCCABYCWCCCTG Vλ : *5′ AgeI Vλ 1 CTGCTACCGGTTCCTGGGCCCAGTCTGTGCTGACKCAG *5′ AgeI Vλ 2 CTGCTACCGGTTCCTGGGCCCAGTCTGCCCTGACTCAG *5′ AgeI Vλ 3 CTGCTACCGGTTCTGTGACCTCCTATGAGCTGACWCAG *5′ AgeI Vλ 4/5 CTGCTACCGGTTCTCTCTCSCAGCYTGTGCTGACTCA *5′ AgeI Vλ 6 CTGCTACCGGTTCTTGGGCCAATTTTATGCTGACTCAG *5′ AgeI Vλ 7/8 CTGCTACCGGTTCCAATTCYCAGRCTGTGGTGACYCAG 3’ PCR2 primers : VH : *3’ D1 (IgG) TTCGGGGAAGTAGTCCTTG Vκ : *3′ Cκ 494 GTGCTGTCCTTGCTGTCCTGCT Vλ : *3′ XhoI Cλ CTCCTCACTCGAGGGYGGGAACAGAGTG 27 monoclonal antibodies were re-expressed by Proteogenix SAS. Briefly, the cDNAs coding for the variable regions of the heavy and light chains were chemically synthesized with optimization for expression in CHO cells and subcloned in ProteoGenix’s proprietary mammalian cells expression vectors containing backbones for human IgG1 heavy chain constant region and human kappa/lambda light chain constant region. An endotoxin-free DNA preparation was done for each construction and vectors were further transfected in XtenCHO cells by XtenCHO transfection protocol, in a total volume of 3.5 ml. Culture medium was collected 8 days after transfection and purified using one-step affinity purification (Protein A). Final QC was performed by A280nm spectrophotometric measurement and qualitative and quantitative analysis by SDS-PAGE. Computational analyses of VDJ sequences: Processed FASTA sequences from single-cell sorted heavy and light chain sequencing were annotated using Igblast v1.19.0 against the human IMGT reference database. Clonal cluster assignment (DefineClones.py) and germline reconstruction (CreateGermlines.py) was performed using the Immcantation/Change-O toolkit3 on all heavy chain V sequences. Sequences that had the same VH-gene, same JH-gene, including ambiguous assignments, and same HCDR3 length with maximal length normalized nucleotide hamming distance of 0.15 were considered as potentially belonging to the same clonal group. Affinity measurement using biolayer interferometry (Octet) Affinity measurements against various type I IFNs were performed using biolayer interferometry assays on an Octet Red96 instrument (Sartorius). Anti-Human Fc Capture (AHC) biosensors (18-5060) were immersed in supernatants from single-cell MBC cultures or re-expressed monoclonal antibodies solutions (5µg/ml) at 25°C for 500 seconds. Biosensors were equilibrated for 5 minutes in 1x PBS buffer with 0.1% BSA and 0,01% Tween 20 surfactant (PBS-BT) prior to measurement. Association was performed for 240s in PBS-BT with individual glycosylated Type I IFNs (Bio-Techne (11014-IF; 10984-IF; 10998-IF; 11017- IF; 11168-IF; 11079-IF; 11018-IF; 11016-IF; 11019-IF; 11156-IF; 11082-IF; 11159-IF); Sigma (H6041; SRP3061; IF014)) at 100nM followed by dissociation for 480s in PBS-BT. Between cycle, biosensor regeneration was performed by alternating 30s cycles of regeneration buffer (glycine HCl, 10 mM, pH 2.0) and 30s of PBS-BT for 3 cycles. Traces were reference sensor (unloaded sensor) and reference well (additional association cycle in the absence of ligand) subtracted and curve fitting was performed using a local 1:1 binding model in the HT Data analysis software 11.1 (ForteBio). For each tested antibody in epitope binning experiments, anti-Human Fc Capture (AHC) biosensors (18-5060) were first immersed in a solution of that re-expressed monoclonal antibody solution (5µg/ml) at 25°C for 600 seconds. Quenching of biosensors was then achieved by incubating loaded biosensors in polyclonal human IgG (10µg/ml) for 300s. Association with rhIFN-α2 (Miltenyi, 130-108-984) or rhIFN-ω1 (Sigma, SRP3061) was then performed for 300s in PBS-BT at 100nM or 300nM for association with rhIFNAR1-Fc or with lower-affinity monoclonal Abs, followed by association of one of the referenced re-expressed monoclonal antibodies at 5µg/ml, rhIFNAR1-Fc (Sinobiological, 13222-H02H) at 10µg/ml or rhIFNAR2-Fc (Sinobiological, 10359-H02H) at 10µg/ml for 300s in PBS-BT. Between cycle, biosensor regeneration was performed by alternating 30s cycles of regeneration buffer (glycine HCl, 10 mM, pH 2.0) and 30s of PBS-BT for 3 cycles. References 1. Crickx, E., Chappert, P., Sokal, A., Weller, S., Azzaoui, I., Vandenberghe, A., Bonnard, G., Rossi, G., Fadeev, T., Storck, S., et al. (2021). Rituximab-resistant splenic memory B cells and newly engaged naive B cells fuel relapses in patients with immune thrombocytopenia. Sci. Transl. Med.13.10.1126/scitranslmed.abc3961. 2. Tiller, T., Meffre, E., Yurasov, S., Tsuiji, M., Nussenzweig, M.C., and Wardemann, H. (2008). Efficient generation of monoclonal antibodies from single human B cells by single cell RT-PCR and expression vector cloning. J. Immunol. Methods 329, 112–124. 10.1016/j.jim.2007.09.017. 3. Gupta, N.T., Vander Heiden, J.A., Uduman, M., Gadala-Maria, D., Yaari, G., and Kleinstein, S.H. (2015). Change-O: a toolkit for analyzing large-scale B cell immunoglobulin repertoire sequencing data. Bioinforma. Oxf. Engl. 31, 3356–3358. 