Anti-BDCA-2 Antibody

Abstract

The present invention relates to antigen binding molecules, in particular antibodies, fragments and variants thereof, that bind to BDCA-2 (CLEC4C), and the use of the antigen binding molecules in treating and / or preventing inflammatory disorders and immune disorders such as autoimmune diseases.

Description

Technical Field

[0001] This invention relates to antigen-binding molecules that bind to BDCA-2 (CLEC4C), particularly antibodies, fragments thereof and variants thereof, and the use of said antigen-binding molecules in the treatment and / or prevention of inflammatory and immune conditions such as autoimmune diseases. Background Technology

[0002] Maintaining the ability to sense microbial nucleic acids while avoiding recognition of one's own DNA and RNA is crucial. The innate immune system appears to have been tailored to distinguish between pathogen-derived exogenous nucleic acids and host-derived native nucleic acids. However, considerable new evidence suggests that Toll-like receptor (TLR) recognition of native nucleic acids can still occur under certain circumstances, despite the different mechanisms the innate immune system has developed to prevent self-recognition. Chronic activated plasmacytoid dendritic cells (pDCs) and their IFN-α production in response to their own nucleic acids are contributing factors in the pathogenesis of some autoimmune diseases, such as scleroderma (SSc), systemic lupus erythematosus (SLE), and Sjögren's syndrome psoriasis (Bekic z, et al. Ann Rheum Dis 2016; 75: 1567-73; Fei T, et al. Sci China Life Sci. 2010; 53: 172-182; van Bon L, et al. Current Opinion in Rheumatology 2011; 23: 505-510; Banchereau J and Pascual V. Immunity 2006; 25: 383392).

[0003] Plasma-like dendritic cells (pDCs) are bone marrow-derived cells that specifically secrete type I IFN (Colonna M, et al. Nat. Immunol. 2004; 5: 1219-1226; Gilliet M, et al. Nat. Rev. Immunol. 2008; 8: 594-606). pDCs are primarily found in peripheral blood and primary and secondary lymphoid organs. pDCs rapidly detect viral nucleic acids endocytosed and delivered to endosomes containing TLR7 and TLR9. The involvement of these receptors leads to the immediate release of type I IFN, providing very early defense against viral infection (Swiecki M and Colonna M. Immunol. Rev. 2010; 234: 142-162). pDCs also secrete type I IFN in response to endogenous nucleic acids released during cell necrosis and / or apoptosis or bound to antinuclear autoantibodies.

[0004] Extensive evidence suggests that autologous nucleic acid recognition is involved in inflammatory and autoimmune diseases. In particular, the contribution of TLRs to autoimmunity has been emphasized in various disease models. A prime example is the role of TLR9 and TLR7 in lupus through the accumulation of autoDNA / RNA via immune complexes (Barrat FJ et al. J. Exp. Med. 2005, 202: 1131-1139; Hagberg N and Ronnblom L Scand. J. Immunol. 2015, 82: 199-207). Another example is the importance of autoantimicrobial peptides in promoting autoimmunity (Lande R et al. Nature 2007, 449; 564-569). It has been shown that TLR overexpression alone is sufficient to induce autoimmunity in, for example, wild-type animals, as demonstrated by TLR7 or TLR8 (Deane, JA et al. Immunity 2007; 27: 801-810; Guiducci C, et al. J. Exp. Med. 2013; 210: 2903-2919).

[0005] SSc is a multisystemic fibrotic disease in which vascular lesions, autoimmunity, and inflammation lead to a variety of life-altering and life-threatening clinical manifestations. SSc has the highest morbidity and mortality rate among rheumatic diseases, with a 10-year mortality rate of 23% to 45% (Mayes MD, et al. Arthritis Rheum. 2003; 48: 2246-2255). It is more prevalent in women, with a ratio of approximately 4:1, and the typical age of onset is between 35 and 55 years. The pathophysiology of SSc is not fully understood, but substantial evidence suggests an interaction between immune dysregulation, endothelial dysfunction, and profibrotic mechanisms.

[0006] Evidence has established the role of pDCs in SSC. pDCs infiltrate the skin of SSC patients and are chronically activated, leading to the secretion of IFNα and CXCL4, both of which are hallmarks of the disease. Ah Kioon et al. (Sci. Transl. Med. 2018; 10: eaam8458) demonstrated that CXCL4 secretion is due to the abnormal presence of TLR8 on pDCs from SSC patients, which is not seen in healthy donors, and that CXCL4 primarily functions by enhancing TLR8 and TLR9-induced IFN production through pDCs. Further research on IFN-induced chemokines in SSC (Liu X, et al. Arthritis Rheum. 2013; 65: 226-35) and reports on CXCL4 as a biomarker for SSC (van Bon L, et al. N Engl J Med. 2014; 370: 433-43) has generated increasing interest in the role of IFN in the progression and early stages of SSC. Another recent paper demonstrated the presence of IFN characteristics prior to the onset of clinical fibrosis (previously associated with active SSc) (Brkic Z et al. Ann Rheum Dis. 2016; 75: 1567-73). Furthermore, in vivo data showed that pDC depletion could prevent disease in a mouse model of scleroderma and reverse fibrosis in mice with confirmed disease (Ah Kioon et al. Sci. Transl. Med. 2018; 10: eaam8458).

[0007] pDCs express multiple receptors that inhibit type I IFN secretion, thereby preventing immune surveillance. One of these receptors is CLEC4C, also known as Blood Dendritic Cell Antigen-2 (BDCA-2) and CD303 (Dzionek A, et al. J. Exp. Med. 2001; 194: 1823-1834). CLEC4C is a type II transmembrane glycoprotein belonging to the C-type lectin (CTL) superfamily (Crocker PR et al. Nat Rev Immunol. 2007; 7: 255-66). BDCA-2 is the most specific marker for human pDCs, expressed only in primates. BDCA-2 consists of a single extracellular carbohydrate recognition domain, a transmembrane region, and a short cytoplasmic domain without a prominent signal transduction motif. BDCA-2 transmits intracellular signals via the associated transmembrane adaptor FcεRγ (recruiting protein tyrosine kinase Syk), thereby inducing protein tyrosine phosphorylation and calcium mobilization (Cao W, et al. PLoS Biol. 2007; 5: e248). Although it promotes the activation of other lymphocytes and bone marrow cells, the FcεRγ-Syk signaling pathway interferes with TLR7 and TLR9-induced pDC activation and inhibits type I IFN secretion (Dzionek A, et al. J. Exp. Med. 2001; 194: 1823-1834).

[0008] pDCs are abnormally activated in peripheral blood or at lesion sites, and produce large amounts of IFNα and other inflammatory cytokines and chemokines in autoimmune diseases such as SLE, SSc, polymyositis and dermatomyositis, psoriasis, Sjögren's syndrome, rheumatoid arthritis, Graves' disease and Hashimoto's disease (Li et al. Front Immunol. 2017; 8: 1268; Eloranta et al. Arthritis Rheum. 2013; 65: 853-863). Summary of the Invention

[0009] In a first aspect of the invention, an antigen-binding molecule or a fragment or variant thereof is provided, comprising a heavy chain variable region containing VHCDR3 and / or a light chain variable region containing VLCDR3, wherein the antigen-binding molecule binds to BDCA-2 (CLEC4C).

[0010] In a second aspect of the invention, an antigen-binding molecule or a fragment or variant thereof is provided, comprising a heavy chain variable region and / or a light chain variable region, each variable region comprising three CDR regions, wherein the antigen-binding molecule binds to BDCA-2 (CLEC4C).

[0011] In a third aspect of the invention, an anti-BDCA-2 (CLEC4C) antigen-binding molecule is provided, wherein the antigen-binding molecule has an equilibrium dissociation constant (K0) for BDCA-2 (CLEC4C) of less than about 2 nM. D In some embodiments, the antigen-binding molecule has an equilibrium dissociation constant (K0) for BDCA-2 (CLEC4C) of less than about 0.01 nM. D ).

[0012] In a fourth aspect of the invention, an anti-BDCA-2 (CLEC4C) antigen-binding molecule is provided, wherein the antigen-binding molecule has a half-maximum inhibitory concentration (IC50) for inhibiting IFN secretion of less than about 2 nM. In some embodiments, the antigen-binding molecule has a half-maximum inhibitory concentration (IC50) for inhibiting IFN secretion of less than about 0.1 nM.

[0013] In a fifth aspect of the invention, an anti-BDCA-2 (CLEC4C) antigen-binding molecule is provided, wherein the antigen-binding molecule has an IC90 of less than about 20 nM for inhibiting IFN secretion. In some embodiments, the antigen-binding molecule has an IC90 of less than about 5 nM for inhibiting IFN secretion.

[0014] In a sixth aspect of the invention, an anti-BDCA-2 (CLEC4C) antigen-binding molecule is provided, wherein the antigen-binding molecule comprises: VHCDR3 comprising an amino acid sequence comprising any one of SEQ ID NO48, 28, 8, 38, 58, 68 and 78; and / or VLCDR3 comprising an amino acid sequence comprising any one of SEQ ID NO34, 24, 44, 4, 14, 54, 64 and 74.

[0015] In a seventh aspect of the invention, an anti-BDCA-2 (CLEC4C) antigen-binding molecule is provided, wherein the antigen-binding molecule comprises: VHCDR1 comprising an amino acid sequence comprising any one of SEQ ID NO 46, 49, 26, 29, 6, 9, 16, 19, 36, 39, 56, 59, 66, 69, 76, and 79; VHCDR2 comprising an amino acid sequence comprising any one of SEQ ID NO 47, 50, 27, 30, 7, 10, 17, 20, 37, 40, 57, 60, 67, 70, 77, and 80; and VHCDR3 comprising an amino acid sequence comprising any one of SEQ ID NO 48, 28, 8, 18, 38, 58, 68, and 78; and / or VLCDR1 comprising an amino acid sequence comprising any one of SEQ ID NO 32, 22, 42, 2, 12, 52, 62, and 72; comprising SEQ ID NO VLCDR2 containing any one of the amino acid sequences 33, 23, 43, 3, 13, 53, 63, and 73; and VLCDR3 containing any one of the amino acid sequences SEQ ID NO 34, 24, 44, 4, 14, 54, 64, and 74.

[0016] In an eighth aspect of the invention, an anti-BDCA-2 (CLEC4C) antigen-binding molecule is provided, wherein the antigen-binding molecule comprises: a heavy chain variable region having an amino acid sequence selected from the group consisting of: SEQ ID NO: 45, SEQ ID NO: 25, SEQ ID NO: 5, SEQ ID NO: 15, SEQ ID NO: 35, SEQ ID NO: 55, SEQ ID NO: 65 and SEQ ID NO: 75; and / or a light chain variable region having an amino acid sequence selected from the group consisting of: SEQ ID NO: 31, SEQ ID NO: 21, SEQ ID NO: 41, SEQ ID NO: 1, SEQ ID NO: 11, SEQ ID NO: 51, SEQ ID NO: 61 and SEQ ID NO: 71.

[0017] In a ninth aspect of the invention, an anti-BDCA-2 (CLEC4C) antigen-binding molecule is provided, wherein the antigen-binding molecule is an antibody that specifically binds to BDCA-2 (CLEC4C) and is selected from the group consisting of: 3E05_var12, 3E05_var6, 3E05_var14, 3E05, 3E05_var1, 3E05_var2, 3E05_var3, 3E05_var4, 3E05_var5, 3E05_var7, 3E05_var8, 3E05_var9, 3E05_var10, 3E05_var11, 3E05_var13, 3E05_var15, 3E05_var16, 21E06, 25E06, and 28B01. The invention also provides fragments and variants derived from said antibody.

[0018] In another aspect of the invention, an antigen-binding molecule or a fragment or variant thereof is provided that binds to BDCA-2 (CLEC4C) and competes with the antigen-binding molecule of any one of the first to ninth aspects of the invention for binding to BDCA-2 (CLEC4C).

[0019] In another aspect of the invention, an antigen-binding molecule is provided that specifically binds to an epitope of BDCA-2 (CLEC4C), the epitope being bound by an antigen-binding molecule of any one of the first to ninth aspects of the invention.

[0020] In another aspect of the invention, an antigen-binding molecule is provided that specifically binds to BDCA-2 (CLEC4C) and inhibits the binding of BDCA-2 (CLEC4C) to the antigen-binding molecule of any one of the first to ninth aspects of the invention.

[0021] In another aspect of the invention, an anti-BDCA-2 (CLEC4C) antigen-binding molecule is provided, comprising 1 to 10, 1 to 5, or 1 to 2 amino acid substitutions for the antigen-binding molecule of any one of the first to ninth aspects of the invention.

[0022] In another aspect of the invention, an anti-BDCA-2 (CLEC4C) antigen-binding molecule is provided, wherein the anti-BDCA-2 (CLEC4C) antigen-binding molecule is a humanized or deimmunized derivative of the anti-BDCA-2 (CLEC4C) antigen-binding molecule of the present invention.

[0023] In another aspect of the invention, an affinity maturation mutant of the antigen-binding molecule or antibody of the invention is provided.

[0024] In another aspect of the invention, a pharmaceutical composition is provided comprising the antigen-binding molecule of the invention or a fragment thereof, variant thereof, or affinity-mature mutant thereof.

[0025] In another aspect of the invention, the use of the antigen-binding molecule or pharmaceutical composition of the invention in medicine is provided.

[0026] In another aspect, the use of the antigen-binding molecules or pharmaceutical compositions of the present invention in the prevention and / or treatment of inflammatory conditions or diseases is provided.

[0027] In another aspect, the use of the antigen-binding molecule or pharmaceutical composition of the present invention in the preparation of a medicament for treating inflammatory conditions or diseases is provided.

[0028] On the other hand, a method is provided for treating or preventing inflammatory conditions or diseases in a subject of need, comprising administering to the subject a therapeutically effective amount of the antigen-binding molecule or pharmaceutical composition of the present invention.

[0029] The invention also provides a nucleic acid encoding the antigen-binding molecule of the present invention. It also provides a vector or plasmid comprising the nucleic acid of the present invention. The invention further provides a host cell comprising the nucleic acid, vector, or plasmid of the present invention.

[0030] The present invention also provides a method for generating cells expressing anti-BDCA-2 (CLEC4C) antigen-binding molecules, comprising transfecting said cells with the plasmid or vector of the present invention. The present invention also provides a method for generating anti-BDCA-2 (CLEC4C) antigen-binding molecules, comprising culturing host cells of the present invention in a cell culture medium under conditions of intracellular expression of a nucleic acid sequence encoding a plasmid or vector, and optionally collecting the anti-BDCA-2 (CLEC4C) antigen-binding molecules from the cell supernatant.

[0031] The present invention also provides a kit containing an anti-BDCA-2 (CLEC4C) antigen-binding molecule or other aspects of the present invention, which optionally also includes instructions for use. Attached Figure Description

[0032] Figure 1 Chimeric mAbs that bind to BDCA-2 expressed in human and cynomolgus monkey cells. The purified mAbs at 5 μg / ml were tested against BDCA-2 expressed in human or cynomolgus monkey cells. Positive controls used were anti-BDCA-2 mAb, AC144 (Miltenyi Biotec, catalog number 130-090-690), and BIIB059 (patent WO2014093396); the negative control was buffer (Ab-free).

[0033] Figure 2Chimeric mAbs that bind to plasmacytoid dendritic cells. The binding of purified mAbs (10 μg / ml) to purified pDCs was tested by flow cytometry. Positive controls used were anti-BDCA-2 mAb, AC144 (Miltenyi Biotech, catalog number 130-090-690), and BIIB059 (patent WO2014093396); the negative control was buffer (Ab-free).

[0034] Figure 3A The effect of chimeric anti-BDCA-2 mAb on inhibiting IFNα from ODN-stimulated pDCs was tested. The inhibition of ODN-induced IFNα from human purified pDCs by mAb concentrations of 1 μg / ml or 0.1 μg / ml was examined. Positive anti-BDCA-2 mAb controls used were AC144 (Miltenyi Biotec, catalog number 130-090-690) and BIIB059 (patent WO2014093396), and the negative control was buffer (Ab-free).

[0035] Figure 3B The chimeric anti-BDCA-2 mAb inhibited IFNα in PBMCs stimulated by TLR9 (ODN, 1 μM). The inhibitory effects of 10 μg / ml, 1 μg / ml, or 0.1 μg / ml mAb on ODN-induced IFNα from human PBMCs (500 K / well) were tested. Negative controls were buffer (control) and 10 μg / ml, 1 μg / ml, or 0.1 μg / ml hIgG1.

[0036] Figure 3C The chimeric anti-BDCA-2 mAb inhibited IFNα from TLR8 (ORN, 1uM)-stimulated PBMCs. The inhibitory effects of 10 μg / ml, 1 μg / ml, or 0.1 μg / ml mAb on ORN-induced IFNα from human PBMCs (500 K / well) were tested. Negative controls were buffer (control) and 10 μg / ml, 1 μg / ml, or 0.1 μg / ml hIgG1.

[0037] Figure 3D The chimeric anti-BDCA-2 mAb inhibited IFNα induced by TLR7 (imiquimod, 1 μM) stimulation in PBMCs. The inhibitory effects of 10 μg / ml, 1 μg / ml, or 0.1 μg / ml mAb on imiquimod-induced IFNα from human PBMCs (500 K / well) were tested. Negative controls were buffer (control) and 10 μg / ml, 1 μg / ml, or 0.1 μg / ml hIgG1.

[0038] Figure 4AChimeric anti-BDCA-2 mAb (10 μg / ml) inhibits the effects of intracellular IFNα and TNFα in healthy pDCs stimulated by ODN. The positive control is anti-BDCA-2 mAb BIIB059 (patent WO2014093396), and the negative control is buffer (Ab-free).

[0039] Figure 4B The chimeric anti-BDCA-2 mAb (10 μg / ml) inhibited TNFα secretion from healthy pDCs stimulated by ODN. The positive control was anti-BDCA-2 mAb BIIB059 (patent WO2014093396), and the negative control was buffer (Ab-free).

[0040] Figure 5 Humanized 3E5 and 28B1 variant mAbs were bound to pDCs by flow cytometry.

[0041] Figure 6A Humanized 28B1 anti-BDCA-2 mAb inhibits IFNα secretion from PBMCs stimulated by ODN. The positive control is anti-BDCA-2 mAb BIIB059 (patent WO2014093396), and the negative control is buffer (Ab-free).

[0042] Figure 6B Humanized 3E5 anti-BDCA-2 mAb inhibits IFNα secretion from PBMCs stimulated by ODN. The positive control is anti-BDCA-2 mAb BIIB059 (patent WO2014093396), and the negative control is buffer (Ab-free).

[0043] Figure 7A and 7B BDCA2 chimeric mAb 3E5 inhibits ODN-stimulated pDC transcriptome activation. Figure 7A Three independent human pDC donors (Lineage-HLA-DR) with and without ODN stimulation were shown. + CD123 + CD304 + Global RNA-seq analysis of ) and pathway analysis of differentially expressed genes (DEG). Figure 7B The inhibition of pDC DEG by 3E5 on ODN-stimulated pDCs was shown, which exhibited an expression profile similar to that of unstimulated pDCs.

[0044] Figure 8A , 8B And 8C. Organoid 3D skin culture and chimeric anti-BDCA-2mAb 3E5 effects. Figure 8A The culture techniques and the gas-liquid interface (ALI) are summarized. Figure 8BHematoxylin and eosin (H&E) staining revealed epithelial-like development in vivo. Figure 8C The study showed that 27 IFN-stimulated genes were upregulated in intraepithelial ODN-stimulated pDC supernatant compared to resting pDC supernatant and chimeric anti-BDCA-2mAb 3E5 inhibition.

[0045] Figure 9A and 9B A xenograft mouse model of human pDC activation. Effects of chimeric anti-BDCA-2mAb 28B1 and 3E5 on interferon gene signatures in mice. Normal human primary pDCs were injected intravenously into NOD-SCID mice, and the dorsal skin was treated with Aldara cream with and without chimeric anti-BDCA-2mAb 3E5 or 28B1 or human IgG (5 mg / kg). Total RNA from triplicate experiments was used to generate cDNA, and qRT-PCR analysis was performed on 78 genes typically upregulated during type I interferon responses. IGS from the Qiagen panel were sorted against differential expression in the hIgG condition and control (Aldara / imiquimod only). The 10 genes with the largest differential expression were selected for analysis.

[0046] Figure 10A , 10B 10C, 10D, and 10E. Three-week pDC and bleomycin-induced skin fibrosis models. Starting from day 0, bleomycin (Bleo) or PBS (control, 100 μl) was subcutaneously (sc) injected every other day into a single site on the shaved back of NOD-SCID mice for 3 weeks. Human PDc (2.5 × 10⁻⁶) was administered. 5 Mice were administered intravenously (iv) on days 0, 7, and 14. Starting from day 1, 3E5 mAb (var_6) or human IgG (2.5 mg / kg, ip) was injected every 5 days (n = 5 ip injections per mouse) (administration schedule shown in [reference needed]). Figure 10E (in Chinese). Using hematoxylin and eosin (H&E). Figure 10A ) or Masson's Tricolor (MT) staining agent ( Figure 10A Formalin-fixed, paraffin-embedded skin tissue from treated mice was stained. Epidermal and dermal skin thickness in the treated groups was shown in [data missing]. Figure 10B and 10C In skin perforation biopsies, total collagen relative to total protein was observed... Figure 10D Medium. Statistical significance (unpaired t-test); P < 0.05*, 0.01**, 0.001***;

[0047] Figure 11A and 11BAlignment of the parental 3E5 sequence with four humanized / deimmunized variants 1 to 4;

[0048] Figure 12A , 12B Sequences of the parental 3E5 heavy and light chain variable sequences, 12C and 12D, and four humanized / deimmunized variants 1 to 4 (SEQ ID NOs 1, 11, 21, 31, 41, 5, 15, 25, 35, and 45) together constitute 16 variant antibodies based on the parental 3E5 antibody. Figures A and B identify 6 CDRs according to the Kabat protocol. Figures C and D identify 6 CDRs according to the Chothia protocol. These figures also provide the SEQ ID NO for each sequence (heavy, light, Kabat, and Chothia-recognized CDRs) associated with the 3E5 parental antibody and its 16 variants (SEQ ID NOs: 1 to 50). In the event of any discrepancy between the sequences in these figures and those in the accompanying sequence listing or elsewhere in this specification, the sequences in these figures shall prevail.

