Anti-BDCA-2 antibodies

Abstract

The present invention provides antigen-binding molecules, in particular antibodies, fragments and variants thereof, that bind to BDCA-2 (CLEC4C), and the use of said antigen-binding molecules for treating and / or preventing inflammatory disease and immune disorders, such as autoimmune disease.SOLUTION: Anti-BDCA-2 (CLEC4C) antigen binding molecules are provided that have a KD for BDCA-2 (2nM) of less than about CLEC4C. Preferred are anti-BDCA-2 (2nM) antigen binding molecules having a half maximal inhibitory concentration (IC50) for inhibiting IFN-secretion of less than about CLEC4C.SELECTED DRAWING: None

Description

[Technical Field]

[0001] 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 said antigen-binding molecules in the treatment and / or prevention of inflammatory disorders and immune disorders, such as autoimmune diseases. [Background technology]

[0002] It is essential for the immune system to avoid recognizing self-DNA and self-RNA while retaining the ability to sense microbial nucleic acids. The innate immune system appears to have refined several different mechanisms to distinguish between exogenous pathogen-derived nucleic acids and self-host-derived nucleic acids. However, despite the different mechanisms the innate immune system has evolved to prevent self-recognition, considerable evidence has emerged that Toll-like receptor (TLR) recognition of self-nucleic acids occurs under certain circumstances. Chronically activated plasmacytoid dendritic cells (pDCs) and the IFNα they produce in response to self-nucleic acids are contributing factors in the pathogenesis of several autoimmune diseases, such as scleroderma (SSc), systemic lupus erythematosus (SLE), Sjögren's syndrome, and psoriasis (Non-Patent Document 1, Non-Patent Document 2, Non-Patent Document 3, Non-Patent Document 4).

[0003] Plasmacytoid dendritic cells (pDCs) are bone marrow-derived cells specialized in secreting type I IFN (Non-Patent Document 5, Non-Patent Document 6). pDCs are primarily found in peripheral blood and primary and secondary lymphoid organs. pDCs rapidly detect viral nucleic acids, which are internalized and transported to endosomes containing TLR7 and TLR9. Ligation of these receptors results in the immediate release of type I IFN, providing very early protection against viral infection (Non-Patent Document 7). pDCs also secrete type I IFN, which is released during cell necrosis and / or apoptosis or in response to endogenous nucleic acids bound to antinuclear autoantibodies.

[0004] Considerable evidence points to the involvement of self-nucleic acid recognition in inflammatory and autoimmune diseases. In particular, the contribution of TLRs to autoimmunity has been highlighted in multiple disease models. A prime example is the role played by TLR9 and TLR7 in lupus following immune complex-mediated accumulation of self-DNA / RNA (Non-Patent Document 8, Non-Patent Document 9). Another example is the importance of self-antimicrobial peptides in promoting autoimmunity (Non-Patent Document 10). Overexpression of TLRs alone, as shown for TLR7 or TLR8, has been shown to be sufficient to induce autoimmunity in otherwise wild-type animals (Non-Patent Document 11, Non-Patent Document 12).

[0005] SSc is a multiorgan fibrotic disorder in which vascular damage, autoimmunity, and inflammation lead to a variety of life-altering and life-threatening clinical symptoms. SSc has the highest morbidity and mortality rates among rheumatic diseases, with a 10-year mortality rate of 23% to 45% (Non-Patent Document 13). There is a female predominance of approximately 4:1, and the typical age of onset is between 35 and 55 years of age. Although the pathophysiology of SSc is not fully understood, substantial evidence indicates an interplay between immunological abnormalities, endothelial dysfunction, and profibrotic mechanisms.

[0006] Evidence points to a role for pDCs in SSc. pDCs infiltrate the skin of SSc patients and become chronically activated, leading to the secretion of IFNα and CXCL4, both hallmarks of the disease. Non-patent document 14 demonstrates that CXCL4 secretion is due to the abnormal presence of TLR8 on pDCs from SSc patients, which is absent in healthy donors, and that CXCL4 acts primarily by enhancing IFN production induced by TLR8 as well as TLR9 by pDCs. Other studies on IFN-inducible chemokines in SSc (Non-patent document 14) have demonstrated that CXCL4 secretion is due to the abnormal presence of TLR8 on pDCs from SSc patients, which is absent in healthy donors, and that CXCL4 acts primarily by enhancing IFN production induced by TLR9 as well as TLR8. The report of CXCL4 as a biomarker for SSc (Patent Document 15) and the report of CXCL4 as a biomarker for SSc (Non-Patent Document 16) have sparked interest in the role of IFNs in the progression and early stages of SSc. Another recent paper has shown that an IFN signature (previously associated with active SSc) is present before the onset of clinical fibrosis (Patent Document 1). In addition, in vivo data have shown that pDC depletion can prevent disease in a mouse model of scleroderma and can reverse fibrosis in mice with established disease (Patent Document 14).

[0007] pDCs express multiple receptors that inhibit type I IFN secretion and prevent immune surveillance. One of these receptors is CLEC4C, also known as blood dendritic cell antigen-2 (BDCA-2) and CD303 (Non-Patent Document 17). CLEC4C is a type II transmembrane glycoprotein belonging to the C-type lectin (CTL) superfamily (Non-Patent Document 18). BDCA-2 is the most specific marker for human pDCs and is expressed only in primates. BDCA-2 consists of a single extracellular carbohydrate-recognition domain, a transmembrane region, and a short cytoplasmic domain, and does not possess any obvious signaling motifs. BDCA-2 transmits intracellular signals via the related transmembrane adaptor FcεRγ, which recruits the protein tyrosine kinase Syk, inducing protein tyrosine phosphorylation and calcium mobilization (Non-Patent Document 19). The FcεRγ-Syk signaling pathway promotes cell activation in other lymphoid and myeloid cells, but prevents pDC activation induced by TLR7 and TLR9 and inhibits type I IFN secretion (Non-Patent Document 17).

[0008] pDCs are abnormally activated in peripheral blood or diseased areas 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 thyroiditis (Non-Patent Documents 20 and 21). [Prior art documents] [Non-patent literature]

[0009]

Non-licensed literature 1

Non-licensed Document 2

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

Non-licensed Document 7

Non-licensed literature 9

Non-licensed literature 10

Non-licensed Document 11

Non-Patent Document 12

Non-Patent Document 13

Non-Patent Document 14

Non-Patent Document 15

Non-Patent Document 16

Non-Patent Document 17

Non-Patent Document 18

Non-Patent Document 19

Non-Patent Document 20

Non-Patent Document 21

Summary of the Invention

[0010] In a first aspect, the present invention provides an antigen-binding molecule, or a fragment or variant thereof, comprising a heavy chain variable region comprising a VH CDR3 and / or a light chain variable region comprising a VL CDR3, wherein the antigen-binding molecule binds to BDCA-2 (CLEC4C), or a fragment or variant thereof.

[0011] In a second aspect, the present invention provides an antigen-binding molecule, or a fragment or variant thereof, comprising a heavy chain variable region and / or a light chain variable region each comprising three CDR regions, wherein the antigen-binding molecule binds to BDCA-2 (CLEC4C), or a fragment or variant thereof.

[0012] In a third aspect of the present invention, a compound having an equilibrium dissociation constant (K) of less than about 2 nM for BDCA-2 (CLEC4C) is D In some embodiments, the antigen binding molecule has an equilibrium dissociation constant (K) of less than about 0.01 nM for BDCA-2 (CLEC4C). D )

[0013] In a fourth aspect of the present invention, there is provided an anti-BDCA-2 (CLEC4C) antigen binding molecule having a median inhibitory concentration (IC50) for inhibition of IFN secretion of less than about 2 nM. In some embodiments, the antigen binding molecule has a median inhibitory concentration (IC50) for inhibition of IFN secretion of less than about 0.1 nM.

[0014] In a fifth aspect of the present invention, there is provided an anti-BDCA-2 (CLEC4C) antigen binding molecule having an IC90 of less than about 20 nM for inhibiting IFN secretion, hi some embodiments, the antigen binding molecule has an IC90 of less than about 5 nM for inhibiting IFN secretion.

[0015] In a sixth aspect of the present invention, there is provided an anti-BDCA-2 (CLEC4C) antigen binding molecule comprising a VHCDR3 comprising any one of the amino acid sequences of SEQ ID NOs: 48, 28, 8, 38, 58, 68 and 78, and / or a VLCDR3 comprising any one of the amino acid sequences of SEQ ID NOs: 34, 24, 44, 4, 14, 54, 64 and 74.

[0016] In a seventh aspect of the present invention, there is provided a VHCDR1 comprising any one of the amino acid sequences of SEQ ID NOs: 46, 49, 26, 29, 6, 9, 16, 19, 36, 39, 56, 59, 66, 69, 76 and 79, a VHCDR2 comprising any one of the amino acid sequences of SEQ ID NOs: 47, 50, 27, 30, 7, 10, 17, 20, 37, 40, 57, 60, 67, 70, 77 and 80, and a VHCDR3 comprising any one of the amino acid sequences of SEQ ID NOs: 48, 28, 8, 18, 38, 58, 68 and 78. and / or a VLCDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 32, 22, 42, 2, 12, 52, 62, and 72, a VLCDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 33, 23, 43, 3, 13, 53, 63, and 73, and a VLCDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 34, 24, 44, 4, 14, 54, 64, and 74.

[0017] In an eighth aspect of the present invention, there is provided an anti-BDCA-2 (CLEC4C) antigen binding molecule comprising 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.

[0018] In a ninth aspect of the present invention, there is provided an anti-BDCA-2 (CLEC4C) antigen-binding molecule that specifically binds to BDCA-2 (CLEC4C) and 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. The present invention also provides fragments and variants derived from the above antibodies.

[0019] In a further aspect, the present invention provides an antigen-binding molecule, or a fragment or variant thereof, that binds to BDCA-2 (CLEC4C) and competes with the antigen-binding molecule of any of the first to ninth aspects of the present invention for binding to BDCA-2 (CLEC4C).

[0020] In a further aspect, the present invention provides an antigen-binding molecule that specifically binds to the epitope of BDCA-2 (CLEC4C) to which the antigen-binding molecule of any of the first to ninth aspects of the present invention binds.

[0021] In a further aspect, the present invention provides an antigen-binding molecule that specifically binds to BDCA-2 (CLEC4C) and inhibits the binding of BDCA-2 (CLEC4C) to the antigen-binding molecule of any of the first to ninth aspects of the present invention.

[0022] A further aspect of the present invention provides an anti-BDCA-2 (CLEC4C) antigen-binding molecule comprising 1 to 10, 1 to 5, or 1 or 2 amino acid substitutions derived from the antigen-binding molecule of any of the first to ninth aspects of the present invention.

[0023] In a further aspect of the present invention, there is provided an anti-BDCA-2 (CLEC4C) antigen binding molecule that is a humanized or deimmunized derivative of the anti-BDCA-2 (CLEC4C) antigen binding molecule of the present invention.

[0024] In a further aspect of the invention, there are provided affinity matured mutants of the antigen-binding molecules or antibodies of the invention.

[0025] In a further aspect of the present invention, there is provided a pharmaceutical composition comprising an antigen-binding molecule of the present invention, or a fragment, variant or affinity matured mutant thereof.

[0026] In a still further aspect of the present invention, there is provided an antigen-binding molecule or a pharmaceutical composition of the present invention for use in medicine.

[0027] In another aspect, there is provided an antigen-binding molecule or pharmaceutical composition of the present invention for use in the prevention and / or treatment of an inflammatory disorder or disease.

[0028] In another aspect, there is provided use of an antigen-binding molecule or pharmaceutical composition of the present invention for the manufacture of a medicament for use in the treatment of an inflammatory disorder or disease.

[0029] In a further aspect, there is provided a method for treating or preventing an inflammatory disorder or disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an antigen-binding molecule or pharmaceutical composition of the present invention.

[0030] Nucleic acids encoding the antigen-binding molecules of the present invention are also provided. The present invention also provides a host cell comprising a nucleic acid, vector or plasmid of the present invention.

[0031] The present invention also provides a method for producing a cell expressing an anti-BDCA-2 (CLEC4C) antigen-binding molecule, comprising transfecting the cell with a plasmid or vector of the present invention. The present invention also provides a method for producing an anti-BDCA-2 (CLEC4C) antigen-binding molecule, comprising culturing a host cell of the present invention in a cell culture medium under conditions that allow intracellular expression of the encoded nucleic acid sequence of the plasmid or vector, and optionally recovering the anti-BDCA-2 (CLEC4C) antigen-binding molecule from the cell supernatant.

[0032] The present invention also provides kits comprising an anti-BDCA-2 (CLEC4C) antigen binding molecule or other aspects of the invention, optionally further comprising instructions for use. [Brief explanation of the drawings]

[0033] [Figure 1] Figure 1 shows binding of chimeric mAbs to human and cynomolgus monkey cells expressing BDCA-2. 5 μg / ml of purified mAb was tested against human- or cynomolgus monkey-expressed BDCA-2. Positive controls used were anti-BDCA-2 mAbs AC144 (Miltenyi Biotec, Cat. No. 130-090-690) and BIIB059 (WO2014093396), and the negative control was buffer (no Ab). [Figure 2] Figure 1 shows binding of chimeric mAbs to plasmacytoid dendritic cells. Purified mAbs (10 μg / ml) were tested for binding to purified pDCs by flow cytometry. Positive controls used were anti-BDCA-2 mAbs AC144 (Miltenyi Biotech, Cat. No. 130-090-690) and BIIB059 (WO2014093396), and the negative control was buffer (no Ab). [Figure 3A]Figure 1 shows the effect of chimeric anti-BDCA-2 mAbs on inhibiting IFNα from ODN-stimulated pDCs. mAbs were tested at 1 μg / ml or 0.1 μg / ml for inhibition of ODN-induced IFNα from human purified pDCs. Positive anti-BDCA-2 mAb controls used were AC144 (Miltenyi Biotec, Cat. No. 130-090-690) and BIIB059 (WO2014093396), and the negative control was buffer (no Ab). [Figure 3B] Figure 1 shows the effect of chimeric anti-BDCA-2 mAbs inhibiting IFNα from TLR9 (ODN, 1 μM) stimulated PBMCs. mAbs were tested at 10 μg / ml, 1 μg / ml, or 0.1 μg / ml for inhibition of ODN-induced IFNα from human PBMCs (500K / well). Negative controls were buffer (control) and hIgG1 at 10 μg / ml, 1 μg / ml, or 0.1 μg / ml. [Figure 3C] Figure 1 shows the effect of chimeric anti-BDCA-2 mAbs on inhibiting IFNα from TLR8 (ORN, 1 μM)-stimulated PBMCs. mAbs were tested at 10 μg / ml, 1 μg / ml, or 0.1 μg / ml for inhibition of ORN-induced IFNα from human PBMCs (500K / well). Negative controls were buffer (control) and hIgG1 at 10 μg / ml, 1 μg / ml, or 0.1 μg / ml. [Figure 3D] Figure 1 shows the effect of chimeric anti-BDCA-2 mAbs to inhibit IFNα from TLR7 (imiquimod, 4 μM)-stimulated PBMCs. mAbs were tested at 10 μg / ml, 1 μg / ml, or 0.1 μg / ml for inhibition of imiquimod-induced IFNα from human PBMCs (500K / well). Negative controls were buffer (control) and hIgG1 at 10 μg / ml, 1 μg / ml, or 0.1 μg / ml. [Figure 4A] Figure 1 shows the effect of chimeric anti-BDCA-2 mAb (10 μg / ml) on inhibiting intracellular IFNα and TNFα from ODN-stimulated healthy pDCs. The positive control was anti-BDCA-2 mAb BIIB059 (WO2014093396), and the negative control was buffer (no Ab). [Figure 4B] Figure 1 shows the effect of chimeric anti-BDCA-2 mAb (10 μg / ml) on inhibiting TNFα secretion from ODN-stimulated healthy pDCs. The positive control was anti-BDCA-2 mAb BIIB059 (WO2014093396), and the negative control was buffer (no Ab). [Figure 5] FIG. 1 shows binding of humanized 3E5 and 28B1 mutant mAbs to pDCs by flow cytometry. [Figure 6A] Figure 1 shows the effect of humanized 28B1 anti-BDCA-2 mAb on inhibiting IFNα secretion from ODN-stimulated PBMCs. The positive control was anti-BDCA-2 mAb BIIB059 (WO2014093396), and the negative control was buffer (no Ab). [Figure 6B] Figure 1 shows the effect of humanized 3E5 anti-BDCA-2 mAb on inhibiting IFNα secretion from ODN-stimulated PBMCs. The positive control was anti-BDCA-2 mAb BIIB059 (WO2014093396), and the negative control was buffer (no Ab). [Figure 7A] Figure 7A shows that chimeric mAb 3E5 inhibition of BDCA2 suppresses ODN-stimulated pDC transcriptome activation. Figure 7A shows global RNA-seq analysis of three independent human pDC donors (lineage-HLA-DR+CD123+CD304+) with and without ODN stimulation, as well as pathway analysis of differentially expressed genes (DEGs). [Figure 7B] Figure 7B shows that chimeric mAb 3E5 inhibition of BDCA2 suppresses ODN-stimulated pDC transcriptome activation. Figure 7B shows that 3E5 inhibition of ODN-stimulated pDC DEGs shows an expression profile similar to that of unstimulated pDCs. [Figure 8A] Figure 8 shows organotypic 3D skin culture and the effect of chimeric anti-BDCA-2 mAb 3E5. Figure 8A shows an overview of the culture method and air-liquid interface (ALI). [Figure 8B]Organotypic 3D skin culture and the effect of chimeric anti-BDCA-2 mAb 3E5. In Figure 8B, hematoxylin and eosin (H&E) staining revealed in vivo-like development of the epithelium. [Figure 8C] Figure 8C shows the effects of organotypic 3D skin culture and chimeric anti-BDCA-2 mAb 3E5. Figure 8C shows 27 IFN-stimulated genes upregulated by ODN-stimulated pDC supernatants in the epithelium compared to expression in the epithelium using resting pDC supernatants and inhibition by chimeric anti-BDCA-2 mAb 3E5. [Figure 9A] Figure 1 shows a xenograft mouse model of human pDC activation. Effect of chimeric anti-BDCA-2 mAbs 28B1 and 3E5 on the mouse interferon gene signature. Normal human primary pDCs were injected via the tail vein into NOD-SCID mice, and the back skin was treated with Aldara cream with and without chimeric anti-BDCA2 mAb 3E5 or 28B1 or human IgG (5 mg / kg). Total RNA from triplicate experiments was used to generate cDNA, and qRT-PCR analysis of 78 genes commonly upregulated during type I interferon responses was performed. IGS from a Qiagen panel were ranked for differential expression in hIgG conditions versus control (Aldara / imiquimod alone). The 10 most differentially expressed genes were selected for analysis. [Figure 9B] Figure 1 shows a xenograft mouse model of human pDC activation. Effect of chimeric anti-BDCA-2 mAbs 28B1 and 3E5 on the mouse interferon gene signature. Normal human primary pDCs were injected via the tail vein into NOD-SCID mice, and the back skin was treated with Aldara cream with and without chimeric anti-BDCA2 mAb 3E5 or 28B1 or human IgG (5 mg / kg). Total RNA from triplicate experiments was used to generate cDNA, and qRT-PCR analysis of 78 genes commonly upregulated during type I interferon responses was performed. IGS from a Qiagen panel were ranked for differential expression in hIgG conditions versus control (Aldara / imiquimod alone). The 10 most differentially expressed genes were selected for analysis. [Figure 10A] Figure 10 shows a 3-week pDC- and bleomycin-induced skin fibrosis model. Bleomycin (Bleo) or PBS (control, 100 μl) was injected sc into a single site on the shaved back of NOD-SCID mice every other day for 3 weeks, starting on day 0. Mice receiving human pDCs (2.5 × 10 cells) were injected iv on days 0, 7, and 14. 3E5 mAb (var_6) or human IgG (2.5 mg / kg ip) was injected once every 5 days starting on day -1 (n = 5 ip injections per mouse) (administration schedule shown in Figure 10E). Formalin-fixed, paraffin-embedded skin tissues from treated mice were stained with hematoxylin and eosin (H&E, Figure 10A) or Masson's trichrome (MT) staining (Figure 10B). [Figure 10B] The epidermal and dermal skin thicknesses in the treatment groups are shown in Figures 10B and 10C. Statistical significance (unpaired t-test): P<0.05*, 0.01**, 0.001*** [Figure 10C] The epidermal and dermal skin thicknesses in the treatment groups are shown in Figures 10B and 10C. Statistical significance (unpaired t-test): P<0.05*, 0.01**, 0.001*** [Figure 10D] Total collagen relative to total protein in skin punch biopsies is shown in Figure 10D. Statistical significance (unpaired t-test); P<0.05*, 0.01**, 0.001*** [Figure 10E] Figure 10B shows a 3-week pDC- and bleomycin-induced skin fibrosis model. Bleomycin (Bleo) or PBS (control, 100 μl) was injected sc into a single site on the shaved back of NOD-SCID mice every other day for 3 weeks, starting on day 0. Mice that received human pDCs (2.5 × 10 cells) were injected iv on days 0, 7, and 14. 3E5 mAb (var_6) or human IgG (2.5 mg / kg ip) was injected once every 5 days (n = 5 ip injections per mouse) starting on day -1 (administration schedule shown in Figure 10E). [Figure 11]FIG. 11A and FIG. 11B show the alignment of the parental 3E5 sequence and the four humanized / deimmunized variants 1-4. [Figures 12A, 12B, 12C, and 12D] Figures 1A-1D show the parental 3E5 heavy and light chain variable sequences, as well as the sequences of four humanized / deimmunized variants 1-4 (SEQ ID NOS: 1, 11, 21, 31, 41, 5, 15, 25, 35, and 45) that together constitute 16 variant antibodies based on the parental 3E5 antibody. Figures A and B identify the six CDRs according to the Kabat scheme. Figures C and D identify the six CDRs according to the Chothia scheme. These figures also provide the respective SEQ ID NOS (SEQ ID NOS: 1-50) for the sequences (heavy, light, and both Kabat and Chothia CDRs) for the 3E5 parent antibody and its 16 variants. In the event of any discrepancies between the sequences in these figures and those in the accompanying sequence listing or elsewhere in this specification, the sequences in these figures shall control. [Figure 13] Figure 13 shows the overlap mapping design of trypsin, chymotrypsin, ASP-N, elastase, and thermolysin peptides using proteolysis for epitope determination. Combining peptides from trypsin, chymotrypsin, elastase, and thermolysin proteolysis resulted in 100% sequence coverage. Amino acid numbering refers to amino acids 45-213 of Q8WTT0, the extracellular domain of BDCA-2; amino acid 1 in Figure 13 corresponds to amino acid 45 of Q8WTT0. DETAILED DESCRIPTION OF THE INVENTION

[0034] As used herein, an "antigen-binding molecule" is a member of a pair of molecules that have binding specificity for each other. Members of an antigen-binding pair may be naturally occurring or wholly or partially synthetically produced. One member of the pair has an area on its surface, which may be a protrusion or a cavity, that specifically binds to, and is therefore complementary to, a particular spatial and polar configuration of the other member of the pair. Thus, the members of the pair have the property of specifically binding to each other. Examples of types of antigen-binding pairs are antigen-antibody, biotin-avidin, hormone-hormone receptor, receptor-ligand, and enzyme-substrate. The present invention generally relates to antigen-antibody type interactions. The antigen-binding molecules used in the present invention specifically bind to BDCA-2 (CLEC4C) or an epitope of BDCA-2 (CLEC4C). The binding affinity of an antigen-binding molecule to BDCA-2 (CLEC4C) or an epitope of BDCA-2 (CLEC4C) is determined by the dissociation constant (K D The binding affinity of an antigen-binding molecule to BDCA-2 (CLEC4C) or an epitope of BDCA-2 (CLEC4C) can be measured using the association constant (K a The K of the antigen-binding molecule of the present invention against the epitope of BDCA-2 (CLEC4C) to which it binds can be measured. D The values ​​are the K values ​​of antigen-binding molecules against surrogate epitopes of BDCA-2 (CLEC4C) or non-BDCA-2 (CLEC4C) epitopes. D lower than the value.

[0035] Antigen-binding molecules that bind to BDCA-2 (CLEC4C) include anti-BDCA-2 (CLEC4C) antibodies and antigen-binding fragments thereof. The antigen-binding molecules used in the present invention are typically antibodies.