10.1093/bioinformatics/btv359. Results: Analysis of patients with AAN-I-IFNs, with or without life threatening COVID-19 To investigate the cellular basis of type I IFN-specific antibody (Ab) responses in patients with life threatening COVID-19, particularly the potential for an acute breach of self-tolerance and recruitment of de novo autoreactive naive B cells through the extrafollicular pathway, we retrospectively analyzed blood samples from patients during the early phase of SARS-CoV-2 infection (i.e. < 15 days after hospitalization) in the context of the COVID Human Genetic Effort international cohort of adult’s patients with COVID-19 pneumonia (www.covidhge.com). We included 28 patients (23M/5F) with documented AAN-I-IFNs and severe COVID-19 (S-CoV) requiring oxygen (WHO scale ≥5, including 25 with life- threatening COVID-19 in intensive care unit from 7 countries (Belgium, Canada, France, Greece, Italy, Sweden, United Arab Emirates), including 25 patients in intensive care units, with a median age of 63 years [21-87] (data not shown). All had serum antibodies neutralizing IFNα and IFNω at a concentration of 0.1 ng/ml and most IFN-α2 at 10ng/ml (25/28, data not shown). As controls, we collected samples at similar time points from patients with severe COVID-19 but no AAN-I-IFNs (n=11) as well as samples from post-pandemic healthy donors (HD, n=14). Finally, we included samples from 18 patients with known, infection-independent, etiologies of AAN-I-IFNs, referred here as identified tolerance defect (ITD) patients. This included inborn error of immunity (IEI) (NF-κB2 deficiency (n=4), APS-1 (n=4), pRD (n=2)), thymoma (thymoma (n=2) or thymoma with Good’s syndrome-immunodeficiency (GS, n=3)) and systemic lupus patients (SLE, n=3)) (data not shown). High affinity and cross-reactive IFN-α2/IFN-ω-specific IgG+ B cells in patients with life threatening COVID-19 and AAN-I-IFNs. Most studies so far have focused on the detection of circulating neutralizing antibodies against type I IFNs. To be able to analyze, at the single cell level, the underlying IFN-α2-specific B cell response, we first optimized a multiparametric flow cytometry allowing simultaneous sorting and phenotyping analysis of IFN-α2-specific B cells. Available markers, including CD21, CD11c and CD71, allowed us to retrospectively identify major memory B cell (MBC) populations using index-sorting data (data not shown) and ex vivo culture of sorted IgG+ IFN- α2 tetramer+ cells confirmed an overall purity above 90% (data not shown). Analysis of all samples from HD, S-CoV and ITD cohorts using this flow cytometry panel showed a detectable IFN-α2 tetramer+ IgG+ B cell population in 24/28 S-CoV patients with AAN-I-IFNs and in 13/18 ITD patients (data not shown), but in none of the control AAN-I-IFN- S-CoV (n=11) and post-pandemic healthy donors (n=14). IFN-α2 tetramer+ IgG+ B cells were rare, often representing only a few tens of cells per vial, especially in some ITD donors with low peripheral B cell counts. Yet, IFN-α2 IgG+ B cells could even be detected in four out of six S-CoV or ITD patients with AAN-I-IFNs at 0.1ng/ml only and in all subgroups of ITD donors (data not shown), albeit only in one out of three SLE patient analyzed. Some of these IFN-α2 IgG+ B cells were further single-cell sorted and monoclonal IgGs containing supernatants from these in vitro cultured cells were assayed for affinity using Biolayer Interferometry (BLI) against IFN-α2 protein. In both AAN-I-IFN+ S-CoV and ITD patients, monoclonal antibodies (mAbs) secreted by differentiated IFN-α2 IgG+ B cells were mostly high affinity binders against IFN- α2, displaying KDs below 10-9 M (77.8 % and 60% of clones respectively). Slightly less than half of these clones appeared cross reactive against IFN-ω (44.4% and 37% of clones respectively), displaying a similar range of affinity against both IFN-ω and IFN-α2 (data not shown). Comparable observations could be made at the level of neutralization potency of these antibodies with 62% of tested supernatants efficiently neutralizing IFN-α2 signaling at 0.1 ng/ml, and around 24.1% neutralizing IFN-ω at a similar concentration (data not shown). Cross-reactivity towards IFN-β was more reduced with less than a quarter of all tested supernatants showing detectable albeit lower affinity (25.8 % and 7.4 % of S-CoV and ITD clones respectively, data not shown) and none of these cross-reactive clones showing detectable in vitro neutralization potency (data not shown). Altogether, these first set of results demonstrated that a clear population of high-affinity IFN-α2 IgG+ circulating B cells, containing potent cross-neutralizers against IFN-α2 and IFN-ω, is readily detectable at an early stage of SARS-CoV-2 infection in AAN-I-IFNs+ S-CoV patients as well as in ITD patients. Highly Mutated