[0049] Figure 13 Overlap mapping design of trypsin, chymotrypsin, ASP-N, elastase, and thermophilic protease peptides was used, and epitopes were determined using proteolysis. Peptides derived from trypsin, chymotrypsin, elastase, and thermophilic protease proteases showed 100% sequence coverage. Amino acid numbers refer to amino acids 45 to 213 of the extracellular domain of BDCA-2 and Q8WTT0. Figure 13 Amino acid 1 in it is amino acid 45 in Q8WTTO. Detailed Implementation

[0050] As used herein, an "antigen-binding molecule" is a member of a pair of molecules that are specific to bind to each other. Members of an antigen-binding pair can be naturally derived or wholly or partially synthetically produced. One member of the pair has a region on its surface, which can be a protrusion or a cavity, that binds specifically to and is complementary to the other member of the pair in terms of specific spatial and polar organization. Thus, the members of the pair possess the property of specifically binding to each other. Examples of types of antigen-binding pairs include antigen-antibody, biotin-avidin, hormone-hormone receptor, receptor-ligand, and enzyme-substrate. This invention generally relates to antigen-antibody type interactions. The antigen-binding molecules used in this invention specifically bind to epitopes of BDCA-2 (CLEC4C). The binding affinity of the antigen-binding molecule to the epitopes of BDCA-2 (CLEC4C) can be expressed using a dissociation constant (K). DThe binding affinity of antigen-binding molecules to epitopes of BDCA-2 (CLEC4C) or BDCA-2 (CLEC4C) can be measured using the association constant (K). a The antigen-binding molecule is used to measure the K-axis of the BDCA-2 (CLEC4C) epitope bound by the antigen-binding molecule of the present invention. D The value will be lower than the K value of the antigen-binding molecule for the substituted epitope of BDCA-2 (CLEC4C) or the non-BDCA-2 (CLEC4C) epitope. D value.

[0051] Antigen-binding molecules that bind to BDCA-2 (CLEC4C) include anti-BDCA-2 (CLEC4C) antibodies and their antigen-binding fragments. The antigen-binding molecules used in this invention are typically antibodies.

[0052] As used herein, the term "antibody" refers to immunoglobulin molecules and the immunoactive portion of immunoglobulin molecules, i.e., molecules containing antigen-binding sites that specifically bind to antigens, whether natural or partially or wholly synthetically produced. The term also encompasses any polypeptide or protein having a binding domain that is an antibody-binding domain or homologous to an antibody-binding domain. Antibodies can be polyclonal or monoclonal. These antibodies can be derived from natural sources or can be produced partially or wholly synthetically. Antibodies are polypeptides that typically consist of two identical heavy chains and two identical light chains (smaller than the heavy chains). There are two types of light chains in mammals, called lambda (λ) and kappa (κ). Each heavy chain and each light chain consists of variable and constant regions. The variable region of the heavy chain is called the VH region, and the variable region of the light chain is called the VL region. For the kappa light chain, the VL region can also be called the VK region. Each variable region of the light and heavy chains includes three complementarity-determining regions (CDRs): CDR1, CDR2, and CDR3. They are named VLCDR1, VLCDR2, VLCDR3, VHCDR1, VHCDR2, and VHCDR3, respectively. Examples of antibodies are immunoglobulin isotypes (e.g., IgG, IgE, IgM, IgD, and IgA) and their isotype subtypes; fragments containing antigen-binding domains such as Fab, F(ab')2, Fv, scFv, dAb, and Fd; and dimeric antibodies.

[0053] Fragments of antibody-antigen binding molecules

[0054] The antigen-binding molecule of the present invention can be an antibody fragment, specifically an antigen-binding fragment of an antibody. The antigen-binding fragment contains one or more antigen-binding regions. It has been shown that fragments of complete antibodies can perform the function of binding antigens. Examples of binding fragments are: (i) Fab fragments consisting of VL, VH, CL, and CH1 domains; (ii) Fd fragments consisting of VH and CH1 domains; (iii) Fv fragments consisting of the VL and VH domains of a single antibody; (iv) dAb fragments consisting of VH domains (Ward, ES et al., Nature 341: 544-546 (1989)); (v) isolated CDR regions; (vi) F(ab′)2 fragments: bivalent fragments containing two linked Fab fragments; (vii) single-chain Fv molecules (scFv) in which the VH and VL domains are linked by a peptide linker that associates the two domains to form an antigen-binding site (Bird et al., Science 242: 423426 (1988); Huston et al., PNAS USA). 85:58795883(1988)); (viii) bispecific single-chain Fv dimer (PCT / US92 / 09965); and (ix) “bisomatic antibody”: a multivalent or multispecific fragment constructed by gene fusion (WO94 / 13804; P. Hollinger et al., Proc. Natl. Acad. Sci. USA 90:6444-6448(1993)). Typically, this fragment is a Fab, F(ab′)2, or Fv fragment or scFv molecule.

[0055] Bimeric antibodies are multimers of polypeptides, each polypeptide comprising a first domain containing a binding region of an immunoglobulin light chain and a second domain containing a binding region of an immunoglobulin heavy chain, the two domains being connected (e.g., via peptide linkers) but not associating with each other to form an antigen-binding site: the antigen-binding site is formed by the association of the first domain of one polypeptide within the multimer with the second domain of another polypeptide within the multimer (WO94 / 13804).

[0056] In the case of using bispecific antibodies, these can be conventional bispecific antibodies that can be manufactured in various ways, such as chemical preparation or hybridoma hybridization (Hollinger & Winter, Current Opinion Biotechnol. 4: 446-449 (1993)), or can be any bispecific antibody fragment mentioned below. It may be preferable to use scFv dimers or bispecific antibodies instead of whole antibodies. Bispecific antibodies and scFvs can be constructed using only variable domains without an Fc region, potentially reducing the effectiveness against idiotype reactions. Other forms of bispecific antibodies include single-chain “Janusins” described in Traunecker et al., EMBO Journal 10: 3655-3659 (1991).

[0057] A bispecific antibody is an antibody that can bind to two target molecules simultaneously (e.g., two antigens or two epitopes). Bispecific antibodies are also called dual-binding antibodies. Examples of bispecific antibody forms include, but are not limited to: (mAb)2, Fcab, F(mAb′)2, tetravalent antibodies, scFv (single-chain variable fragment), bsDb (bispecific bisomatic antibody), scBsDb (single-chain bispecific bisomatic antibody), BiTE (bispecific T-cell adaptor), DART (dual-affinity) retargeting antibody, charge pairs, tandem antibodies, tandem scFv-Fc, Fab-scFv-Fc, Fab-scFv, microantibodies, zybodies, DNL-F(ab)3 (docking-locked trivalent Fab), bssdAb (bispecific single-domain antibody), and keyholes.

[0058] In contrast to bispecific intact antibodies, bispecific dimer antibodies can also be useful because they can be readily constructed and expressed in E. coli. Dimeric antibodies (and many other peptides, such as antibody fragments) with appropriate binding specificity can be easily selected from a library using phage display (WO94 / 13804). If one arm of the dimer antibody is to remain constant, for example, with specificity against antigen X, a library with a variation in the other arm can be prepared, and antibodies with appropriate specificity can be selected.

[0059] The antigen-binding molecules of the present invention can be provided in a form that allows cross-linking between adjacent antigen-binding molecules. For example, antigen-binding molecules containing an Fc region (e.g., those in the form of monoclonal antibodies) allow cross-linking between the Fc regions of two adjacent molecules (and thus allow cross-linking between adjacent BDCA-2 molecules due to co-localization). In some cases, this may promote BDCA2 internalization and inhibit IFN secretion. In other embodiments, the antigen-binding molecules may be provided in a form that does not allow cross-linking between adjacent antigen-binding molecules. For example, antigen-binding molecules lacking an Fc region (e.g., those in the form of Fab or the like) may not cross-link. However, it has been demonstrated that even when the antigen-binding molecules of the present invention are provided in a form that does not allow cross-linking (specifically, antigen-binding molecules having the sequences disclosed herein), they can still promote BDCA2 internalization and inhibit IFN secretion in a dose-dependent manner. This means that two types of antigen-binding molecules (those that allow cross-linking and those that do not) can be provided, thereby increasing the practicality and functionality of the antigen-binding molecules of the present invention compared to the prior art.

[0060] Furthermore, the antigen-binding molecule of the present invention can promote the internalization of BDCA2 and inhibit IFN secretion in a dose-dependent manner, even when the antigen-binding molecule is provided in a monovalent form that binds to BDCA2. For example, antigen-binding molecules in Fab form that bind to BDCA-2 in a monovalent manner (i.e., a ratio of one antigen-binding molecule to one BDCA2 molecule) have been shown to promote the internalization of BDCA2 and inhibit IFN secretion in a dose-dependent manner. This again contrasts with prior art anti-BDCA2 molecules.

[0061] Therefore, in some embodiments, antigen-binding molecules bind BDCA2 in a monovalent manner (i.e., the ratio of one antigen-binding molecule to one BDCA2 molecule). In some embodiments, antigen-binding molecules do not cross-link with each other. The Fab form achieves both objectives because they do not cross-link with each other (due to the lack of the Fc region) and they bind their antigens in a monovalent manner. In some embodiments, the present invention provides antigen-binding molecules having sequences that promote BDCA2 internalization and inhibit IFN secretion (in vitro or in vivo). The advantages of the antigen-binding molecules of the present invention include the ability to promote BDCA2 internalization and inhibit IFN secretion regardless of the ability of antigen-binding molecules to cross-link with each other (and thus co-localize BDCA2 molecules), and regardless of the binding valence (i.e., monovalent or bivalent binding).

[0062] Identity and Homology

[0063] As is known in the art, “identity” refers to the relationship between two or more polypeptide sequences or two or more polynucleotide sequences determined by comparing sequences. In the art, identity also refers to the degree of sequence correlation between polypeptide or polynucleotide sequences (as the case may be), as determined by matching strings of such sequences. While many methods exist for measuring the identity between two polypeptide sequences or two polynucleotide sequences, the methods commonly used to determine identity are coded in computer programs. Preferred computer programs for determining the identity between two sequences include, but are not limited to, the GCG package (Devereux, et al., Nucleic Acids Research, 12, 387 (1984), BLASTP, BLASTN, and FASTA (Atschul et al., J. Molec. Biol. 215, 403 (1990)).

[0064] Amino acid sequences can be compared using programs such as CLUSTAL. These programs compare amino acid sequences and find the optimal alignment by inserting spaces in either sequence, if necessary. Optimal alignment can be determined by calculating amino acid identity or similarity (identity plus conservation of amino acid types). Programs like BLASTx compare the longest stretch of similar sequences and assign a value to the fit. Therefore, comparisons can be obtained even if several similar regions are found, each with a different score. Two types of identity analysis are considered in this invention.

[0065] The percentage identity of two amino acid sequences or two nucleic acid sequences is determined by aligning sequences for optimal comparison purposes (e.g., introducing vacancies in the first sequence to achieve the best alignment) and comparing amino acid residues or nucleotides at the corresponding positions. The “best alignment” is the alignment of the two sequences that yields the highest percentage of identity. The percentage of identity is determined by the number of identical amino acid residues or nucleotides in the compared sequences (i.e., identity % = number of identical positions / total number of positions × 100). Generally, unless the context otherwise specifies or implies, identity % as used herein refers to identity % over the entire length of the molecule.

[0066] The determination of percentage identity between two sequences can be accomplished using mathematical algorithms known to those skilled in the art. An example of a mathematical algorithm for comparing two sequences is the one described in Karlin and Altschul (1990) Proc. Natl. Acad. Sci. USA 87:2264-2268, which was improved in Karlin and Altschul (1993) Proc. Natl. Acad. Sci. USA 90:5873-5877. This algorithm has been incorporated into the BLASTn and BLASTp programs of Altschul, et al. (1990) J. Mol. Biol. 215:403-410. BLAST nucleic acid searches can be performed using the NBLAST program (score = 100, word length = 12) to obtain nucleic acid sequences homologous to the nucleic acid molecules of this invention. BLAST protein searches can be performed using the XBLAST program (score = 50, word length = 3) to obtain amino acid sequences homologous to the protein molecules of this invention. To obtain vacancy alignments for comparative purposes, GappedBLAST can be used as described by Altschul et al. (1997) Nucleic Acids Res. 25: 3389-3402. Alternatively, PSI-Blast can be used to perform iterative searches to detect long-distance relationships (Id.) between molecules. When using the BLAST, Gapped BLAST, and PSI-Blast procedures, the default parameters of the respective procedures (e.g., BLASTp and BLASTp) can be used. See http: / / www.ncbi.nlm.nih.gov. Another example of a mathematical algorithm for sequence alignment is the algorithm of Myers and Miller, CABIOS (1989). This algorithm has been incorporated into the ALIGN program (version 2.0), which is part of the CGC sequence alignment software package. Other algorithms known in the art for sequence analysis include ADVANCE and ADAM as described by Torellis and Robotti (1994) Comput. Appl. Biosci., 10: 3-5; and FASTA as described by Pearson and Lipman (1988) Proc. Natl. Acad. Sci. 85: 2444-8. In FASTA, ktup is a control option that sets the sensitivity and speed of the search.

[0067] Typically, the amino acid sequence of the CDR of the antigen-binding molecule provided in this invention has at least 70% identity at the amino acid level with the amino acid sequence of the CDRs listed below, for example using the default parameters of the BLAST computer program provided by HGMP (Human Genome Mapping Project) (Atschul et al., J. Mol. Biol. 215, 403-410 (1990)). More typically, the CDR sequence has at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% identity at the amino acid level with the sequences listed below. Typically, each CDR sequence of the antigen-binding molecule used in this invention has this level of identity with the amino acid sequence of the CDRs listed below. Alternatively, any 1, 2, 3, 4, or 5 CDRs of the antigen-binding molecule used in this invention have this level of identity with the amino acid sequence of the CDRs listed below.

[0068] The amino acid sequences of the VH and VL regions of the antigen-binding molecule provided by this invention have at least 70% identity at the amino acid level with the amino acid sequences of the VH and VL regions described below, for example using the default parameters of the BLAST computer program provided by HGMP (Human Genome Mapping Project) (Atschul et al., J. Mol. Biol. 215, 403-410 (1990)). More typically, the VH and VL regions have at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% identity at the amino acid level with the sequences shown below. Typically, each VH and VL region of the antigen-binding molecule used in this invention has this level of identity with the amino acid sequences of the VH and VL regions listed below. Alternatively, only one of the VH and VL regions of the antigen-binding molecule used in this invention has this level of identity with the amino acid sequences of the VH and VL regions listed below.

[0069] As used herein, identity is used interchangeably with “homology” and “similarity”. References to a specific identity % also apply to homology % and similarity % %. Homology and similarity can be determined using appropriate algorithms, such as FASTA, BLAST, and Gapped BLAST. Software for performing these analyses is publicly available.

[0070] In some implementations, particularly for any implementation of a sequence having a specific sequence identity with the reference sequence, the sequence identity % can be calculated for sequences of all 6 CDRs without specifying the heavy or light chain variable regions. In this implementation, the sequence variation occurs only in the frame region.

[0071] variants

[0072] This invention also extends to variants of the peptide sequences described below. As used herein, the term "variant" refers to a protein having a similar amino acid sequence and / or retaining the same function. For example, the term "variant" encompasses proteins or polypeptides that include the addition, deletion, substitution, etc., of one or more amino acids. An example of a variant of this invention is a protein comprising a peptide as defined below, in which one or more amino acids are substituted with one or more other amino acids. For example, amino acid substitutions can be made to reduce or eliminate instabilities in the amino acid sequence. Alternatively, if desired, amino acid substitutions can be made to improve antigen affinity or to humanize or deimmunize the antibody. This document provides affinity-matured variants, humanized variants, and deimmunized variants of specified antibodies, as well as variants containing amino acid substitutions to reduce or eliminate any instabilities in the antibody sequence.

[0073] As described above, in some implementations, any substitution may occur only in the frame region. In this implementation, the original CDR sequence is preserved, but mutations may occur in one or more frame regions.

[0074] Variant antigen-binding molecules having one or more amino acid substitutions can retain the functional activity (e.g., EC50, IC50, IC90, and / or Kd) of the antigen-binding molecule from which the variant antigen-binding molecule is derived. The variant antigen-binding molecules of the present invention can be used and formulated in the same manner as the antigen-binding molecules from which they are derived.

[0075] replace

[0076] Technicians know that various amino acids have similar properties. One or more of these amino acids in a substance can often be replaced by one or more other such amino acids without eliminating the desired activity of the substance.

[0077] Therefore, the amino acids glycine, alanine, valine, leucine, and isoleucine can generally be substituted for each other (amino acids with aliphatic side chains). Among these possible substitutions, glycine and alanine are preferred for substitution (because they have relatively short side chains), and valine, leucine, and isoleucine are preferred for substitution (because they have larger hydrophobic aliphatic side chains). Other amino acids that can generally be substituted for each other include: phenylalanine, tyrosine, and tryptophan (amino acids with aromatic side chains); lysine, arginine, and histidine (amino acids with basic side chains); aspartic acid and glutamic acid (amino acids with acidic side chains); asparagine and glutamine (amino acids with amide side chains); and cysteine ​​and methionine (amino acids with sulfur-containing side chains).

[0078] This type of substitution is often referred to as a "conservative" or "semi-conservative" amino acid substitution.

[0079] Naturally occurring amino acids are designated using three-letter and one-letter codes as follows: glycine (G or Gly), alanine (A or Ala), valine (V or Val), leucine (L or Leu), isoleucine (I or Ile), proline (P or Pro), phenylalanine (F or Phe), tyrosine (Y or Tyr), tryptophan (W or Trp), lysine (K or Lys), arginine (R or Arg), histidine (H or His), aspartic acid (D or Asp), glutamic acid (E or Glu), asparagine (N or Asn), glutamine (Q or Gln), cysteine ​​(C or Cys), methionine (M or Met), serine (S or Ser), and threonine (T or Thr). If a residue may be aspartic acid or asparagine, the symbol Asx or B may be used. If a residue may be glutamic acid or glutamine, the symbol Glx or z may be used. Unless the context otherwise requires, references to aspartic acid include aspartate salt, and references to glutamic acid include glutamate salt.

[0080] Amino acid deletions or insertions can also be made relative to the amino acid sequence of the fusion protein described below. Thus, for example, amino acids that do not substantially affect the peptide activity, or at least do not eliminate such activity, can be deleted. Such deletions may be advantageous because the overall length and molecular weight of the peptide can be reduced while still maintaining its activity. This enables a reduction in the amount of peptide required for a particular application, for example, a reduction in dosage levels.

[0081] In some implementations, the following amino acids can be exchanged for conserved amino acid substitution:

[0082] Classification Exchangeable amino acids Fat Glycine, alanine, valine, leucine, isoleucine Hydroxyl or sulfur / selenium-containing Serine, cysteine, threonine, methionine Aromatic Phenylalanine, tyrosine, tryptophan alkaline Histidine, Lysine, Arginine Acids and their amides Aspartate, glutamate, asparagine, glutamine

[0083] Therefore, the term "conservative" amino acid substitution refers to an amino acid substitution in which one or more amino acids in the antibody sequence (e.g., in the CDR, VH, or VL sequences) are replaced by another amino acid of the same class. Conservative amino acid substitutions are preferably located in the CDR region to minimize adverse effects on antibody function. However, conservative amino acid substitutions can also occur within the frame region.

[0084] Amino acid changes relative to the sequences given below can be performed using any suitable technique, such as site-directed mutagenesis or solid-state synthesis.

[0085] It should be understood that amino acid substitutions or insertions within the scope of this invention can be made using naturally occurring or non-naturally occurring amino acids, although naturally occurring amino acids may be preferred. Regardless of whether natural or synthetic amino acids are used, the presence of only L-amino acids may be preferred.

[0086] In one embodiment of the present invention, an antigen-binding molecule or antigen-binding fragment thereof is provided, wherein the antibody-binding domain or antigen-binding domain contains 1 to 10, preferably 1 to 5, amino acid substitutions. For example, in one embodiment of the present invention, an anti-BDCA-2 (CLEC4C) antibody or its antigen-binding fragment is provided, wherein the anti-BDCA-2 (CLEC4C) antibody or its antigen-binding fragment comprises six CDR regions of an antibody selected from the group consisting of 3E05_var12, 3E05_var6, 3E05_var14, 3E05, 3E05_var1, 3E05_var2, 3E05_var3, 3E05_var4, 3E05_var5, 3E05_var7, 3E05_var8, 3E05_var9, 3E05_var10, 3E05_var11, 3E05_var13, 3E05_var15, 3E05_var16, 21E06, 25E06 and 28B01, wherein the antigen-binding molecule has 1 to 10 amino acid substitutions, preferably 1 to 5 amino acid substitutions, in all its CDR regions. In another embodiment of the invention, an anti-BDCA-2 (CLEC4C) antigen-binding molecule or an antigen-binding fragment thereof is provided, wherein the anti-BDCA-2 (CLEC4C) antibody or the antigen-binding fragment thereof comprises the VH and VL sequences of an antibody selected from the group consisting of 3E05_var12, 3E05_var6, 3E05_var14, 3E05, 3E05_var1, 3E05_var2, 3E05_var3, 3E05_var4, 3E05_var5, 3E05_var7, 3E05_var8, 3E05_var9, 3E05_var10, 3E05_var11, 3E05_var13, 3E05_var15, 3E05_var16, 21E06, 25E06 and 28B01, wherein the antigen-binding molecule has 1 to 10 amino acid substitutions, preferably 1 to 5 amino acid substitutions, in its VH and VL sequences.In another embodiment of the invention, an anti-BDCA-2 (CLEC4C) antibody is provided, wherein the anti-BDCA-2 (CLEC4C) antibody is an antibody selected from the group consisting of 3E05_var12, 3E05_var6, 3E05_var14, 3E05, 3E05_var1, 3E05_var2, 3E05_var3, 3E05_var4, 3E05_var5, 3E05_var7, 3E05_var8, 3E05_var9, 3E05_var10, 3E05_var11, 3E05_var13, 3E05_var15, 3E05_var16, 21E06, 25E06, and 28B01, wherein the antibody has 1 to 10 amino acid substitutions, preferably 1 to 5 amino acid substitutions. The substitutions, of course, pertain to the substitution of the original CDR or variable chain sequence of the starting antibody.

[0087] In some embodiments, one or more amino acid substitutions are located in one or more CDR regions. In other embodiments, one or more amino acid substitutions are located in the framework region, i.e., in the variable heavy and light chains, but not in one or more CDR regions. In other embodiments, one or more amino acid substitutions may be located anywhere in the heavy chain variable region and / or the light chain variable region. In some embodiments, amino acid substitutions do not occur in the CDR sequence.

[0088] In some implementations, amino acid substitutions do not adversely affect the antibody's binding specificity and / or affinity. Therefore, the variant antibody may have the same or better functional properties as the antibody from which it was derived.

[0089] Affinity Maturation Variants

[0090] Other variations within the scope of this invention include the antigen-binding molecule of this invention, which is modified to increase its affinity for BDCA-2 (CLEC4C). In one embodiment, the antigen-binding molecule of this invention is an affinity maturation antibody. In one embodiment, the antigen-binding molecule of this invention is a humanized affinity maturation antibody.

[0091] Any known method can be used to increase the affinity of the antigen-binding molecule of the present invention to produce an affinity-matured antibody or a humanized affinity-matured antibody with enhanced affinity for BDCA-2 (CLEC4C).

[0092] This invention provides an affinity-matured variant of the antigen-binding agent. The affinity-matured variant exhibits a higher binding affinity to BDCA-2 (CLEC4C) than the parent antibody. Preferably, the resulting antibody has a binding affinity to BDCA-2 (CLEC4C) at least 20%, at least 30%, at least 40%, and more preferably at least 50% higher than the binding affinity of the parent antibody to BDCA-2 (CLEC4C), for example, as determined by Kd.