[0036] The term "antibody," as used herein, refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain an antigen-binding site that specifically binds an antigen, whether natural or partially or wholly synthetically produced. The term also encompasses any polypeptide or protein having a binding domain that is, or is homologous to, an antibody binding domain. Antibodies can be polyclonal or monoclonal. They may be derived from natural sources or partially or wholly synthetically produced. Antibodies are polypeptides that typically contain two identical heavy chains and two identical, smaller light chains. In mammals, there are two types of light chains, called lambda (λ) and kappa (κ). Each heavy chain and each light chain is composed of a variable region and a constant region. The heavy chain variable region is referred to as the VH region, and the light chain variable region is referred to as the VL region. For kappa light chains, the VL region is sometimes referred to as the VK region. Each of the heavy and light chain variable regions contains three complementarity determining regions (CDRs): CDR1, CDR2, and CDR3, designated VLCDR1, VLCDR2, VLCDR3, VHCDR1, VHCDR2, and VHCDR3, respectively. Examples of antibodies are immunoglobulin isotypes (e.g., IgG, IgE, IgM, IgD, and IgA) and their isotypic subclasses, fragments containing antigen-binding domains such as Fab, F(ab'), Fv, scFv, dAb, Fd, and diabodies.

[0037] Antibody and antigen-binding molecule fragments 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 a whole antibody can perform the function of binding to an antigen. Examples of binding fragments include (i) a Fab fragment consisting of the VL, VH, CL, and CH1 domains, (ii) an Fd fragment consisting of the VH and CH1 domains, (iii) an Fv fragment consisting of the VL and VH domains of a single antibody, (iv) a dAb fragment consisting of the VH domain (Ward, ES et al., Nature 341:544-546 (1989)), (v) an isolated CDR region, (vi) an F(ab')2 fragment, which is a bivalent fragment comprising two linked Fab fragments, and (vii) a single-chain Fv molecule (scFv) in which the VH and VL domains are linked by a peptide linker that enables the two domains to associate to form an antigen-binding site (Bird et al., Science 242:423-426 (1988), Huston et al., PNAS USA 85:5879-5883). (1988)), (viii) bispecific single-chain Fv dimers (International Application PCT / US92 / 09965), and (ix) "diabodies," which are multivalent or multispecific fragments constructed by gene fusion (International Publication WO 94 / 13804; P. Hollinger et al., Proc. Natl. Acad. Sci. USA 90: 6444-6448 (1993)). Typically, the fragments are Fab, F(ab')2, or Fv fragments, or scFv molecules.

[0038] A diabody is a multimer of polypeptides, each polypeptide being an immunoglobulin light chain. The multimer comprises a first domain comprising the binding region of the chain and a second domain comprising the binding region of an immunoglobulin heavy chain, the two domains being linked (e.g., by a peptide linker) but unable to associate with each other to form an antigen-binding site, which is formed by the association of a first domain of one polypeptide in the multimer with a second domain of another polypeptide in the multimer (WO 94 / 13804).

[0039] When bispecific antibodies are used, they may be conventional bispecific antibodies and may be produced in a variety of ways (Hollinger & Winter, Current Opinion Biotechnol. 4:446-449 (1993)), for example, produced chemically or from hybrid hybridomas, or may be any of the bispecific antibody fragments described below. It may be preferable to use scFv dimers or diabodies rather than whole antibodies. Diabodies and scFvs can be constructed using only variable domains, without the Fc region, potentially reducing the effects of anti-idiotypic reaction. Other forms of bispecific antibodies include the single-chain "Janusins" described in Traunecker et al., EMBO Journal 10:3655-3659 (1991).

[0040] Bispecific antibodies are antibodies that can simultaneously bind to two target molecules, such as two antigens or two epitopes. Bispecific antibodies are sometimes referred to as dual-binding antibodies. Examples of bispecific antibody formats include (mAb)2, Fcab, F(mAb')2, quadroma, scFv (single-chain variable fragment), bsDb (bispecific diabody), scBsDb (single-chain bispecific diabody), BiTE (bispecific T cell engaging antibody), DART (dual affinity retargeting antibody), charge pairs, tandem antibody, tandem scFv-Fc, Fab-scFv-Fc, Fab-scFv, minibody, zybody, DNL-F(ab)3 (dock-and-lock trivalent Fab), bssdAb (bispecific single domain antibody), and nobui. Examples of suitable clamping devices include, but are not limited to, knobs-in-holes.

[0041] Bispecific diabodies, in contrast to bispecific whole antibodies, can also be isolated from E. coli. Diabodies (and many other polypeptides, such as antibody fragments) of appropriate binding specificity can be readily selected from libraries using phage display (WO 94 / 13804). If one arm of the diabody is held constant, e.g., specificity for antigen X, another arm can be varied to generate a library and select antibodies of appropriate specificity.

[0042] Antigen binding molecules of the present invention can be provided in a format that allows cross-linking between adjacent antigen binding molecules. For example, antigen binding molecules containing an Fc region (e.g., in a monoclonal antibody format) allow cross-linking between the Fc regions of two adjacent molecules (and thus cross-linking between adjacent BDCA-2 molecules due to colocalization). In some cases, this can promote BDCA2 internalization and inhibition of IFN secretion. In other embodiments, antigen binding molecules can be provided in a format that does not allow cross-linking between adjacent antigen binding molecules. For example, antigen binding molecules lacking an Fc region (e.g., in a Fab format or similar) may not cross-link. Nevertheless, it has been demonstrated that antigen binding molecules of the present invention (specifically, antigen binding molecules having the sequences disclosed herein) can still promote BDCA2 internalization and inhibition of IFN secretion in a dose-dependent manner, even when provided in a format that does not allow cross-linking. This means that both types of antigen binding molecules (formats that allow cross-linking and formats that do not allow cross-linking) can be provided, thereby enhancing the utility and functionality of the antigen binding molecules of the present invention compared to those of the prior art.

[0043] Furthermore, the antigen-binding molecules of the present invention, even when provided in a format in which the antigen-binding molecules bind to BDCA2 monovalently, can dose-dependently promote BDCA2 internalization and inhibition of IFN secretion. For example, antigen-binding molecules in Fab format that bind to BDCA2 monovalently (i.e., at a ratio of one BDCA2 molecule to one antigen-binding molecule) have been shown to dose-dependently promote BDCA2 internalization and inhibition of IFN secretion. This is also in contrast to prior art anti-BDCA2 molecules.

[0044] Thus, in some embodiments, antigen binding molecules bind BDCA2 monovalently (i.e., at a ratio of one BDCA2 molecule to one antigen binding molecule). In some embodiments, antigen binding molecules do not cross-link each other. Fab formats accomplish both of these goals by not cross-linking each other (due to the lack of an Fc region) and by binding their antigen monovalently. In some embodiments, the invention provides antigen binding molecules having sequences that promote BDCA2 internalization and inhibition of IFN secretion (in vitro or in vivo). Advantages of the antigen binding molecules of the invention include their ability to promote BDCA2 internalization and inhibition of IFN secretion regardless of the ability of the antigen binding molecules to cross-link each other (and thus co-localize BDCA2 molecules) and regardless of valency (i.e., monovalent or bivalent binding).

[0045] identity and homology "Identity," as known in the art, is a relationship between two or more polypeptide sequences or two or more polynucleotide sequences, as determined by comparing the sequences. In the art, identity also means the degree of sequence relatedness between polypeptide or polynucleotide sequences, as the case may be, as determined by the match between strings of such sequences. There are many methods for measuring identity between two polypeptide or two polynucleotide sequences, and commonly used methods for determining identity are codified in computer programs. Preferred computer programs for determining identity between two sequences include the GCG program package (Devereux, et al., Nucleic Acids Research, 12, 387 (1984)), BLASTP, BLASTN, and FASTA (Atschul et al., J. Molec. Biol. 215, 403 (1990)), but are not limited to these.

[0046] Programs such as the CLUSTAL program can be used to compare amino acid sequences. This program compares amino acid sequences and finds the optimal alignment by inserting spaces into either sequence as needed. It is possible to calculate amino acid identity or similarity (identity + conservation of amino acid type) for the optimal alignment. Programs such as BLASTx align the longest stretch of similar sequences and assign a value to the goodness of fit. This allows for the finding of several regions of similarity, resulting in comparisons each with a different score. Both types of identity analysis are contemplated in the present invention.

[0047] The percent identity of two amino acid sequences or two nucleic acid sequences is determined by aligning the sequences for optimal comparison (e.g., gaps can be introduced into the initial sequence for best alignment) and comparing the amino acid residues or nucleotides at corresponding positions. The "best alignment" is the alignment of two sequences that results in the highest percent identity. The percent 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 x 100). Generally, references to % identity herein refer to % identity over the entire length of the molecule, unless the context indicates otherwise.

[0048] The determination of percent identity between two sequences can be accomplished using a mathematical algorithm known to those of skill in the art. One example of a mathematical algorithm for comparing two sequences is the Karlin and Altschul (1993) Proc. Natl. Acad. Sci. USA 90:5873-5877, modified as in Karlin and Altschul (1990) Proc. Natl. Acad. Sci. USA 87:2264-2268. NBLAST and XB from Altschul, et al. (1990) J. Mol. Biol. 215:403-410. The LAST program incorporates such an algorithm. BLAST nucleotide searches can be performed using the NBLAST program, score = 100, word length = 12, to obtain nucleotide sequences homologous to the nucleic acid molecules of the present 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 the present invention. To obtain gapped alignments for comparison purposes, Gapped BLAST can be used as described in Altschul et al. (1997) Nucleic Acids Res. 25:3389-3402. Alternatively, PSI-Blast can be used to perform an iterated search that detects distant relationships between molecules (ibid.). When using BLAST, Gapped BLAST, and PSI-Blast programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used. See http: / / www.ncbi.nlm.nih.gov. The following are examples of sequences used for sequence comparison: Another example of a mathematical algorithm is the algorithm of Myers and Miller, CABIOS (1989) The ALIGN program (version 2.0), which is part of the CGC sequence alignment software package, incorporates such an algorithm. Other algorithms for sequence analysis known in the art include ADVANCE and ADAM, described in Torellis and Robotti (1994) Comput. Appl. Biosci., 10:3-5, and FASTA, described in 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.

[0049] Typically, the amino acid sequences of the CDRs of the antigen-binding molecules provided in the present invention are determined by, for example, the default BLAST computer program (Atschul et al., J. Mol. Biol. 215, 403-410 (1990)) provided by the HGMP (Human Genome Mapping Project). Using the above parameters, the CDR sequences have at least 70% identity at the amino acid level to the amino acid sequences of the CDRs listed below. More typically, the CDR sequences 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 to the sequences listed below. Typically, each of the CDR sequences of the antigen-binding molecules used in the present invention has this level of identity to the amino acid sequences of the CDRs listed below. Alternatively, any one, two, three, four or five of the CDRs of the antigen-binding molecules used in the present invention have this level of identity to the amino acid sequences of the CDRs listed below.

[0050] The amino acid sequences of the VH and VL regions of the antigen-binding molecules provided in the present invention can be determined by, for example, the default search of the BLAST computer program (Atschul et al., J. Mol. Biol. 215, 403-410 (1990)) provided by the HGMP (Human Genome Mapping Project). Using these parameters, the VH and VL regions have at least 70% identity at the amino acid level to the amino acid sequences of the VH and VL regions set forth below. 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 to the sequences set forth below. Typically, each of the VH and VL regions of an antigen-binding molecule used in the present invention has this level of identity to the amino acid sequences of the VH and VL regions set forth below. Alternatively, any one of the VH and VL regions of an antigen-binding molecule used in the present invention has this level of identity to the amino acid sequences of the VH and VL regions set forth below.

[0051] Identity, as used herein, is used interchangeably with "homology" and "similarity." Reference to a specific % identity applies equally to % homology and % similarity. Homology and similarity can be calculated using suitable algorithms, such as FASTA, BLAST, and Gapped. This can be determined using BLAST, etc. Software for performing these analyses is publicly available.

[0052] In some embodiments, particularly for any embodiment referencing a sequence with a particular sequence identity to a reference sequence, the % sequence identity can be calculated without including the sequence of all six CDRs of a given heavy or light chain variable region, in which case the sequence variation occurs only in the framework regions.

[0053] Mutants The present invention also extends to variants of the peptide sequences referred to below. As used herein, the term "variant" relates to proteins having a similar amino acid sequence and / or retaining the same function. For example, the term "variant" encompasses proteins or polypeptides containing one or more amino acid additions, deletions, substitutions, etc. One example of a variant of the present invention is a protein comprising a peptide as defined below, except for the substitution of one or more amino acids with one or more other amino acids. Amino acid substitutions can be made, for example, to reduce or eliminate defects in the amino acid sequence. Alternatively, amino acid substitutions can be made to improve antigen affinity or to humanize or deimmunize the antibody, as needed. Affinity-matured, humanized, and deimmunized variants of the specified antibodies, as well as variants containing amino acid substitutions to reduce or eliminate any defects in the antibody sequence, are provided herein.

[0054] As noted above, in some embodiments, any substitutions may occur only in framework regions. In such embodiments, the original CDR sequences are retained, but variations may occur in one or more framework regions.

[0055] Variant antigen-binding molecules with one or more amino acid substitutions may 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 described for the antigen-binding molecule from which they are derived.

[0056] replacement Those skilled in the art recognize that various amino acids have similar properties, and one or more such amino acids of a substance can often be substituted by one or more other such amino acids without eliminating a desired activity of the substance.

[0057] For this reason, the amino acids glycine, alanine, valine, leucine, and isoleucine can often be substituted for one another (amino acids with aliphatic side chains). Of these possible substitutions, glycine and alanine are preferably used to replace one another (because they have relatively short side chains), and valine, leucine, and isoleucine are preferably used to replace one another (because they have more hydrophobic aliphatic side chains). Other amino acids that are often substituted for one another include phenylalanine, tyrosine, and tryptophan (amino acids with aromatic side chains), lysine, arginine, and histidine (amino acids with basic side chains), aspartate and glutamate (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).

[0058] Substitutions of this type are often referred to as "conservative" or "semi-conservative" amino acid substitutions.

[0059] Naturally occurring amino acids may be referred to using the three-letter and one-letter codes as follows: glycine (G or Gly), alanine (A or Ala), valine (V or Val), leucine (Va), riboflavin (Rb), riboflavin (Rc), riboflavin (Rd), riboflavin (Rg), riboflavin (Rh), riboflavin (Rg ... The amino acids include 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). When the residue can be aspartic acid or asparagine, the symbols Asx or B can be used. When the residue can be glutamic acid or glutamine, the symbols Glx or Z can be used. Unless the context indicates otherwise, a reference to aspartic acid includes aspartate and a reference to glutamic acid includes glutamate.

[0060] Amino acid deletions or insertions can also be made to the amino acid sequences of the fusion proteins mentioned below. Thus, for example, amino acids can be deleted that do not substantially affect, or at least do not eliminate, the activity of the polypeptide. Such deletions can be advantageous because they can reduce the overall length and molecular weight of the polypeptide while retaining activity. This can reduce the amount of polypeptide needed for a particular purpose, e.g., reduce dosage levels.

[0061] In some embodiments, the following amino acids may be exchanged for conservative amino acid substitutions:

[0062] TIFF2026004428000001.tif36170

[0063] Thus, reference to a "conservative" amino acid substitution refers to an amino acid substitution in which one or more amino acids in an antibody sequence (e.g., a CDR or VH or VL sequence) are replaced with another amino acid of the same class, as indicated above. Conservative amino acid substitutions may be preferred in the CDR regions to minimize adverse effects on antibody function. However, conservative amino acid substitutions may also occur in the framework regions.

[0064] Amino acid changes to the sequences below can be made using any suitable technique, such as site-directed mutagenesis or solid phase synthesis.

[0065] It will be understood that amino acid substitutions or insertions within the scope of the present invention can be made using naturally occurring or non-naturally occurring amino acids, although naturally occurring amino acids may be preferred. Whether natural or synthetic amino acids are used, it may be preferred that only L-amino acids are present.

[0066] One embodiment of the present invention provides an antigen-binding molecule or antigen-binding fragment thereof, which comprises 1 to 10, preferably 1 to 5, amino acid substitutions in the antibody-binding domain or antigen-binding domain. For example, one embodiment of the present invention provides an anti-BDCA-2 (CLEC4C) antibody or antigen-binding fragment thereof, which includes 3E05_var12, 3E05_var6, 3E05_var14, 3E05, 3E05_var1, 3E05_var2, 3E05_var3, 3E05_var4, 3E05_var5, 3E05_var7, In a further embodiment of the present invention, an anti-BDCA-2 (CLEC4C) antigen-binding molecule or an antigen-binding fragment thereof is provided, which comprises six CDR regions of an antibody selected from the group consisting of 3E05_var8, 3E05_var9, 3E05_var10, 3E05_var11, 3E05_var13, 3E05_var15, 3E05_var16, 21E06, 25E06, and 28B01, and the antigen-binding molecule has 1 to 10 amino acid substitutions, preferably 1 to 5 amino acid substitutions, throughout the CDR regions. The antigen-binding molecule comprises the VH and VL sequences of an antibody selected from the group consisting of 3E05_var7, 3E05_var8, 3E05_var9, 3E05_var10, 3E05_var11, 3E05_var13, 3E05_var15, 3E05_var16, 21E06, 25E06, and 28B01, and the antigen-binding molecule has 1 to 10 amino acid substitutions, preferably 1 to 5 amino acid substitutions, across the VH and VL sequences. In yet a further embodiment of the invention, an anti-BDCA-2 (CLEC4C) antibody is provided, the anti-BDCA-2 (CLEC4C) antibody being 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 are, of course, made relative to the original CDR or variable chain sequence of the starting antibody.

[0067] In some embodiments, the one or more amino acid substitutions are in the CDR region(s). In other embodiments, the one or more amino acid substitutions are in the framework regions, i.e., the variable heavy and light chains, but not in the CDR region(s). In other embodiments, the one or more amino acid substitutions can be at any position within the variable heavy and / or variable light region. In some embodiments, the amino acid substitutions do not occur in the CDR sequences.

[0068] In some embodiments, the amino acid substitutions do not adversely affect the binding specificity and / or affinity of the antibody, and thus the variant antibody may have the same or a superior functional profile as the antibody from which it is derived.

[0069] Affinity maturation mutants Other variants within the scope of the present invention include antigen-binding molecules of the present invention that have been modified to increase their affinity for BDCA-2 (CLEC4C). In one embodiment, the antigen-binding molecules of the present invention are affinity-matured antibodies. In one embodiment, the antigen-binding molecules of the present invention are humanized affinity-matured antibodies.

[0070] Any known method can be used to increase the affinity of the antigen-binding molecules of the invention to produce affinity matured or humanized affinity matured antibodies with increased affinity for BDCA-2 (CLEC4C).

[0071] The present invention provides affinity matured variants of the provided antigen-binding agents. The affinity matured variants bind to BDCA-2 (CLEC4C) with greater affinity than the parent antibody. Preferably, the antibody produced binds to BDCA-2 (CLEC4C) with at least 20%, at least 30%, at least 40%, and more preferably at least 50% greater affinity than the parent antibody binds to BDCA-2 (CLEC4C), as measured, for example, by Kd. It's nice.

[0072] In some embodiments, the invention provides methods for producing antigen-binding molecules of the invention, comprising providing an antigen-binding molecule described herein (e.g., an anti-BDCA-2 (CLEC4C) binding molecule or antibody, or antigen-binding fragment or variant thereof) and subjecting the antibody to affinity maturation, wherein the resulting antibody binds to BDCA-2 (CLEC4C) with greater affinity than the parent antibody. Preferably, the resulting antibody binds to BDCA-2 (CLEC4C) with at least 20%, at least 30%, at least 40%, and more preferably at least 50% greater affinity than the parent antibody binds to BDCA-2 (CLEC4C), as measured, for example, 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.

[0073] Affinity maturation can be carried out according to any suitable method known to those skilled in the art. For example, in vitro antibody display systems are widely used to generate high-affinity, specific antibodies. These systems combine the phenotype (i.e., antibody fragment) with the genotype (i.e., antibody gene) and allow direct antibody sequencing. Several systems have been developed that achieve the display of antibody repertoires and allow subsequent selection of binders, allowing for the selection of even higher affinity variants by increasing the stringency of selection. Antibody fragments can be expressed in yeast, ribosomes, phage display particles, or by direct conjugation to DNA.

[0074] Current antibody affinity maturation methods fall into two categories of mutagenesis: stochastic and non-stochastic. Error-prone polymerase chain reaction (PCR), mutagenesis Bacterial strains and saturation mutagenesis are typical examples of stochastic mutagenesis methods. Non-stochastic methods often use alanine scanning or site-directed mutagenesis to generate a limited collection of specific variants. In addition, shuffling approaches can be used to generate shuffled variants of a parent antibody to further improve antibody affinity.

[0075] Thus, in one embodiment of the present invention, the method of affinity maturation is selected from the group consisting of stochastic mutagenesis (e.g., error-prone polymerase chain reaction (PCR), mutagenized bacterial strains or saturation mutagenesis), non-stochastic mutagenesis (e.g., alanine scanning or site-directed mutagenesis), shuffling (e.g., DNA shuffling, chain shuffling or CDR shuffling), and use of the CRISPR-Cas9 system to introduce modifications.

[0076] Affinity maturation methods are described, for example, in 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 (pages 115-140).

[0077] In some embodiments, a method for preparing a pharmaceutical composition is provided, comprising providing an antibody produced according to the method described above (i.e., producing the antibody by affinity maturation) and co-formulating the antibody with at least one or more pharmaceutically acceptable excipients. The antibody used to prepare the pharmaceutical composition can be an affinity matured variant of 3E05, 21E06, 25E06, or 28B01. The antibody used to prepare the pharmaceutical composition can be an affinity matured 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, ...13, 3E05_var14, 3E05_var15, 3E05_var16, 3E05_var17, 3E05_var18, 3E05_var19, 3E05_var20, 3E05_var21, 3E05_var22, 3E05_var23, 3E05_var24, 3E05_var25, 3E05_var26 The pharmaceutical compositions produced by such methods may also be affinity matured variants of 3E05_var11, 3E05_var13, 3E05_var15, or 3E05_var16. Pharmaceutical compositions made by such methods may be used in the therapeutic methods of the invention as described herein for other anti-BDCA-2 (CLEC4C) binding molecules.

[0078] Thus, antigen-binding molecules that are affinity-matured mutants or variants of the antigen-binding molecules of the present invention are provided. For example, in one embodiment, affinity-matured 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 are provided. Generally, affinity-matured variants have higher affinity for BDCA-2 (CLEC4C), particularly human BDCA-2 (CLEC4C), than the parent antibody (the antibody from which the variant is derived). The present invention also provides antigen-binding molecules and antibodies obtainable or obtained by affinity maturation of the antigen-binding molecules or antibodies of the present invention.

[0079] Other variants The antigen-binding molecules of the present invention are typically antibodies, more typically monoclonal antibodies. In preferred embodiments, the monoclonal antibodies of the present invention are humanized antibodies. In some embodiments, the antibodies are fully human monoclonal antibodies in which human constant regions are used.

[0080] Methods for producing monoclonal antibodies are 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.

[0081] 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 CDR grafting onto a suitable antibody framework scaffold, or remodeling variable surface residues, for example, by site-directed mutagenesis or other commonly used molecular biology techniques (Roguska et al., Protein Eng. 9, 895-904 (1996)).

[0082] Other applicable methods include identifying potential T-cell epitopes within the molecule and then removing them (deimmunization), for example, by site-directed mutagenesis. Humanization of antigen-binding molecules may be desirable when the molecules are used as therapeutic agents. Humanization of the CDR regions or surrounding framework sequences can be performed as desired.

[0083] Monoclonal and other antibodies can be used to generate other antibodies or chimeric molecules that retain the specificity of the original antibody, using techniques of recombinant DNA technology. Such techniques can involve introducing DNA encoding the immunoglobulin variable region or complementarity-determining regions (CDRs) of an antibody into the constant regions or constant regions plus framework regions of a different immunoglobulin. Hybridomas or other cells that produce antibodies can undergo genetic mutations or other changes that may or may not alter the binding specificity of the antibody produced.

[0084] 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 modified to retain, for example, better antigen binding. In such conservatively humanized antibodies, fewer antibody substitutions may be made compared to humanized antibodies.

[0085] In some embodiments, the antigen-binding molecules of the present invention can be prepared by, for example, the method described in Jones et al., "Deimmunization of monoclonal antibodies", Methods Mol Biol, 2009, 525:405-23 (among which: The sequence is deimmunized using the methods described in the publications of the National Institute of Infectious Diseases, Vol. 1, No. 10 / 2009, pp. 111-114, the contents of which are incorporated herein by reference. Deimmunization involves the removal of T cell epitopes from the sequence using a combination of immunological and molecular biological techniques.