and Diverse Repertoire of Preexisting IFN-α2-specific IgG+ B Cells To ascertain whether these high-affinity IFN-α2 IgG+ circulating B cells originated from de novo recruitment of unmutated autoreactive naive B cells through the extrafollicular (EF) pathway or prior germinal center reactions, we next sequenced all IFN-α2-specific cells previously characterized (data not shown) and performed additional single-cell VDJ sequencing on sorted IFN-α2-specific IgG+ cells from other donors. In total, we obtained 153 antibody heavy chains (IgVH) sequences from 10 S-CoV individuals at an early time point (<2 weeks post infection), 74 from 8 S-CoV at a later time point post infection (>3 months), and 128 from 10 ITD patients. IFN-α2-specific clones in early S-CoV harbored high mutation loads (median of 21 mutations per VH, mean of 21.67±0.67), with very few unmutated sequences (data not shown). Sequences isolated from ITD patients harbored slightly higher mutational load (median of 24 mutations per VH, mean of 24.46±0.89, P=0.0171) but this appeared to be mostly driven by sequences from APS-1 patients (data not shown). VH gene usage of S-CoV and ITD patients’ IFN-α2-specific IgG+ B cells clones shared a strong bias towards VH1-8 and VH4-30 gene (data not shown), as well as more specific overrepresentation of VH1-69 and VH1-3 in S-CoV patients, when compared with published IgG memory B cell reference repertoires (29). Most importantly, the observed IFN-α2-specific IgG repertoire in both groups of patients showed signs of clonal expansion yet remained highly diverse in all patients analyzed (data not shown). Overall, these results indicate that IFN-α2-specific B cells in S- CoV patients are a pre-existing MBC population that has undergone extensive germinal center maturation prior to SARS-CoV-2 infection. AAN-I-IFNs from COVID-19 patients target structurally diverse epitopes on IFN-α2 and IFN-ω To unravel the structural basis of IFN-α and ω recognition in S-CoV patients, we first expressed and validated 32 representative antibodies from 7 S-COV patients, including 3 Abs monospecific for IFN-ω (see methods). Competitive binding to IFN-α2 between individual pairs of these antibodies as well as two fully characterized anti-IFN-α2 human or humanized monoclonals (Rontalizumab (B. Maurer, I. Bosanac, S. Shia, M. Kwong, R. Corpuz, R. Vandlen, K. Schmidt, C. Eigenbrot, Structural basis of the broadly neutralizing anti-interferon-α antibody rontalizumab: Neutralizing Anti-Interferon-α Antibody Rontalizumab. Protein Science 24, 1440–1450 (2015)) and Sifalimumab (V. Oganesyan, L. Peng, R. M. Woods, H. Wu, W. F. Dall’Acqua, Structural Insights into the Neutralization Properties of the Fully Human, Anti-interferon Monoclonal Antibody Sifalimumab. J Biol Chem 290, 14979–14985 (2015)) and the two subunits of the Interferon-alpha/beta receptor (IFNAR), revealed three distinct epitope binning groups (data not shown). One group of antibodies solely competed with the high-affinity IFNAR2 subunit (Group I) and contained all the VH1-8 clones as well as Rontalizumab. A second group competed with IFNAR1 and, to a lesser extent IFNAR2 (Group II), while a last one, containing Sifalimumab, solely competed with IFNAR1 (Group III) (Tables A-D). IFN-α2/IFN-ω cross-reactive antibodies belonged exclusively to Group I antibodies, while similar experiment performed with IFN-ω show that IFN-ω monoreactive mAbs clustered as a distinct epitope group (data not shown). These 3 groups of Abs were represented in all donors (data not shown) and IFN-α2 neutralizing antibodies were equally distributed between groups (data not shown), with intragroup differences in neutralization potency mostly related to off-rate of individual antibodies. Crystal structures of AAN-I-INFs complexes with type I IFNs To better delineate the epitopes targeted by antibodies in these 3 groups, we made crystallization trials of various complexes with IFN-α2. We obtained crystals of a binary complex with a Group I mAb (PMAB15/IFN-α2b) (data not shown), a ternary complex with mAbs of groups I and II (PMAB15/PMAB14/IFN-α2b) (data not shown) and a quaternary complex with mAbs belonging to groups I, II and III (PMAB03/PMAB14/PMAB19/IFN-α2b) (data not shown), diffracting to 2.0, 1.8 and 4.0Å resolution, respectively. Type I IFNs are folded as a bundle of five main α-helices termed A through E, with additional short helices in the loops connecting the main helices. Helices A, E and a short helix in the connection between helices A and B (the “AB” loop”) form one side of the molecule, which is recognized by the receptor IFNAR2 subunit, while the central B, C and D helices form the opposite face, recognized by IFNAR1, to make a “sandwich” like signaling complex at the cell surface ( M. R. Walter, The Role of Structure in the Biology of Interferon Signaling. Front. Immunol. 