[0093] In some embodiments, the present invention provides a method for preparing the antigen-binding molecule of the present invention, the method comprising providing an antigen-binding molecule as described herein (e.g., an anti-BDCA-2 (CLEC4C) binding molecule or antibody or an antigen-binding fragment or variant thereof), and subjecting the antibody to affinity maturation, wherein the resulting antibody binds to BDCA-2 (CLEC4C) with a higher affinity than the parent antibody. Preferably, the resulting antibody binds to BDCA-2 (CLEC4C) with an affinity at least 20%, at least 30%, at least 40%, more preferably at least 50% higher than the parent antibody binds to BDCA-2 (CLEC4C), for example, as determined by Kd. Methods for measuring affinity are known in the art and are described in the examples below. Affinity-matured antibodies produced by such methods can be formulated and used as described herein for other anti-BDCA-2 (CLEC4C) binding molecules.

[0094] Affinity maturation can be performed using any suitable method known to those skilled in the art. For example, in vitro antibody display systems are widely used to generate specific antibodies with high affinity. In these systems, the phenotype (i.e., antibody fragment) is bound to the genotype (i.e., antibody gene), allowing for the direct determination of the antibody sequence. Several systems have been developed to display antibody libraries, allowing for subsequent selection of conjugates and, by increasing the stringency of selection, allowing for the selection of variants with progressively higher affinity. Antibody fragments can be expressed in yeast, ribosomes, phage display particles, or by directly binding to DNA.

[0095] Current antibody affinity maturation methods fall into two categories of mutagenesis: random and non-random. Error-prone polymerase chain reaction (PCR), mutant strains, and saturation mutagenesis are typical examples of random mutagenesis methods. Non-random techniques typically use alanine scanning or site-directed mutagenesis to generate a limited set of specific variants. Additionally, shuffling methods to obtain mixed variants of parental antibodies can be used to further enhance antibody affinity.

[0096] Therefore, in one embodiment of the invention, the affinity maturation method is selected from the group consisting of: random mutagenesis (e.g., error-prone polymerase chain reaction (PCR), mutant strains or saturation mutagenesis), non-random mutagenesis (e.g., alanine scanning or site-directed mutagenesis), shuffling (e.g., DNA shuffling, strand shuffling or CDR shuffling), and introducing modification using the CRISPR-Cas9 system.

[0097] Methods for maturation of affinity are described in, for example, Rajpal et al., Proc Natl Acad Sci USA, 2005, 102(24): 8466-71, Steinwand et al., MAbs, 2014, 6(1): 204-18, and Handbook of Therapeutic Antibodies, Wiley, 2014, Chapter 6, Antibody Affinity (pp. 115-140).

[0098] In some embodiments, a method for preparing a pharmaceutical composition is provided, the method comprising providing an antibody prepared according to the above method (i.e., generating an antibody through affinity maturation), and co-formulating the antibody with at least one or more pharmaceutically acceptable excipients. The antibody used to prepare the pharmaceutical composition may be an affinity maturation variant of 3E05, 21E06, 25E06, or 28B01. The antibody used to prepare the pharmaceutical composition may be an affinity maturation variant of 3E05_var12, 3E05_var6, 3E05_var14, 3E05_var1, 3E05_var2, 3E05_var3, 3E05_var4, 3E05_var5, 3E05_var7, 3E05_var8, 3E05_var9, 3E05_var10, 3E05_var11, 3E05_var13, 3E05_var15, or 3E05_var16. Pharmaceutical compositions produced by such methods can be used in the treatments of the present invention as described herein for other anti-BDCA-2 (CLEC4C) binding molecules.

[0099] Therefore, antigen-binding molecules, such as affinity maturation mutants or variants, are provided as antigen-binding molecules of the present invention. For example, in one embodiment, affinity maturation variants of antibodies selected from the group consisting of: 3E05_var12, 3E05_var6, 3E05_var14, 3E05, 3E05_var1, 3E05_var2, 3E05_var3, 3E05_var4, 3E05_var5, 3E05_var7, 3E05_var8, 3E05_var9, 3E05_var10, 3E05_var11, 3E05_var13, 3E05_var15, 3E05_var16, 21E06, 25E06, and 28B01. Generally, affinity maturation mutants have a higher affinity for BDCA-2 (CLEC4C) (especially human BDCA-2 (CLEC4C)) than the parent antibody (the antibody of the derived mutant). The present invention also provides antigen-binding molecules and antibodies that can be obtained or acquired through affinity maturation of the antigen-binding molecules or antibodies of the present invention.

[0100] Other variations

[0101] The antigen-binding molecules of this invention are typically antibodies, and more typically monoclonal antibodies. In a preferred embodiment, the monoclonal antibody of this invention is a humanized antibody. In some embodiments, the antibody is a fully human monoclonal antibody, wherein a human constant region is used.

[0102] The methods used to produce monoclonal antibodies are well known to those skilled in the art, for example, as described in Frenzel et al., “Expression of Recombinant Antibodies”, Front Immunol, 2013, 4:217, the contents of which are incorporated herein by reference.

[0103] The monoclonal antibodies of the present invention can be humanized by modifying the amino acid sequence of the antibody. Methods for reducing the immunogenicity of the antigen-binding molecules of the present invention include transplanting CDRs into a suitable antibody framework scaffold or remodeling of variable surface residues, for example by site-directed mutagenesis or other commonly used molecular biology techniques (Roguska et al Protein Eng. 9895-904 (1996)).

[0104] Other applicable approaches may include identifying potential T-cell epitopes within the molecule and then removing these epitopes, for example, through site-directed mutagenesis (deimmunization). In cases where the antigen-binding molecule is used as a therapeutic agent, humanization of the antigen-binding molecule may be necessary. Humanization of the CDR region or surrounding framework sequences may be performed as needed.

[0105] Monoclonal antibodies and other antibodies can be used to produce additional antibodies or chimeric molecules that retain the specificity of the original antibody using recombinant DNA technology. Such techniques may involve introducing DNA encoding the variable region or complementarity-determining region (CDR) of an immunoglobulin into the constant region or constant region plus frame region of a different immunoglobulin. Hybridomas or other antibody-producing cells may undergo genetic mutations or other changes that may or may not alter the binding specificity of the resulting antibody.

[0106] In one embodiment, the heavy chain variable region and / or the light chain variable region are at least 85% humanized, at least 90% humanized, at least 95% humanized, at least 96% humanized, at least 97% humanized, at least 98% humanized, or at least 99% humanized. In some embodiments, the antibody is conservedly humanized, for example, to retain better antigen binding. In such conservedly humanized antibodies, less antibody substitution can be performed compared to humanized antibodies.

[0107] In some embodiments, the antigen-binding molecule of the present invention is deimmunized, for example using the method described in Jones et al., “Deimmunization of monoclonal antibodies,” Methods Mol Biol, 2009, 525:405-23, the contents of which are incorporated herein by reference. Deimmunization uses combined immunological and molecular biological techniques to remove T-cell epitopes from the sequence.

[0108] Therefore, in some embodiments of the present invention, a deimmunized anti-BDCA-2 (CLEC4C) antigen-binding molecule or antigen-binding fragment thereof is provided, wherein the anti-BDCA-2 (CLEC4C) antigen-binding molecule or antigen-binding fragment thereof comprises a deimmunized variant of six CDR regions of an antibody selected from the group consisting of 3E05_var12, 3E05_var6, 3E05_var14, 3E05, 3E05_var1, 3E05_var2, 3E05_var3, 3E05_var4, 3E05_var5, 3E05_var7, 3E05_var8, 3E05_var9, 3E05_var10, 3E05_var11, 3E05_var13, 3E05_var15, 3E05_var16, 21E06, 25E06, and 28B01. In other embodiments of the present invention, a deimmunized anti-BDCA-2 (CLEC4C) antigen-binding molecule or antigen-binding fragment thereof is provided, wherein the anti-BDCA-2 (CLEC4C) antigen-binding molecule or antigen-binding fragment thereof comprises a deimmunized variant of the VH and / or VL sequence of an antibody selected from the group consisting of 3E05_var12, 3E05_var6, 3E05_var14, 3E05, 3E05_var1, 3E05_var2, 3E05_var3, 3E05_var4, 3E05_var5, 3E05_var7, 3E05_var8, 3E05_var9, 3E05_var10, 3E05_var11, 3E05_var13, 3E05_var15, 3E05_var16, 21E06, 25E06, and 28B01. In another embodiment of the present invention, a deimmunizing anti-BDCA-2 (CLEC4C) antibody is provided, wherein the anti-BDCA-2 (CLEC4C) antibody is an antibody selected from the group consisting of 3E05_var12, 3E05_var6, 3E05_var14, 3E05, 3E05_var1, 3E05_var2, 3E05_var3, 3E05_var4, 3E05_var5, 3E05_var7, 3E05_var8, 3E05_var9, 3E05_var10, 3E05_var11, 3E05_var13, 3E05_var15, 3E05_var16, 21E06, 25E06 and 28B01.

[0109] The antigen-binding molecules and their antigen-binding fragments are based on four parental antibodies: 3E05, 21E06, 25E06, and 28B01. In addition to the parental antibodies, this invention specifically relates to humanized and deimmunized derivatives of one of the parental antibodies, 3E05, including 3E05_var12, 3E05_var6, 3E05_var14, 3E05, 3E05_var1, 3E05_var2, 3E05_var3, 3E05_var4, 3E05_var5, 3E05_var7, 3E05_var8, 3E05_var9, 3E05_var10, 3E05_var11, 3E05_var13, 3E05_var15, and 3E05_var16. In preferred embodiments, the present invention particularly relates to humanized and deimmunized derivatives of 3E05, including 3E05_var12, 3E05_var6, and 3E05_var14. However, humanized and deimmunized derivatives of the remaining three parental antibodies are also provided. The present invention is also based on antibody fragments comprising one or more antigen-binding domains from the parental or humanized / deimmunized antibodies of the present invention, and additional variants, such as antigen-binding domains of the antigen-binding molecules of the present invention comprising one or more conserved amino acid substitutions (e.g., 1 to 10 substitutions, or preferably 1 to 5 substitutions) and affinity-matured variants. All antigen-binding molecules of the present invention specifically bind to BDCA-2 (CLEC4C).

[0110] The humanized and deimmunized variants of the antibodies provided in this article can have at least 90% sequence identity with the original humanized or deimmunized parent sequence, for example, at least 95% sequence identity.

[0111] The antigen-binding molecules of the present invention, particularly antibodies, can be of any suitable type, including IgA, IgD, IgE, IgG, IgM, and IgY, although IgG may be preferred. The IgG1 backbone is likely the most preferred. In relevant embodiments, the constant regions of the antibodies of the present invention can be modified to obtain advantageous effects, such as increased stability and reduced Fcγ receptor interaction. Such modifications include S241P and L248E substitutions in the Fc region. Other suitable modifications are known to those skilled in the art.

[0112] "Specific binding," "specifically binding," and "specific binding" are understood to refer to the binding affinity of anti-BDCA-2 (CLEC4C) antigen-binding molecules for BDCA-2 (CLEC4C) being less than approximately 10. -6 M, 10 -7 M, 10 -8 M, 10 -9 M, 10 -10 M, 10 -11 M or 10-12 The dissociation constant of M (K) d In a preferred embodiment, the dissociation constant is less than 10. -8 M, for example, in 10 -9 M, 10 -10 M, 10 -11 M or 10 -12 Within the range of M. According to some embodiments of the present invention, "specific binding," "specifically binding," and "specific binding" may refer to affinity and / or activity. In some embodiments, the affinity of the anti-BDCA-2 (CLEC4C) antigen-binding molecule is 10. -8 M to 10 -6 M (e.g., about 10) -7 M). In some embodiments of the invention, the affinity of the anti-BDCA-2 (CLEC4C) antigen-binding molecule is about 10. -10 M to 10 -8 M (e.g., about 10) -9 In some embodiments of the invention, the affinity and / or activity of the anti-BDCA-2 (CLEC4C) antigen-binding molecule is about 1 nM to 700 nM, or about 1 to 600 nM, or about 1 to 500 nM, or about 1 to 400 nM, or about 1 to 300 nM.

[0113] Manufacturing instability

[0114] Therapeutic proteins such as antibodies are inherently heterogeneous and complex due to chemical and post-translational modifications (PTMs). Modifications can be caused by numerous factors, such as the host cell system, the manufacturing process, or conditions during storage or manufacturing. Modifications may involve the chemical stability or aggregation potential of the molecule itself and its impact on the intrinsic physical stability of the antibody. Spontaneous modification of amino acid motifs or residues in a given antibody sequence during manufacturing or storage is known as instability. Therefore, antibody sequences can be mutated to address instability, thereby reducing the antibody's susceptibility to modification and degradation.

[0115] Such modifications resulting from instability in the antibody sequence can include glycosylation, deamidation, oxidation, and changes to the C- and N-termini. These modifications may occur during manufacturing. Certain residues and structural or sequence motifs are more susceptible to certain modifications. Examples of modifications leading to instability include Asn N-linked glycosylation, Ser / Thr O-linked glycosylation, Asn deamidation, Asp isomerization / fragmentation, Lys glycosylation, Met / Trp oxidation, free thiols, pyroglutamate, and C-terminal Lys.

[0116] Technicians know that computational tools can be used to predict and identify instabilities in the structures and sequences that may potentially lead to modifications. To minimize the occurrence of modifications, changes can be made to the manufacturing process. Protein engineering is also considered to reduce risk. For example, selective mutations of these instabilities help identify and reduce the risk of modifications that jeopardize antibody stability.

[0117] Aspartate residues (Asp) can undergo spontaneous modification. Motifs containing Aspartate, such as the Asp-Gly sequence, may undergo spontaneous isomerization to form isoflavones. The formation of isoflavone salts may weaken or completely eliminate antibody binding. This is especially important if the Aspartate residue is present in the antibody's CDR.

[0118] Therefore, the aspartic acid residue (Asp) can be replaced by any naturally occurring amino acid to reduce this instability that leads to modification. Alternatively, the aspartic acid residue (Asp) can be replaced by alanine (Ala), glutamine (Gln), or glutamic acid (Glu) to reduce this instability that leads to modification. Optimization of production / formulation can also be investigated to reduce isomerization. Alternatively, the Asp-Gly motif can be modified by replacing the glycine residue with another naturally occurring amino acid to inhibit deamidation rather than by replacing the Asp residue.

[0119] Methionine residues (Met) can undergo spontaneous modification. The presence of methionine (Met) in CDRs, especially when exposed to solvents, can cause problems if methionine is oxidized and interferes with binding. Therefore, methionine residues can be replaced with any other naturally occurring amino acid to reduce this instability that leads to modification. Methionine residues can preferably be replaced with Ala or Leu. Optimization of production / formulation can also be investigated to reduce oxidation.

[0120] Therefore, this article also provides variant antibodies derived from any of 3E05_var12, 3E05_var6, 3E05_var14, 3E05, 3E05_var1, 3E05_var2, 3E05_var3, 3E05_var4, 3E05_var5, 3E05_var7, 3E05_var8, 3E05_var9, 3E05_var10, 3E05_var11, 3E05_var13, 3E05_var15, 3E05_var16, 21E06, 25E06, and 28B01, but containing one or more amino substitutions to address one or more of any of the potential instabilities described above.

[0121] For example, for any antigen-binding molecule defined herein by one or more amino acid sequences, if one or more Met residues are present, the one or more Met residues may be independently replaced by either an Ala residue or a Leu residue. If one or more Asp residues are present, the one or more Asp residues may be independently replaced by either an Ala residue, a Gln residue, or a Glu residue.

[0122] Overview of antigen-binding molecules provided

[0123] The following provides an overview of the antigen-binding molecules provided by this invention, wherein the specified SEQ ID NO. is identified in the accompanying sequence listing. As part of this invention, antigen-binding variants, derivatives thereof, and fragments are also provided:

[0124] Table 1. Overview of parental mouse antibodies and conserved humanized, humanized, and deimmunized versions of the two parental antibodies.

[0127] Table 2 - Combinations of humanized / deimmunized heavy and light chain variable regions yielded 16 antibodies derived from the 3E05 parental antibody.

[0128] Variant Name Light chain SEQ ID NO. Heavy chain SEQ ID NO. 3E05 3E05_VL 1 3E05_VH 5 3E05var1 3E05_VL_1 11 3E05_VH_1 15 3E05var2 3E05_VL_1 11 3E05_VH_2 25 3E05var3 3E05_VL_1 11 3E05_VH_3 35 3E05var4 3E05_VL_1 11 3E05_VH_4 45 3E05var5 3E05_VL_2 21 3E05_VH_1 15 3E05var6 3E05_VL_2 21 3E05_VH_2 25 3E05var7 3E05_VL_2 21 3E05_VH_3 35 3E05var8 3E05_VL_2 21 3E05_VH_4 45 3E05var9 3E05_VL_3 31 3E05_VH_1 15 3E05var10 3E05_VL_3 31 3E05_VH_2 25 3E05var11 3E05_VL_3 31 3E05_VH_3 35 3E05var12 3E05_VL_3 31 3E05_VH_4 45 3E05var13 3E05_VL_4 41 3E05_VH_1 15 3E05var14 3E05_VL_4 41 3E05_VH_2 25 3E05var15 3E05_VL_4 41 3E05_VH_3 35 3E05var16 3E05_VL_4 41 3E05_VH_4 45

[0129] Various embodiments of the invention will now be discussed in more detail.

[0130] Antigen-binding molecules containing vHCDR3 and / or VLCDR3 regions

[0131] In one embodiment, an antibody, fragment thereof, or variant thereof is provided, comprising: a heavy chain variable region comprising a VHCDR3 containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 48, 28, 8, 18, 38, 58, 68, and 78; and / or a light chain variable region comprising a VLCDR3 containing an amino acid sequence consisting of the group consisting of SEQ ID NOs: 34, 24, 44, 4, 14, 54, 64, and 74. Certain amino acids may be substituted to provide one or more variant antibodies as described herein.

[0132] 3E05

[0133] In one embodiment, an antigen-binding molecule, such as an antibody, a fragment thereof, or a variant thereof, is provided, comprising: a heavy chain variable region comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 8); and / or a light chain variable region comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence QQTNEDPPT (SEQ ID NO: 4). In one embodiment, an antigen-binding molecule, such as an antibody, a fragment thereof, or a variant thereof, is provided, comprising: a heavy chain variable region comprising an amino acid sequence having at least 90% identity with the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 8); and / or a light chain variable region comprising an amino acid sequence having at least 90% identity with the amino acid sequence QQTNEDPPT (SEQ ID NO: 4).

[0134] In one embodiment, an antigen-binding molecule is provided, such as an antibody, a fragment thereof, or a variant thereof, comprising: a heavy chain variable region containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 8); and / or a light chain variable region containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 4). In a specific embodiment, the antigen-binding molecule is an antibody or a fragment thereof, wherein the VHCDR3 region of the antibody or fragment thereof is HDYYDGGLYYAMDY (SEQ ID NO: 8) and / or the VLCDR3 region of the antibody or fragment thereof is QQTNEDPPT (SEQ ID NO: 4).

[0135] Amino acid substitutions can be made to provide variant antibodies derived from 3E05, such as providing an antibody, fragment thereof, or variant comprising: a heavy chain variable region containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 8), optionally containing one or two amino acid substitutions; and / or a light chain variable region containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 4), optionally containing one or two amino acid substitutions. The amino acid substitutions can be conserved.

[0136] In one embodiment, the antigen-binding molecule is an antibody or a fragment or variant thereof, wherein the VHCDR3 region of the antibody or a fragment or variant thereof is HDYYDGGLYYAMDY (SEQ ID NO: 8) and / or the VLCDR3 region of the antibody or a fragment or variant thereof is QQTNEDPPT (SEQ ID NO: 4), optionally wherein each Met residue is independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or each Asp residue is independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0137] 3E05_var 1, 5, 9 and 13

[0138] In one embodiment, an antigen-binding molecule, such as an antibody, a fragment thereof, or a variant thereof, is provided, comprising: a heavy chain variable region comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); and / or a light chain variable region comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence QQTNEDPPT (SEQ ID NO: 14). In one embodiment, the heavy chain variable region comprises an amino acid sequence having at least 90% identity with the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18) and / or the light chain variable region comprises an amino acid sequence having at least 90% identity with the amino acid sequence QTTNEDPPT (SEQ ID NO: 14).

[0139] In one embodiment, an antibody, fragment thereof, or variant thereof is provided, comprising: a heavy chain variable region comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); and / or a light chain variable region comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14). In a specific embodiment, an antibody, fragment thereof, or variant thereof is provided, wherein the VHCDR3 region of the antibody or fragment thereof is HDYYDGGLYYAMDY (SEQ ID NO: 18) and / or the VLCDR3 region of the antibody or fragment thereof is QQTNEDPPT (SEQ ID NO: 14).

[0140] Amino acid substitutions can be made to provide variant antibodies derived from 3E05var1, 5, 9, or 13, for example, providing an antibody, fragment thereof, or variant thereof, comprising: a heavy chain variable region containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18), optionally containing one or two amino acid substitutions; and / or a light chain variable region containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 14), optionally containing one or two amino acid substitutions. Amino acid substitutions can be conserved.

[0141] In one embodiment, the antigen-binding molecule is an antibody or a fragment or variant thereof, wherein the VHCDR3 region of the antibody or a fragment or variant thereof is HDYYDGGLYYAMDY (SEQ ID NO: 18) and / or the VLCDR3 region of the antibody or a fragment or variant thereof is QQTNEDPPT (SEQ ID NO: 14), optionally wherein each Met residue is independently replaced by an amino acid selected from the group consisting of Ala and Leu and / or each Asp residue is independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0142] 3E05_var 2, 6, 10 and 14

[0143] In one embodiment, an antigen-binding molecule, such as an antibody, a fragment thereof, or a variant thereof, is provided, comprising: a heavy chain variable region comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); and / or a light chain variable region comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence QQTNEDPPT (SEQ ID NO: 14). In one embodiment, the heavy chain variable region comprises an amino acid sequence having at least 90% identity with the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28) and / or the light chain variable region comprises an amino acid sequence having at least 90% identity with the amino acid sequence QQQTNEDPPT (SEQ ID NO: 14).

[0144] In one embodiment, an antibody, fragment thereof, or variant thereof is provided, comprising: a heavy chain variable region comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); and / or a light chain variable region comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14). In a specific embodiment, an antibody, fragment thereof, or variant thereof is provided, wherein the VHCDR3 region of the antibody or fragment thereof is HDYYDGGLYYAMDY (SEQ ID NO: 28) and / or the VLCDR3 region of the antibody or fragment thereof is QQTNEDPPT (SEQ ID NO: 14).

[0145] Amino acid substitutions can be made to provide variant antibodies derived from 3E05var 2, 6, 10, or 14, for example, providing an antibody, fragment thereof, or variant thereof comprising: a heavy chain variable region containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28), optionally containing one or two amino acid substitutions; and / or a light chain variable region containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 14), optionally containing one or two amino acid substitutions. Amino acid substitutions can be conserved.

