Anti-BDCA-2 antibodies

Abstract

The present application relates to an anti-BDCA-2 antibody. 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 and immune disorders such as autoimmune diseases.

Description

[0001] This application is a divisional application of an application filed on August 5, 2020, with application number 202080070344.3 and invention name “Anti-BDCA-2 Antibody”. Technical Field

[0002] The present invention relates to antigen-binding molecules, particularly antibodies, fragments and variants thereof, that bind to BDCA-2 (CLEC4C), and uses of the antigen-binding molecules in treating and / or preventing inflammatory disorders and immune disorders such as autoimmune diseases. Background Art

[0003] Avoiding recognition of self-DNA and self-RNA while maintaining the ability to sense microbial nucleic acids is crucial. The innate immune system appears to have tailored several different mechanisms to distinguish pathogen-derived foreign nucleic acids from host-derived self-nucleic acids. However, there is considerable emerging evidence that, despite the innate immune system developing different mechanisms to prevent self-recognition, Toll-like receptor (TLR) recognition of self-nucleic acids still occurs under certain circumstances. Chronically activated plasmacytoid dendritic cells (pDCs) and their production of IFN-α in response to self-nucleic acids are contributing factors in the pathogenesis of several autoimmune diseases, such as scleroderma (SSc), systemic lupus erythematosus (SLE), and Sjögren's syndrome psoriasis (Bekic Z, et al. Ann Rheum Dis 2016; 75: 1567-73; Fei T, et al. Sci China Life Sci. 2010; 53: 172-182; van Bon L, et al. Current Opinion in Rheumatology 2011; 23: 505-510; Banchereau J and Pascual V. Immunity 2006; 25: 383-392).

[0004] Plasmacytoid dendritic cells (pDCs) are bone marrow-derived cells that specifically secrete type I IFNs (Colonna M, et al. Nat. Immunol. 2004; 5:1219-1226; Gilliet M, et al. Nat. Rev. Immunol. 2008; 8:594-606). pDCs are primarily found in peripheral blood and primary and secondary lymphoid organs. pDCs rapidly detect viral nucleic acids that are internalized and delivered to endosomes containing TLR7 and TLR9. Engagement of these receptors leads to the immediate release of type I IFNs, providing very early defense against viral infection (Swiecki M and Colonna M. Immunol. Rev. 2010; 234:142-162). pDCs also secrete type I IFNs in response to endogenous nucleic acids released during cell necrosis and / or apoptosis or bound to antinuclear autoantibodies.

[0005] A wealth of evidence indicates that self-nucleic acid recognition is involved in inflammatory and autoimmune diseases. In particular, the contribution of TLRs to autoimmunity has been emphasized in a variety of disease models. A prime example is the role played by TLR9 and TLR7 in lupus following accumulation of self-DNA / RNA via immune complexes (Barrat FJ et al. J. Exp. Med. 2005, 202: 1131-1139; Hagberg N and Ronnblom L Scand. J. Immunol. 2015, 82: 199-207). Another example is the importance of self-antimicrobial peptides in promoting autoimmunity (Lande R et al. Nature 2007, 449; 564-569). It has been shown that overexpression of a single TLR is sufficient to induce autoimmunity in, for example, wild-type animals, as shown for TLR7 or TLR8 (Deane, JA et al. Immunity 2007; 27: 801-810; Guiducci C, et al. J. Exp. Med. 2013; 210: 2903-2919).

[0006] SSc is a multisystem fibrotic disease in which vasculopathy, autoimmunity, and inflammation lead to a variety of life-altering and life-threatening clinical manifestations. SSc has the highest morbidity and mortality among rheumatic diseases, with a 10-year mortality rate of 23% to 45% (Mayes MD, et al. Arthritis Rheum. 2003; 48: 2246-2255). It is more common in women, with a ratio of approximately 4:1, and the average age of onset is 35 to 55 years. The pathophysiology of SSc is not fully understood, but a wealth of evidence suggests that there is an interplay between immune disorders, endothelial dysfunction, and profibrotic mechanisms.

[0007] Evidence suggests 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. Ah Kioon et al. (Sci. Transl. Med. 2018; 10: eaam8458) demonstrated that the secretion of CXCL4 is due to the abnormal presence of TLR8 on pDCs in SSc patients, which is not seen in healthy donors, and that CXCL4 primarily acts by enhancing TLR8- and TLR9-induced IFN production by pDCs. Other studies of IFN-induced chemokines in SSCs (Liu X, et al. Arthritis Rheum. 2013; 65: 226-35) and reports on CXCL4 as a biomarker for SSCs (van Bon L, et al. N Engl J Med. 2014; 370: 433-43) have led to increasing interest in the role of IFNs in the progression and early stages of SSc. Another recent paper showed that an IFN signature (previously associated with active SSc) precedes the onset of clinical fibrosis (Brkic Z et al. Ann Rheum Dis. 2016; 75: 1567-73). Furthermore, in vivo data showed that depletion of pDCs prevented disease in a mouse model of scleroderma and reversed fibrosis in mice with established disease (Ah Kioon et al. Sci. Transl. Med. 2018; 10: eaam8458).

[0008] pDCs express multiple receptors that inhibit type I IFN secretion, thereby preventing immune surveillance. Among these receptors are CLEC4C, also known as blood dendritic cell antigen-2 (BDCA-2), and CD303 (Dzionek A, et al. J. Exp. Med. 2001;194:1823-1834). CLEC4C is a type II transmembrane glycoprotein that belongs to the C-type lectin (CTL) superfamily (Crocker PR et al. Nat Rev Immunol. 2007;7:255-66). BDCA-2 is the most specific marker for human pDCs and is expressed only in primates. BDCA-2 consists of a single extracellular carbohydrate recognition domain, a transmembrane region, and a short cytoplasmic domain without obvious signaling motifs. BDCA-2 transmits intracellular signals through the related transmembrane adaptor FcεRγ (recruiting protein tyrosine kinase Syk), thereby inducing protein tyrosine phosphorylation and calcium mobilization (Cao W, et al. PLoS Biol. 2007; 5: e248). Although it promotes cell activation of other lymphoid and myeloid cells, the FcεRγ-Syk signaling pathway interferes with TLR7 and TLR9-induced pDC activation and inhibits type I IFN secretion (Dzionek A, et al. J. Exp. Med. 2001; 194: 1823-1834).

[0009] pDCs are abnormally activated in the peripheral blood or at the lesion site and produce large amounts of IFNα and other inflammatory cytokines and chemokines in autoimmune diseases such as SLE, SSc, polymyositis and dermatomyositis, psoriasis, Sjögren's syndrome, rheumatoid arthritis, Graves' disease, and Hashimoto's disease (Li et al. Front Immunol. 2017; 8: 1268; Eloranta et al. Arthritis Rheum. 2013; 65: 853-863). Summary of the Invention

[0010] In a first aspect of the present invention, an antigen binding molecule or a fragment or variant thereof is provided, comprising a heavy chain variable region containing VHCDR3 and / or a light chain variable region containing VLCDR3, wherein the antigen binding molecule binds to BDCA-2 (CLEC4C).

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

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

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

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

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

[0016] In a seventh aspect of the present invention, an anti-BDCA-2 (CLEC4C) antigen-binding molecule is provided, wherein the antigen-binding molecule comprises: a VHCDR1 comprising an amino acid sequence of any one of SEQ ID NOs: 46, 49, 26, 29, 6, 9, 16, 19, 36, 39, 56, 59, 66, 69, 76, and 79; a VHCDR2 comprising an 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 an amino acid sequence of any one of SEQ ID NOs: 48, 28, 8, 18, 38, 58, 68, and 78; and / or a VLCDR1 comprising an amino acid sequence of any one of SEQ ID NOs: 32, 22, 42, 2, 12, 52, 62, and 72; a VHCDR2 comprising an amino acid sequence of any one of SEQ ID NOs: 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, an anti-BDCA-2 (CLEC4C) antigen-binding molecule is provided, wherein the antigen-binding molecule comprises: a heavy chain variable region having an amino acid sequence selected from the group consisting of SEQ ID NO:45, SEQ ID NO:25, SEQ ID NO:5, SEQ ID NO:15, SEQ ID NO:35, SEQ ID NO:55, SEQ ID NO:65, and SEQ ID NO:75; and / or a light chain variable region having an amino acid sequence selected from the group consisting of SEQ ID NO:31, SEQ ID NO:21, SEQ ID NO:41, SEQ ID NO:1, SEQ ID NO:11, SEQ ID NO:51, SEQ ID NO:61, and SEQ ID NO:71.