[0086] Thus, in some embodiments of the present invention, there is provided a deimmunized anti-BDCA-2 (CLEC4C) antigen binding molecule or antigen-binding fragment thereof, comprising deimmunized variants of the 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 a further embodiment of the invention, there is provided a deimmunized anti-BDCA-2 (CLEC4C) antigen binding molecule, or antigen-binding fragment thereof, comprising deimmunized variants of VH and / or VL sequences derived from 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 yet a further embodiment of the invention there is provided a deimmunized anti-BDCA-2 (CLEC4C) antibody which is a deimmunized variant 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.

[0087] The antigen-binding molecules and antigen-binding fragments thereof are based on the four parent antibodies 3E05, 21E06, 25E06, and 28B01. In addition to the parent antibodies, the present invention particularly relates to humanized and deimmunized derivatives of one of the parent 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 a preferred embodiment, 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 parent antibodies are also provided. The present invention is also based on antibody fragments comprising one or more antigen-binding domains derived from the parent or humanized / deimmunized antibodies of the present invention, as well as further variants, such as antigen-binding domains with one or more conservative amino acid substitutions (e.g., 1 to 10, or preferably 1 to 5 substitutions) and affinity-matured variants of the antigen-binding molecules of the present invention. All of the antigen-binding molecules of the present invention specifically bind to BDCA-2 (CLEC4C).

[0088] Humanized and deimmunized variants of antibodies provided herein have at least 90% sequence identity, e.g., at least 90% sequence identity, to the original parent sequence(s) that are humanized or deimmunized. There may be at least 95% sequence identity.

[0089] The antigen-binding molecules, particularly antibodies, of the present invention can be of any suitable type, including IgA, IgD, IgE, IgG, IgM, and IgY, although IgG may be preferred. The IgG1 backbone may be most preferred. In related embodiments, the constant regions of the antibodies of the present invention can be modified for beneficial 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.

[0090] "Specific binding," "bind specifically," and "specifically bind" refer to binding of an anti-BDCA-2 (CLEC4C) antigen-binding molecule to BDCA-2 (CLEC4C) with a binding affinity of approximately 10 -6 M, 10 -7 M, 10 -8 M, 10 -9 M, 10 -10 M, 10 -11 M or 10 -12 A dissociation constant (K d In a preferred embodiment, the dissociation constant is 10 -8 Less than M, e.g. 10 -9 M, 10 -10 M, 10 -11 M or 10 -12 According to some embodiments of the present invention, "specific binding" and "specifically bind" may refer to affinity and / or avidity. In some embodiments, the affinity of an anti-BDCA-2 (CLEC4C) antigen-binding molecule is in the range of 10 -8 M~10 -6 M (e.g., about 10 -7 In some embodiments of the present invention, the avidity of the anti-BDCA-2 (CLEC4C) antigen-binding molecule is about 10 -10 M~10 -8 M (e.g., about 10 -9 In some embodiments of the present invention, the affinity and / or avidity of the anti-BDCA-2 (CLEC4C) antigen-binding molecule is about 1 nM to 700 nM, or about 1 nM to 600 nM, or about 1 nM to 500 nM, or about 1 nM to 400 nM, or about 1 nM to 300 nM.

[0091] Manufacturing obstacles Therapeutic proteins such as antibodies are inherently heterogeneous and complex due to chemical and post-translational modifications (PTMs). Modifications can be caused by a number of factors, such as the host cell line, the process used for production, or storage or manufacturing conditions. Modifications can be related to the chemical stability or aggregation potential of the molecule itself and the effect this has on the intrinsic physical stability of the antibody. Amino acid motifs or residues in a given antibody sequence that may undergo spontaneous modification during manufacturing or storage are referred to as lesions. Therefore, mutations can be made to the antibody sequence to address the lesions and reduce the antibody's susceptibility to modification and degradation.

[0092] Such modifications as a result of obstacles in the antibody sequence can include glycosylation, deamidation, oxidation, and C- and N-terminal mutations. Such modifications may occur during manufacturing. Certain residues and structural or sequence motifs are more susceptible to certain modifications. Examples of such obstacles to modification include N-linked glycosylation of Asn, O-linked glycosylation of Ser / Thr, deamidation of Asn, isomerization / fragmentation of Asp, glycation of Lys, oxidation of Met / Trp, free thiol groups, pyroglutamate, and C-terminal Lys.

[0093] Those skilled in the art will recognize that computational tools can be used to predict and identify structural and sequence defects that may potentially cause modifications. Manufacturing processes can be modified to minimize the occurrence of modifications. Protein engineering may also be considered to reduce the risk. For example, selective mutation of these defects can help identify and reduce the risk of modifications that compromise antibody stability.

[0094] Aspartic acid residues (Asp) can undergo spontaneous modifications. Asp-containing motifs, such as Asp-Gly sequences, can undergo spontaneous isomerization to form isoaspartic acid. Isoaspartate formation can weaken or completely abolish antibody binding. This is even more important when Asp residues are found in the CDRs of an antibody.

[0095] Therefore, the aspartic acid residue (Asp) can be substituted with any naturally occurring amino acid to reduce this barrier to modification. Optionally, the aspartic acid residue (Asp) can be substituted with alanine (Ala), glutamine (Gln), or glutamic acid (Glu) to reduce this barrier to modification. Optimization of production / formulation to reduce isomerization may be investigated. Alternatively, the Asp-Gly motif can be modified to inhibit deamidation by substituting the glycine residue with another naturally occurring amino acid, rather than by substituting the Asp residue.

[0096] Methionine residues (Met) can undergo spontaneous modification. The presence of methionine (Met) in CDRs, especially when exposed to solvent, can cause problems if methionine is oxidized, which prevents binding. Therefore, methionine residues can be substituted with any other naturally occurring amino acid to reduce this barrier to modification. Methionine residues can preferably be substituted with Ala or Leu. Optimization of production / formulation to reduce oxidation may be investigated.

[0097] Thus, also provided herein are 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 which include one or more amino substitutions to address one or more of any of the potential problems described above.

[0098] For example, for any antigen-binding molecule defined by one or more amino acid sequences herein, if one or more Met residues are present, each one or more Met residues may be independently substituted with an Ala residue or a Leu residue.If one or more Asp residues are present, each one or more Asp residues may be independently substituted with an Ala residue, a Gln residue, or a Glu residue.

[0099] Overview of antigen-binding molecules provided A summary of the antigen-binding molecules provided by the present invention is provided below, identifying the SEQ ID NOs assigned in the accompanying sequence listing. Antigen-binding variants, derivatives and fragments thereof are also provided as part of the present invention.

[0100] TIFF2026004428000002.tif142170

[0101] TIFF2026004428000003.tif108170

[0102] Various embodiments of the present invention will now be discussed in more detail.

[0103] Antigen-binding molecules comprising VHCDR3 and / or VLCDR3 regions In one embodiment, there is provided an antibody, fragment or variant thereof, comprising a heavy chain variable region comprising a VH CDR3 comprising 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 VL CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 34, 24, 44, 4, 14, 54, 64 and 74. Certain amino acid substitutions may be made to provide one or more of the variant antibodies described herein.

[0104] 3E05 In one embodiment, an antigen-binding molecule, such as an antibody, fragment or 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 to 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 to the amino acid sequence QQTNEDPPT (SEQ ID NO: 4). In one embodiment, an antigen-binding molecule, such as an antibody, fragment or variant thereof, is provided, comprising a heavy chain variable region comprising an amino acid sequence having at least 90% identity to 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 to the amino acid sequence QQTNEDPPT (SEQ ID NO: 4).

[0105] In one embodiment, an antigen-binding molecule, such as an antibody, fragment or variant thereof, is provided, comprising a heavy chain variable region comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 8) and / or a light chain variable region comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 4). In a specific 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: 8), and / or the VLCDR3 region of the antibody or fragment or variant thereof is QQTNEDPPT (SEQ ID NO: 4).

[0106] Amino acid substitutions may be made to provide variant antibodies derived from 3E05, for example, antibodies, fragments or variants thereof, comprising a heavy chain variable region comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 8), optionally containing one or two amino acid substitutions, and / or a light chain variable region comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 4), optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0107] 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: 8), and / or the VLCDR3 region of the antibody or fragment or variant thereof is QQTNEDPPT (SEQ ID NO: 4), optionally wherein Met residues are each independently substituted with an amino acid selected from the group consisting of Ala and Leu, and / or wherein Asp residues are each independently substituted with an amino acid selected from the group consisting of Ala, Gln, and Glu.

[0108] 3E05_var1, 5, 9 and 13 In one embodiment, an antigen-binding molecule, such as an antibody, fragment or 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 to 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 to 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 to 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 to the amino acid sequence QQTNEDPPT (SEQ ID NO: 14).

[0109] In one embodiment, an antibody, fragment 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 or variant thereof is provided, wherein the VHCDR3 region of the antibody or fragment or variant thereof is HDYYDGGLYYAMDY (SEQ ID NO: 18) and / or the VLCDR3 region of the antibody or fragment or variant thereof is QQTNEDPPT (SEQ ID NO: 14).

[0110] Amino acid substitutions may be made to provide variant antibodies derived from 3E05_var1, 5, 9 or 13, for example, antibodies, fragments or variants thereof are provided that comprise a heavy chain variable region comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18), optionally containing one or two amino acid substitutions, and / or a light chain variable region comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14), optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0111] In one embodiment, the antigen-binding molecule is an antibody or a fragment or variant thereof, and the VHCDR3 region of the antibody or fragment or variant thereof is DGGLYYAMDY (SEQ ID NO: 18), and / or the VLCDR3 region of the antibody or fragment or variant thereof is QQTNEDPPT (SEQ ID NO: 14), optionally with Met residues each independently substituted with an amino acid selected from the group consisting of Ala and Leu, and / or with Asp residues each independently substituted with an amino acid selected from the group consisting of Ala, Gln, and Glu.

[0112] 3E05_var2, 6, 10 and 14 In one embodiment, an antigen-binding molecule, such as an antibody, fragment or 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 to 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 to 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 to 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 to the amino acid sequence QQTNEDPPT (SEQ ID NO: 14).

[0113] In one embodiment, an antibody, fragment 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 or variant thereof is provided, wherein the VHCDR3 region of the antibody or fragment or variant thereof is HDYYDGGLYYAMDY (SEQ ID NO: 28) and / or the VLCDR3 region of the antibody or fragment or variant thereof is QQTNEDPPT (SEQ ID NO: 14).

[0114] Amino acid substitutions may be made to provide variant antibodies derived from 3E05_var2, 6, 10 or 14, for example, antibodies, fragments or variants thereof are provided that comprise a heavy chain variable region comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28), optionally containing one or two amino acid substitutions, and / or a light chain variable region comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14), optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0115] 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 comprising one or two amino acid substitutions, and / or the light chain variable region comprises the amino acid sequence QQTNEDPPT (SEQ ID NO: 14), optionally wherein Met residues are each independently substituted with an amino acid selected from the group consisting of Ala and Leu, and / or wherein Asp residues are each independently substituted with an amino acid selected from the group consisting of Ala, Gln, and Glu.

[0116] 3E05_var3, 7, 11 and 15 In one embodiment, an antigen-binding molecule, e.g., an antibody, fragment or 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 to 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 to 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 to 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 to the amino acid sequence QQTNEDPPT (SEQ ID NO: 14).

[0117] In one embodiment, an antibody, fragment 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 or variant thereof is provided, wherein the VH CDR3 region of the antibody or fragment or variant thereof is HDYYDGGLYYAMDY (SEQ ID NO: 38) and / or the VL CDR3 region of the antibody or fragment or variant thereof is QQTNEDPPT (SEQ ID NO: 14).

[0118] Amino acid substitutions may be made to provide variant antibodies derived from 3E05_var3, 7, 11 or 15, for example, antibodies, fragments or variants thereof are provided that comprise a heavy chain variable region comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38), optionally containing one or two amino acid substitutions, and / or a light chain variable region comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14), optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0119] 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 comprising one or two amino acid substitutions, and / or the light chain variable region comprises the amino acid sequence QQTNEDPPT (SEQ ID NO: 14), optionally wherein Met residues are each independently substituted with an amino acid selected from the group consisting of Ala and Leu, and / or wherein Asp residues are each independently substituted with an amino acid selected from the group consisting of Ala, Gln, and Glu.

[0120] 3E05_var4, 8, 12 and 16 In one embodiment, an antigen-binding molecule, such as an antibody, fragment or 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 to 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 to 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 to 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 to the amino acid sequence QQTNEDPPT (SEQ ID NO: 14).

[0121] In one embodiment, an antibody, fragment 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 or variant thereof is provided, wherein the VH CDR3 region of the antibody or fragment or variant thereof is HDYYEGGLYYAMDY (SEQ ID NO: 48) and / or the VL CDR3 region of the antibody or fragment or variant thereof is QQTNEDPPT (SEQ ID NO: 14).

[0122] Amino acid substitutions are provided for mutant antibodies derived from 3E05_var4, 8, 12, or 16. For example, an antibody, fragment, or variant thereof is provided that comprises a heavy chain variable region comprising the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48), optionally containing one or two amino acid substitutions, and / or a light chain variable region comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14), optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0123] 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 Met residues are each independently substituted with an amino acid selected from the group consisting of Ala and Leu, and / or wherein Asp residues are each independently substituted with an amino acid selected from the group consisting of Ala, Gln, and Glu.

[0124] 21E06 In one embodiment, an antigen-binding molecule, such as an antibody, fragment or 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 to 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 to the amino acid sequence QQSNEDPPT (SEQ ID NO: 54). In one embodiment, an antigen-binding molecule, e.g., an antibody, fragment or variant thereof, is provided, comprising a heavy chain variable region comprising an amino acid sequence having at least 90% identity to 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 to the amino acid sequence QQSNEDPPT (SEQ ID NO: 54).

[0125] In one embodiment, an antigen-binding molecule, e.g., an antibody, fragment or variant thereof, is provided, 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 or variant thereof, wherein the VH CDR3 region of the antibody or fragment or variant thereof is HLYYGDYFYVMDY (SEQ ID NO: 58) and / or the VL CDR3 region of the antibody or fragment or variant thereof is QQSNEDPPT (SEQ ID NO: 54).

[0126] Amino acid substitutions may be made to provide variant antibodies derived from 21E06, for example, antibodies, fragments or variants thereof, comprising a heavy chain variable region comprising the amino acid sequence HLYYGDYFYVMDY (SEQ ID NO: 58), optionally containing one or two amino acid substitutions, and / or a light chain variable region comprising the amino acid sequence QQSNEDPPT (SEQ ID NO: 54), optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0127] 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 HLYYGDYFYVMDY (SEQ ID NO: 58), and / or the VLCDR3 region of the antibody or fragment or variant thereof is QQSNEDPPT (SEQ ID NO: 54), optionally wherein Met residues are each independently substituted with an amino acid selected from the group consisting of Ala and Leu, and / or Asp residues are each independently substituted with an amino acid selected from the group consisting of Ala, Gln, and Glu. is substituted with an amino acid selected from

[0128] 25E06 In one embodiment, an antigen-binding molecule, such as an antibody, fragment or 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 to 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 to the amino acid sequence QQSNEDPPT (SEQ ID NO: 64). In one embodiment, an antigen-binding molecule, e.g., an antibody, fragment or variant thereof, is provided, comprising a heavy chain variable region comprising an amino acid sequence having at least 90% identity to 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 to the amino acid sequence QQSNEDPPT (SEQ ID NO: 64).

[0129] In one embodiment, an antigen-binding molecule, e.g., an antibody, fragment or variant thereof, is provided, 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 or variant thereof, wherein the VH CDR3 region of the antibody or fragment or variant thereof is HHYSHYFWYFDV (SEQ ID NO: 68) and / or the VL CDR3 region of the antibody or fragment or variant thereof is QQSNEDPPT (SEQ ID NO: 64).

[0130] Amino acid substitutions may be made to provide variant antibodies derived from 25E06, for example, antibodies, fragments or variants thereof, comprising a heavy chain variable region comprising the amino acid sequence HHYSHYFWYFDV (SEQ ID NO: 68), optionally containing one or two amino acid substitutions, and / or a light chain variable region comprising the amino acid sequence QQSNEDPPT (SEQ ID NO: 64), optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0131] 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 HHYSHYFWYFDV (SEQ ID NO: 68), and / or the VLCDR3 region of the antibody or fragment or variant thereof is QQSNEDPPT (SEQ ID NO: 64), optionally wherein Met residues are each independently substituted with an amino acid selected from the group consisting of Ala and Leu, and / or wherein Asp residues are each independently substituted with an amino acid selected from the group consisting of Ala, Gln, and Glu.

[0132] 28B01 In one embodiment, an antigen-binding molecule, such as an antibody, fragment or 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 to 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 to the amino acid sequence QQSNEDPPT (SEQ ID NO: 74). In one embodiment, a heavy chain variable region comprising an amino acid sequence having at least 90% identity to the amino acid sequence HHYSNYFWYFDV (SEQ ID NO: 78), and / or an amino acid sequence having at least 90% identity to the amino acid sequence QQSNEDPPT (SEQ ID NO: 74).

[0023] The present invention provides an antigen-binding molecule, e.g., an antibody, fragment or variant thereof, comprising a light chain variable region comprising an amino acid sequence having the following structure:

[0133] In one embodiment, an antigen-binding molecule, e.g., an antibody, fragment or variant thereof, is provided, 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 or variant thereof, wherein the VH CDR3 region of the antibody or fragment or variant thereof is HHYSNYFWYFDV (SEQ ID NO: 78) and / or the VL CDR3 region of the antibody or fragment or variant thereof is QQSNEDPPT (SEQ ID NO: 74).

[0134] Amino acid substitutions may be made to provide variant antibodies derived from 28B01, for example, antibodies, fragments or variants thereof, are provided that comprise a heavy chain variable region comprising the amino acid sequence HHYSNYFWYFDV (SEQ ID NO: 78), optionally containing one or two amino acid substitutions, and / or a light chain variable region comprising the amino acid sequence QQSNEDPPT (SEQ ID NO: 74), optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0135] 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 HHYSNYFWYFDV (SEQ ID NO: 78), and / or the VLCDR3 region of the antibody or fragment or variant thereof is QQSNEDPPT (SEQ ID NO: 74), optionally wherein Met residues are each independently substituted with an amino acid selected from the group consisting of Ala and Leu, and / or Asp residues are each independently substituted with an amino acid selected from the group consisting of Ala, Gln, and Glu.

[0136] Heavy and / or light chain CDRs In one embodiment, VHCDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 46, 49, 26, 29, 6, 9, 16, 19, 36, 39, 56, 59, 66, 69, 76 and 79; VHCDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 47, 50, 27, 30, 7, 10, 17, 20, 37, 40, 57, 60, 67, 70, 77 and 80; and a heavy chain variable region comprising a VHCDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 48, 28, 8, 18, 38, 58, 68, and 78; VLCDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 32, 22, 42, 2, 12, 52, 62 and 72; VLCDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 33, 23, 43, 3, 13, 53, 63 and 73; and a light chain variable region comprising a VLCDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 34, 24, 44, 4, 14, 54, 64, and 74; The present invention provides an antibody, fragment or variant thereof comprising:

[0137] Certain amino acid substitutions may be made to provide one or more of the mutant antibodies described herein.

[0138] 3E05 In one embodiment, At least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% similar to the amino acid sequence SYTMS (SEQ ID NO: 6) a heavy chain variable region comprising a VHCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 7), a VHCDR2 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 8), and / or VLCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 2), VLCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence AASTLES (SEQ ID NO: 3), Antibodies, fragments or variants thereof are provided that comprise a light chain variable region comprising a VLCDR2 having 5%, 96%, 97%, 98% or 99% identity, and a VLCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 4).

[0139] In one embodiment, a heavy chain variable region comprising a VHCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 9), a VHCDR2 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence SSGGGNTY (SEQ ID NO: 10), a VHCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 8), and / or VLCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 2), VLCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence AASTLES (SEQ ID NO: 3), Antibodies, fragments or variants thereof are provided that comprise a light chain variable region comprising a VLCDR2 having 5%, 96%, 97%, 98% or 99% identity, and a VLCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 4).

[0140] In one embodiment, a heavy chain variable region comprising a VHCDR1 having at least 90% identity to the amino acid sequence SYTMS (SEQ ID NO: 6), a VHCDR2 having at least 90% identity to the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 7), and a VHCDR3 having at least 90% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 8); and / or An antibody, fragment or variant thereof is provided, comprising a light chain variable region including a VLCDR1 having at least 90% identity to the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 2), a VLCDR2 having at least 90% identity to the amino acid sequence AASTLES (SEQ ID NO: 3), and a VLCDR3 having at least 90% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 4).

[0141] In one embodiment, a heavy chain variable region comprising a VHCDR1 having at least 90% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 9), a VHCDR2 having at least 90% identity to the amino acid sequence SSGGGNTY (SEQ ID NO: 10), and a VHCDR3 having at least 90% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 8); and / or An antibody, fragment or variant thereof is provided, comprising a light chain variable region including a VLCDR1 having at least 90% identity to the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 2), a VLCDR2 having at least 90% identity to the amino acid sequence AASTLES (SEQ ID NO: 3), and a VLCDR3 having at least 90% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 4).

[0142] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 6), a VHCDR2 comprising the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 7), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 8); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 2), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 3), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 4); The present invention provides an antibody, fragment or variant thereof comprising:

[0143] Amino acid substitutions may be made to provide variant antibodies derived from 3E05, for example: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 6), optionally containing one or two amino acid substitutions; a VHCDR2 comprising the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 7), optionally containing one or two amino acid substitutions; and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 8), optionally containing one or two amino acid substitutions; and / or Antibodies, fragments, or variants thereof are provided that comprise a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 2), optionally containing one or two amino acid substitutions; a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 3), optionally containing one or two amino acid substitutions; and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 4), optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0144] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 6), a VHCDR2 comprising the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 7), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 8); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 2), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 3), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 4); Including, Optionally, antibodies, fragments or variants thereof are provided in which Met residues are each independently substituted with an amino acid selected from the group consisting of Ala and Leu, and / or Asp residues are each independently substituted with an amino acid selected from the group consisting of Ala, Gln and Glu.

[0145] In one embodiment, 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 HDYYDGGLYY a heavy chain variable region comprising a VHCDR3 comprising AMDY (SEQ ID NO: 8); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 2), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 3), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 4); The present invention provides an antibody, fragment or variant thereof comprising:

[0146] Amino acid substitutions may be made to provide variant antibodies derived from 3E05, for example: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 9), optionally containing one or two amino acid substitutions, a VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 10), optionally containing one or two amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 8), optionally containing one or two amino acid substitutions; and / or Antibodies, fragments, or variants thereof are provided that comprise a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 2), optionally containing one or two amino acid substitutions; a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 3), optionally containing one or two amino acid substitutions; and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 4), optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0147] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 9), a VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 10), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 8); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 2), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 3), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 4); Including, Optionally, antibodies, fragments or variants thereof are provided in which Met residues are each independently substituted with an amino acid selected from the group consisting of Ala and Leu, and / or Asp residues are each independently substituted with an amino acid selected from the group consisting of Ala, Gln and Glu.

[0148] 3E05_var12 In one embodiment, VHCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence SYTMS (SEQ ID NO: 46), VHCDR2 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 47), a heavy chain variable region comprising a VHCDR2 having 3%, 94%, 95%, 96%, 97%, 98% or 99% identity and a VHCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); and / or VLCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), VLCDR2 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence AASTLES (SEQ ID NO: 33), and the amino acid sequence QQTNEDPPT (SEQ ID NO: 34). Antibodies, fragments or variants thereof are provided that comprise a light chain variable region comprising a VLCDR3 that has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to

[0149] In one embodiment, VHCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 49), VHCDR2 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence SSGGGQTY (SEQ ID NO: 50), a heavy chain variable region comprising a VHCDR2 having 4%, 95%, 96%, 97%, 98% or 99% identity and a VHCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); and / or VLCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94% identity to the amino acid sequence AASTLES (SEQ ID NO: 33), Antibodies, fragments or variants thereof are provided that comprise a light chain variable region comprising a VLCDR2 having 95%, 96%, 97%, 98% or 99% identity, and a VLCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 34).

[0150] In one embodiment, a heavy chain variable region comprising a VHCDR1 having at least 90% identity to the amino acid sequence SYTMS (SEQ ID NO: 46), a VHCDR2 having at least 90% identity to the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 47), and a VHCDR3 having at least 90% identity to the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); and / or An antibody, fragment or variant thereof is provided, comprising a light chain variable region comprising a VLCDR1 having at least 90% identity to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 having at least 90% identity to the amino acid sequence AASTLES (SEQ ID NO: 33), and a VLCDR3 having at least 90% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 34).