[0146] In one embodiment, the antigen-binding molecule is an antibody or a fragment or variant thereof, wherein the VHCDR3 region of the antibody or fragment or variant thereof is HDYYDGGLYYAMDY (SEQ ID NO: 28), optionally containing one or two amino acid substitutions, and / or a light chain variable region containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 14), optionally wherein each Met residue is independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or each Asp residue is independently replaced by an amino acid selected from the group consisting of Ala, Gin and Glu.

[0147] 3E05_var 3, 7, 11 and 15

[0148] In one embodiment, an antigen-binding molecule, such as an antibody, a fragment thereof, or a variant thereof, is provided, comprising: a heavy chain variable region comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); and / or a light chain variable region comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence QQTNEDPPT (SEQ ID NO: 14). In one embodiment, the heavy chain variable region comprises an amino acid sequence having at least 90% identity with the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38) and / or the light chain variable region comprises an amino acid sequence having at least 90% identity with the amino acid sequence QTTNEDPPT (SEQ ID NO: 14).

[0149] In one embodiment, an antibody, fragment thereof, or variant thereof is provided, comprising: a heavy chain variable region comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); and / or a light chain variable region comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14). In a specific embodiment, an antibody, fragment thereof, or variant thereof is provided, wherein the VHCDR3 region of the antibody or fragment thereof is HDYYDGGLYYAMDY (SEQ ID NO: 38) and / or the VLCDR3 region of the antibody or fragment thereof is QQTNEDPPT (SEQ ID NO: 14).

[0150] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 3, 7, 11, or 15, for example, providing an antibody, fragment thereof, or variant thereof, comprising: a heavy chain variable region containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38), optionally containing one or two amino acid substitutions; and / or a light chain variable region containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 14), optionally containing one or two amino acid substitutions. Amino acid substitutions can be conserved amino acid substitutions.

[0151] In one embodiment, the antigen-binding molecule is an antibody or a fragment or variant thereof, wherein the VHCDR3 region of the antibody or fragment or variant thereof is HDYYDGGLYYAMDY (SEQ ID NO: 38), optionally containing one or two amino acid substitutions, and / or a light chain variable region containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 14), optionally wherein each Met residue is independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or each Asp residue is independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0152] 3E05_var 4, 8, 12 and 16

[0153] In one embodiment, an antigen-binding molecule, such as an antibody, a fragment thereof, or a variant thereof, is provided, comprising: a heavy chain variable region comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); and / or a light chain variable region comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence QQTNEDPPT (SEQ ID NO: 14). In one embodiment, the heavy chain variable region comprises an amino acid sequence having at least 90% identity with the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48) and / or the light chain variable region comprises an amino acid sequence having at least 90% identity with the amino acid sequence QQQTNEDPPT (SEQ ID NO: 14).

[0154] In one embodiment, an antibody, fragment thereof, or variant thereof is provided, comprising: a heavy chain variable region comprising the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); and / or a light chain variable region comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14). In a specific embodiment, an antibody, fragment thereof, or variant thereof is provided, wherein the VHCDR3 region of the antibody or fragment thereof is HDYYEGGLYYAMDY (SEQ ID NO: 48) and / or the VLCDR3 region of the antibody or fragment thereof is QQTNEDPPT (SEQ ID NO: 14).

[0155] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 4, 8, 12, or 16, for example, providing an antibody, fragment thereof, or variant thereof comprising: a heavy chain variable region containing the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48), optionally containing one or two amino acid substitutions; and / or a light chain variable region containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 14), optionally containing one or two amino acid substitutions. Amino acid substitutions can be conserved.

[0156] In one embodiment, the antigen-binding molecule is an antibody or a fragment or variant thereof, wherein the VHCDR3 region of the antibody or fragment or variant thereof is HDYYEGGLYYAMDY (SEQ ID NO: 48) and / or the VLCDR3 region of the antibody or fragment or variant thereof is QQTNEDPPT (SEQ ID NO: 14), optionally wherein each Met residue is independently replaced by an amino acid selected from the group consisting of Ala and Leu and / or each Asp residue is independently replaced by an amino acid selected from the group consisting of Ala, G1n and Glu.

[0157] 21E06

[0158] In one embodiment, an antigen-binding molecule, such as an antibody, a fragment thereof, or a variant thereof, is provided, comprising: a heavy chain variable region comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence HLYYGDYFYVMDY (SEQ ID NO: 58); and / or a light chain variable region comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence QQSNEDPPT (SEQ ID NO: 54). In one embodiment, an antigen-binding molecule, such as an antibody, a fragment thereof, or a variant thereof, is provided, comprising: a heavy chain variable region comprising an amino acid sequence having at least 90% identity with the amino acid sequence HLYYGDYFYVMDY (SEQ ID NO: 58); and / or a light chain variable region comprising an amino acid sequence having at least 90% identity with the amino acid sequence QQSNEDPPT (SEQ ID NO: 54).

[0159] In one embodiment, an antigen-binding molecule is provided, such as an antibody, a fragment thereof, or a variant thereof, comprising: a heavy chain variable region comprising the amino acid sequence HLYYGDYFYVMDY (SEQ ID NO: 58); and / or a light chain variable region comprising the amino acid sequence QQSNEDPPT (SEQ ID NO: 54). In a specific embodiment, the antigen-binding molecule is an antibody or a fragment thereof, wherein the VHCDR3 region of the antibody or fragment thereof is HLYYGDYFYVMDY (SEQ ID NO: 58) and / or the VLCDR3 region of the antibody or fragment thereof is QQSNEDPPT (SEQ ID NO: 54).

[0160] Amino acid substitutions can be made to provide variant antibodies derived from 21E06, such as providing an antibody, fragment thereof, or variant comprising: a heavy chain variable region containing the amino acid sequence HLYYGDYFYVMDY (SEQ ID NO: 58), optionally containing one or two amino acid substitutions; and / or a light chain variable region containing the amino acid sequence QQSNEDPPT (SEQ ID NO: 54), optionally containing one or two amino acid substitutions. The amino acid substitutions can be conserved.

[0161] In one embodiment, the antigen-binding molecule is an antibody or a fragment or variant thereof, wherein the VHCDR3 region of the antibody or a fragment or variant thereof is HLYYGDYFYVMDY (SEQ ID NO: 58) and / or the VLCDR3 region of the antibody or a fragment or variant thereof is QQSNEDPPT (SEQ ID NO: 54), optionally wherein each Met residue is independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or each Asp residue is independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0162] 25E06

[0163] In one embodiment, an antigen-binding molecule, such as an antibody, a fragment thereof, or a variant thereof, is provided, comprising: a heavy chain variable region comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence HHYSHYFWYFDV (SEQ ID NO: 68); and / or a light chain variable region comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence QQSNEDPPT (SEQ ID NO: 64). In one embodiment, an antigen-binding molecule, such as an antibody, a fragment thereof, or a variant thereof, is provided, comprising: a heavy chain variable region comprising an amino acid sequence having at least 90% identity with the amino acid sequence HHYSHYFWYFDV (SEQ ID NO: 68); and / or a light chain variable region comprising an amino acid sequence having at least 90% identity with the amino acid sequence QQSNEDPPT (SEQ ID NO: 64).

[0164] In one embodiment, an antigen-binding molecule is provided, such as an antibody, a fragment thereof, or a variant thereof, comprising: a heavy chain variable region comprising the amino acid sequence HHYSHYFWYFDV (SEQ ID NO: 68); and / or a light chain variable region comprising the amino acid sequence QQSNEDPPT (SEQ ID NO: 64). In a specific embodiment, the antigen-binding molecule is an antibody or a fragment thereof, wherein the VHCDR3 region of the antibody or fragment thereof is HHYSHYFWYFDV (SEQ ID NO: 68) and / or the VLCDR3 region of the antibody or fragment thereof is QQSNEDPPT (SEQ ID NO: 64).

[0165] Amino acid substitutions can be made to provide variant antibodies derived from 25E06, for example, providing an antibody, fragment thereof, or variant comprising: a heavy chain variable region containing the amino acid sequence HHYSHYFWYFDV (SEQ ID NO: 68), optionally containing one or two amino acid substitutions; and / or a light chain variable region containing the amino acid sequence QQSNEDPPT (SEQ ID NO: 64), optionally containing one or two amino acid substitutions. The amino acid substitutions can be conserved.

[0166] In one embodiment, the antigen-binding molecule is an antibody or a fragment or variant thereof, wherein the VHCDR3 region of the antibody or a fragment or variant thereof is HHYSHYFWYFDV (SEQ ID NO: 68) and / or the VLCDR3 region of the antibody or a fragment or variant thereof is QQSNEDPPT (SEQ ID NO: 64), optionally wherein each Met residue is independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or each Asp residue is independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0167] 28B01

[0168] In one embodiment, an antigen-binding molecule, such as an antibody, a fragment thereof, or a variant thereof, is provided, comprising: a heavy chain variable region comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence HHYSNYFWYFDV (SEQ ID NO: 78); and / or a light chain variable region comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence QQSNEDPPT (SEQ ID NO: 74). In one embodiment, an antigen-binding molecule, such as an antibody, a fragment thereof, or a variant thereof, is provided, comprising: a heavy chain variable region comprising an amino acid sequence having at least 90% identity with the amino acid sequence HHYSNYFWYFDV (SEQ ID NO: 78); and / or a light chain variable region comprising an amino acid sequence having at least 90% identity with the amino acid sequence QQSNEDPPT (SEQ ID NO: 74).

[0169] In one embodiment, an antigen-binding molecule is provided, such as an antibody, a fragment thereof, or a variant thereof, comprising: a heavy chain variable region comprising the amino acid sequence HHYSNYFWYFDV (SEQ ID NO: 78); and / or a light chain variable region comprising the amino acid sequence QQSNEDPPT (SEQ ID NO: 74). In a specific embodiment, the antigen-binding molecule is an antibody or a fragment thereof, wherein the VHCDR3 region of the antibody or fragment thereof is HHYSNYFWYFDV (SEQ ID NO: 78) and / or the VLCDR3 region of the antibody or fragment thereof is QQSNEDPPT (SEQ ID NO: 74).

[0170] Amino acid substitutions can be made to provide variant antibodies derived from 28B01, for example, providing an antibody, fragment thereof, or variant comprising: a heavy chain variable region containing the amino acid sequence HHYSNYFWYFDV (SEQ ID NO: 78), optionally containing one or two amino acid substitutions; and / or a light chain variable region containing the amino acid sequence QQSNEDPPT (SEQ ID NO: 74), optionally containing one or two amino acid substitutions. The amino acid substitutions can be conserved.

[0171] In one embodiment, the antigen-binding molecule is an antibody or a fragment or variant thereof, wherein the VHCDR3 region of the antibody or a fragment or variant thereof is HHYSNYFWYFDV (SEQ ID NO: 78) and / or the VLCDR3 region of the antibody or a fragment or variant thereof is QQSNEDPPT (SEQ ID NO: 74), optionally wherein each Met residue is independently replaced by an amino acid selected from the group consisting of A1a and Leu, and / or each Asp residue is independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0172] Heavy chain and / or light chain CDR

[0173] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0174] Heavy chain variable region, which includes:

[0175] VHCDR1, which contains an amino acid sequence selected from the group consisting of SEO ID NO: 46, 49, 26, 29, 6, 9, 16, 19, 36, 39, 56, 59, 66, 69, 76 and 79;

[0176] VHCDR2, comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 47, 50, 27, 30, 7, 10, 17, 20, 37, 40, 57, 60, 67, 70, 77 and 80; and

[0177] VHCDR3, comprising an amino acid sequence selected from the group consisting of SEQ INO: 48, 28, 8, 18, 38, 58, 68, and 78; and

[0178] The light chain variable region includes:

[0179] VLCDR1, which contains an amino acid sequence selected from the group consisting of SEQ ID NO: 32, 22, 42, 2, 12, 52, 62 and 72;

[0180] VLCDR2, comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 33, 23, 43, 3, 13, 53, 63, and 73; and

[0181] VLCDR3, which comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 34, 24, 44, 4, 14, 54, 64 and 74.

[0182] Certain amino acid substitutions can be made to provide one or more variant antibodies as described herein.

[0183] 3E05

[0184] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0185] The heavy chain variable region includes VHCDR1 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence SYTMS (SEQ ID NO: 6), VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 7), and VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 6). NO: 8) Includes VHCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity; and / or

[0186] The light chain variable region includes a VLCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 2), a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 3), and a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 2). NO:4) Includes VLCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity.

[0187] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0188] The heavy chain variable region includes VHCDR1 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence GFTFSSY (SEQ ID NO: 9), VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence SSGGGNTY (SEQ ID NO: 10), and VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 9). NO: 8) Includes VHCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity; and / or

[0189] The light chain variable region includes a VLCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 2), a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 3), and a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 2). NO:4) Includes VLCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity.

[0190] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0191] The heavy chain variable region comprises VHCDR1, which has at least 90% identity with respect to the amino acid sequence SYTMS (SEQ ID NO: 6), VHCDR2, which has at least 90% identity with respect to the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 7), and VHCDR3, which has at least 90% identity with respect to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 8); and / or

[0192] The light chain variable region comprises VLCDR1, which has at least 90% identity with respect to the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 2), VLCDR2, which has at least 90% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 3), and VLCDR3, which has at least 90% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 4).

[0193] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0194] The heavy chain variable region comprises VHCDR1, which has at least 90% identity with the amino acid sequence GFTFSSY (SEQ ID NO: 9), VHCDR2, which has at least 90% identity with the amino acid sequence SSGGGNTY (SEQ ID NO: 10), and VHCDR3, which has at least 90% identity with the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 8); and / or

[0195] The light chain variable region comprises VLCDR1, which has at least 90% identity with respect to the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 2), VLCDR2, which has at least 90% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 3), and VLCDR3, which has at least 90% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 4).

[0196] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0197] The heavy chain variable region includes VHCDR1 containing the amino acid sequence SYTMS (SEQ ID NO: 6), VHCDR2 containing the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 7), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 8); and

[0198] The light chain variable region includes VLCDR1 containing the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 2), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 3), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 4).

[0199] Amino acid substitutions can be made to provide variant antibodies derived from 3E05, such as providing an antibody, its fragment, or a variant, including:

[0200] The heavy chain variable region includes VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 6) optionally containing one or two amino acid substitutions, VHCDR2 comprising the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 7) optionally containing one or two amino acid substitutions, and VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 8) optionally containing one or two amino acid substitutions; and / or

[0201] The light chain variable region includes: VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 2) optionally containing one or two amino acid substitutions; VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 3) optionally containing one or two amino acid substitutions; and VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 4) optionally containing one or two amino acid substitutions. The amino acid substitutions can be conserved.

[0202] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0203] The heavy chain variable region includes VHCDR1 containing the amino acid sequence SYTMS (SEQ ID NO: 6), VHCDR2 containing the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 7), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 8); and

[0204] The light chain variable region includes VLCDR1 containing the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 2), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 3), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 4).

[0205] Optionally, each of the Met residues is independently replaced by an amino acid selected from the group consisting of A1a and Leu, and / or each of the Asp residues is independently replaced by an amino acid selected from the group consisting of Ala, G1n and Glu.

[0206] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0207] The heavy chain variable region includes VHCDR1 containing the amino acid sequence GFTFSSY (SEQ ID NO: 9), VHCDR2 containing the amino acid sequence SSGGGNTY (SEQ ID NO: 10), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 8); and

[0208] The light chain variable region includes VLCDR1 containing the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 2), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 3), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 4).

[0209] Amino acid substitutions can be made to provide variant antibodies derived from 3E05, such as providing an antibody, its fragment, or a variant, including:

[0210] The heavy chain variable region includes: VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 9) optionally containing one or two amino acid substitutions; VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 10) optionally containing one or two amino acid substitutions; and VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 8) optionally containing one or two amino acid substitutions; and / or

[0211] The light chain variable region includes: VLCDR1 containing the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 2) with optional one or two amino acid substitutions; VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 3) with optional one or two amino acid substitutions; and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 4) with optional one or two amino acid substitutions. The amino acid substitutions can be conserved.

[0212] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0213] The heavy chain variable region includes VHCDR1 containing the amino acid sequence GFTFSSY (SEQ ID NO: 9), VHCDR2 containing the amino acid sequence SSGGGNTY (SEQ ID NO: 10), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 8); and

[0214] The light chain variable region includes VLCDR1 containing the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 2), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 3), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 4).

[0215] Optionally, each of the Met residues is independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or each of the Asp residues is independently replaced by an amino acid selected from the group consisting of A1a, G1n and G1u.

[0216] 3E05_var 12

[0217] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0218] The heavy chain variable region includes VHCDR1 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence SYTMS (SEQ ID NO: 46), VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 47), and VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 47). NO: 48) Includes VHCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity; and / or

[0219] The light chain variable region includes a VLCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 33), and a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 32). NO: 34) includes VLCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity.

[0220] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0221] The heavy chain variable region includes VHCDR1, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence GFTFSSY (SEQ ID NO: 49); VHCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence SSGGGQTY (SEQ ID NO: 50); and VHCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 49). NO: 48) Includes VHCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity; and / or

[0222] The light chain variable region comprises VLCDR1, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32); VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 33); and VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 32). NO: 34) includes VLCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity.

[0223] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0224] The heavy chain variable region comprises VHCDR1, which has at least 90% identity with respect to the amino acid sequence SYTMS (SEQ ID NO: 46); VHCDR2, which has at least 90% identity with respect to the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 47); and VHCDR3, which has at least 90% identity with respect to the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); and / or

[0225] The light chain variable region comprises VLCDR1, which has at least 90% identity with respect to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), VLCDR2, which has at least 90% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 33), and VLCDR3, which has at least 90% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 34).

[0226] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0227] The heavy chain variable region comprises VHCDR1, which has at least 90% identity with respect to the amino acid sequence GFTFSSY (SEQ ID NO: 49); VHCDR2, which has at least 90% identity with respect to the amino acid sequence SSGGGQTY (SEQ ID NO: 50); and VHCDR3, which has at least 90% identity with respect to the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); and / or

[0228] The light chain variable region comprises VLCDR1, which has at least 90% identity with respect to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), VLCDR2, which has at least 90% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 33), and VLCDR3, which has at least 90% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 34).

[0229] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0230] The heavy chain variable region includes VHCDR1 containing the amino acid sequence SYTMS (SEQ ID NO: 46), VHCDR2 containing the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 47), and VHCDR3 containing the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); and

[0231] The light chain variable region includes VLCDR1 containing the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 33), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 34).

[0232] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var12, such as providing an antibody, its fragment, or a variant, including:

[0233] The heavy chain variable region includes: VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 46) optionally containing one or two amino acid substitutions, VHCDR2 comprising the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 47) optionally containing one or two amino acid substitutions, and VHCDR3 comprising the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48) optionally containing one or two amino acid substitutions; and / or

[0234] The light chain variable region includes: VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32) optionally containing one or two amino acid substitutions; VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33) optionally containing one or two amino acid substitutions; and VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34) optionally containing one or two amino acid substitutions. The amino acid substitutions can be conserved.

[0235] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0236] The heavy chain variable region includes VHCDR1 containing the amino acid sequence SYTMS (SEQ ID NO: 46), VHCDR2 containing the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 47), and VHCDR3 containing the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); and

[0237] The light chain variable region includes VLCDR1 containing the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 33), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 34).

[0238] Optionally, each of the Met residues is independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or each of the Asp residues is independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0239] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0240] The heavy chain variable region includes VHCDR1 containing the amino acid sequence GFTFSSY (SEQ ID NO: 49), VHCDR2 containing the amino acid sequence SSGGGQTY (SEQ ID NO: 50), and VHCDR3 containing the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); and

[0241] The light chain variable region includes VLCDR1 containing the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 33), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 34).

[0242] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var12, such as providing an antibody, its fragment, or a variant, including:

[0243] The heavy chain variable region includes: VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 49) optionally containing one or two amino acid substitutions; VHCDR2 comprising the amino acid sequence SSGGGQTY (SEQ ID NO: 50) optionally containing one or two amino acid substitutions; and VHCDR3 comprising the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48) optionally containing one or two amino acid substitutions; and / or

[0244] The light chain variable region includes: VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32) optionally containing one or two amino acid substitutions; VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33) optionally containing one or two amino acid substitutions; and VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34) optionally containing one or two amino acid substitutions. The amino acid substitutions can be conserved.

[0245] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0246] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence GFTFSSY (SEQ ID NO: 49), VHCDR2 containing the amino acid sequence SSGGGQTY (SEQ ID NO: 50), and VHCDR3 containing the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); and

[0247] The light chain variable region includes: VLCDR1 containing the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 33), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 34);

[0248] Optionally, each of the Met residues is independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or each of the AsD residues is independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0249] Antigen-binding molecules of 3E05_var12 or derived from 3E05_var12 (e.g., antibodies with one or more amino acid substitutions) may have a Kc of less than about 0.01 nM. D The IC50 against IFN secretion is less than about 0.5 M and / or the IC90 against IFN secretion is less than about 5 nM. In one specific embodiment, the antigen-binding molecule of 3E05_var12 or an antigen-binding molecule derived from 3E05_var12 (e.g., an antibody with one or more amino acid substitutions) may have a Kc value of less than about 0.01 nM. D The IC50 for IFN secretion is less than about 0.2 nM, and / or the IC90 for IFN secretion is less than about 2 nM.

[0250] 3E05_var 6

[0251] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0252] The heavy chain variable region includes: VHCDR1 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence SYTMS (SEQ ID NO: 26); VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence YISSGGGNTYYADSVKG (SEQ ID NO: 27); and VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 27). NO: 28) Includes VHCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity; and / or

[0253] The light chain variable region includes: VLCDR1, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22); VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 23); and VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 22). NO: 24) includes VLCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity.

[0254] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0255] The heavy chain variable region includes: VHCDR1, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence GFTFSSY (SEQ ID NO: 29); VHCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence SSGGGNTY (SEQ ID NO: 30); and VHCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 29). NO: 28) Includes VHCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity; and / or

[0256] The light chain variable region includes: VLCDR1, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22); VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 23); and VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 22). NO: 24) includes VLCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity.

[0257] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0258] The heavy chain variable region includes: VHCDR1 with at least 90% identity to the amino acid sequence SYTMS (SEQ ID NO: 26), VHCDR2 with at least 90% identity to the amino acid sequence YISSGGGNTYYADSVKG (SEQ ID NO: 27), and VHCDR3 with at least 90% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); and / or

[0259] The light chain variable region includes: VLCDR1, which has at least 90% identity with respect to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22); VLCDR2, which has at least 90% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 23); and VLCDR3, which has at least 90% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 24).

[0260] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0261] The heavy chain variable region includes: VHCDR1 with at least 90% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 29), VHCDR2 with at least 90% identity to the amino acid sequence SSGGGNTY (SEQ ID NO: 30), and VHCDR3 with at least 90% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); and / or

[0262] The light chain variable region includes: VLCDR1, which has at least 90% identity with respect to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22); VLCDR2, which has at least 90% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 23); and VLCDR3, which has at least 90% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 24).

[0263] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0264] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence SYTMS (SEQ ID NO: 26), VHCDR2 containing the amino acid sequence YISSGGGNTYYADSVKG (SEQ ID NO: 27), and VHCDR containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); and

[0265] The light chain variable region includes: VLCDR1 containing the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 23), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 24).