[0018] In a ninth aspect of the present invention, an anti-BDCA-2 (CLEC4C) antigen binding molecule is provided, wherein the antigen binding molecule is an antibody that specifically binds to BDCA-2 (CLEC4C) and is selected from the group consisting of: 3E05_var12, 3E05_var6, 3E05_var14, 3E05, 3E05_var1, 3E05_var2, 3E05_var3, 3E05_var4, 3E05_var5, 3E05_var7, 3E05_var8, 3E05_var9, 3E05_var10, 3E05_var11, 3E05_var13, 3E05_var15, 3E05_var16, 21E06, 25E06, and 28B01. The present invention also provides fragments and variants derived from the antibodies.

[0019] In another aspect of the present invention, provided is 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 one of the first to ninth aspects of the present invention for binding to BDCA-2 (CLEC4C).

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

[0021] In another aspect of the present invention, provided is 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 one of the first to ninth aspects of the present invention.

[0022] In another aspect of the present invention, an anti-BDCA-2 (CLEC4C) antigen binding molecule is provided, comprising 1 to 10, 1 to 5, or 1 to 2 amino acid substitutions of the antigen binding molecule of any one of the first to ninth aspects of the present invention.

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

[0024] In another aspect of the present invention, an affinity matured mutant of the antigen-binding molecule or antibody of the present invention is provided.

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

[0026] In another aspect of the present invention, use of the antigen-binding molecules or pharmaceutical compositions of the present invention in medicine is provided.

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

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

[0029] In another aspect, provided is a method of 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 invention.

[0030] Also provided are nucleic acids encoding the antigen-binding molecules of the present invention. Also provided are vectors or plasmids comprising the nucleic acids of the present invention. Also provided are host cells comprising the nucleic acids, vectors, or plasmids 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 the host cell of the present invention in a cell culture medium under conditions such that a nucleic acid sequence encoding the plasmid or vector is expressed intracellularly, and optionally collecting the anti-BDCA-2 (CLEC4C) antigen binding molecule from the cell supernatant.

[0032] The present invention also provides a kit comprising an anti-BDCA-2 (CLEC4C) antigen binding molecule or other aspects of the present invention, which kit may optionally further comprise instructions for use.

[0033] The present invention also provides the following items:

[0034] 1. An anti-BDCA-2 (CLEC4C) antigen binding molecule, wherein the antigen binding molecule has an equilibrium dissociation constant (K) for BDCA-2 (CLEC4C) of less than about 2 nM. D ).

[0035] 2. An anti-BDCA-2 (CLEC4C) antigen binding molecule, wherein the antigen binding molecule has a half-maximal inhibitory concentration (IC50) for inhibiting IFN secretion of less than about 2 nM.

[0036] 3. An anti-BDCA-2 (CLEC4C) antigen binding molecule, wherein the antigen binding molecule has an IC90 for inhibiting IFN secretion of less than about 20 nM.

[0037] 4. The anti-BDCA-2 (CLEC4C) antigen binding molecule according to any preceding item, wherein the antigen binding molecule has an equilibrium dissociation constant (K) for BDCA-2 (CLEC4C) of less than about 2 nM. D ), a half-maximal 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.

[0038] 5. The anti-BDCA-2 (CLEC4C) antigen-binding molecule of claim 4, wherein the antigen-binding molecule has an equilibrium dissociation constant (KD) for BDCA-2 (CLEC4C) of less than about 0.01 nM, a half-maximal inhibitory concentration (IC50) for inhibiting IFN secretion of less than about 0.5 nM, and an IC90 for inhibiting IFN secretion of less than about 5 nM.

[0039] 6. The anti-BDCA-2 (CLEC4C) antigen-binding molecule according to any preceding item, wherein the antigen-binding molecule comprises:

[0040] a VHCDR3 comprising the amino acid sequence of any one of SEQ ID NOs 48, 28, 8, 38, 58, 68 and 78; and / or

[0041] A VLCDR3 comprising the amino acid sequence of any one of SEQ ID NOs 34, 24, 44, 4, 14, 54, 64 and 74.

[0042] 7. The anti-BDCA-2 (CLEC4C) antigen-binding molecule according to any preceding item, wherein the antigen-binding molecule comprises:

[0043] a VHCDR1 comprising the amino acid sequence of any one of SEQ ID NOs 46, 49, 26, 29, 6, 9, 16, 19, 36, 39, 56, 59, 66, 69, 76, and 79;

[0044] 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

[0045] a VHCDR3 comprising the amino acid sequence of any one of SEQ ID NOs 48, 28, 8, 18, 38, 58, 68, and 78;

[0046] and / or

[0047] a VLCDR1 comprising the amino acid sequence of any one of SEQ ID NOs 32, 22, 42, 2, 12, 52, 62, and 72;

[0048] a VLCDR2 comprising the amino acid sequence of any one of SEQ ID NOs 33, 23, 43, 3, 13, 53, 63, and 73; and

[0049] A VLCDR3 comprising the amino acid sequence of any one of SEQ ID NOs 34, 24, 44, 4, 14, 54, 64 and 74.

[0050] 8. The anti-BDCA-2 (CLEC4C) antigen-binding molecule according to any preceding item, wherein the antigen-binding molecule is selected from the group consisting of:

[0051] (a) an anti-BDCA-2 (CLEC4C) antigen binding molecule comprising:

[0052] a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SYTMS (SEQ ID NO: 46), a VHCDR2 comprising the amino acid sequence of YISSGGGQTYYPDSVKG (SEQ ID NO: 47), and a VHCDR3 comprising the amino acid sequence of HDYYEGGLYYAMDY (SEQ ID NO: 48); and

[0053] a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 34);

[0054] (b) an anti-BDCA-2 (CLEC4C) antigen binding molecule comprising:

[0055] a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 49), a VHCDR2 comprising the amino acid sequence of SSGGGQTY (SEQ ID NO: 50), and a VHCDR3 comprising the amino acid sequence of HDYYEGGLYYAMDY (SEQ ID NO: 48); and

[0056] a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 34);

[0057] (c) an anti-BDCA-2 (CLEC4C) antigen binding molecule comprising:

[0058] a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SYTMS (SEQ ID NO: 26), a VHCDR2 comprising the amino acid sequence of YISSGGGNTYYADSVKG (SEQ ID NO: 27), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO3: 28); and

[0059] a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 23), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 24);

[0060] (d) an anti-BDCA-2 (CLEC4C) antigen binding molecule comprising:

[0061] a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 29), a VHCDR2 comprising the amino acid sequence of SSGGGNTY (SEQ ID NO: 30), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 28); and

[0062] a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 23), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 24);

[0063] (e) an anti-BDCA-2 (CLEC4C) antigen binding molecule comprising:

[0064] a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SYTMS (SEQ ID NO: 26), a VHCDR2 comprising the amino acid sequence of YISSGGGNTYYADSVKG (SEQ ID NO: 27), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 28); and

[0065] a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 43), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 44);

[0066] (f) an anti-BDCA-2 (CLEC4C) antigen binding molecule comprising:

[0067] a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 29), a VHCDR2 comprising the amino acid sequence of SSGGGNTY (SEQ ID NO: 30), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 28); and