[0151] In one embodiment, a heavy chain variable region comprising a VHCDR1 having at least 90% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 49), a VHCDR2 having at least 90% identity to the amino acid sequence SSGGGQTY (SEQ ID NO: 50), and a VHCDR3 having at least 90% identity to the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); and / or An antibody, fragment or variant thereof is provided, comprising a light chain variable region comprising a VLCDR1 having at least 90% identity to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 having at least 90% identity to the amino acid sequence AASTLES (SEQ ID NO: 33), and a VLCDR3 having at least 90% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 34).

[0152] In one embodiment, VHCDR1 containing the amino acid sequence SYTMS (SEQ ID NO: 46), the amino acid sequence YISS a heavy chain variable region comprising a VHCDR2 comprising GGGQTYYPDSVKG (SEQ ID NO: 47) and a VHCDR3 comprising the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34); The present invention provides an antibody, fragment or variant thereof comprising:

[0153] Amino acid substitutions may be made to provide variant antibodies derived from 3E05_var12, for example: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 46), optionally containing one or two amino acid substitutions; a VHCDR2 comprising the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 47), optionally containing one or two amino acid substitutions; and a VHCDR3 comprising the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48), optionally containing one or two amino acid substitutions; and / or Provided is an antibody, fragment, or variant thereof comprising a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), optionally containing one or two amino acid substitutions, a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33), optionally containing one or two amino acid substitutions, and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34), optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0154] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 46), a VHCDR2 comprising the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 47), and a VHCDR3 comprising the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34); Including, Optionally, antibodies, fragments or variants thereof are provided in which Met residues are each independently substituted with an amino acid selected from the group consisting of Ala and Leu, and / or Asp residues are each independently substituted with an amino acid selected from the group consisting of Ala, Gln and Glu.

[0155] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 49), a VHCDR2 comprising the amino acid sequence SSGGGQTY (SEQ ID NO: 50), and a VHCDR3 comprising the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34); The present invention provides an antibody, fragment or variant thereof comprising:

[0156] Amino acid substitutions may be made to provide variant antibodies derived from 3E05_var12, for example: 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 and / or a heavy chain variable region comprising a VHCDR3 comprising the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48), Provided is an antibody, fragment, or variant thereof comprising a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), optionally containing one or two amino acid substitutions, a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33), optionally containing one or two amino acid substitutions, and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34), optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0157] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 49), a VHCDR2 comprising the amino acid sequence SSGGGQTY (SEQ ID NO: 50), and a VHCDR3 comprising the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34); Including, Optionally, antibodies, fragments or variants thereof are provided in which Met residues are each independently substituted with an amino acid selected from the group consisting of Ala and Leu, and / or Asp residues are each independently substituted with an amino acid selected from the group consisting of Ala, Gln and Glu.

[0158] Antigen-binding molecules of or derived from 3E05_var12 (e.g., antibodies with one or more amino acid substitutions) have a K of less than about 0.01 nM. D In certain embodiments, an antigen-binding molecule of or derived from 3E05_var12 (e.g., an antibody having one or more amino acid substitutions) may have a K of less than about 0.01 nM. D , an IC50 for IFN secretion of less than about 0.2 nM, and / or an IC90 for IFN secretion of less than about 2 nM.

[0159] 3E05_var6 In one embodiment, VHCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence SYTMS (SEQ ID NO: 26), VHCDR2 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence YISSGGGNTYYADSVKG (SEQ ID NO: 27), a heavy chain variable region comprising a VHCDR2 having 3%, 94%, 95%, 96%, 97%, 98% or 99% identity and a VHCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); and / or VLCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94% or 99% identity to the amino acid sequence AASTLES (SEQ ID NO: 23), Antibodies, fragments or variants thereof are provided that comprise a light chain variable region comprising a VLCDR2 having 95%, 96%, 97%, 98% or 99% identity, and a VLCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 24).

[0160] In one embodiment, VHCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 29), VHCDR2 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence SSGGGNTY (SEQ ID NO: 30), a heavy chain variable region comprising a VHCDR2 having 4%, 95%, 96%, 97%, 98% or 99% identity and a VHCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); and / or VLCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94% or 99% identity to the amino acid sequence AASTLES (SEQ ID NO: 23), Antibodies, fragments or variants thereof are provided that comprise a light chain variable region comprising a VLCDR2 having 95%, 96%, 97%, 98% or 99% identity, and a VLCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 24).

[0161] In one embodiment, a heavy chain variable region comprising a VHCDR1 having at least 90% identity to the amino acid sequence SYTMS (SEQ ID NO: 26), a VHCDR2 having at least 90% identity to the amino acid sequence YISSGGGNTYYADSVKG (SEQ ID NO: 27), and a VHCDR3 having at least 90% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); and / or An antibody, fragment or variant thereof is provided, comprising a light chain variable region comprising a VLCDR1 having at least 90% identity to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 having at least 90% identity to the amino acid sequence AASTLES (SEQ ID NO: 23), and a VLCDR3 having at least 90% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 24).

[0162] In one embodiment, a heavy chain variable region comprising a VHCDR1 having at least 90% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 29), a VHCDR2 having at least 90% identity to the amino acid sequence SSGGGNTY (SEQ ID NO: 30), and a VHCDR3 having at least 90% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); and / or An antibody, fragment or variant thereof is provided, comprising a light chain variable region comprising a VLCDR1 having at least 90% identity to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 having at least 90% identity to the amino acid sequence AASTLES (SEQ ID NO: 23), and a VLCDR3 having at least 90% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 24).

[0163] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 26), a VHCDR2 comprising the amino acid sequence YISSGGGNTYYADSVKG (SEQ ID NO: 27), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24); The present invention provides an antibody, fragment or variant thereof comprising:

[0164] Amino acid substitutions may be made to provide variant antibodies derived from 3E05_var6, for example: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 26), optionally containing one or two amino acid substitutions; a VHCDR2 comprising the amino acid sequence YISSGGGNTYYADSVKG (SEQ ID NO: 27), optionally containing one or two amino acid substitutions; and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28), optionally containing one or two amino acid substitutions; and / or Provided is an antibody, fragment, or variant thereof, comprising a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), optionally containing one or two amino acid substitutions, a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23), optionally containing one or two amino acid substitutions, and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24), optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0165] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 26), a VHCDR2 comprising the amino acid sequence YISSGGGNTYYADSVKG (SEQ ID NO: 27), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24); Including, Optionally, an antibody, fragment or variant thereof is provided in which each Met residue is independently substituted with an amino acid selected from the group consisting of Ala and Leu, and / or each Asp residue is independently substituted with an amino acid selected from the group consisting of Ala, Gln and Glu.

[0166] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 29), a VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 30), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24); The present invention provides an antibody, fragment or variant thereof comprising:

[0167] Amino acid substitutions may be made to provide variant antibodies derived from 3E05_var6, for example: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 29), optionally with one or two amino acid substitutions, a VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 30), optionally with one or two amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28), optionally with one or two amino acid substitutions; and / or The amino acid sequence KSSQSVDYDGDSSM optionally containing one or two amino acid substitutions The present invention provides an antibody, fragment, or variant thereof comprising a light chain variable region comprising a VLCDR1 comprising the amino acid sequence N (SEQ ID NO: 22), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23), optionally containing one or two amino acid substitutions, and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24), optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0168] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 29), a VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 30), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24); Including, Optionally, antibodies, fragments or variants thereof are provided in which Met residues are each independently substituted with an amino acid selected from the group consisting of Ala and Leu, and / or Asp residues are each independently substituted with an amino acid selected from the group consisting of Ala, Gln and Glu.

[0169] Antigen-binding molecules of or derived from 3E05_var6 (e.g., antibodies with one or more amino acid substitutions) have a K of less than about 0.01 nM. D In certain embodiments, an antigen-binding molecule of or derived from 3E05_var6 (e.g., an antibody having one or more amino acid substitutions) may have a K of less than about 0.01 nM. D , an IC50 for IFN secretion of less than about 0.1 nM, and / or an IC90 for IFN secretion of less than about 1 nM.

[0170] 3E05_var14 In one embodiment, VHCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence SYTMS (SEQ ID NO: 26), VHCDR2 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence YISSGGGNTYYADSVKG (SEQ ID NO: 27), a heavy chain variable region comprising a VHCDR2 having 3%, 94%, 95%, 96%, 97%, 98% or 99% identity and a VHCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); and / or VLCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94% identity to the amino acid sequence AASTLES (SEQ ID NO: 43), Antibodies, fragments or variants thereof are provided that comprise a light chain variable region comprising a VLCDR2 having 95%, 96%, 97%, 98% or 99% identity, and a VLCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 44).

[0171] In one embodiment, At least 70%, 75%, 8% or more of the amino acid sequence GFTFSSY (SEQ ID NO: 29) a heavy chain variable region comprising a VHCDR1 having 0%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity, a VHCDR2 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence SSGGGNTY (SEQ ID NO: 30), and a VHCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); and / or VLCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94% identity to the amino acid sequence AASTLES (SEQ ID NO: 43), Antibodies, fragments or variants thereof are provided that comprise a light chain variable region comprising a VLCDR2 having 95%, 96%, 97%, 98% or 99% identity, and a VLCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 44).

[0172] In one embodiment, a heavy chain variable region comprising a VHCDR1 having at least 90% identity to the amino acid sequence SYTMS (SEQ ID NO: 26), a VHCDR2 having at least 90% identity to the amino acid sequence YISSGGGNTYYADSVKG (SEQ ID NO: 27), and a VHCDR3 having at least 90% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); and / or An antibody, fragment or variant thereof is provided, comprising a light chain variable region comprising a VLCDR1 having at least 90% identity to the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 having at least 90% identity to the amino acid sequence AASTLES (SEQ ID NO: 43), and a VLCDR3 having at least 90% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 44).

[0173] In one embodiment, a heavy chain variable region comprising a VHCDR1 having at least 90% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 29), a VHCDR2 having at least 90% identity to the amino acid sequence SSGGGNTY (SEQ ID NO: 30), and a VHCDR3 having at least 90% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); and / or An antibody, fragment or variant thereof is provided, comprising a light chain variable region comprising a VLCDR1 having at least 90% identity to the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 having at least 90% identity to the amino acid sequence AASTLES (SEQ ID NO: 43), and a VLCDR3 having at least 90% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 44).

[0174] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 26), a VHCDR2 comprising the amino acid sequence YISSGGGNTYYADSVKG (SEQ ID NO: 27), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 43), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44); The present invention provides an antibody, fragment or variant thereof comprising:

[0175] Amino acid substitutions may be made to provide variant antibodies derived from 3E05_var14, for example: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 26), optionally containing one or two amino acid substitutions; a VHCDR2 comprising the amino acid sequence YISSGGGNTYYADSVKG (SEQ ID NO: 27), optionally containing one or two amino acid substitutions; and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28), optionally containing one or two amino acid substitutions; and / or Provided is an antibody, fragment, or variant thereof, comprising a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), optionally containing one or two amino acid substitutions, a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 43), optionally containing one or two amino acid substitutions, and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44), optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0176] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 26), a VHCDR2 comprising the amino acid sequence YISSGGGNTYYADSVKG (SEQ ID NO: 27), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 43), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44); Including, Optionally, antibodies, fragments or variants thereof are provided in which Met residues are each independently substituted with an amino acid selected from the group consisting of Ala and Leu, and / or Asp residues are each independently substituted with an amino acid selected from the group consisting of Ala, Gln and Glu.

[0177] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 29), a VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 30), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 43), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44); The present invention provides an antibody, fragment or variant thereof comprising:

[0178] Amino acid substitutions may be made to provide variant antibodies derived from 3E05_var14, for example: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 29), optionally with one or two amino acid substitutions, a VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 30), optionally with one or two amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28), optionally with one or two amino acid substitutions; and / or 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 VLCD comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44), optionally containing one or two amino acid substitutions. An antibody, fragment or variant thereof comprising a light chain variable region comprising R3 is provided. The amino acid substitutions may be conservative amino acid substitutions.

[0179] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 29), a VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 30), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 43), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44); Including, Optionally, an antibody, fragment or variant thereof is provided in which each Met residue is independently substituted with an amino acid selected from the group consisting of Ala and Leu, and / or each Asp residue is independently substituted with an amino acid selected from the group consisting of Ala, Gln and Glu.

[0180] Antigen-binding molecules of or derived from 3E05_var14 (e.g., antibodies with one or more amino acid substitutions) have a K of less than about 0.01 nM. D , an IC50 for IFN secretion of less than about 0.5 M, and / or an IC90 for IFN secretion of less than about 5 nM. In certain embodiments, antigen-binding molecules of or derived from 3E05_var14 (e.g., antibodies with one or more amino acid substitutions) may have a K of less than about 0.01 nM. D , an IC50 for IFN secretion of less than about 0.2 nM, and / or an IC90 for IFN secretion of less than about 2 nM.

[0181] 3E05_var1 In one embodiment, VHCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence SYTMS (SEQ ID NO: 16), VHCDR2 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 17), a heavy chain variable region comprising a VHCDR2 having 3%, 94%, 95%, 96%, 97%, 98% or 99% identity and a VHCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); and / or VLCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94% identity to the amino acid sequence AASTLES (SEQ ID NO: 13), Antibodies, fragments or variants thereof are provided that comprise a light chain variable region comprising a VLCDR2 having 95%, 96%, 97%, 98% or 99% identity, and a VLCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 14).

[0182] In one embodiment, VHCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 19), VHCDR2 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence SSGGGNTY (SEQ ID NO: 20), a heavy chain variable region comprising a VHCDR2 having 2%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity and a VHCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); and / or VLCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94% identity to the amino acid sequence AASTLES (SEQ ID NO: 13), Antibodies, fragments or variants thereof are provided that comprise a light chain variable region comprising a VLCDR2 having 95%, 96%, 97%, 98% or 99% identity, and a VLCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 14).

[0183] In one embodiment, a heavy chain variable region comprising a VHCDR1 having at least 90% identity to the amino acid sequence SYTMS (SEQ ID NO: 16), a VHCDR2 having at least 90% identity to the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 17), and a VHCDR3 having at least 90% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); and / or An antibody, fragment or variant thereof is provided, comprising a light chain variable region including a VLCDR1 having at least 90% identity to the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 having at least 90% identity to the amino acid sequence AASTLES (SEQ ID NO: 13), and a VLCDR3 having at least 90% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 14).

[0184] In one embodiment, a heavy chain variable region comprising a VHCDR1 having at least 90% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 19), a VHCDR2 having at least 90% identity to the amino acid sequence SSGGGNTY (SEQ ID NO: 20), and a VHCDR3 having at least 90% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); a light chain variable region comprising a VLCDR1 having at least 90% identity to the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 having at least 90% identity to the amino acid sequence AASTLES (SEQ ID NO: 13), and a VLCDR3 having at least 90% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 14); The present invention provides an antibody, fragment or variant thereof comprising:

[0185] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 16), a VHCDR2 comprising the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 17), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); and / or Antibodies, fragments or variants thereof are provided that comprise a light chain variable region comprising VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 13), and VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14).

[0186] Amino acid substitutions may be made to provide variant antibodies derived from 3E05_var1, for example: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 16), optionally containing one or two amino acid substitutions; a VHCDR2 comprising the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 17), optionally containing one or two amino acid substitutions; and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18), optionally containing one or two amino acid substitutions; and / or Provided is an antibody, fragment, or variant thereof comprising a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), optionally containing one or two amino acid substitutions, a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 13), optionally containing one or two amino acid substitutions, and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14), optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0187] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 16), a VHCDR2 comprising the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 17), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 13), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14); Including, Optionally, antibodies, fragments or variants thereof are provided in which Met residues are each independently substituted with an amino acid selected from the group consisting of Ala and Leu, and / or Asp residues are each independently substituted with an amino acid selected from the group consisting of Ala, Gln and Glu.

[0188] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 19), a VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 20), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 13), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14); The present invention provides an antibody, fragment or variant thereof comprising:

[0189] Amino acid substitutions may be made to provide variant antibodies derived from 3E05_var1, for example: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 19), optionally containing one or two amino acid substitutions, a VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 20), optionally containing one or two amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18), optionally containing one or two amino acid substitutions; and / or Provided is an antibody, fragment, or variant thereof comprising a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), optionally containing one or two amino acid substitutions, a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 13), optionally containing one or two amino acid substitutions, and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14), optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0190] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 19), a VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 20), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 13), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14); Including, Optionally, antibodies, fragments or variants thereof are provided in which Met residues are each independently substituted with an amino acid selected from the group consisting of Ala and Leu, and / or Asp residues are each independently substituted with an amino acid selected from the group consisting of Ala, Gln and Glu.

[0191] Antigen-binding molecules of or derived from 3E05_var1 (e.g., antibodies with one or more amino acid substitutions) have a K of less than about 0.01 nM. D Such antigen binding molecules may additionally or alternatively exhibit an IC50 for IFN secretion of less than about 0.5 nM and / or an IC90 for IFN secretion of less than about 5 nM.

[0192] 3E05_var2 In one embodiment, VHCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence SYTMS (SEQ ID NO: 26), VHCDR2 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence YISSGGGNTYYADSVKG (SEQ ID NO: 27), a heavy chain variable region comprising a VHCDR2 having 3%, 94%, 95%, 96%, 97%, 98% or 99% identity and a VHCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); and / or VLCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94% identity to the amino acid sequence AASTLES (SEQ ID NO: 13), Antibodies, fragments or variants thereof are provided that comprise a light chain variable region comprising a VLCDR2 having 95%, 96%, 97%, 98% or 99% identity, and a VLCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 14).

[0193] In one embodiment, VHCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 29), VHCDR2 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence SSGGGNTY (SEQ ID NO: 30), a heavy chain variable region comprising a VHCDR2 having 4%, 95%, 96%, 97%, 98% or 99% identity and a VHCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); and / or VLCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94% identity to the amino acid sequence AASTLES (SEQ ID NO: 13), Antibodies, fragments or variants thereof are provided that comprise a light chain variable region comprising a VLCDR2 having 95%, 96%, 97%, 98% or 99% identity, and a VLCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 14).

[0194] In one embodiment, a heavy chain variable region comprising a VHCDR1 having at least 90% identity to the amino acid sequence SYTMS (SEQ ID NO: 26), a VHCDR2 having at least 90% identity to the amino acid sequence YISSGGGNTYYADSVKG (SEQ ID NO: 27), and a VHCDR3 having at least 90% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); and / or An antibody, fragment or variant thereof is provided, comprising a light chain variable region including a VLCDR1 having at least 90% identity to the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 having at least 90% identity to the amino acid sequence AASTLES (SEQ ID NO: 13), and a VLCDR3 having at least 90% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 14).

[0195] In one embodiment, a heavy chain variable region comprising a VHCDR1 having at least 90% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 29), a VHCDR2 having at least 90% identity to the amino acid sequence SSGGGNTY (SEQ ID NO: 30), and a VHCDR3 having at least 90% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); and / or An antibody, fragment or variant thereof is provided, comprising a light chain variable region including a VLCDR1 having at least 90% identity to the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 having at least 90% identity to the amino acid sequence AASTLES (SEQ ID NO: 13), and a VLCDR3 having at least 90% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 14).

[0196] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 26), a VHCDR2 comprising the amino acid sequence YISSGGGNTYYADSVKG (SEQ ID NO: 27), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 13), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14); The present invention provides an antibody, fragment or variant thereof comprising:

[0197] Amino acid substitutions may be made to provide variant antibodies derived from 3E05_var2, for example: 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. a heavy chain variable region comprising a VH CDR3 comprising: Provided is an antibody, fragment, or variant thereof comprising a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), optionally containing one or two amino acid substitutions, a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 13), optionally containing one or two amino acid substitutions, and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14), optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0198] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 26), a VHCDR2 comprising the amino acid sequence YISSGGGNTYYADSVKG (SEQ ID NO: 27), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 13), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14); Including, Optionally, antibodies, fragments or variants thereof are provided in which Met residues are each independently substituted with an amino acid selected from the group consisting of Ala and Leu, and / or Asp residues are each independently substituted with an amino acid selected from the group consisting of Ala, Gln and Glu.

[0199] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 29), a VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 30), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 13), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14); The present invention provides an antibody, fragment or variant thereof comprising:

[0200] Amino acid substitutions may be made to provide variant antibodies derived from 3E05_var2, for example: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 29), optionally with one or two amino acid substitutions, a VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 30), optionally with one or two amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28), optionally with one or two amino acid substitutions; and / or Provided is an antibody, fragment, or variant thereof comprising a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), optionally containing one or two amino acid substitutions, a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 13), optionally containing one or two amino acid substitutions, and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14), optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0201] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 29), a VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 30), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12); a light chain variable region comprising a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 13) and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14); Including, Optionally, antibodies, fragments or variants thereof are provided in which Met residues are each independently substituted with an amino acid selected from the group consisting of Ala and Leu, and / or Asp residues are each independently substituted with an amino acid selected from the group consisting of Ala, Gln and Glu.

[0202] Antigen-binding molecules of or derived from 3E05_var2 (e.g., antibodies with one or more amino acid substitutions) have a K of less than about 0.5 nM. D Such antigen binding molecules may additionally or alternatively exhibit an IC50 for IFN secretion of less than about 0.5 nM and / or an IC90 for IFN secretion of less than about 5 nM.

[0203] 3E05_var3 In one embodiment, VHCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence SYTMS (SEQ ID NO: 36), VHCDR2 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 37), a heavy chain variable region comprising a VHCDR2 having 3%, 94%, 95%, 96%, 97%, 98% or 99% identity and a VHCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); and / or VLCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94% identity to the amino acid sequence AASTLES (SEQ ID NO: 13), Antibodies, fragments or variants thereof are provided that comprise a light chain variable region comprising a VLCDR2 having 95%, 96%, 97%, 98% or 99% identity, and a VLCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 14).

[0204] In one embodiment, VHCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 39), VHCDR2 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence SSGGGQTY (SEQ ID NO: 40), a heavy chain variable region comprising a VHCDR2 having 4%, 95%, 96%, 97%, 98% or 99% identity and a VHCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); and / or VLCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), VLCDR2 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence AASTLES (SEQ ID NO: 13), and the amino acid sequence QQTNEDPPT (SEQ ID NO: 14). Antibodies, fragments or variants thereof are provided that comprise a light chain variable region comprising a VLCDR3 that has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to

[0205] In one embodiment, a heavy chain variable region comprising a VHCDR1 having at least 90% identity to the amino acid sequence SYTMS (SEQ ID NO: 36), a VHCDR2 having at least 90% identity to the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 37), and a VHCDR3 having at least 90% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); and / or An antibody, fragment or variant thereof is provided, comprising a light chain variable region including a VLCDR1 having at least 90% identity to the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 having at least 90% identity to the amino acid sequence AASTLES (SEQ ID NO: 13), and a VLCDR3 having at least 90% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 14).

[0206] In one embodiment, a heavy chain variable region comprising a VHCDR1 having at least 90% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 39), a VHCDR2 having at least 90% identity to the amino acid sequence SSGGGQTY (SEQ ID NO: 40), and a VHCDR3 having at least 90% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); and / or An antibody, fragment or variant thereof is provided, comprising a light chain variable region including a VLCDR1 having at least 90% identity to the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 having at least 90% identity to the amino acid sequence AASTLES (SEQ ID NO: 13), and a VLCDR3 having at least 90% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 14).

[0207] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 36), a VHCDR2 comprising the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 37), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 13), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14); The present invention provides an antibody, fragment or variant thereof comprising:

[0208] Amino acid substitutions may be made to provide variant antibodies derived from 3E05_var3, for example: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 36), optionally containing one or two amino acid substitutions; a VHCDR2 comprising the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 37), optionally containing one or two amino acid substitutions; and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38), optionally containing one or two amino acid substitutions; and / or Antibodies, fragments or variants thereof are provided that comprise a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), optionally with one or two amino acid substitutions, a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 13), optionally with one or two amino acid substitutions, and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14), optionally with one or two amino acid substitutions. The acid substitutions may be conservative amino acid substitutions.

[0209] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 36), a VHCDR2 comprising the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 37), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 13), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14); Including, Optionally, an antibody, fragment or variant thereof is provided in which each Met residue is independently substituted with an amino acid selected from the group consisting of Ala and Leu, and / or each Asp residue is independently substituted with an amino acid selected from the group consisting of Ala, Gln and Glu.