[0266] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 6, such as providing an antibody, its fragment, or a variant, including:

[0267] The heavy chain variable region includes: VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 26) optionally containing one or two amino acid substitutions; VHCDR2 comprising the amino acid sequence YISSGGGNTYYADSVKG (SEQ ID NO: 27) optionally containing one or two amino acid substitutions; and VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28) optionally containing one or two amino acid substitutions; and / or

[0268] The light chain variable region includes: VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22) optionally containing one or two amino acid substitutions; VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23) optionally containing one or two amino acid substitutions; and VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24) optionally containing one or two amino acid substitutions. The amino acid substitutions can be conserved.

[0269] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0270] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence SYTMS (SEQ ID NO: 26), VHCDR2 containing the amino acid sequence YISSGGGNTYYADSVKG (SEQ ID NO: 27), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); and

[0271] The light chain variable region includes: VLCDR1 containing the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 23), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 24);

[0272] Optionally, each of the Met residues is independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or each of the Asp residues is independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0273] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0274] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence GFTFSSY (SEQ ID NO: 29), VHCDR2 containing the amino acid sequence SSGGGNTY (SEQ ID NO: 30), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); and

[0275] The light chain variable region includes VLCDR1 containing the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 23), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 24).

[0276] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 6, such as providing an antibody, its fragment, or a variant, including:

[0277] The heavy chain variable region includes: VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 29) optionally containing one or two amino acid substitutions; VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 30) optionally containing one or two amino acid substitutions; and VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28) optionally containing one or two amino acid substitutions; and / or

[0278] The light chain variable region includes: VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22) optionally containing one or two amino acid substitutions; VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23) optionally containing one or two amino acid substitutions; and VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24) optionally containing one or two amino acid substitutions. The amino acid substitutions can be conserved.

[0279] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0280] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence GFTFSSY (SEQ ID NO: 29), VHCDR2 containing the amino acid sequence SSGGGNTY (SEQ ID NO: 30), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); and

[0281] The light chain variable region includes: VLCDR1 containing the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 23), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 24);

[0282] Optionally, each of the Met residues is independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or each of the Asp residues is independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0283] Antigen-binding molecules of 3E05_var 6 or antigen-binding molecules derived from 3E05_var 6 (e.g., antibodies with one or more amino acid substitutions) may have a Kc of less than about 0.01 nM. D The IC50 against IFN secretion is less than about 0.5 M and / or the IC90 against IFN secretion is less than about 5 nM. In one specific embodiment, the antigen-binding molecule of 3E05_var 6 or an antigen-binding molecule derived from 3E05_var 6 (e.g., an antibody with one or more amino acid substitutions) may have a Kc value of less than about 0.01 nM. D IC50 for IFN secretion less than about 0.1 nM, and / or IC90 for IFN secretion less than about 1 nM.

[0284] 3E05_var 14

[0285] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0286] The heavy chain variable region includes: VHCDR1 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence SYTMS (SEQ ID NO: 26); VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence YISSGGGNTYYADSVKG (SEQ ID NO: 27); and VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 27). NO: 28) Includes VHCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity; and / or

[0287] The light chain variable region includes: VLCDR1, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42); VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 43); and VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 42). NO: 44) includes VLCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity.

[0288] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0289] The heavy chain variable region includes: VHCDR1, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence GFTFSSY (SEQ ID NO: 29); VHCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence SSGGGNTY (SEQ ID NO: 30); and VHCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 29). NO: 28) Includes VHCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity; and / or

[0290] The light chain variable region includes: VLCDR1, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42); VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 43); and VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 42). NO: 44) includes VLCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity.

[0291] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0292] The heavy chain variable region includes: VHCDR1 with at least 90% identity to the amino acid sequence SYTMS (SEQ ID NO: 26), VHCDR2 with at least 90% identity to the amino acid sequence YISSGGGNTYYADSVKG (SEQ ID NO: 27), and VHCDR3 with at least 90% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); and / or

[0293] The light chain variable region includes: VLCDR1, which has at least 90% identity with respect to the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42); VLCDR2, which has at least 90% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 43); and VLCDR3, which has at least 90% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 44).

[0294] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0295] The heavy chain variable region includes: VHCDR1 with at least 90% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 29), VHCDR2 with at least 90% identity to the amino acid sequence SSGGGNTY (SEQ ID NO: 30), and VHCDR3 with at least 90% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); and / or

[0296] The light chain variable region includes: VLCDR1, which has at least 90% identity with respect to the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42); VLCDR2, which has at least 90% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 43); and VLCDR3, which has at least 90% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 44).

[0297] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0298] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence SYTMS (SEQ ID NO: 26), VHCDR2 containing the amino acid sequence YISSGGGNTYYADSVKG (SEQ ID NO: 27), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); and / or

[0299] The light chain variable region includes: VLCDR1 containing the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 43), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 44).

[0300] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 14, such as providing an antibody, its fragment, or a variant, including:

[0301] The heavy chain variable region includes: VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 26) optionally containing one or two amino acid substitutions; VHCDR2 comprising the amino acid sequence YISSGGGNTYYADSVKG (SEQ ID NO: 27) optionally containing one or two amino acid substitutions; and VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28) optionally containing one or two amino acid substitutions; and / or

[0302] The light chain variable region comprises: a VLCDR containing the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42) optionally containing one or two amino acid substitutions; a VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 43) optionally containing one or two amino acid substitutions; and a VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 44) optionally containing one or two amino acid substitutions. The amino acid substitutions can be conserved.

[0303] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0304] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence SYTMS (SEQ ID NO: 26), VHCDR2 containing the amino acid sequence YISSGGGNTYYADSVKG (SEQ ID NO: 27), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); and

[0305] The light chain variable region includes: VLCDR1 containing the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 43), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 44);

[0306] Optionally, each of the Met residues is independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or each of the Asp residues is independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0307] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0308] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence GFTFSSY (SEQ ID NO: 29), VHCDR2 containing the amino acid sequence SSGGGNTY (SEQ ID NO: 30), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); and

[0309] The light chain variable region includes: VLCDR1 containing the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 43), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 44).

[0310] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 14, such as providing an antibody, its fragment, or a variant, including:

[0311] The heavy chain variable region includes: VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 29) optionally containing one or two amino acid substitutions; VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 30) optionally containing one or two amino acid substitutions; and VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28) optionally containing one or two amino acid substitutions; and / or

[0312] The light chain variable region includes: VLCDR1 comprising the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42) optionally containing one or two amino acid substitutions; VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 43) optionally containing one or two amino acid substitutions; and VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44) optionally containing one or two amino acid substitutions. The amino acid substitutions can be conserved amino acid substitutions.

[0313] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0314] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence GFTFSSY (SEQ ID NO: 29), VHCDR2 containing the amino acid sequence SSGGGNTY (SEQ ID NO: 30), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); and

[0315] The light chain variable region includes: VLCDR1 containing the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 43), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 44);

[0316] Optionally, each of the Met residues is independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or each of the Asp residues is independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0317] Antigen-binding molecules of 3E05_var14 or derived from 3E05_var14 (e.g., antibodies with one or more amino acid substitutions) may have a Kc of less than about 0.01 nM. D The IC50 against IFN secretion is less than about 0.5 M and / or the IC90 against IFN secretion is less than about 5 nM. In one specific embodiment, the antigen-binding molecule of 3E05_var14 or an antigen-binding molecule derived from 3E05_var14 (e.g., an antibody with one or more amino acid substitutions) may have a Kc value of less than about 0.01 nM. D IC50 for IFN secretion less than about 0.2 nM, and / or IC90 for IFN secretion less than about 2 nM.

[0318] 3E05_var 1

[0319] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0320] The heavy chain variable region includes: VHCDR1 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence SYTMS (SEQ ID NO: 16); VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 17); and VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 17). NO: 18) Includes VHCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity; and / or

[0321] The light chain variable region includes: VLCDR1, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12); VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 13); and VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 12). NO: 14) includes VLCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity.

[0322] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0323] The heavy chain variable region includes: VHCDR1 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence GFTFSSY (SEQ ID NO: 19); VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence SSGGGNTY (SEQ ID NO: 20); and VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 19). NO: 18) Includes VHCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity; and / or

[0324] The light chain variable region includes: VLCDR1, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12); VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 13); and VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 12). NO: 14) includes VLCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity.

[0325] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0326] The heavy chain variable region includes: VHCDR1 with at least 90% identity to the amino acid sequence SYTMS (SEQ ID NO: 16), VHCDR2 with at least 90% identity to the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 17), and VHCDR3 with at least 90% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); and / or

[0327] The light chain variable region includes: VLCDR1, which has at least 90% identity with respect to the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12); VLCDR2, which has at least 90% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 13); and VLCDR3, which has at least 90% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 14).

[0328] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0329] The heavy chain variable region comprises: VHCDR1, which has at least 90% identity with respect to the amino acid sequence GFTFSSY (SEQ ID NO: 19); VHCDR2, which has at least 90% identity with respect to the amino acid sequence SSGGGNTY (SEQ ID NO: 20); and VHCDR3, which has at least 90% identity with respect to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); and

[0330] The light chain variable region includes: VLCDR1, which has at least 90% identity with respect to the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12); VLCDR2, which has at least 90% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 13); and VLCDR3, which has at least 90% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 14).

[0331] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0332] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence SYTMS (SEQ ID NO: 16), VHCDR2 containing the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 17), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); and / or

[0333] The light chain variable region includes: VLCDR1 containing the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 13), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 14).

[0334] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 1, such as providing an antibody, fragment, or variant, including:

[0335] The heavy chain variable region includes: VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 16) optionally containing one or two amino acid substitutions; VHCDR2 comprising the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 17) optionally containing one or two amino acid substitutions; and VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18) optionally containing one or two amino acid substitutions; and / or

[0336] The light chain variable region comprises: VLCDR1 containing the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12) optionally containing one or two amino acid substitutions; VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 13) optionally containing one or two amino acid substitutions; and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 14) optionally containing one or two amino acid substitutions. The amino acid substitutions can be conserved.

[0337] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0338] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence SYTMS (SEQ ID NO: 16), VHCDR2 containing the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 17), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); and

[0339] The light chain variable region includes: VLCDR1 containing the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 13), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 14);

[0340] Optionally, each of the Met residues is independently replaced by an amino acid selected from the group consisting of A1a and Leu, and / or each of the Asp residues is independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0341] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0342] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence GFTFSSY (SEQ ID NO: 19), VHCDR2 containing the amino acid sequence SSGGGNTY (SEQ ID NO: 20), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); and

[0343] The light chain variable region includes: VLCDR1 containing the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 13), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 14).

[0344] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 1, such as providing an antibody, fragment, or variant, including:

[0345] The heavy chain variable region includes: VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 19) optionally containing one or two amino acid substitutions; VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 20) optionally containing one or two amino acid substitutions; and VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18) optionally containing one or two amino acid substitutions; and / or

[0346] The light chain variable region comprises: VLCDR1 containing the amino acid sequence KASOSVDYDGDSSMN (SEQ ID NO: 12) optionally containing one or two amino acid substitutions; VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 13) optionally containing one or two amino acid substitutions; and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 14) optionally containing one or two amino acid substitutions. The amino acid substitutions can be conserved.

[0347] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0348] The heavy chain variable region comprises: VHCDR1 containing the amino acid sequence GFTFSSY (SEQ ID NO: 19), VHCDR2 containing the amino acid sequence SSGGGNTY (SEQ ID NO: 20), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); and

[0349] The light chain variable region includes: VLCDR1 containing the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 13), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 14).

[0350] Optionally, each of the Met residues is independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or each of the Asp residues is independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0351] Antigen-binding molecules of 3E05_var1 or derived from 3E05_var1 (e.g., antibodies with one or more amino acid substitutions) can have a Kc of less than about 0.01 nM. D This antigen-binding molecule may additionally or alternatively exhibit an IC50 of less than about 0.5 nM against IFN secretion and / or an IC90 of less than about 5 nM against IFN secretion.

[0352] 3E05_var 2

[0353] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0354] The heavy chain variable region includes: VHCDR1 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence SYTMS (SEQ ID NO: 26); VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence YISSGGGNTYYADSVKG (SEQ ID NO: 27); and VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 27). NO: 28) Includes VHCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity; and / or

[0355] The light chain variable region includes: VLCDR1, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12); VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 13); and VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 12). No: 14) includes VLCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity.

[0356] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0357] The heavy chain variable region includes: VHCDR1, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence GFTFSSY (SEQ ID NO: 29); VHCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence SSGGGNTY (SEQ ID NO: 30); and VHCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 29). NO: 28) Includes VHCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity; and / or

[0358] The light chain variable region includes: VLCDR1, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12); VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 13); and VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 12). NO: 14) includes VLCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity.

[0359] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0360] The heavy chain variable region includes: VHCDR1 with at least 90% identity to the amino acid sequence SYTMS (SEQ ID NO: 26), VHCDR2 with at least 90% identity to the amino acid sequence YISSGGGNTYYADSVKG (SEQ ID NO: 27), and VHCDR3 with at least 90% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); and / or

[0361] The light chain variable region includes: VLCDR1, which has at least 90% identity with respect to the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12); VLCDR2, which has at least 90% identity with respect to the amino acid sequence AASTLES (SEQ ID No: 13); and VLCDR3, which has at least 90% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID No: 14).

[0362] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0363] The heavy chain variable region includes: VHCDR1 with at least 90% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 29), VHCDR2 with at least 90% identity to the amino acid sequence SSGGGNTY (SEQ ID NO: 30), and VHCDR3 with at least 90% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); and / or

[0364] The light chain variable region includes: VLCDR1, which has at least 90% identity with respect to the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12); VLCDR2, which has at least 90% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 13); and VLCDR3, which has at least 90% identity with respect to the amino acid sequence QQTNEDPPT (SEQ INO: 14).

[0365] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0366] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence SYTMS (SEQ ID NO: 26), VHCDR2 containing the amino acid sequence YISSGGGNTYYADSVKG (SEQ ID NO: 27), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); and

[0367] The light chain variable region includes: VLCDR1 containing the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 13), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 14).

[0368] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 2, such as providing an antibody, fragment, or variant, including:

[0369] The heavy chain variable region includes: VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 26) optionally containing one or two amino acid substitutions; VHCDR2 comprising the amino acid sequence YISSGGGNTYYADSVKG (SEQ ID NO: 27) optionally containing one or two amino acid substitutions; and VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28) optionally containing one or two amino acid substitutions; and / or

[0370] The light chain variable region comprises: VLCDR1 containing the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12) optionally containing one or two amino acid substitutions; VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 13) optionally containing one or two amino acid substitutions; and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 14) optionally containing one or two amino acid substitutions. The amino acid substitutions can be conserved.

[0371] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0372] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence SYTMS (SEQ ID NO: 26), VHCDR2 containing the amino acid sequence YISSGGGNTYYADSVKG (SEQ ID NO: 27), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); and

[0373] The light chain variable region includes: VLCDR1 containing the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 13), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 14).

[0374] Optionally, each of the Met residues is independently replaced by an amino acid selected from the group consisting of A1a and Leu, and / or each of the Asp residues is independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0375] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0376] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence GFTFSSY (SEQ ID NO: 29), VHCDR2 containing the amino acid sequence SSGGGNTY (SEQ ID NO: 30), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); and

[0377] The light chain variable region includes: VLCDR1 containing the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 13), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 14).

[0378] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 2, such as providing an antibody, fragment, or variant, including:

[0379] The heavy chain variable region includes: VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 29) optionally containing one or two amino acid substitutions; VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 30) optionally containing one or two amino acid substitutions; and VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28) optionally containing one or two amino acid substitutions; and / or

[0380] The light chain variable region comprises: VLCDR1 containing the amino acid sequence KASOSVDYDGDSSMN (SEQ ID NO: 12) optionally containing one or two amino acid substitutions; AASTLES (SEQ ID NO: 13) containing the amino acid sequence AASTLES optionally containing one or two amino acid substitutions; and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 14) optionally containing one or two amino acid substitutions. The amino acid substitutions can be conserved amino acid substitutions.

[0381] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0382] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence GFTFSSY (SEQ ID NO: 29), VHCDR2 containing the amino acid sequence SSGGGNTY (SEQ ID NO: 30), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); and

[0383] The light chain variable region includes: VLCDR1 containing the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 13), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 14);

[0384] Optionally, each of the Met residues is independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or each of the Asp residues is independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0385] Antigen-binding molecules of 3E05_var2 or derived from 3E05_var2 (e.g., antibodies with one or more amino acid substitutions) can have a Kc of less than about 0.5 nM. D This antigen-binding molecule may additionally or alternatively exhibit an IC50 of less than about 0.5 nM against IFN secretion and / or an IC90 of less than about 5 nM against IFN secretion.

[0386] 3E05_var 3

[0387] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0388] The heavy chain variable region includes: VHCDR1 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence SYTMS (SEQ ID NO: 36); VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 37); and VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 37). NO: 38) includes VHCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity; and / or

[0389] The light chain variable region includes: VLCDR1, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12); VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 13); and VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 12). NO: 14) includes VLCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity.

[0390] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0391] The heavy chain variable region includes: VHCDR1 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence GFTFSSY (SEQ ID NO: 39); VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence SSGGGQTY (SEQ ID NO: 40); and VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 39). NO: 38) includes VHCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity; and / or

[0392] The light chain variable region includes: VLCDR1, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12); VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 13); and VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 12). NO: 14) includes VLCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity.

[0393] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0394] The heavy chain variable region includes: VHCDR1 with at least 90% identity to the amino acid sequence SYTMS (SEQ ID NO: 36), VHCDR2 with at least 90% identity to the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 37), and VHCDR3 with at least 90% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); and / or

[0395] The light chain variable region includes: VLCDR1, which has at least 90% identity with respect to the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12); VLCDR2, which has at least 90% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 13); and VLCDR3, which has at least 90% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 14).

[0396] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0397] The heavy chain variable region includes: VHCDR1 with at least 90% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 39), VHCDR2 with at least 90% identity to the amino acid sequence SSGGGQTY (SEQ ID NO: 40), and VHCDR3 with at least 90% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); and / or

[0398] The light chain variable region includes: VLCDR1, which has at least 90% identity with respect to the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12); VLCDR2, which has at least 90% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 13); and VLCDR3, which has at least 90% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 14).

[0399] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0400] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence SYTMS (SEQ ID NO: 36), VHCDR2 containing the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 37), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); and

[0401] The light chain variable region includes: VLCDR1 containing the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 13), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 14).

[0402] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 3, such as providing an antibody, fragment, or variant, including:

[0403] The heavy chain variable region includes: VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 36) optionally containing one or two amino acid substitutions; VHCDR2 comprising the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 37) optionally containing one or two amino acid substitutions; and VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38) optionally containing one or two amino acid substitutions; and / or

[0404] The light chain variable region comprises: VLCDR1 containing the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12) optionally containing one or two amino acid substitutions; VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 13) optionally containing one or two amino acid substitutions; and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 14) optionally containing one or two amino acid substitutions. The amino acid substitutions can be conserved.

[0405] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0406] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence SYTMS (SEQ ID NO: 36), VHCDR2 containing the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 37), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); and

[0407] The light chain variable region includes: VLCDR1 containing the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 13), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 14);

[0408] Optionally, each of the Met residues is independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or each of the Asp residues is independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0409] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0410] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence GFTFSSY (SEQ ID NO: 39), VHCDR2 containing the amino acid sequence SSGGGQTY (SEQ ID NO: 40), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); and

[0411] The light chain variable region includes: VLCDR1 containing the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 13), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 14).

[0412] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 3, such as providing an antibody, fragment, or variant, including:

[0413] The heavy chain variable region includes: VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 39) optionally containing one or two amino acid substitutions; VHCDR2 comprising the amino acid sequence SSGGGQTY (SEQ ID NO: 40) optionally containing one or two amino acid substitutions; and VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38) optionally containing one or two amino acid substitutions; and / or

[0414] The light chain variable region comprises: VLCDR1 containing the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12) optionally containing one or two amino acid substitutions; VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 13) optionally containing one or two amino acid substitutions; and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 14) optionally containing one or two amino acid substitutions. The amino acid substitutions can be conserved.

[0415] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0416] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence GFTFSSY (SEQ ID NO: 39), VHCDR2 containing the amino acid sequence SSGGGQTY (SEQ ID NO: 40), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); and

[0417] The light chain variable region includes: VLCDR1 containing the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 13), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 14);

[0418] Optionally, each of the Met residues is independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or each of the Asp residues is independently replaced by an amino acid selected from the group consisting of A1a, G1n and G1u.

[0419] Antigen-binding molecules of 3E05_var3 or derived from 3E05_var3 (e.g., antibodies with one or more amino acid substitutions) can have a Kc of less than about 0.01 nM. D This antigen-binding molecule may additionally or alternatively exhibit an IC50 of less than about 0.5 nM against IFN secretion and / or an IC90 of less than about 5 nM against IFN secretion.

[0420] 3E05_var 4

[0421] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0422] The heavy chain variable region includes: VHCDR1 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence SYTMS (SEQ ID NO: 46); VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 47); and VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 47). NO: 48) Includes VHCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity; and / or

[0423] The light chain variable region includes: VLCDR1, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12); VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 13); and VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 12). NO: 14) includes VLCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity.

[0424] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0425] The heavy chain variable region includes: VHCDR1 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence GFTFSSY (SEQ ID NO: 49); VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence SSGGGQTY (SEQ ID NO: 50); and VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 49). NO: 48) Includes VHCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity; and / or

[0426] The light chain variable region includes: VLCDR1, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12); VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 13); and VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 12). NO: 14) includes VLCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity.

[0427] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0428] The heavy chain variable region includes: VHCDR1 with at least 90% identity to the amino acid sequence SYTMS (SEQ ID NO: 46), VHCDR2 with at least 90% identity to the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 47), and VHCDR3 with at least 90% identity to the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); and / or

[0429] The light chain variable region includes: VLCDR1, which has at least 90% identity with respect to the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12); VLCDR2, which has at least 90% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 13); and VLCDR3, which has at least 90% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 14).

[0430] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0431] The heavy chain variable region includes: VHCDR1 with at least 90% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 49), VHCDR2 with at least 90% identity to the amino acid sequence SSGGGQTY (SEQ ID NO: 50), and VHCDR3 with at least 90% identity to the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); and / or

[0432] The light chain variable region includes: VLCDR1, which has at least 90% identity with respect to the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12); VLCDR2, which has at least 90% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 13); and VLCDR3, which has at least 90% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 14).

[0433] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0434] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence SYTMS (SEQ ID NO: 46), VHCDR2 containing the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 47), and VHCDR3 containing the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); and

[0435] The light chain variable region includes: VLCDR1 containing the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 13), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 14).