[0068] a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 43), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 44);

[0069] (g) an anti-BDCA-2 (CLEC4C) antigen binding molecule comprising:

[0070] a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SYTMS (SEQ ID NO: 6), a VHCDR2 comprising the amino acid sequence of YISSGGGNTYYPDSVKG (SEQ ID NO: 7), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 8); and

[0071] a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of KASQSVDYDGDSSMN (SEQ ID NO: 2), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 3), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 4);

[0072] (h) an anti-BDCA-2 (CLEC4C) antigen binding molecule comprising:

[0073] a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 9), a VHCDR2 comprising the amino acid sequence of SSGGGNTY (SEQ ID NO: 10), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 8); and

[0074] a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of KASQSVDYDGDSSMN (SEQ ID NO: 2), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 3), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 4);

[0075] (i) an anti-BDCA-2 (CLEC4C) antigen binding molecule comprising:

[0076] a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SYTMS (SEQ ID NO: 16), a VHCDR2 comprising the amino acid sequence of YISSGGGNTYYPDSVKG (SEQ ID NO: 17), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 18); and

[0077] a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 13), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 14);

[0078] (j) an anti-BDCA-2 (CLEC4C) antigen binding molecule comprising:

[0079] a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 19), a VHCDR2 comprising the amino acid sequence of SSGGGNTY (SEQ ID NO: 20), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 18); and

[0080] a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 13), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 14);

[0081] (k) an anti-BDCA-2 (CLEC4C) antigen binding molecule comprising:

[0082] a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SYTMS (SEQ ID NO: 26), a VHCDR2 comprising the amino acid sequence of YISSGGGNTYYADSVKG (SEQ ID NO: 27), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 28); and

[0083] a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 13), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 14);

[0084] (1) an anti-BDCA-2 (CLEC4C) antigen binding molecule comprising:

[0085] a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 29), a VHCDR2 comprising the amino acid sequence of SSGGGNTY (SEQ ID NO: 30), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 28); and

[0086] a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 13), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 14);

[0087] (m) an anti-BDCA-2 (CLEC4C) antigen binding molecule comprising:

[0088] a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SYTMS (SEQ ID NO: 36), a VHCDR2 comprising the amino acid sequence of YISSGGGQTYYPDSVKG (SEQ ID NO: 37), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 38); and

[0089] a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 13), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 14);

[0090] (n) an anti-BDCA-2 (CLEC4C) antigen binding molecule comprising:

[0091] a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 39), a VHCDR2 comprising the amino acid sequence of SSGGGQTY (SEQ ID NO: 40), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 38); and

[0092] a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 13), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 14);

[0093] (o) Anti-BDCA-2 (CLEC4C) antigen binding molecules comprising:

[0094] a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SYTMS (SEQ ID NO: 46), a VHCDR2 comprising the amino acid sequence of YISSGGGQTYYPDSVKG (SEQ ID NO: 47), and a VHCDR3 comprising the amino acid sequence of HDYYEGGLYYAMDY (SEQ ID NO: 48); and

[0095] a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 13), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 14);

[0096] (p) an anti-BDCA-2 (CLEC4C) antigen binding molecule comprising:

[0097] a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 49), a VHCDR2 comprising the amino acid sequence of SSGGGQTY (SEQ ID NO: 50), and a VHCDR3 comprising the amino acid sequence of HDYYEGGLYYAMDY (SEQ ID NO: 48); and

[0098] a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 13), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 14);

[0099] (q) an anti-BDCA-2 (CLEC4C) antigen binding molecule comprising:

[0100] a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SYTMS (SEQ ID NO: 16), a VHCDR2 comprising the amino acid sequence of YISSGGGNTYYPDSVKG (SEQ ID NO: 17), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 18); and

[0101] a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 23), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 24);

[0102] (r) an anti-BDCA-2 (CLEC4C) antigen binding molecule comprising:

[0103] a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 19), a VHCDR2 comprising the amino acid sequence of SSGGGNTY (SEQ ID NO: 20), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 18); and

[0104] a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 23), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 24);

[0105] (s) Anti-BDCA-2 (CLEC4C) antigen binding molecules comprising:

[0106] a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SYTMS (SEQ ID NO: 36), a VHCDR2 comprising the amino acid sequence of YISSGGGQTYYPDSVKG (SEQ ID NO: 37), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 38); and

[0107] a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 23), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 24);

[0108] (t) an anti-BDCA-2 (CLEC4C) antigen binding molecule comprising:

[0109] a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 39), a VHCDR2 comprising the amino acid sequence of SSGGGQTY (SEQ ID NO: 40), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 38); and

[0110] a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 23), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 24);

[0111] (u) an anti-BDCA-2 (CLEC4C) antigen binding molecule comprising:

[0112] a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SYTMS (SEQ ID NO: 46), a VHCDR2 comprising the amino acid sequence of YISSGGGQTYYPDSVKG (SEQ ID NO: 47), and a VHCDR3 comprising the amino acid sequence of HDYYEGGLYYAMDY (SEQ ID NO: 48); and

[0113] a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 23), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 24);

[0114] (v) an anti-BDCA-2 (CLEC4C) antigen binding molecule comprising:

[0115] a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 49), a VHCDR2 comprising the amino acid sequence of SSGGGQTY (SEQ ID NO: 50), and a VHCDR3 comprising the amino acid sequence of HDYYEGGLYYAMDY (SEQ ID NO: 48); and

[0116] a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 23), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 24);

[0117] (w) an anti-BDCA-2 (CLEC4C) antigen binding molecule comprising:

[0118] a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SYTMS (SEQ ID NO: 16), a VHCDR2 comprising the amino acid sequence of YISSGGGNTYYPDSVKG (SEQ ID NO: 17), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 18); and

[0119] a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 34);

[0120] (x) an anti-BDCA-2 (CLEC4C) antigen binding molecule comprising:

[0121] a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 19), a VHCDR2 comprising the amino acid sequence of SSGGGNTY (SEQ ID NO: 20), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 18); and

[0122] a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 34);

[0123] (y) an anti-BDCA-2 (CLEC4C) antigen binding molecule comprising:

[0124] a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SYTMS (SEQ ID NO: 26), a VHCDR2 comprising the amino acid sequence of YISSGGGNTYYADSVKG (SEQ ID NO: 27), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 28); and

[0125] a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 34);

[0126] (z) an anti-BDCA-2 (CLEC4C) antigen binding molecule comprising:

[0127] a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 29), a VHCDR2 comprising the amino acid sequence of SSGGGNTY (SEQ ID NO: 30), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 28); and

[0128] a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 34);

[0129] (aa) An anti-BDCA-2 (CLEC4C) antigen binding molecule comprising:

[0130] a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SYTMS (SEQ ID NO: 36), a VHCDR2 comprising the amino acid sequence of YISSGGGQTYYPDSVKG (SEQ ID NO: 37), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 38); and

[0131] a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 34);

[0132] (bb) an anti-BDCA-2 (CLEC4C) antigen binding molecule comprising:

[0133] a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 39), a VHCDR2 comprising the amino acid sequence of SSGGGQTY (SEQ ID NO: 40), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 38); and

[0134] a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 34);

[0135] (cc) anti-BDCA-2 (CLEC4C) antigen binding molecules, including

[0136] a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SYTMS (SEQ ID NO: 16), a VHCDR2 comprising the amino acid sequence of YISSGGGNTYYPDSVKG (SEQ ID NO: 17), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 18); and

[0137] a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 43), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 44);

[0138] (dd) an anti-BDCA-2 (CLEC4C) antigen binding molecule comprising:

[0139] a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 19), a VHCDR2 comprising the amino acid sequence of SSGGGNTY (SEQ ID NO: 20), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 18); and

[0140] a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 43), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 44);

[0141] (ee) an anti-BDCA-2 (CLEC4C) antigen binding molecule comprising:

[0142] a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SYTMS (SEQ ID NO: 36), a VHCDR2 comprising the amino acid sequence of YISSGGGQTYYPDSVKG (SEQ ID NO: 37), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 38); and

[0143] a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 43), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 44);

[0144] (ff) an anti-BDCA-2 (CLEC4C) antigen binding molecule comprising:

[0145] a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 39), a VHCDR2 comprising the amino acid sequence of SSGGGQTY (SEQ ID NO: 40), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 38); and

[0146] a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 43), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 44);

[0147] (gg) an anti-BDCA-2 (CLEC4C) antigen binding molecule comprising:

[0148] a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SYTMS (SEQ ID NO: 46), a VHCDR2 comprising the amino acid sequence of YISSGGGQTYYPDSVKG (SEQ ID NO: 47), and a VHCDR3 comprising the amino acid sequence of HDYYEGGLYYAMDY (SEQ ID NO: 48); and

[0149] a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 43), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 44);

[0150] (hh) Anti-BDCA-2 (CLEC4C) antigen binding molecules comprising:

[0151] a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 49), a VHCDR2 comprising the amino acid sequence of SSGGGQTY (SEQ ID NO: 50), and a VHCDR3 comprising the amino acid sequence of HDYYEGGLYYAMDY (SEQ ID NO: 48); and

[0152] a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of KASQSVDYDGDSSMN (SEQ ID NO: 42), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 43), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 44);

[0153] (ii) an anti-BDCA-2 (CLEC4C) antigen binding molecule comprising:

[0154] a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SYTIS (SEQ ID NO: 56), a VHCDR2 comprising the amino acid sequence of YISSGGDNAYYPDSVKG (SEQ ID NO: 57), and a VHCDR3 comprising the amino acid sequence of HLYYGDYFYVMDY (SEQ ID NO: 58); and

[0155] a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of KASQSVDYDGDNCLH (SEQ ID NO: 52), a VLCDR2 comprising the amino acid sequence of AASNLES (SEQ ID NO: 53), and a VLCDR3 comprising the amino acid sequence of QQSNEDPPT (SEQ ID NO: 54);

[0156] (jj) an anti-BDCA-2 (CLEC4C) antigen binding molecule comprising:

[0157] a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 59), a VHCDR2 comprising the amino acid sequence of SSGGDN (SEQ ID NO: 60), and a VHCDR3 comprising the amino acid sequence of HLYYGDYFYVMDY (SEQ ID NO: 58); and

[0158] a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of KASQSVDYDGDNCLH (SEQ ID NO: 52), a VLCDR2 comprising the amino acid sequence of AASNLES (SEQ ID NO: 53), and a VLCDR3 comprising the amino acid sequence of QQSNEDPPT (SEQ ID NO: 54);

[0159] (kk) an anti-BDCA-2 (CLEC4C) antigen binding molecule comprising:

[0160] a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SYTMS (SEQ ID NO: 66), a VHCDR2 comprising the amino acid sequence of YISGVGGDTYYPDSVKG (SEQ ID NO: 67), and a VHCDR3 comprising the amino acid sequence of HHYSHYFWYFDV (SEQ ID NO: 68); and

[0161] a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of KASQSVDYDGDGFMN (SEQ ID NO: 62), a VLCDR2 comprising the amino acid sequence of AASNLES (SEQ ID NO: 63), and a VLCDR3 comprising the amino acid sequence of QQSNEDPPT (SEQ ID NO: 64);

[0162] (11) an anti-BDCA-2 (CLEC4C) antigen-binding molecule comprising:

[0163] a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 69), a VHCDR2 comprising the amino acid sequence of SGVGGD (SEQ ID NO: 70), and a VHCDR3 comprising the amino acid sequence of HHYSHYFWYFDV (SEQ ID NO: 68); and

[0164] a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of KASQSVDYDGDGFMN (SEQ ID NO: 62), a VLCDR2 comprising the amino acid sequence of AASNLES (SEQ ID NO: 63), and a VLCDR3 comprising the amino acid sequence of QQSNEDPPT (SEQ ID NO: 64);

[0165] (mm) anti-BDCA-2 (CLEC4C) antigen binding molecule, comprising:

[0166] a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of YYTMS (SEQ ID NO: 76), a VHCDR2 comprising the amino acid sequence of YISSGGDNAYYPDSVRG (SEQ ID NO: 77), and a VHCDR3 comprising the amino acid sequence of HHYSNYFWYFDV (SEQ ID NO: 78); and

[0167] a light chain variable region comprising VLCDR1 comprising the amino acid sequence of KASQSVDYAGDSYVN (SEQ ID NO: 72), VLCDR2 comprising the amino acid sequence of AASNLES (SEQ ID NO: 73), and VLCDR3 comprising the amino acid sequence of QQSNEDPPT (SEQ ID NO: 74); and

[0168] (nn) Anti-BDCA-2 (CLEC4C) antigen binding molecules comprising:

[0169] a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of GFTFSYY (SEQ ID NO: 79), a VHCDR2 comprising the amino acid sequence of SSGGDN (SEQ ID NO: 80), and a VHCDR3 comprising the amino acid sequence of HHYSNYFWYFDV (SEQ ID NO: 78); and

[0170] The light chain variable region comprises a VLCDR1 comprising the amino acid sequence of KASQSVDYAGDSYVN (SEQ ID NO: 72), a VLCDR2 comprising the amino acid sequence of AASNLES (SEQ ID NO: 73), and a VLCDR3 comprising the amino acid sequence of QQSNEDPPT (SEQ ID NO: 74).

[0171] 9. The anti-BDCA-2 (CLEC4C) antigen-binding molecule according to any preceding item, wherein the antigen-binding molecule comprises:

[0172] a heavy chain variable region that is at least 80% identical 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;

[0173] and / or

[0174] 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.

[0175] 10. The anti-BDCA-2 (CLEC4C) antigen-binding molecule according to any preceding item, wherein the antigen-binding molecule comprises:

[0176] 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;

[0177] and / or

[0178] 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.

[0179] 11. The anti-BDCA-2 (CLEC4C) antigen-binding molecule according to any preceding item, wherein the antigen-binding molecule is selected from the group consisting of:

[0180] 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;

[0181] 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;

[0182] 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;

[0183] 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;

[0184] 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;

[0185] 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;

[0186] 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;

[0187] 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;

[0188] 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;

[0189] 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;

[0190] 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;

[0191] 1) 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;

[0192] 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;

[0193] 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;

[0194] 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;

[0195] 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;

[0196] 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;

[0197] 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;

[0198] 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

[0199] 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.

[0200] 12. The anti-BDCA-2 (CLEC4C) antigen binding molecule of any preceding item, wherein the anti-BDCA-2 (CLEC4C) antigen binding molecule 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.

[0201] 13. The anti-BDCA-2 (CLEC4C) antibody according to item 12, wherein the antibody comprises 1 or 2 amino acid substitutions in all 6 CDR regions.

[0202] 14. The anti-BDCA-2 (CLEC4C) antibody according to item 12 or 13, wherein the antibody comprises 1 or 2 amino acid substitutions in one or more framework regions.

[0203] 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 items 1 to 14 for binding to BDCA-2 (CLEC4C).

[0204] 16. The anti-BDCA-2 (CLEC4C) antigen-binding molecule according to any preceding item, wherein the antigen-binding molecule is an antibody or an antigen-binding fragment or derivative thereof.

[0205] 17. The anti-BDCA-2 (CLEC4C) antigen-binding molecule according to item 16, wherein the antigen-binding fragment or derivative of the antigen-binding molecule is Fab, F(ab')2, Fv, scFv, dAb, Fd, or diabody.

[0206] 18. The anti-BDCA-2 (CLEC4C) antigen-binding molecule according to any one of items 1 to 17, wherein the anti-BDCA-2 (CLEC4C) antigen-binding molecule is a monoclonal antibody.