[0210] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 39), a VHCDR2 comprising the amino acid sequence SSGGGQTY (SEQ ID NO: 40), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 13), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14); The present invention provides an antibody, fragment or variant thereof comprising:

[0211] Amino acid substitutions may be made to provide variant antibodies derived from 3E05_var3, for example: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 39), optionally containing one or two amino acid substitutions, a VHCDR2 comprising the amino acid sequence SSGGGQTY (SEQ ID NO: 40), optionally containing one or two amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38), optionally containing one or two amino acid substitutions; and / or Provided is an antibody, fragment, or variant thereof comprising a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), optionally containing one or two amino acid substitutions, a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 13), optionally containing one or two amino acid substitutions, and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14), optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0212] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 39), a VHCDR2 comprising the amino acid sequence SSGGGQTY (SEQ ID NO: 40), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 13), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14); Including, Optionally, an antibody, fragment or variant thereof is provided, wherein each Met residue is independently substituted with an amino acid selected from the group consisting of Ala and Leu, and / or each Asp residue is independently substituted with an amino acid selected from the group consisting of Ala, Gln and Glu. do.

[0213] Antigen-binding molecules of or derived from 3E05_var3 (e.g., antibodies with one or more amino acid substitutions) have a K of less than about 0.01 nM. D Such antigen binding molecules may additionally or alternatively exhibit an IC50 for IFN secretion of less than about 0.5 nM and / or an IC90 for IFN secretion of less than about 5 nM.

[0214] 3E05_var4 In one embodiment, VHCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence SYTMS (SEQ ID NO: 46), VHCDR2 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 47), a heavy chain variable region comprising a VHCDR2 having 3%, 94%, 95%, 96%, 97%, 98% or 99% identity and a VHCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); and / or VLCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94% identity to the amino acid sequence AASTLES (SEQ ID NO: 13), Antibodies, fragments or variants thereof are provided that comprise a light chain variable region comprising a VLCDR2 having 95%, 96%, 97%, 98% or 99% identity, and a VLCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 14).

[0215] In one embodiment, VHCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 49), VHCDR2 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence SSGGGQTY (SEQ ID NO: 50), a heavy chain variable region comprising a VHCDR2 having 4%, 95%, 96%, 97%, 98% or 99% identity and a VHCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); and / or VLCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94% identity to the amino acid sequence AASTLES (SEQ ID NO: 13), Antibodies, fragments or variants thereof are provided that comprise a light chain variable region comprising a VLCDR2 having 95%, 96%, 97%, 98% or 99% identity, and a VLCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 14).

[0216] In one embodiment, Has at least 90% identity to the amino acid sequence SYTMS (SEQ ID NO: 46) a heavy chain variable region comprising a VHCDR1, a VHCDR2 having at least 90% identity to the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 47), and a VHCDR3 having at least 90% identity to the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); and / or An antibody, fragment or variant thereof is provided, comprising a light chain variable region including a VLCDR1 having at least 90% identity to the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 having at least 90% identity to the amino acid sequence AASTLES (SEQ ID NO: 13), and a VLCDR3 having at least 90% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 14).

[0217] In one embodiment, a heavy chain variable region comprising a VHCDR1 having at least 90% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 49), a VHCDR2 having at least 90% identity to the amino acid sequence SSGGGQTY (SEQ ID NO: 50), and a VHCDR3 having at least 90% identity to the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); and / or An antibody, fragment or variant thereof is provided, comprising a light chain variable region including a VLCDR1 having at least 90% identity to the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 having at least 90% identity to the amino acid sequence AASTLES (SEQ ID NO: 13), and a VLCDR3 having at least 90% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 14).

[0218] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 46), a VHCDR2 comprising the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 47), and a VHCDR3 comprising the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 13), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14); The present invention provides an antibody, fragment or variant thereof comprising:

[0219] Amino acid substitutions may be made to provide variant antibodies derived from 3E05_var4, for example: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 46), optionally containing one or two amino acid substitutions; a VHCDR2 comprising the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 47), optionally containing one or two amino acid substitutions; and a VHCDR3 comprising the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48), optionally containing one or two amino acid substitutions; and / or Provided is an antibody, fragment, or variant thereof comprising a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), optionally containing one or two amino acid substitutions, a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 13), optionally containing one or two amino acid substitutions, and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14), optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0220] In one embodiment, a heavy chain variable region comprising VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 46), VHCDR2 comprising the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 47), and VHCDR3 comprising the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); , a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 13), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14); Including, Optionally, antibodies, fragments or variants thereof are provided in which Met residues are each independently substituted with an amino acid selected from the group consisting of Ala and Leu, and / or Asp residues are each independently substituted with an amino acid selected from the group consisting of Ala, Gln and Glu.

[0221] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 49), a VHCDR2 comprising the amino acid sequence SSGGGQTY (SEQ ID NO: 50), and a VHCDR3 comprising the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 13), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14); The present invention provides an antibody, fragment or variant thereof comprising:

[0222] Amino acid substitutions may be made to provide variant antibodies derived from 3E05_var4, for example: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 49), optionally containing one or two amino acid substitutions, a VHCDR2 comprising the amino acid sequence SSGGGQTY (SEQ ID NO: 50), optionally containing one or two amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); and / or Provided is an antibody, fragment, or variant thereof comprising a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), optionally containing one or two amino acid substitutions, a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 13), optionally containing one or two amino acid substitutions, and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14), optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0223] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 49), a VHCDR2 comprising the amino acid sequence SSGGGQTY (SEQ ID NO: 50), and a VHCDR3 comprising the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 13), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14); Including, Optionally, antibodies, fragments or variants thereof are provided in which Met residues are each independently substituted with an amino acid selected from the group consisting of Ala and Leu, and / or Asp residues are each independently substituted with an amino acid selected from the group consisting of Ala, Gln and Glu.

[0224] Antigen-binding molecules of or derived from 3E05_var4 (e.g., antibodies with one or more amino acid substitutions) have a K of less than about 0.01 nM. D Such antigen binding molecules may additionally or alternatively exhibit an IC50 for IFN secretion of less than about 0.5 nM and / or an IC90 for IFN secretion of less than about 5 nM.

[0225] 3E05_var5 In one embodiment, VHCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence SYTMS (SEQ ID NO: 16), VHCDR2 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 17), a heavy chain variable region comprising a VHCDR2 having 3%, 94%, 95%, 96%, 97%, 98% or 99% identity and a VHCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); and / or VLCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94% or 99% identity to the amino acid sequence AASTLES (SEQ ID NO: 23), Antibodies, fragments or variants thereof are provided that comprise a light chain variable region comprising a VLCDR2 having 95%, 96%, 97%, 98% or 99% identity, and a VLCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 24).

[0226] In one embodiment, VHCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 19), VHCDR2 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence SSGGGNTY (SEQ ID NO: 20), a heavy chain variable region comprising a VHCDR2 having 4%, 95%, 96%, 97%, 98% or 99% identity and a VHCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); and / or VLCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94% or 99% identity to the amino acid sequence AASTLES (SEQ ID NO: 23), Antibodies, fragments or variants thereof are provided that comprise a light chain variable region comprising a VLCDR2 having 95%, 96%, 97%, 98% or 99% identity, and a VLCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 24).

[0227] In one embodiment, a heavy chain variable region comprising a VHCDR1 having at least 90% identity to the amino acid sequence SYTMS (SEQ ID NO: 16), a VHCDR2 having at least 90% identity to the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 17), and a VHCDR3 having at least 90% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); and / or VLCDR1 having at least 90% identity to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), VLCDR2 having at least 90% identity to the amino acid sequence AASTLES (SEQ ID NO: 23), and the amino acid sequence QQTNEDP Antibodies, fragments or variants thereof, comprising a light chain variable region comprising a VLCDR3 having at least 90% identity to PT (SEQ ID NO: 24) are provided.

[0228] In one embodiment, a heavy chain variable region comprising a VHCDR1 having at least 90% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 19), a VHCDR2 having at least 90% identity to the amino acid sequence SSGGGNTY (SEQ ID NO: 20), and a VHCDR3 having at least 90% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); and / or An antibody, fragment or variant thereof is provided, comprising a light chain variable region comprising a VLCDR1 having at least 90% identity to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 having at least 90% identity to the amino acid sequence AASTLES (SEQ ID NO: 23), and a VLCDR3 having at least 90% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 24).

[0229] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 16), a VHCDR2 comprising the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 17), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24); The present invention provides an antibody, fragment or variant thereof comprising:

[0230] Amino acid substitutions may be made to provide variant antibodies derived from 3E05_var5, for example: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 16), optionally containing one or two amino acid substitutions; a VHCDR2 comprising the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 17), optionally containing one or two amino acid substitutions; and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18), optionally containing one or two amino acid substitutions; and / or Provided is an antibody, fragment, or variant thereof, comprising a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), optionally containing one or two amino acid substitutions, a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23), optionally containing one or two amino acid substitutions, and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24), optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0231] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 16), a VHCDR2 comprising the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 17), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24); Including, Optionally, the Met residues are each independently substituted with an amino acid selected from the group consisting of Ala and Leu, and / or the Asp residues are each independently substituted with an amino acid selected from the group consisting of Ala, Gln, and Glu. Antibodies, fragments or variants thereof are provided in which the amino acid residues are substituted with amino acids selected from the group:

[0232] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 19), a VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 20), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24); The present invention provides an antibody, fragment or variant thereof comprising:

[0233] Amino acid substitutions may be made to provide variant antibodies derived from 3E05_var5, for example: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 19), optionally containing one or two amino acid substitutions, a VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 20), optionally containing one or two amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18), optionally containing one or two amino acid substitutions; and / or Provided is an antibody, fragment, or variant thereof, comprising a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), optionally containing one or two amino acid substitutions, a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23), optionally containing one or two amino acid substitutions, and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24), optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0234] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 19), a VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 20), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24); Including, Optionally, antibodies, fragments or variants thereof are provided in which Met residues are each independently substituted with an amino acid selected from the group consisting of Ala and Leu, and / or Asp residues are each independently substituted with an amino acid selected from the group consisting of Ala, Gln and Glu.

[0235] Antigen-binding molecules of or derived from 3E05_var5 (e.g., antibodies with one or more amino acid substitutions) have a K of less than about 0.01 nM. D Such antigen binding molecules may additionally or alternatively exhibit an IC50 for IFN secretion of less than about 0.5 nM and / or an IC90 for IFN secretion of less than about 5 nM.

[0236] 3E05_var7 In one embodiment, VHCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence SYTMS (SEQ ID NO: 36); a heavy chain variable region comprising a VHCDR2 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); and / or VLCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94% or 99% identity to the amino acid sequence AASTLES (SEQ ID NO: 23), Antibodies, fragments or variants thereof are provided that comprise a light chain variable region comprising a VLCDR2 having 95%, 96%, 97%, 98% or 99% identity, and a VLCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 24).

[0237] In one embodiment, VHCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 39), VHCDR2 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence SSGGGQTY (SEQ ID NO: 40), a heavy chain variable region comprising a VHCDR2 having 4%, 95%, 96%, 97%, 98% or 99% identity and a VHCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); and / or VLCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94% or 99% identity to the amino acid sequence AASTLES (SEQ ID NO: 23), Antibodies, fragments or variants thereof are provided that comprise a light chain variable region comprising a VLCDR2 having 95%, 96%, 97%, 98% or 99% identity, and a VLCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 24).

[0238] In one embodiment, a heavy chain variable region comprising a VHCDR1 having at least 90% identity to the amino acid sequence SYTMS (SEQ ID NO: 36), a VHCDR2 having at least 90% identity to the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 37), and a VHCDR3 having at least 90% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); and / or An antibody, fragment or variant thereof is provided, comprising a light chain variable region comprising a VLCDR1 having at least 90% identity to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 having at least 90% identity to the amino acid sequence AASTLES (SEQ ID NO: 23), and a VLCDR3 having at least 90% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 24).

[0239] In one embodiment, VHCDR1 having at least 90% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 39), a heavy chain variable region comprising a VHCDR2 having 90% identity and a VHCDR3 having at least 90% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); and / or An antibody, fragment or variant thereof is provided, comprising a light chain variable region comprising a VLCDR1 having at least 90% identity to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 having at least 90% identity to the amino acid sequence AASTLES (SEQ ID NO: 23), and a VLCDR3 having at least 90% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 24).

[0240] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 36), a VHCDR2 comprising the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 37), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24); The present invention provides an antibody, fragment or variant thereof comprising:

[0241] Amino acid substitutions may be made to provide variant antibodies derived from 3E05_var7, for example: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 36), optionally containing one or two amino acid substitutions; a VHCDR2 comprising the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 37), optionally containing one or two amino acid substitutions; and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38), optionally containing one or two amino acid substitutions; and / or Provided is an antibody, fragment, or variant thereof, comprising a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), optionally containing one or two amino acid substitutions, a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23), optionally containing one or two amino acid substitutions, and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24), optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0242] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 36), a VHCDR2 comprising the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 37), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24); Including, Optionally, an antibody, fragment or variant thereof is provided in which each Met residue is independently substituted with an amino acid selected from the group consisting of Ala and Leu, and / or each Asp residue is independently substituted with an amino acid selected from the group consisting of Ala, Gln and Glu.

[0243] In one embodiment, 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 HDYYDGGLY a heavy chain variable region comprising a VHCDR3 comprising YAMDY (SEQ ID NO: 38); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24); The present invention provides an antibody, fragment or variant thereof comprising:

[0244] Amino acid substitutions may be made to provide variant antibodies derived from 3E05_var7, for example: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 39), optionally containing one or two amino acid substitutions, a VHCDR2 comprising the amino acid sequence SSGGGQTY (SEQ ID NO: 40), optionally containing one or two amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38), optionally containing one or two amino acid substitutions; and / or Provided is an antibody, fragment, or variant thereof, comprising a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), optionally containing one or two amino acid substitutions, a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23), optionally containing one or two amino acid substitutions, and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24), optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0245] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 39), a VHCDR2 comprising the amino acid sequence SSGGGQTY (SEQ ID NO: 40), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24); Including, Optionally, an antibody, fragment or variant thereof is provided in which each Met residue is independently substituted with an amino acid selected from the group consisting of Ala and Leu, and / or each Asp residue is independently substituted with an amino acid selected from the group consisting of Ala, Gln and Glu.

[0246] Antigen-binding molecules of or derived from 3E05_var7 (e.g., antibodies with one or more amino acid substitutions) have a K of less than about 0.01 nM. D Such antigen binding molecules may additionally or alternatively exhibit an IC50 for IFN secretion of less than about 0.5 nM and / or an IC90 for IFN secretion of less than about 5 nM.

[0247] 3E05_var8 In one embodiment, VHCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence SYTMS (SEQ ID NO: 46), VHCDR2 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 47), a heavy chain variable region comprising a VHCDR2 having 3%, 94%, 95%, 96%, 97%, 98% or 99% identity and a VHCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); and / or At least 7 amino acid sequences for the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22) Provided are antibodies, fragments or variants thereof comprising a light chain variable region comprising a VLCDR1 having 0%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity, a VLCDR2 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence AASTLES (SEQ ID NO: 23), and a VLCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 24).

[0248] In one embodiment, VHCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 49), VHCDR2 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence SSGGGQTY (SEQ ID NO: 50), a heavy chain variable region comprising a VHCDR2 having 4%, 95%, 96%, 97%, 98% or 99% identity and a VHCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); and / or VLCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94% or 99% identity to the amino acid sequence AASTLES (SEQ ID NO: 23), Antibodies, fragments or variants thereof are provided that comprise a light chain variable region comprising a VLCDR2 having 95%, 96%, 97%, 98% or 99% identity, and a VLCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 24).

[0249] In one embodiment, a heavy chain variable region comprising a VHCDR1 having at least 90% identity to the amino acid sequence SYTMS (SEQ ID NO: 46), a VHCDR2 having at least 90% identity to the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 47), and a VHCDR3 having at least 90% identity to the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); and / or An antibody, fragment or variant thereof is provided, comprising a light chain variable region comprising a VLCDR1 having at least 90% identity to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 having at least 90% identity to the amino acid sequence AASTLES (SEQ ID NO: 23), and a VLCDR3 having at least 90% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 24).

[0250] In one embodiment, a heavy chain variable region comprising a VHCDR1 having at least 90% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 49), a VHCDR2 having at least 90% identity to the amino acid sequence SSGGGQTY (SEQ ID NO: 50), and a VHCDR3 having at least 90% identity to the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); and / or VLCDR1 having at least 90% identity to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), VLCDR2 having at least 90% identity to the amino acid sequence AASTLES (SEQ ID NO: 23), and the amino acid sequence QQTNEDP Antibodies, fragments or variants thereof, comprising a light chain variable region comprising a VLCDR3 having at least 90% identity to PT (SEQ ID NO: 24) are provided.

[0251] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 46), a VHCDR2 comprising the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 47), and a VHCDR3 comprising the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24); The present invention provides an antibody, fragment or variant thereof comprising:

[0252] Amino acid substitutions may be made to provide variant antibodies derived from 3E05_var8, for example: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 46), optionally containing one or two amino acid substitutions; a VHCDR2 comprising the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 47), optionally containing one or two amino acid substitutions; and a VHCDR3 comprising the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48), optionally containing one or two amino acid substitutions; and / or Provided is an antibody, fragment, or variant thereof, comprising a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), optionally containing one or two amino acid substitutions, a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23), optionally containing one or two amino acid substitutions, and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24), optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0253] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 46), a VHCDR2 comprising the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 47), and a VHCDR3 comprising the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24); Including, Optionally, an antibody, fragment or variant thereof is provided in which each Met residue is independently substituted with an amino acid selected from the group consisting of Ala and Leu, and / or each Asp residue is independently substituted with an amino acid selected from the group consisting of Ala, Gln and Glu.

[0254] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 49), a VHCDR2 comprising the amino acid sequence SSGGGQTY (SEQ ID NO: 50), and a VHCDR3 comprising the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24); The present invention provides an antibody, fragment or variant thereof comprising:

[0255] Amino acid substitutions may be made to provide variant antibodies derived from 3E05_var8, for example: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 49), optionally with one or two amino acid substitutions, a VHCDR2 comprising the amino acid sequence SSGGGQTY (SEQ ID NO: 50), optionally with one or two amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48), optionally with one or two amino acid substitutions; and / or Provided is an antibody, fragment, or variant thereof, comprising a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), optionally containing one or two amino acid substitutions, a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23), optionally containing one or two amino acid substitutions, and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24), optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0256] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 49), a VHCDR2 comprising the amino acid sequence SSGGGQTY (SEQ ID NO: 50), and a VHCDR3 comprising the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24); Including, Optionally, antibodies, fragments or variants thereof are provided in which Met residues are each independently substituted with an amino acid selected from the group consisting of Ala and Leu, and / or Asp residues are each independently substituted with an amino acid selected from the group consisting of Ala, Gln and Glu.

[0257] Antigen-binding molecules of or derived from 3E05_var8 (e.g., antibodies with one or more amino acid substitutions) have a K of less than about 0.01 nM. D Such antigen binding molecules may additionally or alternatively exhibit an IC50 for IFN secretion of less than about 0.5 nM and / or an IC90 for IFN secretion of less than about 5 nM.

[0258] 3E05_var9 In one embodiment, VHCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence SYTMS (SEQ ID NO: 16), VHCDR2 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 17), a heavy chain variable region comprising a VHCDR2 having 3%, 94%, 95%, 96%, 97%, 98% or 99% identity and a VHCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); and / or VLCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), VLCDR2 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence AASTLES (SEQ ID NO: 33), and VLCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 34). Antibodies, fragments or variants thereof comprising a light chain variable region comprising a VLCDR3 that has 94%, 95%, 96%, 97%, 98% or 99% identity thereto are provided.

[0259] In one embodiment, VHCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 19), VHCDR2 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence SSGGGNTY (SEQ ID NO: 20), a heavy chain variable region comprising a VHCDR2 having 4%, 95%, 96%, 97%, 98% or 99% identity and a VHCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); and / or VLCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94% identity to the amino acid sequence AASTLES (SEQ ID NO: 33), Antibodies, fragments or variants thereof are provided that comprise a light chain variable region comprising a VLCDR2 having 95%, 96%, 97%, 98% or 99% identity, and a VLCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 34).

[0260] In one embodiment, a heavy chain variable region comprising a VHCDR1 having at least 90% identity to the amino acid sequence SYTMS (SEQ ID NO: 16), a VHCDR2 having at least 90% identity to the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 17), and a VHCDR3 having at least 90% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); and / or An antibody, fragment or variant thereof is provided, comprising a light chain variable region comprising a VLCDR1 having at least 90% identity to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 having at least 90% identity to the amino acid sequence AASTLES (SEQ ID NO: 33), and a VLCDR3 having at least 90% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 34).

[0261] In one embodiment, a heavy chain variable region comprising a VHCDR1 having at least 90% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 19), a VHCDR2 having at least 90% identity to the amino acid sequence SSGGGNTY (SEQ ID NO: 20), and a VHCDR3 having at least 90% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); and / or An antibody, fragment or variant thereof is provided, comprising a light chain variable region comprising a VLCDR1 having at least 90% identity to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 having at least 90% identity to the amino acid sequence AASTLES (SEQ ID NO: 33), and a VLCDR3 having at least 90% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 34).

[0262] In one embodiment, 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 H a heavy chain variable region comprising a VHCDR3 comprising DYYDGGLYYAMDY (SEQ ID NO: 18); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34); The present invention provides an antibody, fragment or variant thereof comprising:

[0263] Amino acid substitutions may be made to provide variant antibodies derived from 3E05_var9, for example: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 16), optionally containing one or two amino acid substitutions; a VHCDR2 comprising the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 17), optionally containing one or two amino acid substitutions; and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18), optionally containing one or two amino acid substitutions; and / or Provided is an antibody, fragment, or variant thereof comprising a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), optionally containing one or two amino acid substitutions, a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33), optionally containing one or two amino acid substitutions, and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34), optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0264] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 16), a VHCDR2 comprising the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 17), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34); Including, Optionally, antibodies, fragments or variants thereof are provided in which Met residues are each independently substituted with an amino acid selected from the group consisting of Ala and Leu, and / or Asp residues are each independently substituted with an amino acid selected from the group consisting of Ala, Gln and Glu.

[0265] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 19), a VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 20), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34); The present invention provides an antibody, fragment or variant thereof comprising:

[0266] Amino acid substitutions may be made to provide variant antibodies derived from 3E05_var9, for example: 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 a heavy chain variable region comprising Provided is an antibody, fragment, or variant thereof comprising a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), optionally containing one or two amino acid substitutions, a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33), optionally containing one or two amino acid substitutions, and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34), optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0267] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 19), a VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 20), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34); Including, Optionally, antibodies, fragments or variants thereof are provided in which Met residues are each independently substituted with an amino acid selected from the group consisting of Ala and Leu, and / or Asp residues are each independently substituted with an amino acid selected from the group consisting of Ala, Gln and Glu.

[0268] Antigen-binding molecules of or derived from 3E05_var9 (e.g., antibodies with one or more amino acid substitutions) have a K of less than about 0.01 nM. D Such antigen binding molecules may additionally or alternatively exhibit an IC50 for IFN secretion of less than about 0.5 nM and / or an IC90 for IFN secretion of less than about 5 nM.

[0269] 3E05_var10 In one embodiment, VHCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence SYTMS (SEQ ID NO: 26), VHCDR2 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence YISSGGGNTYYADSVKG (SEQ ID NO: 27), a heavy chain variable region comprising a VHCDR2 having 3%, 94%, 95%, 96%, 97%, 98% or 99% identity and a VHCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); and / or VLCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94% identity to the amino acid sequence AASTLES (SEQ ID NO: 33), Antibodies, fragments or variants thereof are provided that comprise a light chain variable region comprising a VLCDR2 having 95%, 96%, 97%, 98% or 99% identity, and a VLCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 34).

[0270] In one embodiment, A sequence of at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 1109%, 1110%, 112 a heavy chain variable region comprising a VHCDR1 having 8% or 99% identity, a VHCDR2 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence SSGGGNTY (SEQ ID NO: 30), and a VHCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); and / or VLCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94% identity to the amino acid sequence AASTLES (SEQ ID NO: 33), Antibodies, fragments or variants thereof are provided that comprise a light chain variable region comprising a VLCDR2 having 95%, 96%, 97%, 98% or 99% identity, and a VLCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 34).

[0271] In one embodiment, a heavy chain variable region comprising a VHCDR1 having at least 90% identity to the amino acid sequence SYTMS (SEQ ID NO: 26), a VHCDR2 having at least 90% identity to the amino acid sequence YISSGGGNTYYADSVKG (SEQ ID NO: 27), and a VHCDR3 having at least 90% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); and / or An antibody, fragment or variant thereof is provided, comprising a light chain variable region comprising a VLCDR1 having at least 90% identity to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 having at least 90% identity to the amino acid sequence AASTLES (SEQ ID NO: 33), and a VLCDR3 having at least 90% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 34).