[0436] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var4, such as providing an antibody, fragment, or variant, including:

[0437] The heavy chain variable region includes: VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 46) optionally containing one or two amino acid substitutions; VHCDR2 comprising the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 47) optionally containing one or two amino acid substitutions; and VHCDR3 comprising the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48) optionally containing one or two amino acid substitutions; and / or

[0438] The light chain variable region comprises: VLCDR1 containing the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12) optionally containing one or two amino acid substitutions; VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 13) optionally containing one or two amino acid substitutions; and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 14) optionally containing one or two amino acid substitutions. The amino acid substitutions can be conserved.

[0439] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0440] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence SYTMS (SEQ ID NO: 46), VHCDR2 containing the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 47), and VHCDR3 containing the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); and

[0441] The light chain variable region includes: VLCDR1 containing the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 13), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 14);

[0442] Optionally, each of the Met residues is independently replaced by an amino acid selected from the group consisting of A1a and Leu, and / or each of the Asp residues is independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0443] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0444] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence GFTFSSY (SEQ ID NO: 49), VHCDR2 containing the amino acid sequence SSGGGQTY (SEQ ID NO: 50), and VHCDR3 containing the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); and

[0445] The light chain variable region includes: VLCDR1 containing the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 13), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 14).

[0446] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 4, such as providing an antibody, its fragment, or a variant, including:

[0447] The heavy chain variable region includes: VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 49) optionally containing one or two amino acid substitutions; VHCDR2 comprising the amino acid sequence SSGGGQTY (SEQ ID NO: 50) optionally containing one or two amino acid substitutions; and VHCDR3 comprising the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); and / or

[0448] The light chain variable region comprises: VLCDR1 containing the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12) optionally containing one or two amino acid substitutions; VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 13) optionally containing one or two amino acid substitutions; and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 14) optionally containing one or two amino acid substitutions. The amino acid substitutions can be conserved.

[0449] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0450] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence GFTFSSY (SEQ ID NO: 49), VHCDR2 containing the amino acid sequence SSGGGQTY (SEQ ID NO: 50), and VHCDR3 containing the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); and

[0451] The light chain variable region includes: VLCDR1 containing the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 13), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 14);

[0452] Optionally, each of the Met residues is independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or each of the Asp residues is independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0453] Antigen-binding molecules of 3E05_var4 or antigen-binding molecules derived from 3E05_var4 (e.g., antibodies with one or more amino acid substitutions) can have a Kc of less than about 0.01 nM. D This antigen-binding molecule may additionally or alternatively exhibit an IC50 of less than about 0.5 nM against IFN secretion and / or an IC90 of less than about 5 nM against IFN secretion.

[0454] 3E05_var 5

[0455] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0456] The heavy chain variable region includes: VHCDR1 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence SYTMS (SEQ ID NO: 16); VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 17); and VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 17). NO: 18) Includes VHCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity; and / or

[0457] The light chain variable region includes: VLCDR1, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22); VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 23); and VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 22). NO: 24) includes VLCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity.

[0458] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0459] The heavy chain variable region includes: VHCDR1 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence GFTFSSY (SEQ ID NO: 19); VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence SSGGGNTY (SEQ ID NO: 20); and VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 19). NO: 18) Includes VHCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity; and / or

[0460] The light chain variable region includes: VLCDR1, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22); VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 23); and VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 22). NO: 24) includes VLCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity.

[0461] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0462] The heavy chain variable region includes: VHCDR1 with at least 90% identity to the amino acid sequence SYTMS (SEQ ID NO: 16), VHCDR2 with at least 90% identity to the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 17), and VHCDR3 with at least 90% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); and / or

[0463] The light chain variable region includes: VLCDR1, which has at least 90% identity with respect to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22); VLCDR2, which has at least 90% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 23); and VLCDR3, which has at least 90% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 24).

[0464] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0465] The heavy chain variable region includes: VHCDR1 with at least 90% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 19), VHCDR2 with at least 90% identity to the amino acid sequence SSGGGNTY (SEQ ID NO: 20), and VHCDR3 with at least 90% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); and / or

[0466] The light chain variable region includes: VLCDR1, which has at least 90% identity with respect to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22); VLCDR2, which has at least 90% identity with respect to the amino acid sequence AASTLES (SEQ ID No: 23); and VLCDR3, which has at least 90% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID No: 24).

[0467] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0468] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence SYTMS (SEQ ID NO: 16), VHCDR2 containing the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 17), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); and

[0469] The light chain variable region includes: VLCDR1 containing the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 23), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 24).

[0470] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 5, such as providing an antibody, its fragment, or a variant, including:

[0471] The heavy chain variable region includes: VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 16) optionally containing one or two amino acid substitutions; VHCDR2 comprising the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 17) optionally containing one or two amino acid substitutions; and VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18) optionally containing one or two amino acid substitutions; and / or

[0472] The light chain variable region includes: VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22) optionally containing one or two amino acid substitutions; VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23) optionally containing one or two amino acid substitutions; and VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24) optionally containing one or two amino acid substitutions. The amino acid substitutions can be conserved.

[0473] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0474] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence SYTMS (SEQ ID NO: 16), VHCDR2 containing the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 17), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); and

[0475] The light chain variable region includes: VLCDR1 containing the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 23), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 24);

[0476] Optionally, each of the Met residues is independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or each of the Asp residues is independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0477] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0478] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence GFTFSSY (SEQ ID NO: 19), VHCDR2 containing the amino acid sequence SSGGGNTY (SEQ ID NO: 20), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); and

[0479] The light chain variable region includes: VLCDR1 containing the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 23), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 24).

[0480] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 5, such as providing an antibody, its fragment, or a variant, including:

[0481] The heavy chain variable region includes: VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 19) optionally containing one or two amino acid substitutions; VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 20) optionally containing one or two amino acid substitutions; and VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18) optionally containing one or two amino acid substitutions; and / or

[0482] The light chain variable region includes: VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22) optionally containing one or two amino acid substitutions; VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23) optionally containing one or two amino acid substitutions; and VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24) optionally containing one or two amino acid substitutions. The amino acid substitutions can be conserved.

[0483] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0484] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence GFTFSSY (SEQ ID NO: 19), VHCDR2 containing the amino acid sequence SSGGGNTY (SEQ ID NO: 20), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); and

[0485] The light chain variable region includes: VLCDR1 containing the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 23), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 24);

[0486] Optionally, each of the Met residues is independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or each of the Asp residues is independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0487] Antigen-binding molecules of 3E05_var5 or derived from 3E05_var5 (e.g., antibodies with one or more amino acid substitutions) can have a Kc of less than about 0.01 nM. D This antigen-binding molecule may additionally or alternatively exhibit an IC50 of less than about 0.5 nM against IFN secretion and / or an IC90 of less than about 5 nM against IFN secretion.

[0488] 3E05_var 7

[0489] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0490] The heavy chain variable region includes: VHCDR1 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence SYTMS (SEQ ID NO: 36); VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 37); and VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 37). NO: 38) includes VHCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity; and / or

[0491] The light chain variable region includes: VLCDR1, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22); VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 23); and VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 22). NO: 24) includes VLCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity.

[0492] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0493] The heavy chain variable region includes: VHCDR1 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence GFTFSSY (SEQ ID NO: 39); VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence SSGGGQTY (SEQ ID NO: 40); and VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 39). NO: 38) includes VHCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity; and / or

[0494] The light chain variable region includes: VLCDR1, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22); VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 23); and VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 22). NO: 24) includes VLCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity.

[0495] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0496] The heavy chain variable region includes: VHCDR1 with at least 90% identity to the amino acid sequence SYTMS (SEQ ID NO: 36), VHCDR2 with at least 90% identity to the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 37), and VHCDR3 with at least 90% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); and / or

[0497] The light chain variable region includes: VLCDR1, which has at least 90% identity with respect to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22); VLCDR2, which has at least 90% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 23); and VLCDR3, which has at least 90% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 24).

[0498] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0499] The heavy chain variable region includes: VHCDR1 with at least 90% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 39), VHCDR2 with at least 90% identity to the amino acid sequence SSGGGQTY (SEQ ID NO: 40), and VHCDR3 with at least 90% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); and / or

[0500] The light chain variable region includes: VLCDR1, which has at least 90% identity with respect to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22); VLCDR2, which has at least 90% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 23); and VLCDR3, which has at least 90% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 24).

[0501] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0502] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence SYTMS (SEQ ID NO: 36), VHCDR2 containing the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 37), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); and

[0503] The light chain variable region includes: VLCDR1 containing the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 23), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 24).

[0504] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 7, such as providing an antibody, its fragment, or a variant, including:

[0505] The heavy chain variable region includes: VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 36) optionally containing one or two amino acid substitutions; VHCDR2 comprising the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 37) optionally containing one or two amino acid substitutions; and VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38) optionally containing one or two amino acid substitutions; and / or

[0506] The light chain variable region includes: VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22) optionally containing one or two amino acid substitutions; VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23) optionally containing one or two amino acid substitutions; and VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24) optionally containing one or two amino acid substitutions. The amino acid substitutions can be conserved.

[0507] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0508] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence SYTMS (SEQ ID NO: 36), VHCDR2 containing the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 37), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); and

[0509] The light chain variable region includes: VLCDR1 containing the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 23), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 24);

[0510] Optionally, each of the Met residues is independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or each of the Asp residues is independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0511] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0512] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence GFTFSSY (SEQ ID NO: 39), VHCDR2 containing the amino acid sequence SSGGGQTY (SEQ ID NO: 40), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); and

[0513] The light chain variable region includes: VLCDR1 containing the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 23), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 24).

[0514] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 7, such as providing an antibody, its fragment, or a variant, including:

[0515] The heavy chain variable region includes: VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 39) optionally containing one or two amino acid substitutions; VHCDR2 comprising the amino acid sequence SSGGGQTY (SEQ ID NO: 40) optionally containing one or two amino acid substitutions; and VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38) optionally containing one or two amino acid substitutions; and / or

[0516] The light chain variable region includes: VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22) optionally containing one or two amino acid substitutions; VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23) optionally containing one or two amino acid substitutions; and VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24) optionally containing one or two amino acid substitutions. The amino acid substitutions can be conserved.

[0517] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0518] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence GFTFSSY (SEQ ID NO: 39), VHCDR2 containing the amino acid sequence SSGGGQTY (SEQ ID NO: 40), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); and

[0519] The light chain variable region includes: VLCDR1 containing the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 23), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 24);

[0520] Optionally, each of the Met residues is independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or each of the Asp residues is independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0521] Antigen-binding molecules of 3E05_var7 or derived from 3E05_var7 (e.g., antibodies with one or more amino acid substitutions) can have a Kc of less than about 0.01 nM. D This antigen-binding molecule may additionally or alternatively exhibit an IC50 of less than about 0.5 nM against IFN secretion and / or an IC90 of less than about 5 nM against IFN secretion.

[0522] 3E05_var 8

[0523] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0524] The heavy chain variable region includes: VHCDR1 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence SYTMS (SEQ ID NO: 46); VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 47); and VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 47). NO: 48) Includes VHCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity; and / or

[0525] The light chain variable region includes: VLCDR1, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22); VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 23); and VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 22). NO: 24) includes VLCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity.

[0526] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0527] The heavy chain variable region includes: VHCDR1 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence GFTFSSY (SEQ ID NO: 49); VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence SSGGGQTY (SEQ ID NO: 50); and VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 49). NO: 48) Includes VHCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity; and / or

[0528] The light chain variable region includes: VLCDR1, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22); VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 23); and VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 22). NO: 24) includes VLCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity.

[0529] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0530] The heavy chain variable region includes: VHCDR1 with at least 90% identity to the amino acid sequence SYTMS (SEQ ID NO: 46), VHCDR2 with at least 90% identity to the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 47), and VHCDR3 with at least 90% identity to the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); and / or

[0531] The light chain variable region includes: VLCDR1, which has at least 90% identity with respect to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22); VLCDR2, which has at least 90% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 23); and VLCDR3, which has at least 90% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 24).

[0532] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0533] The heavy chain variable region includes: VHCDR1 with at least 90% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 49), VHCDR2 with at least 90% identity to the amino acid sequence SSGGGQTY (SEQ ID NO: 50), and VHCDR3 with at least 90% identity to the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); and / or

[0534] The light chain variable region includes: VLCDR1, which has at least 90% identity with respect to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22); VLCDR2, which has at least 90% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 23); and VLCDR3, which has at least 90% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 24).

[0535] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0536] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence SYTMS (SEQ ID NO: 46), VHCDR2 containing the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 47), and VHCDR3 containing the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); and

[0537] The light chain variable region includes: VLCDR1 containing the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 23), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 24).

[0538] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 8, such as providing an antibody, its fragment, or a variant, including:

[0539] The heavy chain variable region includes: VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 46) optionally containing one or two amino acid substitutions; VHCDR2 comprising the amino acid sequence YISSGGGOTYYPDSVKG (SEQ ID NO: 47) optionally containing one or two amino acid substitutions; and VHCDR3 comprising the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48) optionally containing one or two amino acid substitutions; and / or

[0540] The light chain variable region includes: VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22) optionally containing one or two amino acid substitutions; VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23) optionally containing one or two amino acid substitutions; and VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24) optionally containing one or two amino acid substitutions. The amino acid substitutions can be conserved.

[0541] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0542] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence SYTMS (SEQ ID NO: 46), VHCDR2 containing the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 47), and VHCDR3 containing the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); and

[0543] The light chain variable region includes: VLCDR1 containing the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 23), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 24);

[0544] Optionally, each of the Met residues is independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or each of the Asp residues is independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0545] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0546] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence GFTFSSY (SEQ ID NO: 49), VHCDR2 containing the amino acid sequence SSGGGQTY (SEQ ID NO: 50), and VHCDR3 containing the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); and

[0547] The light chain variable region includes: VLCDR1 containing the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 23), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 24).

[0548] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 8, such as providing an antibody, its fragment, or a variant, including:

[0549] The heavy chain variable region includes: VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 49) optionally containing one or two amino acid substitutions; VHCDR2 comprising the amino acid sequence SSGGGQTY (SEQ ID NO: 50) optionally containing one or two amino acid substitutions; and VHCDR3 comprising the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48) optionally containing one or two amino acid substitutions; and / or

[0550] The light chain variable region includes: VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22) optionally containing one or two amino acid substitutions; VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23) optionally containing one or two amino acid substitutions; and VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24) optionally containing one or two amino acid substitutions. The amino acid substitutions can be conserved.

[0551] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0552] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence GFTFSSY (SEQ ID NO: 49), VHCDR2 containing the amino acid sequence SSGGGQTY (SEQ ID NO: 50), and VHCDR3 containing the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); and

[0553] The light chain variable region includes: VLCDR1 containing the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 23), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 24);

[0554] Optionally, each of the Met residues is independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or each of the Asp residues is independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0555] Antigen-binding molecules of 3E05_var 8 or antigen-binding molecules derived from 3E05_var 8 (e.g., antibodies with one or more amino acid substitutions) may have a Kc of less than about 0.01 nM. D This antigen-binding molecule may additionally or alternatively exhibit an IC50 of less than about 0.5 nM against IFN secretion and / or an IC90 of less than about 5 nM against IFN secretion.

[0556] 3E05_var 9

[0557] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0558] The heavy chain variable region includes: VHCDR1 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence SYTMS (SEQ ID NO: 16); VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 17); and VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 17). NO: 18) Includes VHCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity; and / or

[0559] The light chain variable region includes: VLCDR1, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32); VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 33); and VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 32). NO: 34) includes VLCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity.

[0560] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0561] The heavy chain variable region includes: VHCDR1 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence GFTFSSY (SEQ ID NO: 19); VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence SSGGGNTY (SEQ ID NO: 20); and VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 19). NO: 18) Includes VHCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity; and / or

[0562] The light chain variable region includes: VLCDR1, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32); VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 33); and VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 32). NO: 34) includes VLCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity.

[0563] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0564] The heavy chain variable region includes: VHCDR1 with at least 90% identity to the amino acid sequence SYTMS (SEQ ID NO: 16), VHCDR2 with at least 90% identity to the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 17), and VHCDR3 with at least 90% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); and / or

[0565] The light chain variable region includes: VLCDR1, which has at least 90% identity with respect to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32); VLCDR2, which has at least 90% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 33); and VLCDR3, which has at least 90% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 34).

[0566] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0567] The heavy chain variable region includes: VHCDR1 with at least 90% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 19), VHCDR2 with at least 90% identity to the amino acid sequence SSGGGNTY (SEQ ID NO: 20), and VHCDR3 with at least 90% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); and / or

[0568] The light chain variable region includes: VLCDR1, which has at least 90% identity with respect to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32); VLCDR2, which has at least 90% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 33); and VLCDR3, which has at least 90% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 34).

[0569] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0570] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence SYTMS (SEQ ID NO: 16), VHCDR2 containing the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 17), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); and

[0571] The light chain variable region includes: VLCDR1 containing the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 33), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 34).

[0572] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 9, such as providing an antibody, its fragment, or a variant, including:

[0573] The heavy chain variable region includes: VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 16) optionally containing one or two amino acid substitutions; VHCDR2 comprising the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID No: 17) optionally containing one or two amino acid substitutions; and VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18) optionally containing one or two amino acid substitutions; and / or

[0574] The light chain variable region comprises: VLCDR1 containing the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID No: 32) with optional one or two amino acid substitutions; VLCDR2 containing the amino acid sequence AASTLES (SEQ ID No: 33) with optional one or two amino acid substitutions; and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID No: 34) with optional one or two amino acid substitutions. The amino acid substitutions can be conserved.

[0575] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0576] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence SYTMS (SEQ ID NO: 16), VHCDR2 containing the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 17), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); and

[0577] The light chain variable region includes: VLCDR1 containing the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 33), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 34);

[0578] Optionally, each of the Met residues is independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or each of the AsD residues is independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0579] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0580] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence GFTFSSY (SEQ ID NO: 19), VHCDR2 containing the amino acid sequence SSGGGNTY (SEQ ID NO: 20), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); and

[0581] The light chain variable region includes: VLCDR1 containing the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 33), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 34).

[0582] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 9, such as providing an antibody, its fragment, or a variant, including:

[0583] The heavy chain variable region includes: VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 19) optionally containing one or two amino acid substitutions; VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 20) optionally containing one or two amino acid substitutions; and VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18) optionally containing one or two amino acid substitutions; and / or

[0584] The light chain variable region includes: VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32) optionally containing one or two amino acid substitutions; VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33) optionally containing one or two amino acid substitutions; and VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34) optionally containing one or two amino acid substitutions. The amino acid substitutions can be conserved.

[0585] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0586] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence GFTFSSY (SEQ ID NO: 19), VHCDR2 containing the amino acid sequence SSGGGNTY (SEQ ID NO: 20), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); and

[0587] The light chain variable region includes: VLCDR1 containing the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 33), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 34);

[0588] Optionally, each of the Met residues is independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or each of the AsD residues is independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0589] Antigen-binding molecules of 3E05_var9 or antigen-binding molecules derived from 3E05_var9 (e.g., antibodies with one or more amino acid substitutions) can have a Kc of less than about 0.01 nM. D This antigen-binding molecule may additionally or alternatively exhibit an IC50 of less than about 0.5 nM against IFN secretion and / or an IC90 of less than about 5 nM against IFN secretion.

[0590] 3E05_var 10

[0591] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0592] The heavy chain variable region includes: VHCDR1 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence SYTMS (SEQ ID NO: 26); VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence YISSGGGNTYYADSVKG (SEQ ID NO: 27); and VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 27). NO: 28) Includes VHCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity; and / or

[0593] The light chain variable region includes: VLCDR1, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32); VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 33); and VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 32). NO: 34) includes VLCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity.

[0594] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0595] The heavy chain variable region includes: VHCDR1, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence GFTFSSY (SEQ ID NO: 29); VHCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence SSGGGNTY (SEQ ID NO: 30); and VHCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 29). NO: 28) Includes VHCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity; and / or

[0596] The light chain variable region includes: VLCDR1, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32); VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 33); and VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 32). NO: 34) includes VLCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity.

[0597] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0598] The heavy chain variable region includes: VHCDR1 with at least 90% identity to the amino acid sequence SYTMS (SEQ ID NO: 26), VHCDR2 with at least 90% identity to the amino acid sequence YISSGGGNTYYADSVKG (SEQ ID NO: 27), and VHCDR3 with at least 90% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); and / or

[0599] The light chain variable region includes: VLCDR1, which has at least 90% identity with respect to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32); VLCDR2, which has at least 90% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 33); and VLCDR3, which has at least 90% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 34).

[0600] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0601] The heavy chain variable region includes: VHCDR1 with at least 90% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 29), VHCDR2 with at least 90% identity to the amino acid sequence SSGGGNTY (SEQ ID NO: 30), and VHCDR3 with at least 90% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); and / or

[0602] The light chain variable region includes: VLCDR1, which has at least 90% identity with respect to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32); VLCDR2, which has at least 90% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 33); and VLCDR3, which has at least 90% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 34).

[0603] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0604] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence SYTMS (SEQ ID NO: 26), VHCDR2 containing the amino acid sequence YISSGGGNTYYADSVKG (SEQ ID NO: 27), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); and

[0605] The light chain variable region includes: VLCDR1 containing the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 33), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 34).

[0606] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 10, such as providing an antibody, its fragment, or a variant, including:

[0607] The heavy chain variable region includes: VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 26) optionally containing one or two amino acid substitutions; VHCDR2 comprising the amino acid sequence YISSGGGNTYYADSVKG (SEQ ID NO: 27) optionally containing one or two amino acid substitutions; and VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28) optionally containing one or two amino acid substitutions; and / or

[0608] The light chain variable region includes: VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32) optionally containing one or two amino acid substitutions; VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33) optionally containing one or two amino acid substitutions; and VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34) optionally containing one or two amino acid substitutions. The amino acid substitutions can be conserved.

[0609] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0610] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence SYTMS (SEQ ID NO: 26), VHCDR2 containing the amino acid sequence YISSGGGNTYYADSVKG (SEQ ID NO: 27), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); and

[0611] The light chain variable region includes: VLCDR1 containing the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 33), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 34);

[0612] Optionally, each of the Met residues is independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or each of the Asp residues is independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0613] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0614] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence GFTFSSY (SEQ ID NO: 29), VHCDR2 containing the amino acid sequence SSGGGNTY (SEQ ID NO: 30), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); and

[0615] The light chain variable region includes: VLCDR1 containing the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 33), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 34).

[0616] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 10, such as providing an antibody, its fragment, or a variant, including:

[0617] The heavy chain variable region includes: VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 29) optionally containing one or two amino acid substitutions; VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 30) optionally containing one or two amino acid substitutions; and VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28) optionally containing one or two amino acid substitutions; and / or

[0618] The light chain variable region includes: VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32) optionally containing one or two amino acid substitutions; VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33) optionally containing one or two amino acid substitutions; and VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34) optionally containing one or two amino acid substitutions. The amino acid substitutions can be conserved.