[0207] 19. The anti-BDCA-2 (CLEC4C) antibody or antigen-binding fragment or derivative thereof according to any one of items 16 to 18, wherein the antibody or antigen-binding fragment or derivative thereof is an IgA, IgD, IgE, IgG, IgM or IgY antibody or antigen-binding fragment or derivative thereof, optionally wherein the antibody or antigen-binding fragment or derivative thereof is an IgG antibody or antigen-binding fragment or derivative thereof, further optionally wherein the antibody or antigen-binding fragment or derivative thereof is an IgG1 antibody or antigen-binding fragment or derivative thereof.

[0208] 20. The anti-BDCA-2 (CLEC4C) antigen binding molecule according to any preceding item, wherein the antigen binding molecule reduces IFNα secretion when administered in vivo or in vitro.

[0209] 21. A pharmaceutical composition comprising the anti-BDCA-2 (CLEC4C) antigen binding molecule of any preceding item and a pharmaceutically acceptable excipient.

[0210] 22. Use of the anti-BDCA-2 (CLEC4C) antigen-binding molecule according to any one of items 1 to 20, or the pharmaceutical composition according to item 21, in medicine.

[0211] 23. Use of the anti-BDCA-2 (CLEC4C) antigen binding molecule according to any one of items 1 to 20, or the pharmaceutical composition according to item 21, in treating or preventing an inflammatory disorder or disease or an autoimmune disorder or disease.

[0212] 24. An anti-BDCA-2 (CLEC4C) antigen binding molecule, pharmaceutical composition, or kit for use according to claim 23, wherein the inflammatory disorder or disease or autoimmune disorder or disease is selected from the group consisting of systemic sclerosis, fibrosis (e.g., cutaneous 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 1 diabetes, Sjögren's disease, and Hashimoto's disease.

[0213] 25. The anti-BDCA-2 (CLEC4C) antigen binding molecule, pharmaceutical composition, or kit for use as described in item 23, wherein the inflammatory disease is systemic sclerosis, fibrosis (such as cutaneous fibrosis), or pemphigus vulgaris. BRIEF DESCRIPTION OF THE DRAWINGS

[0214] Figure 1Chimeric mAbs that bind to BDCA-2 expressed in human and cynomolgus macaque cells. Purified mAbs at 5 μg / ml were tested against BDCA-2 expressed in either human or cynomolgus macaque cells. Positive controls used were the anti-BDCA-2 mAbs, AC144 (Miltenyi Biotec, catalog number 130-090-690) and BIIB059 (patent WO2014093396), and the negative control was buffer (no Ab).

[0215] Figure 2 Chimeric mAb binding to plasmacytoid dendritic cells. Purified mAb (10 μg / ml) was tested for binding to purified pDCs by flow cytometry. Positive controls used were anti-BDCA-2 mAb, AC144 (Miltenyi Biotech, catalog number 130-090-690), and BIIB059 (patent WO2014093396). The negative control was buffer (no Ab).

[0216] Figure 3A Chimeric anti-BDCA-2 mAbs inhibited IFNα production from ODN-stimulated pDCs. mAbs at 1 μg / ml or 0.1 μg / ml were tested for their ability to inhibit ODN-induced IFNα production from purified human pDCs. Positive anti-BDCA-2 mAb controls used were AC144 (Miltenyi Biotec, catalog number 130-090-690) and BIIB059 (patent WO2014093396), and the negative control was buffer (no Ab).

[0217] Figure 3B Chimeric anti-BDCA-2 mAb inhibits IFNα from TLR9 (ODN, 1 μM)-stimulated PBMCs. mAb at 10 μg / ml, 1 μg / ml, or 0.1 μg / ml was tested for its ability to inhibit 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.

[0218] Figure 3C Chimeric anti-BDCA-2 mAb inhibits IFNα from TLR8 (ORN, 1 μM)-stimulated PBMCs. mAb at 10 μg / ml, 1 μg / ml, or 0.1 μg / ml was tested for its ability to inhibit IFNα induced by ORN from human PBMCs (500K / well). Negative controls were buffer (control) and hIgG1 at 10 μg / ml, 1 μg / ml, or 0.1 μg / ml.

[0219] Figure 3DChimeric anti-BDCA-2 mAb inhibits IFNα from TLR7 (imiquimod, 1 μM)-stimulated PBMCs. mAb at 10 μg / ml, 1 μg / ml, or 0.1 μg / ml was tested 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.

[0220] Figure 4A Chimeric anti-BDCA-2 mAb (10 μg / ml) inhibited the effects of intracellular IFNα and TNFα in healthy pDCs stimulated with ODN. The positive control was anti-BDCA-2 mAb BIIB059 (patent WO2014093396), and the negative control was buffer (no Ab).

[0221] Figure 4B The effect of chimeric anti-BDCA-2 mAb (10 μg / ml) on the inhibition of TNFα secretion from healthy pDCs stimulated with ODN. The positive control was anti-BDCA-2 mAb BIIB059 (patent WO2014093396), and the negative control was buffer (no Ab).

[0222] Figure 5 Binding of humanized 3E5 and 28B1 variant mAbs to pDCs by flow cytometry;

[0223] Figure 6A The humanized 28B1 anti-BDCA-2 mAb inhibits IFNα secretion from ODN-stimulated PBMCs. The positive control is the anti-BDCA-2 mAb BIIB059 (patent WO2014093396), and the negative control is buffer (no Ab).

[0224] Figure 6B The humanized 3E5 anti-BDCA-2 mAb inhibits IFNα secretion from ODN-stimulated PBMCs. The positive control is the anti-BDCA-2 mAb BIIB059 (patent WO2014093396), and the negative control is buffer (no Ab).

[0225] Figure 7A and 7B BDCA2 chimeric mAb 3E5 inhibits ODN-stimulated pDC transcriptome activation. Figure 7A Three independent human pDC donors with and without ODN stimulation are shown (Lineage - HLA-DR + CD123 + CD304 +) and pathway analysis of differentially expressed genes (DEGs). Figure 7B Shown is the inhibition of DEGs in ODN-stimulated pDCs by 3E5, which exhibited an expression profile similar to that of unstimulated pDCs;

[0226] Figure 8A 、 8B and 8C. Organotypic 3D skin culture and the effect of chimeric anti-BDCA-2 mAb 3E5. Figure 8A Cultivation techniques and the air-liquid interface (ALI) are outlined. Figure 8B : Hematoxylin and eosin (H&E) staining showed epithelial-like development in vivo. Figure 8C Shown are 27 IFN-stimulated genes whose expression is upregulated in the epithelium by supernatants of intraepithelial ODN-stimulated pDCs relative to supernatants of resting pDCs and inhibition by the chimeric anti-BDCA-2 mAb 3E5;

[0227] Figure 9A and 9B .Xenograft mouse model of human pDC activation. Effects of chimeric anti-BDCA-2 mAbs 28B1 and 3E5 on mouse interferon gene signature. Normal human primary pDCs were tail vein injected into NOD-SCID mice, and the dorsal skin was treated with Aldara cream with and without chimeric anti-BDCA-2 mAbs 3E5 or 28B1 or human IgG (5 mg / kg). Total RNA from triplicate experiments was used to generate cDNA, and qRT-PCR analysis was performed for 78 genes commonly upregulated during type I interferon responses. IGS from the Qiagen panel were aligned for differential expression in the hIgG condition versus the control (Aldara / imiquimod only). The 10 most differentially expressed genes were selected for analysis;