11, 606489 (2020) ;C. Thomas, I. Moraga, D. Levin, P. O. Krutzik, Y. Podoplelova, A. Trejo, C. Lee, G. Yarden, S. E. Vleck, J. S. Glenn, G. P. Nolan, J. Piehler, G. Schreiber, K. C. Garcia, Structural linkage between ligand discrimination and receptor activation by type I interferons. Cell 146, 621–632 (2011)). The X-ray structures show that the epitope of both group I antibodies overlaps with the IFNAR2 binding site (data not shown), with that of PMAB15 spanning the short helix in the A-B loop and helix E, as previously described for Rontalizumab (PDB 4Z5R) ((B. Maurer, I. Bosanac, S. Shia, M. Kwong, R. Corpuz, R. Vandlen, K. Schmidt, C. Eigenbrot, Structural basis of the broadly neutralizing anti-interferon-α antibody rontalizumab: Neutralizing Anti-Interferon-α Antibody Rontalizumab. Protein Science 24, 1440–1450 (2015)), while PMAB03 also contacts helix A. The epitope of PMAB14 (Group II) involves mostly helix D, in a surface that is away from the membrane side in the sandwich complex on cells, and partially clashes with the IFNAR1 N-terminal fibronectin type III domain (termed SD1) on the cell surface complex. Of interest, binding of PMAB14 to IFNA2 had a small yet detectable impact on both the position of IFNA2’s A-B loop and the binding of PMAB15 in ternary complex 2. Finally, the epitope of PMAB19 (Group III) lies at the opposite side of IFN-α2 compared to Group I mAbs, encompassing residues on helices B and C, as previously described for Sifalimumab (PDB 4YPG)( (V. Oganesyan, L. Peng, R. M. Woods, H. Wu, W. F. Dall’Acqua, Structural Insights into the Neutralization Properties of the Fully Human, Anti-interferon Monoclonal Antibody Sifalimumab. J Biol Chem 290, 14979–14985 (2015)), and clashing with the SD2 and SD3 domains of IFNAR1. Together, these data reveal the contact sites of members of all 3 competition groups resulting from our epitope-binning experiments. AI-based structural predictions of the isolated mAbs in complex with IFN^^^^ reveals four unique classes of AAN-I-IFNs The recent release of the artificial intelligence (AI) prediction server AlphaFold 3 (ABRAMSON, Josh, ADLER, Jonas, DUNGER, Jack, et al. Accurate structure prediction of biomolecular interactions with AlphaFold 3. Nature, 2024, p. 1-3.), which predicts antibody/antigen complexes with higher confidence than previous AlphaFold versions, allowed us to extend the above observations to most of the sequenced anti-IFN-α2 mAbs in our dataset, including mAbs from ITD patients. Of the 198 IGH/IGL analyzed, the structures of 95 were predicted with very high (“very high”, n=61) to moderate confidence (“confident”, n=34) (chain pair interface-predicted TM (ipTM) score for both IgH and IgL interaction with IFN-α2 > 0.8 or 0.6 respectively (ABRAMSON, Josh, ADLER, Jonas, DUNGER, Jack, et al. Accurate structure prediction of biomolecular interactions with AlphaFold 3. Nature, 2024, p.1-3.), and were kept for further analysis. This included 22 of our re-expressed monoclonals (data not shown), with perfect agreement between “very high” to “confident” predicted epitopes and the different groups identified by epitope binning (data not shown). This also included three of the mAbs in our X-ray crystallography data and the predicted structures for these three mAbs were essentially identical to the experimental X-ray structures (data not shown). In total, AlphaFold 3 predicted binding residues highlighted 4 unique classes of binding to IFN-α2 (data not shown), with Class I and Class II encompassing all Group I and II epitope binning group members respectively, and Group III members being further separated in two classes. One of these classes competes with some of the Class II antibodies, in line with epitope binning data, with epitope on helices B and C of IFN-α2 (Class III), like PMAB19. Another smaller group, further away from Class II antibodies, binds to helices A and C of IFN-α2 (Class IV) (data not shown). Similar predictions of the complexes of IFN-ω with cross-reactive IFN-α2/IFN-ω (data not shown) or IFN-ω monoreactive mAbs, showed that cross-reactive mAbs were seen mostly in Class I but also in Class III binding groups, alongside IFN-ω monoreactive mAbs tested in epitope binning experiment (data not shown). A separate group of IFN-ω monoreactive mAbs, isolated from the spleen of an AAB organ donor, were also found in a Class IV-like binding group, slightly shifted towards Class I binding sites compared to IFN-α2 Class IV, with residues on Helix A and F of IFN-ω (data not shown). Overall, Class I mAbs appeared to dominate the anti-IFN-α2 response in both S-CoV and ITD patients (Figure S6B), while Class IV antibodies were rare in S-CoV patients and were not observed in ITD patients. These frequencies, however, must be taken with caution as IGHV usage (e.g. IGHV3-23), targeted epitopes (e.g. Class II) and CDR3 length likely all impact the accuracy of the AlphaFold3 predictions