[0272] In one embodiment, a heavy chain variable region comprising a VHCDR1 having at least 90% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 29), a VHCDR2 having at least 90% identity to the amino acid sequence SSGGGNTY (SEQ ID NO: 30), and a VHCDR3 having at least 90% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); and / or An antibody, fragment or variant thereof is provided, comprising a light chain variable region comprising a VLCDR1 having at least 90% identity to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 having at least 90% identity to the amino acid sequence AASTLES (SEQ ID NO: 33), and a VLCDR3 having at least 90% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 34).

[0273] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 26), a VHCDR2 comprising the amino acid sequence YISSGGGNTYYADSVKG (SEQ ID NO: 27), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34); The present invention provides an antibody, fragment or variant thereof comprising:

[0274] Amino acid substitutions may be made to provide variant antibodies derived from 3E05_var10, for example: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 26), optionally containing one or two amino acid substitutions; a VHCDR2 comprising the amino acid sequence YISSGGGNTYYADSVKG (SEQ ID NO: 27), optionally containing one or two amino acid substitutions; and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28), optionally containing one or two amino acid substitutions; and / or Provided is an antibody, fragment, or variant thereof comprising a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), optionally containing one or two amino acid substitutions, a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33), optionally containing one or two amino acid substitutions, and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34), optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0275] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 26), a VHCDR2 comprising the amino acid sequence YISSGGGNTYYADSVKG (SEQ ID NO: 27), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34); Including, Optionally, antibodies, fragments or variants thereof are provided in which Met residues are each independently substituted with an amino acid selected from the group consisting of Ala and Leu, and / or Asp residues are each independently substituted with an amino acid selected from the group consisting of Ala, Gln and Glu.

[0276] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 29), a VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 30), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34); The present invention provides an antibody, fragment or variant thereof comprising:

[0277] Amino acid substitutions may be made to provide variant antibodies derived from 3E05_var10, for example: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 29), optionally with one or two amino acid substitutions, a VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 30), optionally with one or two amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28), optionally with one or two amino acid substitutions; and / or Antibodies, fragments or variants thereof are provided that comprise a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), optionally with one or two amino acid substitutions, a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33), optionally with one or two amino acid substitutions, and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34), optionally with one or two amino acid substitutions. The acid substitutions may be conservative amino acid substitutions.

[0278] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 29), a VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 30), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34); Including, Optionally, an antibody, fragment or variant thereof is provided in which each Met residue is independently substituted with an amino acid selected from the group consisting of Ala and Leu, and / or each Asp residue is independently substituted with an amino acid selected from the group consisting of Ala, Gln and Glu.

[0279] Antigen-binding molecules of or derived from 3E05_var10 (e.g., antibodies with one or more amino acid substitutions) have a K of less than about 1 nM. D Such antigen binding molecules may additionally or alternatively exhibit an IC50 for IFN secretion of less than about 0.5 nM and / or an IC90 for IFN secretion of less than about 5 nM.

[0280] 3E05_var11 In one embodiment, VHCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence SYTMS (SEQ ID NO: 36), VHCDR2 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 37), a heavy chain variable region comprising a VHCDR2 having 3%, 94%, 95%, 96%, 97%, 98% or 99% identity and a VHCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); and / or VLCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94% identity to the amino acid sequence AASTLES (SEQ ID NO: 33), Antibodies, fragments or variants thereof are provided that comprise a light chain variable region comprising a VLCDR2 having 95%, 96%, 97%, 98% or 99% identity, and a VLCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 34).

[0281] In one embodiment, a VHCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 39), a VHCDR2 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence SSGGGQTY (SEQ ID NO: 40), and a VHCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38). and / or a heavy chain variable region comprising VLCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94% identity to the amino acid sequence AASTLES (SEQ ID NO: 33), Antibodies, fragments or variants thereof are provided that comprise a light chain variable region comprising a VLCDR2 having 95%, 96%, 97%, 98% or 99% identity, and a VLCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 34).

[0282] In one embodiment, a heavy chain variable region comprising a VHCDR1 having at least 90% identity to the amino acid sequence SYTMS (SEQ ID NO: 36), a VHCDR2 having at least 90% identity to the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 37), and a VHCDR3 having at least 90% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); and / or An antibody, fragment or variant thereof is provided, comprising a light chain variable region comprising a VLCDR1 having at least 90% identity to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 having at least 90% identity to the amino acid sequence AASTLES (SEQ ID NO: 33), and a VLCDR3 having at least 90% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 34).

[0283] In one embodiment, a heavy chain variable region comprising a VHCDR1 having at least 90% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 39), a VHCDR2 having at least 90% identity to the amino acid sequence SSGGGQTY (SEQ ID NO: 40), and a VHCDR3 having at least 90% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); and / or An antibody, fragment or variant thereof is provided, comprising a light chain variable region comprising a VLCDR1 having at least 90% identity to the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 having at least 90% identity to the amino acid sequence AASTLES (SEQ ID NO: 33), and a VLCDR3 having at least 90% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 34).

[0284] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 36), a VHCDR2 comprising the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 37), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34); The present invention provides an antibody, fragment or variant thereof comprising:

[0285] Amino acid substitutions may be made to provide variant antibodies derived from 3E05_var11, for example: 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 YISSGGGQTYYPDSVKG (SEQ ID NO: 38), optionally containing one or two amino acid substitutions. and / or a heavy chain variable region comprising a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38) comprising the amino acid substitution: Provided is an antibody, fragment, or variant thereof comprising a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), optionally containing one or two amino acid substitutions, a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33), optionally containing one or two amino acid substitutions, and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34), optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0286] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 36), a VHCDR2 comprising the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 37), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34); Including, Optionally, antibodies, fragments or variants thereof are provided in which Met residues are each independently substituted with an amino acid selected from the group consisting of Ala and Leu, and / or Asp residues are each independently substituted with an amino acid selected from the group consisting of Ala, Gln and Glu.

[0287] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 39), a VHCDR2 comprising the amino acid sequence SSGGGQTY (SEQ ID NO: 40), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34); The present invention provides an antibody, fragment or variant thereof comprising:

[0288] Amino acid substitutions may be made to provide variant antibodies derived from 3E05_var11, for example: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 39), optionally containing one or two amino acid substitutions, a VHCDR2 comprising the amino acid sequence SSGGGQTY (SEQ ID NO: 40), optionally containing one or two amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38), optionally containing one or two amino acid substitutions; and / or Provided is an antibody, fragment, or variant thereof comprising a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), optionally containing one or two amino acid substitutions, a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33), optionally containing one or two amino acid substitutions, and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34), optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0289] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 39), a VHCDR2 comprising the amino acid sequence SSGGGQTY (SEQ ID NO: 40), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34); Including, Optionally, antibodies, fragments or variants thereof are provided in which Met residues are each independently substituted with an amino acid selected from the group consisting of Ala and Leu, and / or Asp residues are each independently substituted with an amino acid selected from the group consisting of Ala, Gln and Glu.

[0290] Antigen-binding molecules of or derived from 3E05_var11 (e.g., antibodies with one or more amino acid substitutions) have a K of less than about 1 nM. D Such antigen binding molecules may additionally or alternatively exhibit an IC50 for IFN secretion of less than about 0.5 nM and / or an IC90 for IFN secretion of less than about 5 nM.

[0291] 3E05_var13 In one embodiment, VHCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence SYTMS (SEQ ID NO: 16), VHCDR2 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 17), a heavy chain variable region comprising a VHCDR2 having 3%, 94%, 95%, 96%, 97%, 98% or 99% identity and a VHCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); and / or VLCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94% identity to the amino acid sequence AASTLES (SEQ ID NO: 43), Antibodies, fragments or variants thereof are provided that comprise a light chain variable region comprising a VLCDR2 having 95%, 96%, 97%, 98% or 99% identity, and a VLCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 44).

[0292] In one embodiment, VHCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 19), VHCDR2 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence SSGGGNTY (SEQ ID NO: 20), a heavy chain variable region comprising a VHCDR2 having 4%, 95%, 96%, 97%, 98% or 99% identity and a VHCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); and / or VLCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence AASTLES (SEQ ID NO: 43). and a VLCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 44).

[0293] In one embodiment, a heavy chain variable region comprising a VHCDR1 having at least 90% identity to the amino acid sequence SYTMS (SEQ ID NO: 16), a VHCDR2 having at least 90% identity to the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 17), and a VHCDR3 having at least 90% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); and / or An antibody, fragment or variant thereof is provided, comprising a light chain variable region comprising a VLCDR1 having at least 90% identity to the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 having at least 90% identity to the amino acid sequence AASTLES (SEQ ID NO: 43), and a VLCDR3 having at least 90% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 44).

[0294] In one embodiment, a heavy chain variable region comprising a VHCDR1 having at least 90% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 19), a VHCDR2 having at least 90% identity to the amino acid sequence SSGGGNTY (SEQ ID NO: 20), and a VHCDR3 having at least 90% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); and / or An antibody, fragment or variant thereof is provided, comprising a light chain variable region comprising a VLCDR1 having at least 90% identity to the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 having at least 90% identity to the amino acid sequence AASTLES (SEQ ID NO: 43), and a VLCDR3 having at least 90% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 44).

[0295] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 16), a VHCDR2 comprising the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 17), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 43), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44); The present invention provides an antibody, fragment or variant thereof comprising:

[0296] Amino acid substitutions may be made to provide variant antibodies derived from 3E05_var13, for example: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 16), optionally containing one or two amino acid substitutions; a VHCDR2 comprising the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 17), optionally containing one or two amino acid substitutions; and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18), optionally containing one or two amino acid substitutions; and / or 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 VLCD comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44), optionally containing one or two amino acid substitutions. An antibody, fragment or variant thereof comprising a light chain variable region comprising R3 is provided. The amino acid substitutions may be conservative amino acid substitutions.

[0297] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 16), a VHCDR2 comprising the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 17), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 43), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44); Including, Optionally, antibodies, fragments or variants thereof are provided in which Met residues are each independently substituted with an amino acid selected from the group consisting of Ala and Leu, and / or Asp residues are each independently substituted with an amino acid selected from the group consisting of Ala, Gln and Glu.

[0298] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 19), a VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 20), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 43), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44); The present invention provides an antibody, fragment or variant thereof comprising:

[0299] Amino acid substitutions may be made to provide variant antibodies derived from 3E05_var13, for example: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 19), optionally containing one or two amino acid substitutions, a VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 20), optionally containing one or two amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18), optionally containing one or two amino acid substitutions; and / or Provided is an antibody, fragment, or variant thereof, comprising a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), optionally containing one or two amino acid substitutions, a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 43), optionally containing one or two amino acid substitutions, and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44), optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0300] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 19), a VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 20), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 43), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44); Including, Optionally, the Met residues are each independently substituted with an amino acid selected from the group consisting of Ala and Leu, and / or the Asp residues are each independently substituted with an amino acid selected from the group consisting of Ala, Gln, and Glu. Antibodies, fragments or variants thereof are provided in which the amino acid residues are substituted with amino acids selected from the group:

[0301] Antigen-binding molecules of or derived from 3E05_var13 (e.g., antibodies with one or more amino acid substitutions) have a K of less than about 0.01 nM. DSuch antigen binding molecules may additionally or alternatively exhibit an IC50 for IFN secretion of less than about 0.5 nM and / or an IC90 for IFN secretion of less than about 5 nM.

[0302] 3E05_var15 In one embodiment, VHCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence SYTMS (SEQ ID NO: 36), VHCDR2 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 37), a heavy chain variable region comprising a VHCDR2 having 3%, 94%, 95%, 96%, 97%, 98% or 99% identity and a VHCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); and / or VLCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94% identity to the amino acid sequence AASTLES (SEQ ID NO: 43), Antibodies, fragments or variants thereof are provided that comprise a light chain variable region comprising a VLCDR2 having 95%, 96%, 97%, 98% or 99% identity, and a VLCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 44).

[0303] In one embodiment, VHCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 39), VHCDR2 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence SSGGGQTY (SEQ ID NO: 40), a heavy chain variable region comprising a VHCDR2 having 4%, 95%, 96%, 97%, 98% or 99% identity and a VHCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); and / or VLCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94% identity to the amino acid sequence AASTLES (SEQ ID NO: 43), Antibodies, fragments or variants thereof are provided that comprise a light chain variable region comprising a VLCDR2 having 95%, 96%, 97%, 98% or 99% identity, and a VLCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 44).

[0304] In one embodiment, a heavy chain variable region comprising a VHCDR1 having at least 90% identity to the amino acid sequence SYTMS (SEQ ID NO: 36), a VHCDR2 having at least 90% identity to the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 37), and a VHCDR3 having at least 90% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); and / or An antibody, fragment or variant thereof is provided, comprising a light chain variable region comprising a VLCDR1 having at least 90% identity to the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 having at least 90% identity to the amino acid sequence AASTLES (SEQ ID NO: 43), and a VLCDR3 having at least 90% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 44).

[0305] In one embodiment, a heavy chain variable region comprising a VHCDR1 having at least 90% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 39), a VHCDR2 having at least 90% identity to the amino acid sequence SSGGGQTY (SEQ ID NO: 40), and a VHCDR3 having at least 90% identity to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); and / or An antibody, fragment or variant thereof is provided, comprising a light chain variable region comprising a VLCDR1 having at least 90% identity to the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 having at least 90% identity to the amino acid sequence AASTLES (SEQ ID NO: 43), and a VLCDR3 having at least 90% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 44).

[0306] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 36), a VHCDR2 comprising the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 37), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 43), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44); The present invention provides an antibody, fragment or variant thereof comprising:

[0307] Amino acid substitutions may be made to provide variant antibodies derived from 3E05_var15, for example: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 36), optionally containing one or two amino acid substitutions; a VHCDR2 comprising the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 37), optionally containing one or two amino acid substitutions; and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38), optionally containing one or two amino acid substitutions; and / or Provided is an antibody, fragment, or variant thereof, comprising a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), optionally containing one or two amino acid substitutions, a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 43), optionally containing one or two amino acid substitutions, and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44), optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0308] In one embodiment, 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 H a heavy chain variable region comprising a VHCDR3 comprising DYYDGGLYYAMDY (SEQ ID NO: 38); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 43), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44); Including, Optionally, antibodies, fragments or variants thereof are provided in which Met residues are each independently substituted with an amino acid selected from the group consisting of Ala and Leu, and / or Asp residues are each independently substituted with an amino acid selected from the group consisting of Ala, Gln and Glu.

[0309] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 39), a VHCDR2 comprising the amino acid sequence SSGGGQTY (SEQ ID NO: 40), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 43), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44); The present invention provides an antibody, fragment or variant thereof comprising:

[0310] Amino acid substitutions may be made to provide variant antibodies derived from 3E05_var15, for example: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 39), optionally containing one or two amino acid substitutions, a VHCDR2 comprising the amino acid sequence SSGGGQTY (SEQ ID NO: 40), optionally containing one or two amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38), optionally containing one or two amino acid substitutions; and / or Provided is an antibody, fragment, or variant thereof, comprising a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), optionally containing one or two amino acid substitutions, a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 43), optionally containing one or two amino acid substitutions, and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44), optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0311] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 39), a VHCDR2 comprising the amino acid sequence SSGGGQTY (SEQ ID NO: 40), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 43), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44); Including, Optionally, an antibody, fragment or variant thereof is provided in which each Met residue is independently substituted with an amino acid selected from the group consisting of Ala and Leu, and / or each Asp residue is independently substituted with an amino acid selected from the group consisting of Ala, Gln and Glu.

[0312] Antigen-binding molecules of or derived from 3E05_var15 (e.g., antibodies with one or more amino acid substitutions) have a K of less than about 0.01 nM. D Such antigen-binding molecules may additionally or alternatively have an IC50 of less than about 0.5 nM for IFN secretion. and / or may exhibit an IC90 for IFN secretion of less than about 5 nM.

[0313] 3E05_var16 In one embodiment, VHCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence SYTMS (SEQ ID NO: 46), VHCDR2 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 47), a heavy chain variable region comprising a VHCDR2 having 3%, 94%, 95%, 96%, 97%, 98% or 99% identity and a VHCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); and / or VLCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94% identity to the amino acid sequence AASTLES (SEQ ID NO: 43), Antibodies, fragments or variants thereof are provided that comprise a light chain variable region comprising a VLCDR2 having 95%, 96%, 97%, 98% or 99% identity, and a VLCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 44).

[0314] In one embodiment, VHCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 49), VHCDR2 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence SSGGGQTY (SEQ ID NO: 50), a heavy chain variable region comprising a VHCDR2 having 4%, 95%, 96%, 97%, 98% or 99% identity and a VHCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); and / or VLCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94% identity to the amino acid sequence AASTLES (SEQ ID NO: 43), Antibodies, fragments or variants thereof are provided that comprise a light chain variable region comprising a VLCDR2 having 95%, 96%, 97%, 98% or 99% identity, and a VLCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 44).

[0315] In one embodiment, a heavy chain variable region comprising a VHCDR1 having at least 90% identity to the amino acid sequence SYTMS (SEQ ID NO: 46), a VHCDR2 having at least 90% identity to the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 47), and a VHCDR3 having at least 90% identity to the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); and / or At least 9 amino acid sequences for the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42) An antibody, fragment or variant thereof is provided, comprising a light chain variable region comprising VLCDR1 having 0% identity to the amino acid sequence AASTLES (SEQ ID NO: 43), VLCDR2 having at least 90% identity to the amino acid sequence AASTLES (SEQ ID NO: 43), and VLCDR3 having at least 90% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 44).

[0316] In one embodiment, a heavy chain variable region comprising a VHCDR1 having at least 90% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 49), a VHCDR2 having at least 90% identity to the amino acid sequence SSGGGQTY (SEQ ID NO: 50), and a VHCDR3 having at least 90% identity to the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); and / or An antibody, fragment or variant thereof is provided, comprising a light chain variable region comprising a VLCDR1 having at least 90% identity to the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 having at least 90% identity to the amino acid sequence AASTLES (SEQ ID NO: 43), and a VLCDR3 having at least 90% identity to the amino acid sequence QQTNEDPPT (SEQ ID NO: 44).

[0317] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 46), a VHCDR2 comprising the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 47), and a VHCDR3 comprising the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 43), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44); The present invention provides an antibody, fragment or variant thereof comprising:

[0318] Amino acid substitutions may be made to provide variant antibodies derived from 3E05_var16, for example: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 46), optionally containing one or two amino acid substitutions; a VHCDR2 comprising the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 47), optionally containing one or two amino acid substitutions; and a VHCDR3 comprising the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48), optionally containing one or two amino acid substitutions; and / or Provided is an antibody, fragment, or variant thereof, comprising a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), optionally containing one or two amino acid substitutions, a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 43), optionally containing one or two amino acid substitutions, and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44), optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0319] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 46), a VHCDR2 comprising the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 47), and a VHCDR3 comprising the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 43), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44); Including, Optionally, an antibody, fragment or variant thereof is provided in which each Met residue is independently substituted with an amino acid selected from the group consisting of Ala and Leu, and / or each Asp residue is independently substituted with an amino acid selected from the group consisting of Ala, Gln and Glu.

[0320] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 49), a VHCDR2 comprising the amino acid sequence SSGGGQTY (SEQ ID NO: 50), and a VHCDR3 comprising the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 43), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44); The present invention provides an antibody, fragment or variant thereof comprising:

[0321] Amino acid substitutions may be made to provide variant antibodies derived from 3E05_var16, for example: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 49), optionally with one or two amino acid substitutions, a VHCDR2 comprising the amino acid sequence SSGGGQTY (SEQ ID NO: 50), optionally with one or two amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48), optionally with one or two amino acid substitutions; and / or Provided is an antibody, fragment, or variant thereof, comprising a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), optionally containing one or two amino acid substitutions, a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 43), optionally containing one or two amino acid substitutions, and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44), optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0322] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 49), a VHCDR2 comprising the amino acid sequence SSGGGQTY (SEQ ID NO: 50), and a VHCDR3 comprising the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 43), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44); Including, Optionally, antibodies, fragments or variants thereof are provided in which Met residues are each independently substituted with an amino acid selected from the group consisting of Ala and Leu, and / or Asp residues are each independently substituted with an amino acid selected from the group consisting of Ala, Gln and Glu.

[0323] Antigen-binding molecules of or derived from 3E05_var16 (e.g., antibodies with one or more amino acid substitutions) have a K of less than about 0.01 nM. D Such antigen binding molecules may additionally or alternatively exhibit an IC50 for IFN secretion of less than about 0.5 nM and / or an IC90 for IFN secretion of less than about 5 nM.

[0324] 21E06 In one embodiment, At least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% of the amino acid sequence SYTIS (SEQ ID NO: 56) or 99% identity to the amino acid sequence YISSGGDNAYYPDSVKG (SEQ ID NO: 57), a VHCDR2 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence YISSGGDNAYYPDSVKG (SEQ ID NO: 57), and a VHCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence HLYYGDYFYVMDY (SEQ ID NO: 58), and / or VLCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence KASQSVDYDGDNCLH (SEQ ID NO: 52), at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94% identity to the amino acid sequence AASNLES (SEQ ID NO: 53), Antibodies, fragments or variants thereof are provided that comprise a light chain variable region comprising a VLCDR2 having 95%, 96%, 97%, 98% or 99% identity and a VLCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence QQSNEDPPT (SEQ ID NO: 54).

[0325] In one embodiment, a heavy chain variable region comprising a VHCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 59), a VHCDR2 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence SSGGDN (SEQ ID NO: 60), and a VHCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence HLYYGDYFYVMDY (SEQ ID NO: 58); and / or VLCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence KASQSVDYDGDNCLH (SEQ ID NO: 52), at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94% identity to the amino acid sequence AASNLES (SEQ ID NO: 53), Antibodies, fragments or variants thereof are provided that comprise a light chain variable region comprising a VLCDR2 having 95%, 96%, 97%, 98% or 99% identity and a VLCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence QQSNEDPPT (SEQ ID NO: 54).

[0326] In one embodiment, a heavy chain variable region comprising a VHCDR1 having at least 90% identity to the amino acid sequence SYTIS (SEQ ID NO: 56), a VHCDR2 having at least 90% identity to the amino acid sequence YISSGGDNAYYPDSVKG (SEQ ID NO: 57), and a VHCDR3 having at least 90% identity to the amino acid sequence HLYYGDYFYVMDY (SEQ ID NO: 58); and / or An antibody, fragment or variant thereof is provided, comprising a light chain variable region comprising a VLCDR1 having at least 90% identity to the amino acid sequence KASQSVDYDGDNCLH (SEQ ID NO: 52), a VLCDR2 having at least 90% identity to the amino acid sequence AASNLES (SEQ ID NO: 53), and a VLCDR3 having at least 90% identity to the amino acid sequence QQSNEDPPT (SEQ ID NO: 54).

[0327] In one embodiment, a heavy chain variable region comprising a VHCDR1 having at least 90% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 59), a VHCDR2 having at least 90% identity to the amino acid sequence SSGGDN (SEQ ID NO: 60), and a VHCDR3 having at least 90% identity to the amino acid sequence HLYYGDYFYVMDY (SEQ ID NO: 58); and / or An antibody, fragment or variant thereof is provided, comprising a light chain variable region comprising a VLCDR1 having at least 90% identity to the amino acid sequence KASQSVDYDGDNCLH (SEQ ID NO: 52), a VLCDR2 having at least 90% identity to the amino acid sequence AASNLES (SEQ ID NO: 53), and a VLCDR3 having at least 90% identity to the amino acid sequence QQSNEDPPT (SEQ ID NO: 54).