[0228] Figure 10A 、 10B , 10C, 10D, and 10E. Three-week pDC- and bleomycin-induced skin fibrosis model. Starting from day 0, bleomycin (Bleo) or PBS (control, 100 μl) was injected subcutaneously (sc) into a single site on the shaved back of NOD-SCID mice every other day for 3 weeks. 5 Mice were injected intravenously (iv) on days 0, 7, and 14. Starting from day -1, 3E5 mAb (var-6) or human IgG (2.5 mg / kg, ip) was injected once every 5 days (n = 5 ip injections per mouse) (the administration schedule is shown in Figure 10E Hematoxylin and eosin (H&E, Figure 10A ) or Masson's trichrome (MT) stain ( Figure 10A) Formalin-fixed, paraffin-embedded skin tissue from treated mice was stained. Epidermal and dermal skin thickness in the treated groups are shown in Figure 10B and 10C 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***;

[0229] Figure 11A and 11B Alignment of the parental 3E5 sequence and four humanized / deimmunized variants 1 to 4;

[0230] Figure 12A 、 12B , 12C and 12D. The sequences of the parental 3E5 heavy and light chain variable sequences and four humanized / deimmunized variants 1 to 4 (SEQ ID NOs 1, 11, 21, 31, 41, 5, 15, 25, 35 and 45), together constituting 16 variant antibodies based on the parental 3E5 antibody. Figures A and B identify 6 CDRs according to the Kabat scheme. Figures C and D identify 6 CDRs according to the Chothia scheme. These figures also provide the SEQ ID NOs for each sequence (heavy, light, Kabat and Chothia-identified CDRs) associated with the 3E5 parent antibody and its 16 variants (SEQ ID NOs: 1 to 50). If there are any differences between the sequences of these figures and the sequences in the accompanying sequence listing or elsewhere in this specification, the sequences of these figures shall prevail;

[0231] Figure 13 Overlap mapping of trypsin, chymotrypsin, ASP-N, elastase, and thermolysin peptides was designed, and epitopes were determined using proteolysis. 100% of the sequence was covered by combining peptides proteolytically hydrolyzed by trypsin, chymotrypsin, elastase, and thermolysin. Amino acid numbering refers to the extracellular domain of BDCA-2, amino acids 45 to 213 of Q8WTT0, where Figure 13 Amino acid 1 in is amino acid 45 in Q8WTTO. DETAILED DESCRIPTION

[0232] As used herein, an "antigen binding molecule" is a member of a pair of molecules that have binding specificity for each other. The members of the antigen binding pair can be naturally derived or wholly or partially synthetically produced. One member of the pair has an area on its surface that can be a protrusion or a cavity that specifically binds to a specific spatial and polar organization of the other member of the pair and is therefore complementary to it. Therefore, the members of the pair have the property of specifically binding to each other. Examples of types of antigen binding pairs include antigen-antibody, biotin-avidin, hormone-hormone receptor, receptor-ligand, and enzyme-substrate. The present invention generally relates to antigen-antibody type interactions. The antigen binding molecules used in the present invention specifically bind to an epitope of BDCA-2 (CLEC4C) or BDCA-2 (CLEC4C). The binding affinity of the antigen binding molecule to the epitope of BDCA-2 (CLEC4C) or BDCA-2 (CLEC4C) can be measured using 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 ) is measured. The K of the antigen-binding molecule for the BDCA-2 (CLEC4C) epitope bound by the antigen-binding molecule of the present invention is D The K value will be lower than the K value of the antigen-binding molecule for the substituted epitope of BDCA-2 (CLEC4C) or the non-BDCA-2 (CLEC4C) epitope. D value.

[0233] Antigen-binding molecules that bind to BDCA-2 (CLEC4C) include anti-BDCA-2 (CLEC4C) antibodies and antigen-binding fragments thereof. Antigen-binding molecules used in the present invention are typically antibodies.

[0234] As used herein, the term "antibody" refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain an antigen-binding site that specifically binds to an antigen, whether natural or partially or wholly synthetically produced. The term also encompasses any polypeptide or protein having a binding domain that is an antibody binding domain or is homologous to an antibody binding domain. Antibodies can be polyclonal or monoclonal. These antibodies can be derived from natural sources, or they can be produced partially or wholly synthetically. Antibodies are polypeptides that typically comprise two identical heavy chains and two identical light chains (smaller than the heavy chains). There are two types of light chains in mammals, called lambda (λ) and kappa (κ). Each heavy chain and each light chain consists of a variable region and a constant region. The heavy chain variable region is called the VH region, and the light chain variable region is called the VL region. For kappa light chains, the VL region can also be called the VK region. Each variable region of the light and heavy chains includes three complementarity determining regions (CDRs): CDR1, CDR2, and CDR3. They are 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 isotype subtypes; fragments comprising antigen binding domains such as Fab, F(ab')2, Fv, scFv, dAb, Fd; and diabodies.

[0235] Fragments of antibodies and antigen-binding molecules

[0236] The antigen binding molecules of the present invention can be antibody fragments, specifically antigen binding fragments of antibodies. Antigen binding fragments contain one or more antigen binding regions. It has been shown that fragments of intact antibodies can perform the function of binding to antigens. Examples of binding fragments are: (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) isolated CDR regions; (vi) a F(ab')2 fragment: a bivalent fragment comprising two linked Fab fragments; (vii) a single-chain Fv molecule (scFv), in which the VH domain and the VL domain are connected by a peptide linker that allows the two domains to associate to form the antigen binding site (Bird et al., Science 242:423-426 (1988); Huston et al., PNAS USA 85:58795883 (1988)); (viii) bispecific single-chain Fv dimers (PCT / US92 / 09965); and (ix) "diabodies": multivalent or multispecific fragments constructed by gene fusion (WO94 / 13804; P. Hollinger et al., Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993)). Typically, the fragment is a Fab, F(ab')2 or Fv fragment or a scFv molecule.

[0237] Diabodies are multimers of polypeptides, each polypeptide comprising a first domain comprising the binding region of an immunoglobulin light chain and a second domain comprising the binding region of an immunoglobulin heavy chain, wherein the two domains are connected (e.g., by a peptide linker) but cannot associate with each other to form an antigen binding site: the antigen binding site is formed by the association of the first domain of one polypeptide within the multimer with the second domain of another polypeptide within the multimer (WO94 / 13804).

[0238] Where bispecific antibodies are used, these may be conventional bispecific antibodies (Hollinger & Winter, Current Opinion Biotechnol. 4: 446-449 (1993)) that can be produced in various ways, such as chemical preparation or hybridoma hybridization, or may be any of the bispecific antibody fragments mentioned below. It may be preferred to use scFv dimers or diabodies rather than whole antibodies. Diabodies and scFvs can be constructed using only the variable domains without an Fc region, potentially reducing the effectiveness of anti-idiotypic responses. Other forms of bispecific antibodies include single-chain "Janusins" described in Traunecker et al., EMBO Journal 10: 3655-3659 (1991).

[0239] A bispecific antibody is an antibody that can bind to two target molecules (e.g., two antigens or two epitopes) simultaneously. Bispecific antibodies may also be referred to as bibinding antibodies. Examples of bispecific antibody formats include, but are not limited to: (mAb)2, Fcab, F(mAb')2, tetravalent diabodies, scFv (single-chain variable fragment), bsDb (bispecific diabody), scBsDb (single-chain bispecific diabody), BiTE (bispecific T cell engager), DART (dual affinity retargeting antibody), charge pair, tandem antibodies, tandem scFv-Fc, Fab-scFv-Fc, Fab-scFv, minibodies, zybodies, DNL-F(ab)3 (docking-locked trivalent Fab), bssdAb (bispecific single-domain antibody), and keyholes.

[0240] In contrast to bispecific whole antibodies, bispecific diabodies may also be useful because they can be easily constructed and expressed in E. coli. Diabodies (and many other polypeptides, such as antibody fragments) with appropriate binding specificities can be easily selected from libraries using phage display (WO 94 / 13804). If one arm of the diabody is to be kept constant, for example, with specificity for antigen X, a library can be prepared in which the other arm is varied and antibodies with appropriate specificity selected.