to some degree (Figure S6B-D). Nonetheless, these results clearly highlight the diversity of epitope targets at the level of individual donor, covering the entire surface of type I IFNs. Structural basis for AAN-I-IFNs cross-reactivity Alignment of the amino acid sequences of all IFN-α and IFN-ω (data not shown), confirmed the conserved nature of most predicted binding residues between IFN-α2 and IFN-ω on the A- B- loop, explaining the cross-reactivity of most of the Class I mAbs. However, key mutations in the A-B loop can be seen in other IFN-α and affinity measurements confirmed that most Class I antibodies are poor binders of IFN-α1 (12/14 tested with KD>10-7M) and around half of them did not recognize all or part of IFN-α4/5/7/8/10/16/17 and 21. While additional point mutation experiments are warranted, this still points towards T14A and M16I mutations, common in IFN-α4/5/7/8/10/16/17 and 21 with predicted contact residues at L15/M16 for all affected Class I mAbs, as well as the F27S mutation in IFN-α1 as key contact sites on type I IFNs. The K31M mutation, also unique to IFN-α1 doesn’t impair binding as much, as seen for the one Class II mAbs tested with predicted binding at that site (PMAB08). The picture was mostly reversed for all other classes of mAbs, with poorly conserved binding sites between IFN-α and IFN-ω along Helix A (Class IV mAbs), C (Class III mAbs) and D (Class II mAbs) (data not shown), likely explaining the constrained possibility for cross-reactivity with overall only 1 cross-reactive mAb found in these three classes in our dataset (Class III) (data not shown), alongside the one previously described by Meyer et al (23) (AH-19D11; also predicted to be Class III). In contrast, Class II and Class III mAbs mostly displayed broad reactivity towards all IFN-α, in line with very conserved residues on Helix D between all IFN-α for example (data not shown). Overall, the observed cross-reactivity correlated well with the conserved residues across Type I IFNs. Conclusion: Identification of neutralizing auto-antibodies in patients remains a complex task and generally requires specific techniques to enrich antigen-specific cells due to their rarity. Our innovative approach utilized IFN-α2 and IFN- tetramers to selectively isolate and examine the precision of type I IFN memory B cells (MBC). Offering a first comprehensive view, our research maps the interactions with type I IFNs in humans, examining both patients with unexplained severe infections possessing neutralizing autoantibodies and those with known immunity disorders. We also applied epitope binning, crystallography, and AI predictions to analyze these antibodies in detail. Leveraging AlphaFold 3, we confidently identified targeted epitopes in a substantial number of tested mAbs, leading to an unprecedented mapping of over a hundred type-I IFN-specific antibodies into four distinctive classes of antibody binding to IFNα and IFNω, each varying significantly in their targeting capabilities. Tables: Table A: Epitope binning against IFN-α2: Antibodies listed in column 1 (mAb_ID) represented all identified IFN-α2 binders and were tested for competitive binding against eight representative anti-IFN-α2 monoclonal antibodies isolated from severe COVID-19 patients and spanning one binding site identified on IFN-α2 (Group1: PMAB03, PMAB15 and PMAB18; Group 2: PMAB02, PMAB14, GMAB06 and Group 3: PMAB19 and GMAB03) as well as recombinant human Interferon alpha/beta receptor (IFNAR) 2 and IFNFAR1 proteins fused with the Fc region of human IgG1 at the C-terminus. Tested monoclonal antibodies were loaded as saturating antibody (1st, row) on AHC biosensors and data shows row and column- normalized values of maximal binding measured by biolayer interferometry for each competing Ab (2nd, column)) after an association step with IFN-α2. mAb_I PMAB0 PMAB1 PMAB1 PMAB0 PMAB1 GMAB0 PMAB1 GMAB0 IFNAR2- IFNAR1- D 3 5 8 2 4 6 9 3 Fc Fc PMAB1 97,7 100,0 54,5 100,0 76,3 9,1 2,4 9,2 100,0 50,6 9 PMAB0 81,7 61,5 100,0 52,1 75,6 12,0 9,2 14,8 88,5 22,7 6 PMAB0 90,6 51,1 100,0 58,5 84,1 12,9 9,7 13,9 102,4 19,3 9 PMAB1 70,5 66,6 96,2 78,4 100,0 23,6 20,0 20,2 113,5 30,1 2 PMAB3 100,0 34,0 100,0 58,4 79,9 7,4 9,0 8,2 58,9 30,0 4 GMAB0 100,0 70,4 58,3 61,9 93,0 94,5 11,8 8,9 61,0 10,0 3 Table B: Affinity measurements against all Type I IFNs: Antibodies listed in column 1 (mAb_ID) represent all identified IFN-α2 or IFN-ω1 binders and were tested for binding against all members of the Type I IFN family expressed in their glycosylated form (re-expressed in HEK293 cells). Data represent calculated KD values (M) as measured by biolayer interferometry at a ligand concentration of 100nM. mAbs with no detectable binding are listed with KD >1.00E-7 while mAbs who did not display any significant dissociation from ligand over the time frame of the measurements are listed with KD >1.00E-12.