[0328] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTIS (SEQ ID NO: 56), a VHCDR2 comprising the amino acid sequence YISSGGDNAYYPDSVKG (SEQ ID NO: 57), and a VHCDR3 comprising the amino acid sequence HLYYGDYFYVMDY (SEQ ID NO: 58); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDNCLH (SEQ ID NO: 52), a VLCDR2 comprising the amino acid sequence AASNLES (SEQ ID NO: 53), and a VLCDR3 comprising the amino acid sequence QQSNEDPPT (SEQ ID NO: 54); The present invention provides an antibody, fragment or variant thereof comprising:

[0329] Amino acid substitutions may be made to provide variant antibodies derived from 21E06, for example: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTIS (SEQ ID NO: 56), optionally containing one or two amino acid substitutions; a VHCDR2 comprising the amino acid sequence YISSGGDNAYYPDSVKG (SEQ ID NO: 57), optionally containing one or two amino acid substitutions; and a VHCDR3 comprising the amino acid sequence HLYYGDYFYVMDY (SEQ ID NO: 58), optionally containing one or two amino acid substitutions; and / or Provided is an antibody, fragment, or variant thereof, comprising a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDNCLH (SEQ ID NO: 52), optionally containing one or two amino acid substitutions, a VLCDR2 comprising the amino acid sequence AASNLES (SEQ ID NO: 53), optionally containing one or two amino acid substitutions, and a VLCDR3 comprising the amino acid sequence QQSNEDPPT (SEQ ID NO: 54), optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0330] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTIS (SEQ ID NO: 56), a VHCDR2 comprising the amino acid sequence YISSGGDNAYYPDSVKG (SEQ ID NO: 57), and a VHCDR3 comprising the amino acid sequence HLYYGDYFYVMDY (SEQ ID NO: 58); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDNCLH (SEQ ID NO: 52), a VLCDR2 comprising the amino acid sequence AASNLES (SEQ ID NO: 53), and a VLCDR3 comprising the amino acid sequence QQSNEDPPT (SEQ ID NO: 54); Including, Optionally, antibodies, fragments or variants thereof are provided in which Met residues are each independently substituted with an amino acid selected from the group consisting of Ala and Leu, and / or Asp residues are each independently substituted with an amino acid selected from the group consisting of Ala, Gln and Glu.

[0331] In one embodiment, 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 HLYYGDYFYVM a heavy chain variable region comprising a VHCDR3 comprising DY (SEQ ID NO: 58); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDNCLH (SEQ ID NO: 52), a VLCDR2 comprising the amino acid sequence AASNLES (SEQ ID NO: 53), and a VLCDR3 comprising the amino acid sequence QQSNEDPPT (SEQ ID NO: 54); The present invention provides an antibody, fragment or variant thereof comprising:

[0332] Amino acid substitutions may be made to provide variant antibodies derived from 21E06, for example: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 59), optionally with one or two amino acid substitutions, a VHCDR2 comprising the amino acid sequence SSGGDN (SEQ ID NO: 60), optionally with one or two amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HLYYGDYFYVMDY (SEQ ID NO: 58), optionally with one or two amino acid substitutions; and / or Provided is an antibody, fragment, or variant thereof, comprising a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDNCLH (SEQ ID NO: 52), optionally containing one or two amino acid substitutions, a VLCDR2 comprising the amino acid sequence AASNLES (SEQ ID NO: 53), optionally containing one or two amino acid substitutions, and a VLCDR3 comprising the amino acid sequence QQSNEDPPT (SEQ ID NO: 54), optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0333] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 59), a VHCDR2 comprising the amino acid sequence SSGGDN (SEQ ID NO: 60), and a VHCDR3 comprising the amino acid sequence HLYYGDYFYVMDY (SEQ ID NO: 58); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDNCLH (SEQ ID NO: 52), a VLCDR2 comprising the amino acid sequence AASNLES (SEQ ID NO: 53), and a VLCDR3 comprising the amino acid sequence QQSNEDPPT (SEQ ID NO: 54); Including, Optionally, an antibody, fragment or variant thereof is provided in which each Met residue is independently substituted with an amino acid selected from the group consisting of Ala and Leu, and / or each Asp residue is independently substituted with an amino acid selected from the group consisting of Ala, Gln and Glu.

[0334] 25E06 In one embodiment, VHCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence SYTMS (SEQ ID NO: 66), at least 70%, 75%, 80%, 85%, 90%, 91%, 92% identity to the amino acid sequence YISGVGGDTYYPDSVKG (SEQ ID NO: 67), a heavy chain variable region comprising a VHCDR2 having 93%, 94%, 95%, 96%, 97%, 98% or 99% identity and a VHCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence HHYSHYFWYFDV (SEQ ID NO: 68); and / or VLCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence KASQSVDYDGDGFMN (SEQ ID NO: 62), VLCDR2 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence AASNLES (SEQ ID NO: 63), and the amino acid sequence QQSNEDPPT (SEQ ID NO: 64). Antibodies, fragments or variants thereof are provided that comprise a light chain variable region comprising a VLCDR3 that has at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to

[0335] In one embodiment, a heavy chain variable region comprising a VHCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 69), a VHCDR2 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence SGVGGD (SEQ ID NO: 70), and a VHCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence HHYSHYFWYFDV (SEQ ID NO: 68); and / or VLCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence KASQSVDYDGDGFMN (SEQ ID NO: 62), at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94% identity to the amino acid sequence AASNLES (SEQ ID NO: 63), Antibodies, fragments or variants thereof are provided that comprise a light chain variable region comprising a VLCDR2 having 95%, 96%, 97%, 98% or 99% identity and a VLCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence QQSNEDPPT (SEQ ID NO: 64).

[0336] In one embodiment, a heavy chain variable region comprising a VHCDR1 having at least 90% identity to the amino acid sequence SYTMS (SEQ ID NO: 66), a VHCDR2 having at least 90% identity to the amino acid sequence YISGVGGDTYYPDSVKG (SEQ ID NO: 67), and a VHCDR3 having at least 90% identity to the amino acid sequence HHYSHYFWYFDV (SEQ ID NO: 68); and / or An antibody, fragment or variant thereof is provided, comprising a light chain variable region comprising a VLCDR1 having at least 90% identity to the amino acid sequence KASQSVDYDGDGFMN (SEQ ID NO: 62), a VLCDR2 having at least 90% identity to the amino acid sequence AASNLES (SEQ ID NO: 63), and a VLCDR3 having at least 90% identity to the amino acid sequence QQSNEDPPT (SEQ ID NO: 64).

[0337] In one embodiment, a heavy chain variable region comprising a VHCDR1 having at least 90% identity to the amino acid sequence GFTFSSY (SEQ ID NO: 69), a VHCDR2 having at least 90% identity to the amino acid sequence SGVGGD (SEQ ID NO: 70), and a VHCDR3 having at least 90% identity to the amino acid sequence HHYSHYFWYFDV (SEQ ID NO: 68); and / or An antibody, fragment or variant thereof is provided, comprising a light chain variable region comprising a VLCDR1 having at least 90% identity to the amino acid sequence KASQSVDYDGDGFMN (SEQ ID NO: 62), a VLCDR2 having at least 90% identity to the amino acid sequence AASNLES (SEQ ID NO: 63), and a VLCDR3 having at least 90% identity to the amino acid sequence QQSNEDPPT (SEQ ID NO: 64).

[0338] In one embodiment, VHCDR1 containing the amino acid sequence SYTMS (SEQ ID NO: 66), amino acid sequence YISG a heavy chain variable region comprising a VHCDR2 comprising VGGDTYYPDSVKG (SEQ ID NO: 67) and a VHCDR3 comprising the amino acid sequence HHYSHYFWYFDV (SEQ ID NO: 68); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDGFMN (SEQ ID NO: 62), a VLCDR2 comprising the amino acid sequence AASNLES (SEQ ID NO: 63), and a VLCDR3 comprising the amino acid sequence QQSNEDPPT (SEQ ID NO: 64); The present invention provides an antibody, fragment or variant thereof comprising:

[0339] Amino acid substitutions may be made to provide variant antibodies derived from 25E06, for example: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 66), optionally containing one or two amino acid substitutions; a VHCDR2 comprising the amino acid sequence YISGVGGDTYYPDSVKG (SEQ ID NO: 67), optionally containing one or two amino acid substitutions; and a VHCDR3 comprising the amino acid sequence HHYSHYFWYFDV (SEQ ID NO: 68), optionally containing one or two amino acid substitutions; and / or Provided is an antibody, fragment, or variant thereof comprising a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDGFMN (SEQ ID NO: 62), optionally containing one or two amino acid substitutions, a VLCDR2 comprising the amino acid sequence AASNLES (SEQ ID NO: 63), optionally containing one or two amino acid substitutions, and a VLCDR3 comprising the amino acid sequence QQSNEDPPT (SEQ ID NO: 64), optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0340] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 66), a VHCDR2 comprising the amino acid sequence YISGVGGDTYYPDSVKG (SEQ ID NO: 67), and a VHCDR3 comprising the amino acid sequence HHYSHYFWYFDV (SEQ ID NO: 68); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDGFMN (SEQ ID NO: 62), a VLCDR2 comprising the amino acid sequence AASNLES (SEQ ID NO: 63), and a VLCDR3 comprising the amino acid sequence QQSNEDPPT (SEQ ID NO: 64); Including, Optionally, antibodies, fragments or variants thereof are provided in which Met residues are each independently substituted with an amino acid selected from the group consisting of Ala and Leu, and / or Asp residues are each independently substituted with an amino acid selected from the group consisting of Ala, Gln and Glu.

[0341] In one embodiment, A heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 69), a VHCDR2 comprising the amino acid sequence SGVGGD (SEQ ID NO: 70), and a VHCDR3 comprising the amino acid sequence HHYSHYFWYFDV (SEQ ID NO: 68); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDGFMN (SEQ ID NO: 62), a VLCDR2 comprising the amino acid sequence AASNLES (SEQ ID NO: 63), and a VLCDR3 comprising the amino acid sequence QQSNEDPPT (SEQ ID NO: 64); The present invention provides an antibody, fragment or variant thereof comprising:

[0342] Amino acid substitutions may be made to provide variant antibodies derived from 25E06, for example: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 69), optionally with one or two amino acid substitutions, a VHCDR2 comprising the amino acid sequence SGVGGD (SEQ ID NO: 70), optionally with one or two amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HHYSHYFWYFDV (SEQ ID NO: 68), optionally with one or two amino acid substitutions; and / or Provided is an antibody, fragment, or variant thereof comprising a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDGFMN (SEQ ID NO: 62), optionally containing one or two amino acid substitutions, a VLCDR2 comprising the amino acid sequence AASNLES (SEQ ID NO: 63), optionally containing one or two amino acid substitutions, and a VLCDR3 comprising the amino acid sequence QQSNEDPPT (SEQ ID NO: 64), optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0343] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 69), a VHCDR2 comprising the amino acid sequence SGVGGD (SEQ ID NO: 70), and a VHCDR3 comprising the amino acid sequence HHYSHYFWYFDV (SEQ ID NO: 68); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDGFMN (SEQ ID NO: 62), a VLCDR2 comprising the amino acid sequence AASNLES (SEQ ID NO: 63), and a VLCDR3 comprising the amino acid sequence QQSNEDPPT (SEQ ID NO: 64); Including, Optionally, antibodies, fragments or variants thereof are provided in which Met residues are each independently substituted with an amino acid selected from the group consisting of Ala and Leu, and / or Asp residues are each independently substituted with an amino acid selected from the group consisting of Ala, Gln and Glu.

[0344] 28B01 In one embodiment, VHCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence YYTMS (SEQ ID NO: 76), at least 70%, 75%, 80%, 85%, 90%, 91%, 92% identity to the amino acid sequence YISSGGDNAYYPDSVRG (SEQ ID NO: 77), a heavy chain variable region comprising a VHCDR2 having 93%, 94%, 95%, 96%, 97%, 98% or 99% identity and a VHCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence HHYSNYFWYFDV (SEQ ID NO: 78); and / or VLCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence KASQSVDYAGDSYVN (SEQ ID NO: 72), at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94% identity to the amino acid sequence AASNLES (SEQ ID NO: 73), Antibodies, fragments or variants thereof are provided that comprise a light chain variable region comprising a VLCDR2 having 95%, 96%, 97%, 98% or 99% identity, and a VLCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence QQSNEDPPT (SEQ ID NO: 74).

[0345] In one embodiment, a heavy chain comprising a VHCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence GFTFSYY (SEQ ID NO: 79), a VHCDR2 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence SSGGDN (SEQ ID NO: 80), and a VHCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence HHYSNYFWYFDV (SEQ ID NO: 78). variable region, and / or VLCDR1 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence KASQSVDYAGDSYVN (SEQ ID NO: 72), at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94% identity to the amino acid sequence AASNLES (SEQ ID NO: 73), Antibodies, fragments or variants thereof are provided that comprise a light chain variable region comprising a VLCDR2 having 95%, 96%, 97%, 98% or 99% identity, and a VLCDR3 having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence QQSNEDPPT (SEQ ID NO: 74).

[0346] In one embodiment, a heavy chain variable region comprising a VHCDR1 having at least 90% identity to the amino acid sequence YYTMS (SEQ ID NO: 76), a VHCDR2 having at least 90% identity to the amino acid sequence YISSGGDNAYYPDSVRG (SEQ ID NO: 77), and a VHCDR3 having at least 90% identity to the amino acid sequence HHYSNYFWYFDV (SEQ ID NO: 78); and / or An antibody, fragment or variant thereof is provided, comprising a light chain variable region comprising a VLCDR1 having at least 90% identity to the amino acid sequence KASQSVDYAGDSYVN (SEQ ID NO: 72), a VLCDR2 having at least 90% identity to the amino acid sequence AASNLES (SEQ ID NO: 73), and a VLCDR3 having at least 90% identity to the amino acid sequence QQSNEDPPT (SEQ ID NO: 74).

[0347] In one embodiment, a heavy chain variable region comprising a VHCDR1 having at least 90% identity to the amino acid sequence GFTFSYY (SEQ ID NO: 79), a VHCDR2 having at least 90% identity to the amino acid sequence SSGGDN (SEQ ID NO: 80), and a VHCDR3 having at least 90% identity to the amino acid sequence HHYSNYFWYFDV (SEQ ID NO: 78); and / or An antibody, fragment or variant thereof is provided, comprising a light chain variable region comprising a VLCDR1 having at least 90% identity to the amino acid sequence KASQSVDYAGDSYVN (SEQ ID NO: 72), a VLCDR2 having at least 90% identity to the amino acid sequence AASNLES (SEQ ID NO: 73), and a VLCDR3 having at least 90% identity to the amino acid sequence QQSNEDPPT (SEQ ID NO: 74).

[0348] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence YYTMS (SEQ ID NO: 76), a VHCDR2 comprising the amino acid sequence YISSGGDNAYYPDSVRG (SEQ ID NO: 77), and a VHCDR3 comprising the amino acid sequence HHYSNYFWYFDV (SEQ ID NO: 78); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYAGDSYVN (SEQ ID NO: 72), a VLCDR2 comprising the amino acid sequence AASNLES (SEQ ID NO: 73), and a VLCDR3 comprising the amino acid sequence QQSNEDPPT (SEQ ID NO: 74); The present invention provides an antibody, fragment or variant thereof comprising:

[0349] Amino acid substitutions may be made to provide variant antibodies derived from 28B01, for example: 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. a heavy chain variable region comprising an HCDR3, and / or Provided is an antibody, fragment, or variant thereof comprising a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYAGDSYVN (SEQ ID NO: 72), optionally containing one or two amino acid substitutions, a VLCDR2 comprising the amino acid sequence AASNLES (SEQ ID NO: 73), optionally containing one or two amino acid substitutions, and a VLCDR3 comprising the amino acid sequence QQSNEDPPT (SEQ ID NO: 74), optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0350] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence YYTMS (SEQ ID NO: 76), a VHCDR2 comprising the amino acid sequence YISSGGDNAYYPDSVRG (SEQ ID NO: 77), and a VHCDR3 comprising the amino acid sequence HHYSNYFWYFDV (SEQ ID NO: 78); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYAGDSYVN (SEQ ID NO: 72), a VLCDR2 comprising the amino acid sequence AASNLES (SEQ ID NO: 73), and a VLCDR3 comprising the amino acid sequence QQSNEDPPT (SEQ ID NO: 74); Including, Optionally, antibodies, fragments or variants thereof are provided in which Met residues are each independently substituted with an amino acid selected from the group consisting of Ala and Leu, and / or Asp residues are each independently substituted with an amino acid selected from the group consisting of Ala, Gln and Glu.

[0351] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSYY (SEQ ID NO: 79), a VHCDR2 comprising the amino acid sequence SSGGDN (SEQ ID NO: 80), and a VHCDR3 comprising the amino acid sequence HHYSNYFWYFDV (SEQ ID NO: 78); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYAGDSYVN (SEQ ID NO: 72), a VLCDR2 comprising the amino acid sequence AASNLES (SEQ ID NO: 73), and a VLCDR3 comprising the amino acid sequence QQSNEDPPT (SEQ ID NO: 74); The present invention provides an antibody, fragment or variant thereof comprising:

[0352] Amino acid substitutions may be made to provide variant antibodies derived from 28B01, for example: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSYY (SEQ ID NO: 79), optionally with one or two amino acid substitutions, a VHCDR2 comprising the amino acid sequence SSGGDN (SEQ ID NO: 80), optionally with one or two amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HHYSNYFWYFDV (SEQ ID NO: 78), optionally with one or two amino acid substitutions; and / or Provided is an antibody, fragment, or variant thereof comprising a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYAGDSYVN (SEQ ID NO: 72), optionally containing one or two amino acid substitutions, a VLCDR2 comprising the amino acid sequence AASNLES (SEQ ID NO: 73), optionally containing one or two amino acid substitutions, and a VLCDR3 comprising the amino acid sequence QQSNEDPPT (SEQ ID NO: 74), optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0353] In one embodiment, a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSYY (SEQ ID NO: 79), a VHCDR2 comprising the amino acid sequence SSGGDN (SEQ ID NO: 80), and a VHCDR3 comprising the amino acid sequence HHYSNYFWYFDV (SEQ ID NO: 78); 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 Q a light chain variable region comprising a VLCDR3 comprising QSNEDPPT (SEQ ID NO: 74); Including, Optionally, antibodies, fragments or variants thereof are provided in which Met residues are each independently substituted with an amino acid selected from the group consisting of Ala and Leu, and / or Asp residues are each independently substituted with an amino acid selected from the group consisting of Ala, Gln and Glu.

[0354] Heavy and / or light chain variable regions In one embodiment, the present invention provides an antigen binding molecule, particularly an antibody, that binds 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 to 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 at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to 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.

[0355] In one embodiment, the antibody binds BDCA-2 (CLEC4C) and 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.

[0356] In one embodiment, the antibody binds BDCA-2 (CLEC4C) and 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, optionally, wherein Met residues are each independently substituted with an amino acid selected from the group consisting of Ala and Leu, and / or Asp residues are each independently substituted with an amino acid selected from the group consisting of Ala, Gln, and Glu.

[0357] In one embodiment, an antigen binding molecule, such as an antibody, variant or fragment thereof, is provided, wherein the antigen binding molecule comprises a heavy chain variable region and a light chain variable region selected from the group consisting of: (a) 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 (or comprising VH and VL sequences at least 90% identical to SEQ ID NO: 45 and SEQ ID NO: 31, respectively); (b) a VH comprising the amino acid sequence of SEQ ID NO: 25 and a VL comprising the amino acid sequence of SEQ ID NO: 21 (or comprising VH and VL sequences at least 90% identical to SEQ ID NO: 25 and SEQ ID NO: 21, respectively); (c) a VH comprising the amino acid sequence of SEQ ID NO: 25 and a VL comprising the amino acid sequence of SEQ ID NO: 41 (or comprising VH and VL sequences at least 90% identical to SEQ ID NO: 25 and SEQ ID NO: 41, respectively); (d) a VH comprising the amino acid sequence of SEQ ID NO: 5 and a VL comprising the amino acid sequence of SEQ ID NO: 1 (or comprising VH and VL sequences at least 90% identical to SEQ ID NO: 5 and SEQ ID NO: 1, respectively); (e) a VH comprising the amino acid sequence of SEQ ID NO: 15 and a VL comprising the amino acid sequence of SEQ ID NO: 11 (or comprising VH and VL sequences at least 90% identical to SEQ ID NO: 15 and SEQ ID NO: 11, respectively); (f) a VH comprising the amino acid sequence of SEQ ID NO: 25 and a VL comprising the amino acid sequence of SEQ ID NO: 11 (or comprising VH and VL sequences at least 90% identical to SEQ ID NO: 25 and SEQ ID NO: 11, respectively); (g) a VH comprising the amino acid sequence of SEQ ID NO: 35 and a VL comprising the amino acid sequence of SEQ ID NO: 11 (or comprising VH and VL sequences at least 90% identical to SEQ ID NO: 35 and SEQ ID NO: 11, respectively); (h) a VH comprising the amino acid sequence of SEQ ID NO: 45 and a VL comprising the amino acid sequence of SEQ ID NO: 11 (or comprising VH and VL sequences at least 90% identical to SEQ ID NO: 45 and SEQ ID NO: 11, respectively); (i) a VH comprising the amino acid sequence of SEQ ID NO: 15 and a VL comprising the amino acid sequence of SEQ ID NO: 21 (or comprising VH and VL sequences at least 90% identical to SEQ ID NO: 15 and SEQ ID NO: 21, respectively); (j) a VH comprising the amino acid sequence of SEQ ID NO: 35 and a VL comprising the amino acid sequence of SEQ ID NO: 21 (or comprising VH and VL sequences at least 90% identical to SEQ ID NO: 35 and SEQ ID NO: 21, respectively); (k) a VH comprising the amino acid sequence of SEQ ID NO: 45 and a VL comprising the amino acid sequence of SEQ ID NO: 21 (or comprising VH and VL sequences at least 90% identical to SEQ ID NO: 45 and SEQ ID NO: 21, respectively); (l) a VH comprising the amino acid sequence of SEQ ID NO: 15 and a VL comprising the amino acid sequence of SEQ ID NO: 31 (or comprising VH and VL sequences at least 90% identical to SEQ ID NO: 15 and SEQ ID NO: 31, respectively); (m) a VH comprising the amino acid sequence of SEQ ID NO: 25 and a VL comprising the amino acid sequence of SEQ ID NO: 31 (or comprising VH and VL sequences at least 90% identical to SEQ ID NO: 25 and SEQ ID NO: 31, respectively); (n) a VH comprising the amino acid sequence of SEQ ID NO: 35 and a VL comprising the amino acid sequence of SEQ ID NO: 31 (or comprising VH and VL sequences at least 90% identical to SEQ ID NO: 35 and SEQ ID NO: 31, respectively); (o) a VH comprising the amino acid sequence of SEQ ID NO: 15 and a VL comprising the amino acid sequence of SEQ ID NO: 41 (or comprising VH and VL sequences at least 90% identical to SEQ ID NO: 15 and SEQ ID NO: 41, respectively); (p) a VH comprising the amino acid sequence of SEQ ID NO: 35 and a VL comprising the amino acid sequence of SEQ ID NO: 41 (or comprising VH and VL sequences at least 90% identical to SEQ ID NO: 35 and SEQ ID NO: 41, respectively); (q) a VH comprising the amino acid sequence of SEQ ID NO: 45 and a VL comprising the amino acid sequence of SEQ ID NO: 41 (or comprising VH and VL sequences at least 90% identical to SEQ ID NO: 45 and SEQ ID NO: 41, respectively); (r) a VH comprising the amino acid sequence of SEQ ID NO: 55 and a VL comprising the amino acid sequence of SEQ ID NO: 51 (or comprising VH and VL sequences at least 90% identical to SEQ ID NO: 55 and SEQ ID NO: 51, respectively); (s) a VH comprising the amino acid sequence of SEQ ID NO: 65 and a VL comprising the amino acid sequence of SEQ ID NO: 61 (or comprising VH and VL sequences at least 90% identical to SEQ ID NO: 65 and SEQ ID NO: 61, respectively); and (t) a VH comprising the amino acid sequence of SEQ ID NO: 75 and a VL comprising the amino acid sequence of SEQ ID NO: 71 (or comprising VH and VL sequences at least 90% identical to SEQ ID NO: 75 and SEQ ID NO: 71, respectively).