[0241] The antigen-binding molecules of the present invention can be provided in a form that allows cross-linking between adjacent antigen-binding molecules. For example, antigen-binding molecules containing an Fc region (such as those in the form of monoclonal antibodies) allow cross-linking between the Fc regions of two adjacent molecules (and therefore allow cross-linking between adjacent BDCA-2 molecules due to co-localization). In some cases, this may promote the internalization of BDCA2 and inhibit IFN secretion. In other embodiments, the antigen-binding molecules can be provided in a form that does not allow cross-linking between adjacent antigen-binding molecules. For example, antigen-binding molecules lacking an Fc region (such as those in the form of Fabs or the like) may not cross-link. However, it has been demonstrated that even if the antigen-binding molecules of the present invention (specifically, antigen-binding molecules having the sequences disclosed herein) are provided in a form that does not allow cross-linking, they can still promote the internalization of BDCA2 and inhibit IFN secretion in a dose-dependent manner. This means that two types of antigen-binding molecules can be provided (those in a form that allow cross-linking and those in a form that do not), thereby increasing the practicality and functionality of the antigen-binding molecules of the present invention compared to the prior art.

[0242] Furthermore, the antigen-binding molecules of the present invention are able to promote BDCA2 internalization and inhibit IFN secretion in a dose-dependent manner, even when the antigen-binding molecules are provided in a monovalent manner that binds to BDCA2. For example, antigen-binding molecules in the form of Fabs that bind to BDCA-2 in a monovalent manner (i.e., a ratio of one antigen-binding molecule to one BDCA2 molecule) have been shown to promote BDCA2 internalization and inhibit IFN secretion in a dose-dependent manner. This is in contrast to prior art anti-BDCA2 molecules.

[0243] Thus, in some embodiments, the antigen-binding molecules bind to BDCA2 in a monovalent manner (i.e., a ratio of one antigen-binding molecule to one BDCA2 molecule). In some embodiments, the antigen-binding molecules do not cross-link with each other. Fab formats achieve both of these goals because they do not cross-link with each other (due to the lack of an Fc region) and they bind their antigens in a monovalent manner. In some embodiments, the present invention provides antigen-binding molecules having sequences that promote BDCA2 internalization and inhibit IFN secretion (in vitro or in vivo). Advantages of the antigen-binding molecules of the present invention include the ability to promote BDCA2 internalization and inhibit IFN secretion, regardless of the ability of the antigen-binding molecules to cross-link with each other (and thus co-localize with BDCA2 molecules), and regardless of the binding valency (i.e., monovalent or bivalent binding).

[0244] Identity and homology

[0245] " identity " as known in the art is the relationship between two or more peptide sequences or two or more polynucleotide sequences determined by comparing sequences. In the art, identity also means the sequence relatedness between polypeptide or polynucleotide sequence (as the case may be), as determined by the coupling between the character string of this sequence. Although there are many methods for measuring the identity between two peptide sequences or two polynucleotide sequences, the method generally used for determining identity is codified in a computer program. Preferred computer programs for determining the identity between two sequences include but are not limited to GCG program packages ((Devereux, et al., Nucleic Acids Research, 12,387 (1984), BLASTP, BLASTN and FASTA (Atschul et al., J.Molec.Biol.215,403 (1990)).

[0246] Amino acid sequences can be compared using a program such as the CLUSTAL program. This program compares amino acid sequences and finds the optimal alignment by inserting spaces in either sequence as appropriate. Amino acid identity or similarity (identity plus conservation of amino acid types) can be calculated for optimal alignment. Programs such as BLASTx compare the longest stretch of similar sequences and assign a value to the fit. Therefore, comparisons can be obtained when several similar regions are found, each with different scores. Two types of identity analysis are contemplated in the present invention.

[0247] The percent identity of two amino acid sequences or two nucleic acid sequences is determined by aligning the sequences for optimal comparison purposes (e.g., gaps can be introduced in the first sequence to optimally align with the sequence) and comparing the amino acid residues or nucleotides at corresponding positions. "Optimal alignment" is the alignment of two sequences that yields 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 × 100). Generally, unless the context otherwise specifies or implies, the % identity mentioned herein refers to the % identity over the entire length of the molecule.

[0248] The determination of percent identity between two sequences can be accomplished using mathematical algorithms known to those skilled in the art. An example of a mathematical algorithm for comparing two sequences is the algorithm of Karlin and Altschul (1990) Proc. Natl. Acad. Sci. USA 87:2264-2268, which was modified in Karlin and Altschul (1993) Proc. Natl. Acad. Sci. USA 90:5873-5877. This algorithm has been incorporated into the BLASTn and BLASTp programs of Altschul, et al. (1990) J. Mol. Biol. 215:403-410. BLAST nucleic acid searches can be performed with the NBLAST program (score = 100, wordlength = 12) to obtain nucleic acid sequences homologous to the nucleic acid molecules of the invention. BLAST protein searches can be performed with the XBLAST program (score = 50, wordlength = 3) to obtain amino acid sequences homologous to the protein molecules of the 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 iterative search to detect distant relationships (Id.) between molecules. When using BLAST, Gapped BLAST, and PSI-Blast programs, the default parameters of each program (e.g., BLASTp and BLASTp) can be used. See http: / / www.ncbi.nlm.nih.gov. Another example of a mathematical algorithm for sequence comparison 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, has incorporated this algorithm. Other algorithms for sequence analysis known in the art include ADVANCE and ADAM as described in Torellis and Robotti (1994) Comput. Appl. Biosci., 10: 3-5; and FASTA as 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.

[0249] Typically, the amino acid sequence of the CDR of the antigen binding molecules provided in the present invention has at least 70% homogeneity with the amino acid sequence of following CDR on the amino acid level, for example, using the default parameters of the BLAST computer program (Atschul et al., J.Mol.Biol.215,403-410 (1990)) provided by HGMP (Human Genome Atlas Project). More typically, the CDR sequence has at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or at least 99% homogeneity with the sequence as shown below on the amino acid level. Typically, each CDR sequence of the antigen binding molecules used in the present invention has the homogeneity of this level with the amino acid sequence of the CDR listed below. Selectively, any 1,2,3,4 or 5 CDR of the antigen binding molecules used in the present invention has the homogeneity of this level with the amino acid sequence of the CDR listed below.

[0250] The amino acid sequences of the VH and VL regions of the antigen binding molecules provided by the present invention have at least 70% identity at the amino acid level with the amino acid sequences of the following VH and VL regions, for example, using the default parameters of the BLAST computer program (Atschul et al., J. Mol. Biol. 215, 403-410 (1990)) provided by HGMP (Human Genome Atlas Project). More typically, the VH and VL regions have at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or at least 99% identity at the amino acid level with the sequences shown below. Typically, each VH and VL region of the antigen binding molecules used in the present invention has this level of identity with the amino acid sequences of the VH and VL regions listed below. Alternatively, only one of the VH and VL regions of the antigen-binding molecules used in the present invention has this level of identity with the amino acid sequences of the VH and VL regions listed below.

[0251] As used herein, identity can be used interchangeably with "homology" and "similarity." References to specific % identity also apply to % homology and % similarity. Homology and similarity can be determined using appropriate algorithms, such as FASTA, BLAST, and Gapped BLAST. Software for performing these analyses is publicly available.

[0252] In some embodiments, particularly any embodiments in which a reference sequence has a particular sequence identity to a reference sequence, the percent sequence identity can be calculated without specifying the sequence of all six CDRs of the heavy or light chain variable region. In such embodiments, the sequence variations occur only in the framework regions.