Table C: Neutralization potency against IFN-α2 and IFN-ω1: Antibodies listed in column 1 (mAb_ID) represent all identified IFN-α2 or IFN-ω1 binders and were tested for in vitro blocking activity of anti–IFN-α2 and anti–IFN-ω1 signalling at a 1ng/ml final concentration of each cytokine. Data represent calculated IC50 values (ng/ml). mAb_ID IFN-α2 - IFN-ω1 - 1ng/ml 1ng/ml PMAB19 20,42 >1000 PMAB06 76,12 >1000 PMAB09 6,926 >1000 PMAB12 38,66 >1000 PMAB34 1,957 >1000 GMAB03 8,4 Unstable REFERENCES: Throughout this application, various references describe the state of the art to which this invention pertains. The disclosures of these references are hereby incorporated by reference into the present disclosure.

Claims

CLAIMS: 1. A monoclonal antibody or an antigen-binding fragment thereof that binds to binds to IFN-α polypeptides and that blocks the binding of said polypeptides to IFNAR1.
2. The monoclonal antibody or the antigen-binding fragment according to claim 1 that binds to IFN-α2 and that does not bind to IFN-ω1.
3. The monoclonal antibody or the antigen-binding fragment according to claim 2 thatbinds to IFN-α2 with a KD lower than 1×10-7 M, preferably binds to at least IFN- α1, IFN-α2, IFN-α4, IFN-α5, IFN-α8, IFN-α10, and IFN-α21 with a KD lower than 1×10-7 M.
4. The monoclonal antibody or the antigen-binding fragment according to any one of claims 1 to 4 that is a neutralizing antibody. will block the IFNAR1-binding of IFN-α2.
5. The monoclonal antibody or the antigen-binding fragment according to any one of claims 1 to 4 that binds to IFN-α2 with a KD of about 1×10-7 M or less and blocks IFN- α2 signalling with an IC50 of about 10ng/mL or lower.
6. The monoclonal antibody or the antigen-binding fragment according to any one of claims 1 to 4 that binds to a conformational epitope IFN-α2 that comprises i) one or more amino acid residues in the Helix B selected from the group consisting of P54, H57, E58, Q61, F64, N65, and S68 in SEQ ID NO:3 and ii) one or more amino acid residues in the Helix D selected from the group consisting of Y85, T86, Y89, Q90, L92, N93, E96, A97, V99, I100, and Q101 in SEQ ID NO:3.
7. The monoclonal antibody or the antigen-binding fragment according to claim 5 that cross-competes for binding to IFN-α2 with - the monoclonal antibody comprising a VH domain having the H-CDR1 as set forth in SEQ ID NO:22, the H-CDR2 as set forth in SEQ ID NO:23 and the H-CDR3 as set forth in SEQ ID NO:24 and a VL domain having the L-CDR1 as set forth in SEQ ID NO:26, the L-CDR2 as set forth in SEQ ID NO:27 and the L-CDR3 as set forth in SEQ ID NO:28, or - the monoclonal antibody comprising a VH domain having the H-CDR1 as set forth in SEQ ID NO:38, the H-CDR2 as set forth in SEQ ID NO:39 and the H-CDR3 as set forth in SEQ ID NO:40 and a VL domain having the L-CDR1 as set forth in SEQ ID NO:42, the L-CDR2 as set forth in SEQ ID NO:43 and the L-CDR3 as set forth in SEQ ID NO:44, or - the monoclonal antibody comprising a VH domain having the H-CDR1 as set forth in SEQ ID NO:6, the H-CDR2 as set forth in SEQ ID NO: 7 and the H-CDR3 as set forth in SEQ ID NO:8 and a VL domain having the L-CDR1 as set forth in SEQ ID NO:10, the L-CDR2 as set forth in SEQ ID NO:11 and the L-CDR3 as set forth in SEQ ID NO:12, or - the monoclonal antibody comprising a VH domain having the H-CDR1 as set forth in SEQ ID NO:14, the H-CDR2 as set forth in SEQ ID NO: 15 and the H-CDR3 as set forth in SEQ ID NO:16 and a VL domain having the L-CDR1 as set forth in SEQ ID NO:18, the L-CDR2 as set forth in SEQ ID NO:19 and the L-CDR3 as set forth in SEQ ID NO:20, or - the monoclonal antibody comprising a VH domain having the H-CDR1 as set forth in SEQ ID NO:30, the H-CDR2 as set forth in SEQ ID NO:31 and the H-CDR3 as set forth in SEQ ID NO:32 and a VL domain having the L-CDR1 as set forth in SEQ ID NO:34, the L-CDR2 as set forth in SEQ ID NO:35 and the L-CDR3 as set forth in SEQ ID NO:36. - .