[0358] In one embodiment, an antigen binding molecule, such as an antibody, variant or fragment thereof, is provided. The antigen-binding molecule comprises a heavy chain variable region and a light chain variable region selected from the group consisting of: (a) 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; (b) VH comprising the amino acid sequence of SEQ ID NO: 25 and VL comprising the amino acid sequence of SEQ ID NO: 21; (c) VH comprising the amino acid sequence of SEQ ID NO: 25 and VL comprising the amino acid sequence of SEQ ID NO: 41; (d) VH comprising the amino acid sequence of SEQ ID NO: 5 and VL comprising the amino acid sequence of SEQ ID NO: 1; (e) VH comprising the amino acid sequence of SEQ ID NO: 15 and VL comprising the amino acid sequence of SEQ ID NO: 11; (f) VH comprising the amino acid sequence of SEQ ID NO: 25 and VL comprising the amino acid sequence of SEQ ID NO: 11; (g) VH comprising the amino acid sequence of SEQ ID NO: 35 and VL comprising the amino acid sequence of SEQ ID NO: 11; (h) VH comprising the amino acid sequence of SEQ ID NO: 45 and VL comprising the amino acid sequence of SEQ ID NO: 11; (i) a VH comprising the amino acid sequence of SEQ ID NO: 15 and a VL comprising the amino acid sequence of SEQ ID NO: 21; (j) VH comprising the amino acid sequence of SEQ ID NO: 35 and VL comprising the amino acid sequence of SEQ ID NO: 21; (k) VH comprising the amino acid sequence of SEQ ID NO: 45 and VL comprising the amino acid sequence of SEQ ID NO: 21; (l) VH comprising the amino acid sequence of SEQ ID NO: 15 and VL comprising the amino acid sequence of SEQ ID NO: 31; (m) a VH comprising the amino acid sequence of SEQ ID NO: 25 and a VL comprising the amino acid sequence of SEQ ID NO: 31; (n) a VH comprising the amino acid sequence of SEQ ID NO: 35 and a VL comprising the amino acid sequence of SEQ ID NO: 31; (o) VH comprising the amino acid sequence of SEQ ID NO: 15 and VL comprising the amino acid sequence of SEQ ID NO: 41; (p) a VH comprising the amino acid sequence of SEQ ID NO: 35 and a VL comprising the amino acid sequence of SEQ ID NO: 41; (q) a VH comprising the amino acid sequence of SEQ ID NO: 45 and a VL comprising the amino acid sequence of SEQ ID NO: 41; (r) VH comprising the amino acid sequence of SEQ ID NO: 55 and VL comprising the amino acid sequence of SEQ ID NO: 51; (s) a VH comprising the amino acid sequence of SEQ ID NO: 65 and a VL comprising the amino acid sequence of SEQ ID NO: 61; and (t) VH comprising the amino acid sequence of SEQ ID NO: 75 and VL comprising the amino acid sequence of SEQ ID NO: 71.

[0359] In one embodiment, an antigen binding molecule, such as an antibody, variant or fragment thereof, is provided, wherein the antigen binding molecule comprises a heavy chain variable region and a light chain variable region selected from the group consisting of: (a) a VH comprising the amino acid sequence of SEQ ID NO: 45, optionally containing up to five amino acid substitutions, and a VL comprising the amino acid sequence of SEQ ID NO: 31, optionally containing up to five amino acid substitutions; (b) a VH comprising the amino acid sequence of SEQ ID NO: 25, optionally with up to five amino acid substitutions, and a VL comprising the amino acid sequence of SEQ ID NO: 21, optionally with up to five amino acid substitutions; (c) a VH comprising the amino acid sequence of SEQ ID NO: 25, optionally containing up to five amino acid substitutions, and a VL comprising the amino acid sequence of SEQ ID NO: 41, optionally containing up to five amino acid substitutions; (d) a VH comprising the amino acid sequence of SEQ ID NO: 5, optionally with up to five amino acid substitutions, and a VL comprising the amino acid sequence of SEQ ID NO: 1, optionally with up to five amino acid substitutions; (e) a VH comprising the amino acid sequence of SEQ ID NO: 15, optionally containing up to five amino acid substitutions, and a VL comprising the amino acid sequence of SEQ ID NO: 11, optionally containing up to five amino acid substitutions; (f) a VH comprising the amino acid sequence of SEQ ID NO: 25, optionally containing up to five amino acid substitutions, and a VL comprising the amino acid sequence of SEQ ID NO: 11, optionally containing up to five amino acid substitutions; (g) a VH comprising the amino acid sequence of SEQ ID NO: 35, optionally containing up to five amino acid substitutions, and a VL comprising the amino acid sequence of SEQ ID NO: 11, optionally containing up to five amino acid substitutions; (h) a VH comprising the amino acid sequence of SEQ ID NO: 45, optionally containing up to five amino acid substitutions, and a VL comprising the amino acid sequence of SEQ ID NO: 11, optionally containing up to five amino acid substitutions; (i) a VH comprising the amino acid sequence of SEQ ID NO: 15, optionally containing up to five amino acid substitutions, and a VL comprising the amino acid sequence of SEQ ID NO: 21, optionally containing up to five amino acid substitutions; (j) a VH comprising the amino acid sequence of SEQ ID NO: 35, optionally containing up to five amino acid substitutions, and a VL comprising the amino acid sequence of SEQ ID NO: 21, optionally containing up to five amino acid substitutions; (k) a VH comprising the amino acid sequence of SEQ ID NO: 45, optionally containing up to five amino acid substitutions, and a VL comprising the amino acid sequence of SEQ ID NO: 21, optionally containing up to five amino acid substitutions; (l) a VH comprising the amino acid sequence of SEQ ID NO: 15, optionally containing up to five amino acid substitutions, and a VL comprising the amino acid sequence of SEQ ID NO: 31, optionally containing up to five amino acid substitutions; (m) a VH comprising the amino acid sequence of SEQ ID NO: 25, optionally containing up to five amino acid substitutions, and a VL comprising the amino acid sequence of SEQ ID NO: 31, optionally containing up to five amino acid substitutions; (n) a VH comprising the amino acid sequence of SEQ ID NO: 35, optionally containing up to five amino acid substitutions, and a VL comprising the amino acid sequence of SEQ ID NO: 31, optionally containing up to five amino acid substitutions; (o) a VH comprising the amino acid sequence of SEQ ID NO: 15, optionally containing up to five amino acid substitutions, and a VL comprising the amino acid sequence of SEQ ID NO: 41, optionally containing up to five amino acid substitutions; (p) a VH comprising the amino acid sequence of SEQ ID NO: 35, optionally containing up to five amino acid substitutions, and a VL comprising the amino acid sequence of SEQ ID NO: 41, optionally containing up to five amino acid substitutions; (q) a VH comprising the amino acid sequence of SEQ ID NO: 45, optionally containing up to five amino acid substitutions, and a VL comprising the amino acid sequence of SEQ ID NO: 41, optionally containing up to five amino acid substitutions; (r) a VH comprising the amino ...

Claims

1. Equilibrium dissociation constant (K) of less than about 2 nM for BDCA-2 (CLEC4C) Ｄ ) an anti-BDCA-2 (CLEC4C) antigen-binding molecule having

2. An anti-BDCA-2 (CLEC4C) antigen binding molecule having a 50% inhibitory concentration (IC50) of less than about 2 nM for inhibition of IFN secretion.

3. An anti-BDCA-2 (CLEC4C) antigen binding molecule having an IC90 of less than about 20 nM for inhibition of IFN secretion.

4. Equilibrium dissociation constant (K) of less than about 2 nM for BDCA-2 (CLEC4C) Ｄ ), a 50% inhibitory concentration (IC50) for inhibition of IFN secretion of less than about 2 nM, and an IC90 for inhibition of IFN secretion of less than about 20 nM.

5. an equilibrium dissociation constant (K) of less than about 0.01 nM for BDCA-2 (CLEC4C) Ｄ 5. The anti-BDCA-2 (CLEC4C) antigen binding molecule of claim 4, having a 50% inhibitory concentration (IC50) of less than about 0.5 nM for inhibition of IFN secretion, and an IC90 of less than about 5 nM for inhibition of IFN secretion.

6. a VHCDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 48, 28, 8, 38, 58, 68 and 78, and / or 10. The anti-BDCA-2 (CLEC4C) antigen binding molecule of any one of the preceding claims, comprising a VLCDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 34, 24, 44, 4, 14, 54, 64 and 74.

7. VHCDR1 comprising any one of the amino acid sequences of SEQ ID NOs: 46, 49, 26, 29, 6, 9, 16, 19, 36, 39, 56, 59, 66, 69, 76 and 79; a VHCDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 47, 50, 27, 30, 7, 10, 17, 20, 37, 40, 57, 60, 67, 70, 77, and 80; and a VHCDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 48, 28, 8, 18, 38, 58, 68 and 78; and / or VLCDR1 comprising any one of the amino acid sequences of SEQ ID NOs: 32, 22, 42, 2, 12, 52, 62 and 72; A VLCDR2 comprising any one of the amino acid sequences of SEQ ID NOs: 33, 23, 43, 3, 13, 53, 63 and 73; and 10. The anti-BDCA-2 (CLEC4C) antigen binding molecule of any one of the preceding claims, comprising a VLCDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 34, 24, 44, 4, 14, 54, 64 and 74.

8. (a) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO:46), a VHCDR2 comprising the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO:47), and a VHCDR3 comprising the amino acid sequence HDYEGGLYYAMDY (SEQ ID NO:48); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34); an anti-BDCA-2 (CLEC4C) antigen-binding molecule comprising (b) VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 49), a heavy chain variable region comprising a VHCDR2 comprising the sequence SSGGGQTY (SEQ ID NO: 50), a VHCDR3 comprising the amino acid sequence HDYEGGLYYAMDY (SEQ ID NO: 48); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34); an anti-BDCA-2 (CLEC4C) antigen-binding molecule comprising (c) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 26), a VHCDR2 comprising the amino acid sequence YISSGGGNTYYADSVKG (SEQ ID NO: 27), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24); an anti-BDCA-2 (CLEC4C) antigen-binding molecule comprising (d) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 29), a VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 30), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24); an anti-BDCA-2 (CLEC4C) antigen-binding molecule comprising (e) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 26), a VHCDR2 comprising the amino acid sequence YISSGGGNTYYADSVKG (SEQ ID NO: 27), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 43), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44); an anti-BDCA-2 (CLEC4C) antigen-binding molecule comprising (f) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 29), a VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 30), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 43), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44); an anti-BDCA-2 (CLEC4C) antigen-binding molecule comprising (g) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 6), a VHCDR2 comprising the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 7), and a VHCDR3 comprising the amino acid sequence HDYDGGLYYAMDY (SEQ ID NO: 8); and a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 2), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 3), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 4); an anti-BDCA-2 (CLEC4C) antigen-binding molecule comprising (h) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 9), a VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 10), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 8); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 2), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 3), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 4); an anti-BDCA-2 (CLEC4C) antigen-binding molecule comprising (i) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 16), a VHCDR2 comprising the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 17), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 13), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14); an anti-BDCA-2 (CLEC4C) antigen-binding molecule comprising (j) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 19), a VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 20), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 13), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14); an anti-BDCA-2 (CLEC4C) antigen-binding molecule comprising (k) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 26), a VHCDR2 comprising the amino acid sequence YISSGGGNTYYADSVKG (SEQ ID NO: 27), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 13), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14); an anti-BDCA-2 (CLEC4C) antigen-binding molecule comprising (l) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 29), a VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 30), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 13), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14); an anti-BDCA-2 (CLEC4C) antigen-binding molecule comprising (m) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 36), a VHCDR2 comprising the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 37), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 13), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14); an anti-BDCA-2 (CLEC4C) antigen-binding molecule comprising (n) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 39), a VHCDR2 comprising the amino acid sequence SSGGGQTY (SEQ ID NO: 40), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 13), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14); an anti-BDCA-2 (CLEC4C) antigen-binding molecule comprising (o) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 46), a VHCDR2 comprising the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 47), and a VHCDR3 comprising the amino acid sequence HDYEGGLYYAMDY (SEQ ID NO: 48); VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), a light chain variable region comprising a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 13) and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14); an anti-BDCA-2 (CLEC4C) antigen-binding molecule comprising (p) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 49), a VHCDR2 comprising the amino acid sequence SSGGGQTY (SEQ ID NO: 50), and a VHCDR3 comprising the amino acid sequence HDYEGGLYYAMDY (SEQ ID NO: 48); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 13), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14); an anti-BDCA-2 (CLEC4C) antigen-binding molecule comprising (q) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 16), a VHCDR2 comprising the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 17), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24); an anti-BDCA-2 (CLEC4C) antigen-binding molecule comprising (r) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 19), a VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 20), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24); an anti-BDCA-2 (CLEC4C) antigen-binding molecule comprising (s) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 36), a VHCDR2 comprising the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 37), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24); an anti-BDCA-2 (CLEC4C) antigen-binding molecule comprising (t) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 39), a VHCDR2 comprising the amino acid sequence SSGGGQTY (SEQ ID NO: 40), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24); an anti-BDCA-2 (CLEC4C) antigen-binding molecule comprising (u) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 46), a VHCDR2 comprising the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 47), and a VHCDR3 comprising the amino acid sequence HDYEGGLYYAMDY (SEQ ID NO: 48); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24); an anti-BDCA-2 (CLEC4C) antigen-binding molecule comprising (v) VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 49), VHCDR2 comprising the amino acid sequence SSGGGQTY (SEQ ID NO: 50), and VHCDR3 comprising the amino acid sequence HDYYEGG a heavy chain variable region comprising a VHCDR3 comprising LYYAMDY (SEQ ID NO: 48); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24); an anti-BDCA-2 (CLEC4C) antigen-binding molecule comprising (w) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 16), a VHCDR2 comprising the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 17), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34); an anti-BDCA-2 (CLEC4C) antigen-binding molecule comprising (x) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 19), a VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 20), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34); an anti-BDCA-2 (CLEC4C) antigen-binding molecule comprising (y) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 26), a VHCDR2 comprising the amino acid sequence YISSGGGNTYYADSVKG (SEQ ID NO: 27), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34); an anti-BDCA-2 (CLEC4C) antigen-binding molecule comprising (z) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 29), a VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 30), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34); an anti-BDCA-2 (CLEC4C) antigen-binding molecule comprising (aa) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 36), a VHCDR2 comprising the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 37), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34); an anti-BDCA-2 (CLEC4C) antigen-binding molecule comprising (bb) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 39), a VHCDR2 comprising the amino acid sequence SSGGGQTY (SEQ ID NO: 40), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34); an anti-BDCA-2 (CLEC4C) antigen-binding molecule comprising (cc) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 16), a VHCDR2 comprising the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 17), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 43), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44); an anti-BDCA-2 (CLEC4C) antigen-binding molecule comprising (dd) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 19), a VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 20), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 43), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44); an anti-BDCA-2 (CLEC4C) antigen-binding molecule comprising (ee) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 36), a VHCDR2 comprising the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 37), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 43), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44); an anti-BDCA-2 (CLEC4C) antigen-binding molecule comprising (ff) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 39), a VHCDR2 comprising the amino acid sequence SSGGGQTY (SEQ ID NO: 40), and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 43), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44); an anti-BDCA-2 (CLEC4C) antigen-binding molecule comprising (gg) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 46), a VHCDR2 comprising the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 47), and a VHCDR3 comprising the amino acid sequence HDYEGGLYYAMDY (SEQ ID NO: 48); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 43), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44); an anti-BDCA-2 (CLEC4C) antigen-binding molecule comprising (hh) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 49), a VHCDR2 comprising the amino acid sequence SSGGGQTY (SEQ ID NO: 50), and a VHCDR3 comprising the amino acid sequence HDYEGGLYYAMDY (SEQ ID NO: 48); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 42), a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 43), and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44); an anti-BDCA-2 (CLEC4C) antigen-binding molecule comprising (ii) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTIS (SEQ ID NO: 56), a VHCDR2 comprising the amino acid sequence YISSGGDNAYYPDSVKG (SEQ ID NO: 57), and a VHCDR3 comprising the amino acid sequence HLYYGDYFYVMDY (SEQ ID NO: 58); VLCDR1 comprising the amino acid sequence KASQSVDYDGDNCLH (SEQ ID NO: 52), a light chain variable region comprising a VLCDR2 comprising the amino acid sequence AASNLES (SEQ ID NO: 53) and a VLCDR3 comprising the amino acid sequence QQSNEDPPT (SEQ ID NO: 54); an anti-BDCA-2 (CLEC4C) antigen-binding molecule comprising (jj) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 59), a VHCDR2 comprising the amino acid sequence SSGGDN (SEQ ID NO: 60), and a VHCDR3 comprising the amino acid sequence HLYYGDYFYVMDY (SEQ ID NO: 58); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDNCLH (SEQ ID NO: 52), a VLCDR2 comprising the amino acid sequence AASNLES (SEQ ID NO: 53), and a VLCDR3 comprising the amino acid sequence QQSNEDPPT (SEQ ID NO: 54); an anti-BDCA-2 (CLEC4C) antigen-binding molecule comprising (kk) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 66), a VHCDR2 comprising the amino acid sequence YISGVGGDTYYPDSVKG (SEQ ID NO: 67), and a VHCDR3 comprising the amino acid sequence HHYSHYFWYFDV (SEQ ID NO: 68); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDGFMN (SEQ ID NO: 62), a VLCDR2 comprising the amino acid sequence AASNLES (SEQ ID NO: 63), and a VLCDR3 comprising the amino acid sequence QQSNEDPPT (SEQ ID NO: 64); an anti-BDCA-2 (CLEC4C) antigen-binding molecule comprising (11) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 69), a VHCDR2 comprising the amino acid sequence SGVGGD (SEQ ID NO: 70), and a VHCDR3 comprising the amino acid sequence HHYSHYFWYFDV (SEQ ID NO: 68); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYDGDGFMN (SEQ ID NO: 62), a VLCDR2 comprising the amino acid sequence AASNLES (SEQ ID NO: 63), and a VLCDR3 comprising the amino acid sequence QQSNEDPPT (SEQ ID NO: 64); an anti-BDCA-2 (CLEC4C) antigen-binding molecule comprising (mm) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence YYTMS (SEQ ID NO: 76), a VHCDR2 comprising the amino acid sequence YISSGGDNAYYPDDSVRG (SEQ ID NO: 77), and a VHCDR3 comprising the amino acid sequence HHYSNYFWYFDV (SEQ ID NO: 78); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYAGDSYVN (SEQ ID NO: 72), a VLCDR2 comprising the amino acid sequence AASNLES (SEQ ID NO: 73), and a VLCDR3 comprising the amino acid sequence QQSNEDPPT (SEQ ID NO: 74); an anti-BDCA-2 (CLEC4C) antigen-binding molecule comprising: (nn) a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence GFTFSYY (SEQ ID NO: 79), a VHCDR2 comprising the amino acid sequence SSGGDN (SEQ ID NO: 80), and a VHCDR3 comprising the amino acid sequence HHYSNYFWYFDV (SEQ ID NO: 78); a light chain variable region comprising a VLCDR1 comprising the amino acid sequence KASQSVDYAGDSYVN (SEQ ID NO: 72), a VLCDR2 comprising the amino acid sequence AASNLES (SEQ ID NO: 73), and a VLCDR3 comprising the amino acid sequence QQSNEDPPT (SEQ ID NO: 74); an anti-BDCA-2 (CLEC4C) antigen-binding molecule comprising 10. The anti-BDCA-2 (CLEC4C) antigen-binding molecule of any one of the preceding claims, selected from the group consisting of:

9. a heavy chain variable region having at least 80% identity to 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 at least 80% identity to 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; The anti-BDCA-2 (CLEC4C) antigen-binding molecule of any one of the preceding claims, comprising child.

10. a heavy chain variable region comprising 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 comprising 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; 10. The anti-BDCA-2 (CLEC4C) antigen binding molecule of any one of the preceding claims, comprising:

11. a) 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; b) a VH comprising the amino acid sequence of SEQ ID NO: 25 and a VL comprising the amino acid sequence of SEQ ID NO: 21; c) VH comprising the amino acid sequence of SEQ ID NO: 25 and VL comprising the amino acid sequence of SEQ ID NO: 41; d) VH comprising the amino acid sequence of SEQ ID NO: 5 and VL comprising the amino acid sequence of SEQ ID NO: 1; e) VH comprising the amino acid sequence of SEQ ID NO: 15 and VL comprising the amino acid sequence of SEQ ID NO: 11; f) VH comprising the amino acid sequence of SEQ ID NO: 25 and VL comprising the amino acid sequence of SEQ ID NO: 11; g) VH comprising the amino acid sequence of SEQ ID NO: 35 and VL comprising the amino acid sequence of SEQ ID NO: 11; h) a VH comprising the amino acid sequence of SEQ ID NO: 45 and a VL comprising the amino acid sequence of SEQ ID NO: 11; i) a VH comprising the amino acid sequence of SEQ ID NO: 15 and a VL comprising the amino acid sequence of SEQ ID NO: 21; j) VH comprising the amino acid sequence of SEQ ID NO: 35 and VL comprising the amino acid sequence of SEQ ID NO: 21; k) VH comprising the amino acid sequence of SEQ ID NO: 45 and VL comprising the amino acid sequence of SEQ ID NO: 21; l) VH comprising the amino acid sequence of SEQ ID NO: 15 and VL comprising the amino acid sequence of SEQ ID NO: 31; m) VH comprising the amino acid sequence of SEQ ID NO: 25 and VL comprising the amino acid sequence of SEQ ID NO: 31; n) VH comprising the amino acid sequence of SEQ ID NO: 35 and VL comprising the amino acid sequence of SEQ ID NO: 31; o) VH comprising the amino acid sequence of SEQ ID NO: 15 and VL comprising the amino acid sequence of SEQ ID NO: 41; p) VH comprising the amino acid sequence of SEQ ID NO: 35 and VL comprising the amino acid sequence of SEQ ID NO: 41; q) VH comprising the amino acid sequence of SEQ ID NO: 45 and VL comprising the amino acid sequence of SEQ ID NO: 41; r) VH comprising the amino acid sequence of SEQ ID NO: 55 and VL comprising the amino acid sequence of SEQ ID NO: 51; s) a VH comprising the amino acid sequence of SEQ ID NO: 65 and a VL comprising the amino acid sequence of SEQ ID NO: 61; and t) VH comprising the amino acid sequence of SEQ ID NO: 75 and VL comprising the amino acid sequence of SEQ ID NO: 71; 10. The anti-BDCA-2 (CLEC4C) antigen-binding molecule of any one of the preceding claims, selected from the group consisting of:

12. 3. The anti-BDCA-2 (CLEC4C) antigen binding molecule of any one of the preceding claims, which 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.

13. 13. The anti-BDCA-2 (CLEC4C) antibody of claim 12, comprising one or two amino acid substitutions across all six CDR regions.

14. 14. The anti-BDCA-2 (CLEC4C) antibody of claim 12 or 13, comprising one or two amino acid substitutions in one or more framework regions.

15. An anti-BDCA-2 (CLEC4C) antigen-binding molecule that specifically binds to BDCA-2 (CLEC4C) and competes with the antigen-binding molecule of any one of claims 1 to 14 for binding to BDCA-2 (CLEC4C).

16. 10. The anti-BDCA-2 (CLEC4C) antigen-binding molecule of any one of the preceding claims, which is an antibody or an antigen-binding fragment or derivative thereof.

17. 17. The anti-BDCA-2 (CLEC4C) antigen-binding molecule of claim 16, wherein the antigen-binding fragment or derivative of the antibody is a Fab, F(ab')2, Fv, scFv, dAb, Fd, or diabody.

18. The anti-BDCA-2 (CLEC4C) antigen-binding molecule of any one of claims 1 to 17, which is a monoclonal antibody.

19. 19. The anti-BDCA-2 (CLEC4C) antibody or antigen-binding fragment or derivative thereof of any one of claims 16 to 18, which is an IgA, IgD, IgE, IgG, IgM, or IgY antibody, or an antigen-binding fragment or derivative thereof, optionally an IgG antibody or antigen-binding fragment or derivative thereof, and further optionally an IgG1 antibody or antigen-binding fragment or derivative thereof.

20. 10. The anti-BDCA-2 (CLEC4C) antigen binding molecule of any one of the preceding claims, which reduces IFNα secretion when administered in vivo or in vitro.

21. 10. A pharmaceutical composition comprising the anti-BDCA-2 (CLEC4C) antigen binding molecule of any one of the preceding claims and a pharmaceutically acceptable excipient.

22. The anti-BDCA-2 (CLEC4C) antigen-binding molecule of any one of claims 1 to 20 or the pharmaceutical composition of claim 21, for use in medicine.

23. The anti-BDCA-2 (CLEC4C) antigen-binding molecule of any one of claims 1 to 20 or the pharmaceutical composition of claim 21, for use in the treatment or prevention of an inflammatory disorder or disease or an autoimmune disorder or disease.

24. The anti-BDCA-2 (CLEC4C) antigen-binding molecule or pharmaceutical composition or kit for use according to claim 23, wherein the inflammatory or autoimmune disorder or disease is selected from the group consisting of systemic sclerosis, fibrosis (such as dermal 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, morphea, type I diabetes, Sjogren's disease, and Hashimoto's thyroiditis.

25. The anti-BDCA-2 (CLEC4C) antigen-binding molecule, pharmaceutical composition, or kit for use according to claim 23, wherein the inflammatory disease is systemic sclerosis, fibrosis (such as dermal fibrosis), or pemphigus vulgaris.

Images