[0619] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0620] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence GFTFSSY (SEQ ID NO: 29), VHCDR2 containing the amino acid sequence SSGGGNTY (SEQ ID NO: 30), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); and

[0621] The light chain variable region includes: VLCDR1 containing the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 33), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 34);

[0622] Optionally, each of the Met residues is independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or each of the Asp residues is independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0623] Antigen-binding molecules of 3E05_var 10 or antigen-binding molecules derived from 3E05_var 10 (e.g., antibodies with one or more amino acid substitutions) may have a Kc of less than about 1 nM. D This antigen-binding molecule may additionally or alternatively exhibit an IC50 of less than about 0.5 nM against IFN secretion and / or an IC90 of less than about 5 nM against IFN secretion.

[0624] 3E05_var 11

[0625] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0626] The heavy chain variable region includes: VHCDR1 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence SYTMS (SEQ ID NO: 36); VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 37); and VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 37). NO: 38) includes VHCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity; and / or

[0627] The light chain variable region includes: VLCDR1, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32); VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 33); and VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 32). NO: 34) includes VLCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity.

[0628] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0629] The heavy chain variable region includes: VHCDR1 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence GFTFSSY (SEQ ID NO: 39); VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence SSGGGQTY (SEQ ID NO: 40); and VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 39). NO: 38) includes VHCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity; and / or

[0630] The light chain variable region includes: VLCDR1, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32); VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 33); and VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 32). NO: 34) includes VLCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity.

[0631] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0632] The heavy chain variable region includes: VHCDR1 with at least 90% identity to the amino acid sequence SYTMS (SEQ ID NO: 36), VHCDR2 with at least 90% identity to the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 37), and VHCDR3 with at least 90% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); and / or

[0633] The light chain variable region includes: VLCDR1, which has at least 90% identity with respect to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32); VLCDR2, which has at least 90% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 33); and VLCDR3, which has at least 90% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 34).

[0634] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0635] The heavy chain variable region includes: VHCDR1 with at least 90% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 39), VHCDR2 with at least 90% identity to the amino acid sequence SSGGGQTY (SEQ ID NO: 40), and VHCDR3 with at least 90% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); and / or

[0636] The light chain variable region includes: VLCDR1, which has at least 90% identity with respect to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32); VLCDR2, which has at least 90% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 33); and VLCDR3, which has at least 90% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 34).

[0637] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0638] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence SYTMS (SEQ ID NO: 36), VHCDR2 containing the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 37), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); and

[0639] The light chain variable region includes: VLCDR1 containing the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 33), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 34).

[0640] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 11, such as providing an antibody, its fragment, or a variant, including:

[0641] The heavy chain variable region includes: VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 36) optionally containing one or two amino acid substitutions; VHCDR2 comprising the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 37) optionally containing one or two amino acid substitutions; and VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38) optionally containing one or two amino acid substitutions; and / or

[0642] The light chain variable region includes: VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32) optionally containing one or two amino acid substitutions; VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33) optionally containing one or two amino acid substitutions; and VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34) optionally containing one or two amino acid substitutions. The amino acid substitutions can be conserved.

[0643] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0644] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence SYTMS (SEQ ID NO: 36), VHCDR2 containing the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 37), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); and

[0645] The light chain variable region includes: VLCDR1 containing the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 33), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 34);

[0646] Optionally, each of the Met residues is independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or each of the Asp residues is independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0647] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0648] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence GFTFSSY (SEQ ID NO: 39), VHCDR2 containing the amino acid sequence SSGGGQTY (SEQ ID NO: 40), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); and

[0649] The light chain variable region includes: VLCDR1 containing the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 33), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 34).

[0650] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 11, such as providing an antibody, its fragment, or a variant, including:

[0651] The heavy chain variable region includes: VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 39) optionally containing one or two amino acid substitutions; VHCDR2 comprising the amino acid sequence SSGGGQTY (SEQ ID NO: 40) optionally containing one or two amino acid substitutions; and VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38) optionally containing one or two amino acid substitutions; and / or

[0652] The light chain variable region includes: VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32) optionally containing one or two amino acid substitutions; VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33) optionally containing one or two amino acid substitutions; and VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34) optionally containing one or two amino acid substitutions. The amino acid substitutions can be conserved.

[0653] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0654] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence GFTFSSY (SEQ ID NO: 39), VHCDR2 containing the amino acid sequence SSGGGQTY (SEQ ID NO: 40), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); and

[0655] The light chain variable region includes: VLCDR1 containing the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 33), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 34);

[0656] Optionally, each of the Met residues is independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or each of the Asp residues is independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0657] Antigen-binding molecules of 3E05_var11 or antigen-binding molecules derived from 3E05_var11 (e.g., antibodies with one or more amino acid substitutions) can have a Kc of less than about 1 nM. D This antigen-binding molecule may additionally or alternatively exhibit an IC50 of less than about 0.5 nM against IFN secretion and / or an IC90 of less than about 5 nM against IFN secretion.

[0658] 3E05_var 13

[0659] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0660] The heavy chain variable region includes: VHCDR1 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence SYTMS (SEQ ID NO: 16); VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 17); and VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 17). NO: 18) Includes VHCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity; and / or

[0661] The light chain variable region includes: VLCDR1, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42); VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 43); and VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 42). NO: 44) includes VLCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity.

[0662] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0663] The heavy chain variable region includes: VHCDR1 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence GFTFSSY (SEQ ID NO: 19); VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence SSGGGNTY (SEQ ID NO: 20); and VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 19). NO: 18) Includes VHCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity; and / or

[0664] The light chain variable region includes: VLCDR1, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42); VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 43); and VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 42). NO: 44) includes VLCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity.

[0665] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0666] The heavy chain variable region includes: VHCDR1 with at least 90% identity to the amino acid sequence SYTMS (SEQ ID NO: 16), VHCDR2 with at least 90% identity to the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 17), and VHCDR3 with at least 90% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); and / or

[0667] The light chain variable region includes: VLCDR1, which has at least 90% identity with respect to the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42); VLCDR2, which has at least 90% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 43); and VLCDR3, which has at least 90% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 44).

[0668] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0669] The heavy chain variable region includes: VHCDR1 with at least 90% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 19), VHCDR2 with at least 90% identity to the amino acid sequence SSGGGNTY (SEQ ID NO: 20), and VHCDR3 with at least 90% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); and / or

[0670] The light chain variable region includes: VLCDR1, which has at least 90% identity with respect to the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42); VLCDR2, which has at least 90% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 43); and VLCDR3, which has at least 90% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 44).

[0671] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0672] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence SYTMS (SEQ ID NO: 16), VHCDR2 containing the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 17), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); and

[0673] The light chain variable region includes: VLCDR1 containing the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 43), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 44).

[0674] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 13, such as providing an antibody, its fragment, or a variant, including:

[0675] The heavy chain variable region includes: VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 16) optionally containing one or two amino acid substitutions; VHCDR2 comprising the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 17) optionally containing one or two amino acid substitutions; and VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18) optionally containing one or two amino acid substitutions; and / or

[0676] The light chain variable region includes: VLCDR1 comprising the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42) optionally containing one or two amino acid substitutions; VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 43) optionally containing one or two amino acid substitutions; and VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44) optionally containing one or two amino acid substitutions. The amino acid substitutions can be conserved amino acid substitutions.

[0677] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0678] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence SYTMS (SEQ ID NO: 16), VHCDR2 containing the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 17), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); and

[0679] The light chain variable region includes: VLCDR1 containing the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 43), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 44);

[0680] Optionally, each of the Met residues is independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or each of the Asp residues is independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0681] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0682] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence GFTFSSY (SEQ ID NO: 19), VHCDR2 containing the amino acid sequence SSGGGNTY (SEQ ID NO: 20), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); and

[0683] The light chain variable region includes: VLCDR1 containing the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 43), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 44).

[0684] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 13, such as providing an antibody, its fragment, or a variant, including:

[0685] The heavy chain variable region includes: VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 19) optionally containing one or two amino acid substitutions; VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 20) optionally containing one or two amino acid substitutions; and VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18) optionally containing one or two amino acid substitutions; and / or

[0686] The light chain variable region includes: VLCDR1 comprising the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42) optionally containing one or two amino acid substitutions; VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 43) optionally containing one or two amino acid substitutions; and VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44) optionally containing one or two amino acid substitutions. The amino acid substitutions can be conserved amino acid substitutions.

[0687] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0688] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence GFTFSSY (SEQ ID NO: 19), VHCDR2 containing the amino acid sequence SSGGGNTY (SEQ ID NO: 20), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); and

[0689] The light chain variable region includes: VLCDR1 containing the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 43), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 44);

[0690] Optionally, each of the Met residues is independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or each of the Asp residues is independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0691] Antigen-binding molecules of 3E05_var13 or derived from 3E05_var13 (e.g., antibodies with one or more amino acid substitutions) may have a Kc of less than about 0.01 nM. D This antigen-binding molecule may additionally or alternatively exhibit an IC50 of less than about 0.5 nM against IFN secretion and / or an IC90 of less than about 5 nM against IFN secretion.

[0692] 3E05_var 15

[0693] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0694] The heavy chain variable region includes: VHCDR1 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence SYTMS (SEQ ID NO: 36); VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 37); and VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 37). NO: 38) includes VHCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity; and / or

[0695] The light chain variable region includes: VLCDR1, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42); VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 43); and VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 42). NO: 44) includes VLCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity.

[0696] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0697] The heavy chain variable region includes: VHCDR1 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence GFTFSSY (SEQ ID NO: 39); VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence SSGGGQTY (SEQ ID NO: 40); and VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 39). NO: 38) includes VHCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity; and / or

[0698] The light chain variable region includes: VLCDR1, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42); VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 43); and VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 42). NO: 44) includes VLCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity.

[0699] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0700] The heavy chain variable region includes: VHCDR1 with at least 90% identity to the amino acid sequence SYTMS (SEQ ID No: 36), VHCDR2 with at least 90% identity to the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID No: 37), and VHCDR3 with at least 90% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID No: 38); and / or

[0701] The light chain variable region includes: VLCDR1, which has at least 90% identity with respect to the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42); VLCDR2, which has at least 90% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 43); and VLCDR3, which has at least 90% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 44).

[0702] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0703] The heavy chain variable region includes: VHCDR1 with at least 90% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 39), VHCDR2 with at least 90% identity to the amino acid sequence SSGGGQTY (SEQ ID NO: 40), and VHCDR3 with at least 90% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); and / or

[0704] The light chain variable region includes: VLCDR1, which has at least 90% identity with respect to the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42); VLCDR2, which has at least 90% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 43); and VLCDR3, which has at least 90% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 44).

[0705] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0706] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence SYTMS (SEQ ID NO: 36), VHCDR2 containing the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 37), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); and

[0707] The light chain variable region includes: VLCDR1 containing the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 43), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 44).

[0708] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 15, such as providing an antibody, its fragment, or a variant, including:

[0709] The heavy chain variable region includes: VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 36) optionally containing one or two amino acid substitutions; VHCDR2 comprising the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 37) optionally containing one or two amino acid substitutions; and VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38) optionally containing one or two amino acid substitutions; and / or

[0710] The light chain variable region includes: VLCDR1 comprising the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42) optionally containing one or two amino acid substitutions; VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 43) optionally containing one or two amino acid substitutions; and VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44) optionally containing one or two amino acid substitutions. The amino acid substitutions can be conserved amino acid substitutions.

[0711] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0712] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence SYTMS (SEQ ID NO: 36), VHCDR2 containing the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 37), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); and

[0713] The light chain variable region includes: VLCDR1 containing the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 43), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 44);

[0714] Optionally, each of the Met residues is independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or each of the Asp residues is independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0715] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0716] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence GFTFSSY (SEQ ID NO: 39), VHCDR2 containing the amino acid sequence SSGGGQTY (SEQ ID NO: 40), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); and

[0717] The light chain variable region includes: VLCDR1 containing the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 43), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 44).

[0718] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 15, such as providing an antibody, its fragment, or a variant, including:

[0719] The heavy chain variable region includes: VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 39) optionally containing one or two amino acid substitutions; VHCDR2 comprising the amino acid sequence SSGGGQTY (SEQ ID NO: 40) optionally containing one or two amino acid substitutions; and VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38) optionally containing one or two amino acid substitutions; and / or

[0720] The light chain variable region includes: VLCDR1 comprising the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42) optionally containing one or two amino acid substitutions; VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 43) optionally containing one or two amino acid substitutions; and VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44) optionally containing one or two amino acid substitutions. The amino acid substitutions can be conserved amino acid substitutions.

[0721] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0722] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence GFTFSSY (SEQ ID NO: 39), VHCDR2 containing the amino acid sequence SSGGGQTY (SEQ ID NO: 40), and VHCDR3 containing the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); and

[0723] The light chain variable region includes: VLCDR1 containing the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 43), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 44);

[0724] Optionally, each of the Met residues is independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or each of the Asp residues is independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0725] Antigen-binding molecules of 3E05_var15 or antigen-binding molecules derived from 3E05_var15 (e.g., antibodies with one or more amino acid substitutions) may have a Kc of less than about 0.01 nM. D This antigen-binding molecule may additionally or alternatively exhibit an IC50 of less than about 0.5 nM against IFN secretion and / or an IC90 of less than about 5 nM against IFN secretion.

[0726] 3E05_var 16

[0727] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0728] The heavy chain variable region includes: VHCDR1 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence SYTMS (SEQ ID NO: 46); VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 47); and VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 47). NO: 48) Includes VHCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity; and / or

[0729] The light chain variable region includes: VLCDR1, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42); VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 43); and VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 42). NO: 44) includes VLCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity.

[0730] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0731] The heavy chain variable region includes: VHCDR1 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence GFTFSSY (SEQ ID NO: 49); VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence SSGGGQTY (SEQ ID NO: 50); and VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 49). NO: 48) Includes VHCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity; and / or

[0732] The light chain variable region includes: VLCDR1, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42); VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 43); and VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 42). NO: 44) includes VLCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity.

[0733] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0734] The heavy chain variable region includes: VHCDR1 with at least 90% identity to the amino acid sequence SYTMS (SEQ ID NO: 46), VHCDR2 with at least 90% identity to the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 47), and VHCDR3 with at least 90% identity to the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); and / or

[0735] The light chain variable region includes: VLCDR1, which has at least 90% identity with respect to the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42); VLCDR2, which has at least 90% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 43); and VLCDR3, which has at least 90% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 44).

[0736] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0737] The heavy chain variable region includes: VHCDR1 with at least 90% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 49), VHCDR2 with at least 90% identity to the amino acid sequence SSGGGQTY (SEQ ID NO: 50), and VHCDR3 with at least 90% identity to the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); and / or

[0738] The light chain variable region includes: VLCDR1, which has at least 90% identity with respect to the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42); VLCDR2, which has at least 90% identity with respect to the amino acid sequence AASTLES (SEQ ID NO: 43); and VLCDR3, which has at least 90% identity with respect to the amino acid sequence QQTNEDPPT (SEQ ID NO: 44).

[0739] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0740] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence SYTMS (SEQ ID NO: 46), VHCDR2 containing the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 47), and VHCDR3 containing the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); and

[0741] The light chain variable region includes: VLCDR1 containing the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 43), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 44).

[0742] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 16, such as providing an antibody, its fragment, or a variant, including:

[0743] The heavy chain variable region includes: VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 46) optionally containing one or two amino acid substitutions; VHCDR2 comprising the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 47) optionally containing one or two amino acid substitutions; and VHCDR3 comprising the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48) optionally containing one or two amino acid substitutions; and / or

[0744] The light chain variable region includes: VLCDR1 comprising the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42) optionally containing one or two amino acid substitutions; VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 43) optionally containing one or two amino acid substitutions; and VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44) optionally containing one or two amino acid substitutions. The amino acid substitutions can be conserved amino acid substitutions.

[0745] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0746] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence SYTMS (SEQ ID NO: 46), VHCDR2 containing the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 47), and VHCDR3 containing the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); and

[0747] The light chain variable region includes: VLCDR1 containing the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 43), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 44);

[0748] Optionally, each of the Met residues is independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or each of the Asp residues is independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0749] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0750] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence GFTFSSY (SEQ ID NO: 49), VHCDR2 containing the amino acid sequence SSGGGQTY (SEQ ID NO: 50), and VHCDR3 containing the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); and

[0751] The light chain variable region includes: VLCDR1 containing the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 43), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 44).

[0752] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 16, such as providing an antibody, its fragment, or a variant, including:

[0753] The heavy chain variable region includes: VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 49) optionally containing one or two amino acid substitutions; VHCDR2 comprising the amino acid sequence SSGGGQTY (SEQ ID NO: 50) optionally containing one or two amino acid substitutions; and VHCDR3 comprising the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48) optionally containing one or two amino acid substitutions; and / or

[0754] The light chain variable region includes: VLCDR1 comprising the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42) optionally containing one or two amino acid substitutions; VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 43) optionally containing one or two amino acid substitutions; and VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44) optionally containing one or two amino acid substitutions. The amino acid substitutions can be conserved amino acid substitutions.

[0755] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0756] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence GFTFSSY (SEQ ID NO: 49), VHCDR2 containing the amino acid sequence SSGGGQTY (SEQ ID NO: 50), and VHCDR3 containing the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); and

[0757] The light chain variable region includes: VLCDR1 containing the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), VLCDR2 containing the amino acid sequence AASTLES (SEQ ID NO: 43), and VLCDR3 containing the amino acid sequence QQTNEDPPT (SEQ ID NO: 44);

[0758] Optionally, each of the Met residues is independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or each of the Asp residues is independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0759] Antigen-binding molecules of 3E05_var 16 or antigen-binding molecules derived from 3E05_var 16 (e.g., antibodies with one or more amino acid substitutions) may have a Kc of less than about 0.01 nM. D This antigen-binding molecule may additionally or alternatively exhibit an IC50 of less than about 0.5 nM against IFN secretion and / or an IC90 of less than about 5 nM against IFN secretion.

[0760] 21E06

[0761] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0762] The heavy chain variable region includes: VHCDR1, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence SYTIS (SEQ ID NO: 56); VHCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence YISSGGDNAYYPDSVKG (SEQ ID NO: 57); and VHCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence HLYYGDYFYVMDY (SEQ ID NO: 57). NO: 58) includes VHCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity; and / or

[0763] The light chain variable region includes: VLCDR1, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence KASQSVDYDGDNCLH (SEQ ID NO: 52); VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence AASNLES (SEQ ID NO: 53); and VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence QQSNEDPPT (SEQ ID NO: 52). NO: 54) includes VLCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity.

[0764] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0765] The heavy chain variable region includes: VHCDR1, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence GFTFSSY (SEQ ID NO: 59); VHCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence SSGGDN (SEQ ID NO: 60); and VHCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence HLYYGDYFYVMDY (SEQ ID NO: 59). NO: 58) includes VHCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity; and / or

[0766] The light chain variable region includes: VLCDR1, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence KASQSVDYDGDNCLH (SEQ ID NO: 52); VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence AASNLES (SEQ ID NO: 53); and VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence QQSNEDPPT (SEQ ID NO: 52). NO: 54) includes VLCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity.

[0767] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0768] The heavy chain variable region includes: VHCDR1, which has at least 90% identity with respect to the amino acid sequence SYTIS (SEQ ID NO: 56); VHCDR2, which has at least 90% identity with respect to the amino acid sequence YISSGGDNAYYPDSVKG (SEQ ID NO: 57); and VHCDR3, which has at least 90% identity with respect to the amino acid sequence HLYYGDYFYVMDY (SEQ ID NO: 58); and / or

[0769] The light chain variable region includes: VLCDR1, which has at least 90% identity with respect to the amino acid sequence KASQSVDYDGDNCLH (SEQ ID NO: 52); VLCDR2, which has at least 90% identity with respect to the amino acid sequence AASNLES (SEQ ID NO: 53); and VLCDR3, which has at least 90% identity with respect to the amino acid sequence QQSNEDPPT (SEQ ID NO: 54).

[0770] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0771] The heavy chain variable region includes: VHCDR1, which has at least 90% identity with respect to the amino acid sequence GFTFSSY (SEQ ID NO: 59); VHCDR2, which has at least 90% identity with respect to the amino acid sequence SSGGDN (SEQ ID NO: 60); and VHCDR3, which has at least 90% identity with respect to the amino acid sequence HLYYGDYFYVMDY (SEQ ID NO: 58); and / or

[0772] The light chain variable region includes: VLCDR1, which has at least 90% identity with respect to the amino acid sequence KASQSVDYDGDNCLH (SEQ ID NO: 52); VLCDR2, which has at least 90% identity with respect to the amino acid sequence AASNLES (SEQ ID NO: 53); and VLCDR3, which has at least 90% identity with respect to the amino acid sequence QQSNEDPPT (SEQ ID NO: 54).

[0773] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0774] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence SYTIS (SEQ ID NO: 56), VHCDR2 containing the amino acid sequence YISSGGDNAYYPDSVKG (SEQ ID NO: 57), and VHCDR3 containing the amino acid sequence HLYYGDYFYVMDY (SEQ ID NO: 58); and

[0775] The light chain variable region includes: VLCDR1 containing the amino acid sequence KASQSVDYDGDNCLH (SEQ ID NO: 52), VLCDR2 containing the amino acid sequence AASNLES (SEQ ID NO: 53), and VLCDR3 containing the amino acid sequence QQSNEDPPT (SEQ ID NO: 54).

[0776] Amino acid substitutions can be made to provide variant antibodies derived from 21E06, such as providing an antibody, its fragment, or a variant, including:

[0777] The heavy chain variable region includes: VHCDR1 comprising the amino acid sequence SYTIS (SEQ ID NO: 56) optionally containing one or two amino acid substitutions; VHCDR2 comprising the amino acid sequence YISSGGDNAYYPDSVKG (SEQ ID NO: 57) optionally containing one or two amino acid substitutions; and VHCDR3 comprising the amino acid sequence HLYYGDYFYVMDY (SEQ ID NO: 58) optionally containing one or two amino acid substitutions; and / or

[0778] The light chain variable region comprises: VLCDR1 containing the amino acid sequence KASQSVDYDGDNCLH (SEQ ID NO: 52) optionally containing one or two amino acid substitutions; VLCDR2 containing the amino acid sequence AASNLES (SEQ ID NO: 53) optionally containing one or two amino acid substitutions; and VLCDR3 containing the amino acid sequence QQSNEDPPT (SEQ ID NO: 54) optionally containing one or two amino acid substitutions. The amino acid substitutions can be conserved amino acid substitutions.

[0779] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0780] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence SYTIS (SEQ ID NO: 56), VHCDR2 containing the amino acid sequence YISSGGDNAYYPDSVKG (SEQ ID NO: 57), and VHCDR3 containing the amino acid sequence HLYYGDYFYVMDY (SEQ ID NO: 58); and

[0781] The light chain variable region includes: VLCDR1 containing the amino acid sequence KASQSVDYDGDNCLH (SEQ ID NO: 52), VLCDR2 containing the amino acid sequence AASNLES (SEQ ID NO: 53), and VLCDR3 containing the amino acid sequence QQSNEDPPT (SEQ ID NO: 54).