8. The monoclonal antibody or the antigen-binding fragment according to any one of claims 1 to 4 that binds to a conformational epitope IFN-α2 that comprises i) one or more amino acid residues in the Helix A selected from the group consisting of D2, Q5, T6, H7, L9, G10, R12, and R13 in SEQ ID NO:3 and ii) one or more amino acid residues in the Helix C selected from the group consisting of D82, Y85, T86, E87, Y89, Q90, Q91, N93, and D94 in SEQ ID NO:3.
9. The monoclonal antibody or the antigen-binding fragment according to claim 8 that cross-competes for binding to IFN-α2 with the monoclonal antibody comprising a VH domain having the H-CDR1 as set forth in SEQ ID NO:46, the H-CDR2 as set forth in SEQ ID NO:47 and the H-CDR3 as set forth in SEQ ID NO:48 and a VL domain having the L-CDR1 as set forth in SEQ ID NO:50, the L-CDR2 as set forth in SEQ ID NO:51 and the L-CDR3 as set forth in SEQ ID NO:52
10. The monoclonal antibody or the antigen-binding fragment according to any one of claims 1 to 9 that comprises - a VH domain having the H-CDR1 as set forth in SEQ ID NO:22, the H-CDR2 as set forth in SEQ ID NO:23 and the H-CDR3 as set forth in SEQ ID NO:24 and a VL domain having the L-CDR1 as set forth in SEQ ID NO:26, the L-CDR2 as set forth in SEQ ID NO:27 and the L-CDR3 as set forth in SEQ ID NO:28, or - a VH domain having the H-CDR1 as set forth in SEQ ID NO:38, the H-CDR2 as set forth in SEQ ID NO:39 and the H-CDR3 as set forth in SEQ ID NO:40 and a VL domain having the L-CDR1 as set forth in SEQ ID NO:42, the L-CDR2 as set forth in SEQ ID NO:43 and the L-CDR3 as set forth in SEQ ID NO:44, or - a VH domain having the H-CDR1 as set forth in SEQ ID NO:6, the H-CDR2 as set forth in SEQ ID NO: 7 and the H-CDR3 as set forth in SEQ ID NO:8 and a VL domain having the L-CDR1 as set forth in SEQ ID NO:10, the L-CDR2 as set forth in SEQ ID NO:11 and the L-CDR3 as set forth in SEQ ID NO:12, or - a VH domain having the H-CDR1 as set forth in SEQ ID NO:14, the H-CDR2 as set forth in SEQ ID NO: 15 and the H-CDR3 as set forth in SEQ ID NO:16 and a VL domain having the L-CDR1 as set forth in SEQ ID NO:18, the L-CDR2 as set forth in SEQ ID NO:19 and the L-CDR3 as set forth in SEQ ID NO:20, or - a VH domain having the H-CDR1 as set forth in SEQ ID NO:30, the H-CDR2 as set forth in SEQ ID NO:31 and the H-CDR3 as set forth in SEQ ID NO:32 and a VL domain having the L-CDR1 as set forth in SEQ ID NO:34, the L-CDR2 as set forth in SEQ ID NO:35 and the L-CDR3 as set forth in SEQ ID NO:36, or - a VH domain having the H-CDR1 as set forth in SEQ ID NO:46, the H-CDR2 as set forth in SEQ ID NO:47 and the H-CDR3 as set forth in SEQ ID NO:48 and a VL domain having the L-CDR1 as set forth in SEQ ID NO:50, the L-CDR2 as set forth in SEQ ID NO:51 and the L-CDR3 as set forth in SEQ ID NO:52.