[0782] Optionally, each of the Met residues is independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or each of the Asp residues is independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0783] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0784] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence GFTFSSY (SEQ ID NO: 59), VHCDR2 containing the amino acid sequence SSGGDN (SEQ ID NO: 60), and VHCDR3 containing the amino acid sequence HLYYGDYFYVMDY (SEQ ID NO: 58); and

[0785] The light chain variable region includes: VLCDR1 containing the amino acid sequence KASQSVDYDGDNCLH (SEQ ID NO: 52), VLCDR2 containing the amino acid sequence AASNLES (SEQ ID NO: 53), and VLCDR3 containing the amino acid sequence QQSNEDPPT (SEQ ID NO: 54).

[0786] Amino acid substitutions can be made to provide variant antibodies derived from 21E06, such as providing an antibody, its fragment, or a variant, including:

[0787] The heavy chain variable region includes: VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 59) optionally containing one or two amino acid substitutions; VHCDR2 comprising the amino acid sequence SSGGDN (SEQ ID NO: 60) optionally containing one or two amino acid substitutions; and VHCDR3 comprising the amino acid sequence HLYYGDYFYVMDY (SEQ ID NO: 58) optionally containing one or two amino acid substitutions; and / or

[0788] The light chain variable region comprises: VLCDR1 containing the amino acid sequence KASQSVDYDGDNCLH (SEQ ID NO: 52) optionally containing one or two amino acid substitutions; VLCDR2 containing the amino acid sequence AASNLES (SEQ ID NO: 53) optionally containing one or two amino acid substitutions; and VLCDR3 containing the amino acid sequence QQSNEDPPT (SEQ ID NO: 54) optionally containing one or two amino acid substitutions. The amino acid substitutions can be conserved amino acid substitutions.

[0789] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0790] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence GFTFSSY (SEQ ID NO: 59), VHCDR2 containing the amino acid sequence SSGGDN (SEQ ID NO: 60), and VHCDR3 containing the amino acid sequence HLYYGDYFYVMDY (SEQ ID NO: 58); and

[0791] The light chain variable region includes: VLCDR1 containing the amino acid sequence KASQSVDYDGDNCLH (SEQ ID NO: 52), VLCDR2 containing the amino acid sequence AASNLES (SEQ ID NO: 53), and VLCDR3 containing the amino acid sequence QQSNEDPPT (SEQ ID NO: 54).

[0792] Optionally, each of the Met residues is independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or each of the Asp residues is independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0793] 25E06

[0794] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0795] The heavy chain variable region includes: VHCDR1 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence SYTMS (SEQ ID NO: 66); VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence YISGVGGDTYYPDSVKG (SEQ ID NO: 67); and VHCDR2 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity relative to the amino acid sequence HHYSHYFWYFDV (SEQ ID NO: 67). NO: 68) includes VHCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity; and / or

[0796] The light chain variable region includes: VLCDR1, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence KASQSVDYDGDGFMN (SEQ ID NO: 62); VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence AASNLES (SEQ ID NO: 63); and VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence QQSNEDPPT (SEQ ID NO: 63). NO: 64) includes VLCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity.

[0797] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0798] The heavy chain variable region includes: VHCDR1, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence GFTFSSY (SEQ ID NO: 69); VHCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence SGVGGD (SEQ ID NO: 70); and VHCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence HHYSHYFWYFDV (SEQ ID NO: 69). NO: 68) includes VHCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity; and / or

[0799] The light chain variable region includes: VLCDR1, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence KASQSVDYDGDGFMN (SEQ ID NO: 62); VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence AASNLES (SEQ ID NO: 63); and VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence QQSNEDPPT (SEQ ID NO: 63). NO: 64) includes VLCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity.

[0800] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0801] The heavy chain variable region includes: VHCDR1 with at least 90% identity to the amino acid sequence SYTMS (SEQ ID NO: 66), VHCDR2 with at least 90% identity to the amino acid sequence YISGVGGDTYYPDSVKG (SEQ ID NO: 67), and VHCDR3 with at least 90% identity to the amino acid sequence HHYSHYFWYFDV (SEQ ID NO: 68); and / or

[0802] The light chain variable region includes: VLCDR1, which has at least 90% identity with respect to the amino acid sequence KASQSVDYDGDGFMN (SEQ ID NO: 62); VLCDR2, which has at least 90% identity with respect to the amino acid sequence AASNLES (SEQ ID NO: 63); and VLCDR3, which has at least 90% identity with respect to the amino acid sequence QQSNEDPPT (SEQ ID NO: 64).

[0803] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0804] The heavy chain variable region includes: VHCDR1, which has at least 90% identity with respect to the amino acid sequence GFTFSSY (SEQ ID NO: 69); VHCDR2, which has at least 90% identity with respect to the amino acid sequence SGVGGD (SEQ ID NO: 70); and VHCDR3, which has at least 90% identity with respect to the amino acid sequence HHYSHYFWYFDV (SEQ ID NO: 68); and / or

[0805] The light chain variable region includes: VLCDR1, which has at least 90% identity with respect to the amino acid sequence KASQSVDYDGDGFMN (SEQ ID NO: 62); VLCDR2, which has at least 90% identity with respect to the amino acid sequence AASNLES (SEQ ID NO: 63); and VLCDR3, which has at least 90% identity with respect to the amino acid sequence QQSNEDPPT (SEQ ID NO: 64).

[0806] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0807] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence SYTMS (SEQ ID NO: 66), VHCDR2 containing the amino acid sequence YISGVGGDTYYPDSVKG (SEQ ID NO: 67), and VHCDR3 containing the amino acid sequence HHYSHYFWYFDV (SEQ ID NO: 68); and

[0808] The light chain variable region includes: VLCDR1 containing the amino acid sequence KASQSVDYDGDGFMN (SEQ ID NO: 62), VLCDR2 containing the amino acid sequence AASNLES (SEQ ID NO: 63), and VLCDR3 containing the amino acid sequence QQSNEDPPT (SEQ ID NO: 64).

[0809] Amino acid substitutions can be made to provide variant antibodies derived from 25E06, such as providing an antibody, its fragment, or a variant, including:

[0810] The heavy chain variable region includes: VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 66) optionally containing one or two amino acid substitutions; VHCDR2 comprising the amino acid sequence YISGVGGDTYYPDSVKG (SEQ ID NO: 67) optionally containing one or two amino acid substitutions; and VHCDR3 comprising the amino acid sequence HHYSHYFWYFDV (SEQ ID NO: 68) optionally containing one or two amino acid substitutions; and / or

[0811] The light chain variable region includes: VLCDR1 comprising the amino acid sequence KASQSVDYDGDGFMN (SEQ ID NO: 62) optionally containing one or two amino acid substitutions; VLCDR2 comprising the amino acid sequence AASNLES (SEQ ID NO: 63) optionally containing one or two amino acid substitutions; and VLCDR3 comprising the amino acid sequence QQSNEDPPT (SEQ ID NO: 64) optionally containing one or two amino acid substitutions. The amino acid substitutions can be conserved amino acid substitutions.

[0812] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0813] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence SYTMS (SEQ ID NO: 66), VHCDR2 containing the amino acid sequence YISGVGGDTYYPDSVKG (SEQ ID NO: 67), and VHCDR3 containing the amino acid sequence HHYSHYFWYFDV (SEQ ID NO: 68); and

[0814] The light chain variable region includes: VLCDR1 containing the amino acid sequence KASQSVDYDGDGFMN (SEQ ID NO: 62), VLCDR2 containing the amino acid sequence AASNLES (SEQ ID NO: 63), and VLCDR3 containing the amino acid sequence QQSNEDPPT (SEQ ID NO: 64);

[0815] Optionally, each of the Met residues is independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or each of the Asp residues is independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0816] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0817] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence GFTFSSY (SEQ ID NO: 69), VHCDR2 containing the amino acid sequence SGVGGD (SEQ ID NO: 70), and VHCDR3 containing the amino acid sequence HHYSHYFWYFDV (SEQ ID NO: 68); and

[0818] The light chain variable region includes: VLCDR1 containing the amino acid sequence KASQSVDYDGDGFMN (SEQ ID NO: 62), VLCDR2 containing the amino acid sequence AASNLES (SEQ ID NO: 63), and VLCDR3 containing the amino acid sequence QQSNEDPPT (SEQ ID NO: 64).

[0819] Amino acid substitutions can be made to provide variant antibodies derived from 25E06, such as providing an antibody, its fragment, or a variant, including:

[0820] The heavy chain variable region includes: VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 69) optionally containing one or two amino acid substitutions; VHCDR2 comprising the amino acid sequence SGVGGD (SEQ ID NO: 70) optionally containing one or two amino acid substitutions; and VHCDR3 comprising the amino acid sequence HHYSHYFWYFDV (SEQ ID NO: 68) optionally containing one or two amino acid substitutions; and / or

[0821] The light chain variable region includes: VLCDR1 comprising the amino acid sequence KASQSVDYDGDGFMN (SEQ ID NO: 62) optionally containing one or two amino acid substitutions; VLCDR2 comprising the amino acid sequence AASNLES (SEQ ID NO: 63) optionally containing one or two amino acid substitutions; and VLCDR3 comprising the amino acid sequence QQSNEDPPT (SEQ ID NO: 64) optionally containing one or two amino acid substitutions. The amino acid substitutions can be conserved amino acid substitutions.

[0822] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0823] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence GFTFSSY (SEQ ID NO: 69), VHCDR2 containing the amino acid sequence SGVGGD (SEQ ID NO: 70), and VHCDR3 containing the amino acid sequence HHYSHYFWYFDV (SEQ ID NO: 68); and

[0824] The light chain variable region includes: VLCDR1 containing the amino acid sequence KASQSVDYDGDGFMN (SEQ ID NO: 62), VLCDR2 containing the amino acid sequence AASNLES (SEQ ID NO: 63), and VLCDR3 containing the amino acid sequence QQSNEDPPT (SEQ ID NO: 64);

[0825] Optionally, each of the Met residues is independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or each of the Asp residues is independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0826] 28B01

[0827] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0828] The heavy chain variable region includes: VHCDR1, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence YYTMS (SEQ ID NO: 76); VHCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence YISSGGDNAYYPDSVRG (SEQ ID NO: 77); and VHCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence HHYSNYFWYFDV (SEQ ID NO: 77). NO: 78) includes VHCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity; and / or

[0829] The light chain variable region includes: VLCDR1, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence KASQSVDYAGDSYVN (SEQ ID NO: 72); VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence AASNLES (SEQ ID NO: 73); and VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence QQSNEDPPT (SEQ ID NO: 72). NO: 74) includes VLCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity.

[0830] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0831] The heavy chain variable region includes: VHCDR1, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence GFTFSYY (SEQ ID NO: 79); VHCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence SSGGDN (SEQ ID NO: 80); and VHCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence HHYSNYFWYFDV (SEQ ID NO: 79). NO: 78) includes VHCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity; and / or

[0832] The light chain variable region includes: VLCDR1, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence KASQSVDYAGDSYVN (SEQ ID NO: 72); VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence AASNLES (SEQ ID NO: 73); and VLCDR2, which has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with respect to the amino acid sequence QQSNEDPPT (SEQ ID NO: 72). NO: 74) includes VLCDR3 with at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity.

[0833] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0834] The heavy chain variable region includes: VHCDR1, which has at least 90% identity with respect to the amino acid sequence YYTMS (SEQ ID NO: 76); VHCDR2, which has at least 90% identity with respect to the amino acid sequence YISSGGDNAYYPDSVRG (SEQ ID NO: 77); and VHCDR3, which has at least 90% identity with respect to the amino acid sequence HHYSNYFWYFDV (SEQ ID NO: 78); and / or

[0835] The light chain variable region includes: VLCDR1, which has at least 90% identity with respect to the amino acid sequence KASQSVDYAGDSYVN (SEQ ID NO: 72); VLCDR2, which has at least 90% identity with respect to the amino acid sequence AASNLES (SEQ ID NO: 73); and VLCDR3, which has at least 90% identity with respect to the amino acid sequence QQSNEDPPT (SEQ ID NO: 74).

[0836] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0837] The heavy chain variable region includes: VHCDR1, which has at least 90% identity with respect to the amino acid sequence GFTFSYY (SEQ ID NO: 79); VHCDR2, which has at least 90% identity with respect to the amino acid sequence SSGGDN (SEQ ID NO: 80); and VHCDR3, which has at least 90% identity with respect to the amino acid sequence HHYSNYFWYFDV (SEQ ID NO: 78); and / or

[0838] The light chain variable region includes: VLCDR1, which has at least 90% identity with respect to the amino acid sequence KASQSVDYAGDSYVN (SEQ ID NO: 72); VLCDR2, which has at least 90% identity with respect to the amino acid sequence AASNLES (SEQ ID NO: 73); and VLCDR3, which has at least 90% identity with respect to the amino acid sequence QQSNEDPPT (SEQ ID NO: 74).

[0839] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0840] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence YYTMS (SEQ ID NO: 76), VHCDR2 containing the amino acid sequence YISSGGDNAYYPDSVRG (SEQ ID NO: 77), and VHCDR3 containing the amino acid sequence HHYSNYFWYFDV (SEQ ID NO: 78); and

[0841] The light chain variable region includes: VLCDR1 containing the amino acid sequence KASQSVDYAGDSYVN (SEQ ID NO: 72), VLCDR2 containing the amino acid sequence AASNLES (SEQ ID NO: 73), and VLCDR3 containing the amino acid sequence QQSNEDPPT (SEQ ID NO: 74).

[0842] Amino acid substitutions can be made to provide variant antibodies derived from 28B01, such as providing an antibody, its fragment, or a variant, including:

[0843] The heavy chain variable region includes: VHCDR1 comprising the amino acid sequence YYTMS (SEQ ID NO: 76) optionally containing one or two amino acid substitutions; VHCDR2 comprising the amino acid sequence YISSGGDNAYYPDSVRG (SEQ ID NO: 77) optionally containing one or two amino acid substitutions; and VHCDR3 comprising the amino acid sequence HHYSNYFWYFDV (SEQ ID NO: 78) optionally containing one or two amino acid substitutions; and / or

[0844] The light chain variable region comprises: VLCDR1 containing the amino acid sequence KASQSVDYAGDSYVN (SEQ ID NO: 72) optionally containing one or two amino acid substitutions; VLCDR2 containing the amino acid sequence AASNLES (SEQ ID NO: 73) optionally containing one or two amino acid substitutions; and VLCDR3 containing the amino acid sequence QQSNEDPPT (SEQ ID NO: 74) optionally containing one or two amino acid substitutions. The amino acid substitutions can be conserved amino acid substitutions.

[0845] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0846] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence YYTMS (SEQ ID NO: 76), VHCDR2 containing the amino acid sequence YISSGGDNAYYPDSVRG (SEQ ID NO: 77), and VHCDR3 containing the amino acid sequence HHYSNYFWYFDV (SEQ ID NO: 78); and

[0847] The light chain variable region includes: VLCDR1 containing the amino acid sequence KASQSVDYAGDSYVN (SEQ ID NO: 72), VLCDR2 containing the amino acid sequence AASNLES (SEQ ID NO: 73), and VLCDR3 containing the amino acid sequence QQSNEDPPT (SEQ ID NO: 74);

[0848] Optionally, each of the Met residues is independently replaced by an amino acid selected from the group consisting of A1a and Leu, and / or each of the Asp residues is independently replaced by an amino acid selected from the group consisting of A1a, G1n and G1u.

[0849] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0850] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence GFTFSYY (SEQ ID NO: 79), VHCDR2 containing the amino acid sequence SSGGDN (SEQ ID NO: 80), and VHCDR3 containing the amino acid sequence HHYSNYFWYFDV (SEQ ID NO: 78); and

[0851] The light chain variable region includes: VLCDR1 containing the amino acid sequence KASQSVDYAGDSYVN (SEQ ID NO: 72), VLCDR2 containing the amino acid sequence AASNLES (SEQ ID NO: 73), and VLCDR3 containing the amino acid sequence QQSNEDPPT (SEQ ID NO: 74).

[0852] Amino acid substitutions can be made to provide variant antibodies derived from 28B01, such as providing an antibody, its fragment, or a variant, including:

[0853] The heavy chain variable region includes: VHCDR1 comprising the amino acid sequence GFTFSYY (SEQ ID NO: 79) optionally containing one or two amino acid substitutions; VHCDR2 comprising the amino acid sequence SSGGDN (SEQ ID NO: 80) optionally containing one or two amino acid substitutions; and VHCDR3 comprising the amino acid sequence HHYSNYFWYFDV (SEQ ID NO: 78) optionally containing one or two amino acid substitutions; and / or

[0854] The light chain variable region comprises: VLCDR1 containing the amino acid sequence KASQSVDYAGDSYVN (SEQ ID NO: 72) optionally containing one or two amino acid substitutions; VLCDR2 containing the amino acid sequence AASNLES (SEQ ID NO: 73) optionally containing one or two amino acid substitutions; and VLCDR3 containing the amino acid sequence QQSNEDPPT (SEQ ID NO: 74) optionally containing one or two amino acid substitutions. The amino acid substitutions can be conserved amino acid substitutions.

[0855] In one embodiment, an antibody, a fragment thereof, or a variant thereof is provided, comprising:

[0856] The heavy chain variable region includes: VHCDR1 containing the amino acid sequence GFTFSYY (SEQ ID NO: 79), VHCDR2 containing the amino acid sequence SSGGDN (SEQ ID NO: 80), and VHCDR3 containing the amino acid sequence HHYSNYFWYFDV (SEQ ID NO: 78); and

[0857] The light chain variable region includes: VLCDR1 containing the amino acid sequence KASQSVDYAGDSYVN (SEQ ID NO: 72), VLCDR2 containing the amino acid sequence AASNLES (SEQ ID NO: 73), and VLCDR3 containing the amino acid sequence QQSNEDPPT (SEQ ID NO: 74);

[0858] Optionally, each of the Met residues is independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or each of the Asp residues is independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0859] Heavy chain variable region and / or light chain variable region

[0860] In one embodiment, the present invention provides an antigen-binding molecule, particularly an antibody binding to BDCA-2 (CLEC4C), comprising: a heavy chain variable region having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with an amino acid sequence selected from the group consisting of SEQ ID NO: 45, SEQ ID NO: 25, SEQ ID NO: 5, SEQ ID NO: 15, SEQ ID NO: 35, SEQ ID NO: 55, SEQ ID NO: 65, and SEQ ID NO: 75; and / or a heavy chain variable region having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with an amino acid sequence sele...

Claims

1. An anti-BDCA-2 antigen-binding molecule, wherein the anti-BDCA-2 antigen-binding molecule has an equilibrium dissociation constant (K) for BDCA-2 of less than 2 nM. D ), and wherein the antigen binding molecule comprises: A heavy chain variable region, comprising a VHCDR1 consisting of SEQ ID NO: 46, a VHCDR2 consisting of SEQ ID NO: 47, and a VHCDR3 consisting of SEQ ID NO: 48; and a light chain variable region comprising VLCDR1 consisting of SEQ ID NO:32, VLCDR2 consisting of SEQ ID NO:33, and VLCDR3 consisting of SEQ ID NO:34; or a heavy chain variable region comprising a VHCDR1 consisting of SEQ ID NO: 49, a VHCDR2 consisting of SEQ ID NO: 50, and a VHCDR3 consisting of SEQ ID NO: 48; and A light chain variable region comprising VLCDR1 consisting of SEQ ID NO:32, VLCDR2 consisting of SEQ ID NO:33, and VLCDR3 consisting of SEQ ID NO:

34.

2. The anti-BDCA-2 antigen-binding molecule according to claim 1, wherein the antigen-binding molecule comprises: a heavy chain variable region that is at least 80% identical to the amino acid sequence of SEQ ID NO: 45; and / or A light chain variable region, which has at least 80% identity with the amino acid sequence of SEQ ID NO:

31.

3. The anti-BDCA-2 antigen-binding molecule of claim 1, wherein the antigen-binding molecule comprises: a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 45; and / or A light chain variable region comprising the amino acid sequence of SEQ ID NO:

31. 4 . The anti-BDCA-2 antigen-binding molecule of claim 1 , wherein the antigen-binding molecule comprises a VH comprising the amino acid sequence of SEQ ID NO: 45 and a VL comprising the amino acid sequence of SEQ ID NO:

31. 5 . The anti-BDCA-2 antigen-binding molecule of claim 1 , wherein the antigen-binding molecule is an antibody or an antigen-binding fragment thereof. 6 . The anti-BDCA-2 antigen binding molecule of claim 5 , wherein the antigen binding fragment is Fab, F(ab′) 2 , Fv, scFv or diabody.

7. The anti-BDCA-2 antigen-binding molecule according to claim 5, wherein The anti-BDCA-2 antigen binding molecule is a monoclonal antibody.

8. The anti-BDCA-2 antigen binding molecule according to any one of claims 5 to 7, wherein the antibody or antigen binding fragment thereof is an IgA, IgD, IgE, IgG, IgM or IgY antibody or antigen binding fragment thereof. 9 . The anti-BDCA-2 antigen-binding molecule of claim 8 , wherein the antibody or antigen-binding fragment thereof is an IgG antibody or antigen-binding fragment thereof. 10 . The anti-BDCA-2 antigen-binding molecule of claim 9 , wherein the antibody or antigen-binding fragment thereof is an IgG1 antibody or antigen-binding fragment thereof.

11. The anti-BDCA-2 antigen binding molecule of claim 1, wherein the antigen binding molecule has a half maximal inhibitory concentration (IC) for inhibiting IFN secretion of less than 2 nM. 50 ).

12. The anti-BDCA-2 antigen binding molecule of claim 11, wherein the antigen binding molecule has an IC for inhibiting IFN secretion of less than 20 nM. 90 .

13. The anti-BDCA-2 antigen binding molecule of claim 12, wherein the antigen binding molecule has an equilibrium dissociation constant (K) for BDCA-2 of less than 0.01 nM. D ), less than 0.5 nM of the half maximal inhibitory concentration (IC 50 ), and an IC of less than 5 nM for inhibition of IFN secretion 90 . 14 . The anti-BDCA-2 antigen binding molecule of claim 1 , wherein the antigen binding molecule reduces the secretion of IFNα when administered in vivo or in vitro. 15 . A pharmaceutical composition comprising the anti-BDCA-2 antigen binding molecule of any one of claims 1 to 14 and a pharmaceutically acceptable excipient.

16. Use of the anti-BDCA-2 antigen binding molecule according to any one of claims 1 to 14, or the pharmaceutical composition according to claim 15, in the preparation of a medicament for treating or preventing an inflammatory disease or an autoimmune disease, wherein the inflammatory disease or the autoimmune disease is a BDCA-2-mediated disease.

17. The use according to claim 16, wherein the inflammatory disease or autoimmune disease is selected from the group consisting of systemic sclerosis, fibrosis, pemphigus vulgaris, systemic lupus erythematosus (SLE), cutaneous lupus, discoid lupus, lupus nephritis, polymyositis and dermatomyositis, psoriasis, rheumatoid arthritis, Graves' disease, morphea, inflammatory bowel disease, type I diabetes, Sjögren's disease and Hashimoto's disease.

18. The use according to claim 16, wherein the inflammatory disease is systemic sclerosis, fibrosis or pemphigus vulgaris.

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