11. The antibody or the antigen-binding fragment according to claim 10 that comprises: - a VH domain having an amino acid sequence having at least 70% of identity with the amino acid sequence as set forth in SEQ ID NO:21 and a VL domain having an amino acid sequence having at least 70% of identity with the amino acid sequence as set forth in SEQ ID NO:25, or - a VH domain having an amino acid sequence having at least 70% of identity with the amino acid sequence as set forth in SEQ ID NO:37 and a VL domain having an amino acid sequence having at least 70% of identity with the amino acid sequence as set forth in SEQ ID NO:41, or - a VH domain having an amino acid sequence having at least 70% of identity with the amino acid sequence as set forth in SEQ ID NO:5 and a VL domain having an amino acid sequence having at least 70% of identity with the amino acid sequence as set forth in SEQ ID NO:9, or - a VH domain having an amino acid sequence having at least 70% of identity with the amino acid sequence as set forth in SEQ ID NO:13 and a VL domain having an amino acid sequence having at least 70% of identity with the amino acid sequence as set forth in SEQ ID NO:17, or - a VH domain having an amino acid sequence having at least 70% of identity with the amino acid sequence as set forth in SEQ ID NO:29 and a VL domain having an amino acid sequence having at least 70% of identity with the amino acid sequence as set forth in SEQ ID NO:33, or - a VH domain having an amino acid sequence having at least 70% of identity with the amino acid sequence as set forth in SEQ ID NO:37 and a VL domain having an amino acid sequence having at least 70% of identity with the amino acid sequence as set forth in SEQ ID NO:41, or - a VH domain having an amino acid sequence having at least 70% of identity with the amino acid sequence as set forth in SEQ ID NO:45 and a VL domain having an amino acid sequence having at least 70% of identity with the amino acid sequence as set forth in SEQ ID NO:49.
12. The antibody or the antigen-binding fragment according to claim 11 that comprises: - a VH domain having the amino acid as set forth in SEQ ID NO:21 and a VL domain having the amino acid sequence as set forth in SEQ ID NO:25, or - a VH domain having the amino acid as set forth in SEQ ID NO:37 and a VL domain having the amino acid sequence as set forth in SEQ ID NO:41, or - a VH domain having the amino acid as set forth in SEQ ID NO:5 and a VL domain having the amino acid sequence as set forth in SEQ ID NO:9, or - a VH domain having the amino acid as set forth in SEQ ID NO:13 and a VL domain having the amino acid sequence as set forth in SEQ ID NO:17, or - a VH domain having the amino acid as set forth in SEQ ID NO:21 and a VL domain having the amino acid sequence as set forth in SEQ ID NO:25, or - a VH domain having the amino acid as set forth in SEQ ID NO:29 and a VL domain having the amino acid sequence as set forth in SEQ ID NO:33, or - a VH domain having the amino acid as set forth in SEQ ID NO:37 and a VL domain having the amino acid sequence as set forth in SEQ ID NO:41, or - a VH domain having the amino acid as set forth in SEQ ID NO:55 and a VL domain having the amino acid sequence as set forth in SEQ ID NO:49.
13. A polynucleotide encoding the antibody or the antigen-binding fragment according to any one of claims 1 to 12.
14. A vector comprising the polynucleotide according to claim 13.
15. A host cell which has been transfected, infected or transformed by the polynucleotide according to claim 10 and/or the vector according to claim 14.
16. The antibody or the antigen-binding fragment according to any one of claims 1 to 12 for use as a drug
17. A method of therapy in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the antibody or the antigen-binding fragment according to any one of claims 1 to 12.
18. The method according to claim 17 for the treatment of an autoimmune inflammatory disease or a type 1 interferonopathy.
19. A pharmaceutical composition comprising, consisting of or consisting essentially of the antibody or the antigen-binding fragment according to any of claims 1 to 12.
20. A method for detecting the presence of a IFN-αpolypeptide in a sample comprising contacting the sample with one or more antibodies according to any one of claims 1 to 12 under conditions that allow an immunocomplex of IFN-αpolypeptide and the antibodies to form wherein detection of the immunocomplex indicates the presence of a IFN-αpolypeptide in the sample.
21. The method of claim 20 for determining whether a subject has or is at risk of having an autoimmune inflammatory disease and more particularly a type 1 interferonopathy wherein high levels of IFN-αpolypeptides indicate that the subject has or is at risk of having an autoimmune inflammatory disease and more particularly a type 1 interferonopathy.
22. The method of claim 20 for determining whether a subject has or is at risk of having a viral disease and/or to progress to a severe form of the viral disease wherein low levels of IFNα polypeptides indicate that the subject is at risk of having a viral infection and/or to progress to a severe form of the viral disease.
23. A method for determining whether a subject is at risk of having a viral infection and/or at risk to progress to a sever from a viral disease comprising i) detecting the presence of one or more IFN-α autoantibodies in a sample obtained from the subject, ii) determining the neutralizing activity of said autoantibodies, iii) comparing the neutralizing activity of said autoantibodies with the neutralizing activity of an antibody according to any one of claims 1 to 12 and iv) concluding that the patient the subject is at risk of having a viral infection and/or to progress to a severe form of the viral disease wherein the neutralizing activity of the autoantibodies substantially the same or higher than the neutralizing activity of the antibody according to any one of claims 1 to 12.
24. A kit or device comprising at least one antibody according to any one of claims 1 to 12 optionally immobilized or not on a solid support.
PCT/EP2025/064682 2024-05-28 2025-05-27 ANTI-IFN-α2 MONOCLONAL ANTIBODIES Pending WO2025247924A1 (en)

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