[0253] Variants

[0254] The present invention also extends to variants of peptide sequences described below. As used herein, the term "variant" refers to proteins with similar amino acid sequences and / or retaining the same function. For example, the term "variant" encompasses proteins or polypeptides comprising one or more amino acid additions, deletions, replacements, etc. An example of a variant of the present invention is a protein comprising one or more amino acid peptides as defined below and replacing one or more amino acids with one or more other amino acids. For example, amino acid replacements can be performed to reduce or eliminate the instability (liabilities) in the amino acid sequence. Alternatively, if desired, amino acid replacements can be performed to improve antigen affinity or to humanize or deimmunize the antibody. Affinity maturation variants, humanized variants, and deimmunization variants of a given antibody are provided herein, as well as variants comprising amino acid replacements to reduce or eliminate any instability in the antibody sequence.

[0255] As described above, in some embodiments, any substitution may occur only in the framework region. In this embodiment, the original CDR sequence is retained, but the variation may occur in one or more framework regions.

[0256] Variant antigen binding molecules with one or more amino acid substitutions can retain the functional activity (e.g., EC50, IC50, IC90, and / or Kd) of the antigen binding molecules from which the variant antigen binding molecules were 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 molecules from which the variant antigen binding molecules were derived.

[0257] replace

[0258] The skilled artisan is aware that various amino acids have similar properties. One or more such amino acids of a substance can generally be replaced by one or more other such amino acids without abolishing the desired activity of the substance.

[0259] Thus, the amino acids glycine, alanine, valine, leucine, and isoleucine are generally interchangeable (amino acids with aliphatic side chains). Of these possible substitutions, glycine and alanine are preferably substituted for each other (because they have relatively short side chains), and valine, leucine, and isoleucine are preferably substituted for each other (because they have larger, hydrophobic, aliphatic side chains). Other amino acids that are generally interchangeable include: phenylalanine, tyrosine, and tryptophan (amino acids with aromatic side chains); lysine, arginine, and histidine (amino acids with basic side chains); aspartic acid and glutamic acid (amino acids with acidic side chains); asparagine and glutamine (amino acids with amide side chains); and cysteine ​​and methionine (amino acids with sulfur-containing side chains).

[0260] Substitutions of this nature are often referred to as "conservative" or "semi-conservative" amino acid substitutions.

[0261] Using a three-letter and one-letter code, the naturally occurring amino acids may be referred to as follows: glycine (G or Gly), alanine (A or Ala), valine (V or Val), leucine (L or Leu), isoleucine (I or Ile), proline (P or Pro), phenylalanine (F or Phe), tyrosine (Y or Tyr), tryptophan (W or Trp), lysine (K or Lys), arginine (R or Arg), histidine (H or His), aspartic acid (D or Asp), glutamic acid (E or Glu), asparagine (N or Asn), glutamine (Q or Gln), cysteine ​​(C or Cys), methionine (M or Met), serine (S or Ser), and threonine (T or Thr). If the residue is likely to be aspartic acid or asparagine, the symbols Asx or B may be used. If the residue is likely to be glutamic acid or glutamine, the symbols Glx or Z may be used. Unless the context dictates otherwise, reference to aspartic acid includes aspartate and reference to glutamic acid includes glutamate.

[0262] Amino acid deletions or insertions can also be made relative to the amino acid sequence of the fusion protein described below. Thus, for example, amino acids that have no substantial effect on the activity of the polypeptide, or at least that do not eliminate such activity, can be deleted. Such deletions can be advantageous because the overall length and molecular weight of the polypeptide can be reduced while still maintaining activity. This can reduce the amount of polypeptide required for a particular application, for example, by reducing dosage levels.

[0263] In some embodiments, the following amino acids can be exchanged with each other to make conservative amino acid substitutions:

[0264] Classification Exchangeable amino acids Fatty Acids Glycine, alanine, valine, leucine, isoleucine Hydroxyl or sulfur / selenium Serine, cysteine, threonine, methionine Aromatic Phenylalanine, tyrosine, tryptophan Alkaline Histidine, lysine, arginine Acid and its amide Aspartate, glutamate, asparagine, glutamine

[0265] 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., in a CDR or in a VH or VL sequence) are replaced with another amino acid from the same class as described above. Conservative amino acid substitutions may preferably be made in the CDR region to minimize adverse effects on antibody function. However, conservative amino acid substitutions may also occur in the framework region.

[0266] Amino acid changes relative to the sequences given below can be made using any suitable technique, for example by site-directed mutagenesis or solid-state synthesis.

[0267] It should be understood that amino acid substitutions or insertions within the scope of the present invention can be performed using naturally occurring or non-naturally occurring amino acids, although naturally occurring amino acids may be preferred. Regardless of whether natural or synthetic amino acids are used, it may be preferred that only L-amino acids are present.

[0268] In one embodiment of the present invention, provided are antigen-binding molecules of the present invention or antigen-binding fragments thereof, comprising 1 to 10, preferably 1 to 5, amino acid substitutions in the antibody-binding domain or antigen-binding domain. For example, in one embodiment of the present invention, an anti-BDCA-2 (CLEC4C) antibody or an antigen-binding fragment thereof is provided, wherein the anti-BDCA-2 (CLEC4C) antibody or antigen-binding fragment thereof comprises six CDR regions of an antibody selected from the group consisting of 3E05_var12, 3E05_var6, 3E05_var14, 3E05, 3E05_var1, 3E05_var2, 3E05_var3, 3E05_var4, 3E05_var5, 3E05_var7, 3E05_var8, 3E05_var9, 3E05_var10, 3E05_var11, 3E05_var13, 3E05_var15, 3E05_var16, 21E06, 25E06, and 28B01, wherein the antigen-binding molecule has 1 to 10 amino acid substitutions, preferably 1 to 5 amino acid substitutions, in all of its CDR regions. In another embodiment of the present invention, an anti-BDCA-2 (CLEC4C) antigen-binding molecule or an antigen-binding fragment thereof is provided, wherein the anti-BDCA-2 (CLEC4C) antibody or antigen-binding fragment thereof comprises the VH and VL sequences of an antibody selected from the group consisting of 3E05_var12, 3E05_var6, 3E05_var14, 3E05, 3E05_var1, 3E05_var2, 3E05_var3, 3E05_var4, 3E05_var5, 3E05_var7, 3E05_var8, 3E05_var9, 3E05_var10, 3E05_var11, 3E05_var13, 3E05_var15, 3E05_var16, 21E06, 25E06, and 28B01, wherein the antigen-binding molecule has 1 to 10 amino acid substitutions, preferably 1 to 5 amino acid substitutions, in its VH and VL sequences.In another embodiment of the present invention, an anti-BDCA-2 (CLEC4C) antibody is provided, wherein the anti-BDCA-2 (CLEC4C) antibody is an antibody selected from the group consisting of 3E05_var12, 3E05_var6, 3E05_var14, 3E05, 3E05_var1, 3E05_var2, 3E05_var3, 3E05_var4, 3E05_var5, 3E05_var7, 3E05_var8, 3E05_var9, 3E05_var10, 3E05_var11, 3E05_var13, 3E05_var15, 3E05_var16, 21E06, 25E06, and 28B01, wherein the antibody has 1 to 10 amino acid substitutions, preferably 1 to 5 amino acid substitutions. The substitutions are of course with respect to the original CDR or variable chain sequences of the starting antibody.

[0269] In some embodiments, one or more amino acid substitutions are located in one or more CDR regions. In other embodiments, one or more amino acid substitutions are located in the framework regions, i.e., in the variable heavy and light chains, but not in one or more CDR regions. In other embodiments, one or more amino acid substitutions may be located anywhere in the heavy chain variable region and / or the light chain variable region. In some embodiments, the amino acid substitutions do not occur in the CDR sequences.

[0270] In some embodiments, the amino acid substitution does not adversely affect the binding specificity and / or affinity of the antibody.Thus, the variant antibody may have the same or better functional properties as the antibody from which the variant antibody was derived.

[0271] affinity matured variants

[0272] Other variants within the scope of the present invention include antigen-binding molecules of the invention that have been modified to increase affinity for BDCA-2 (CLEC4C). In one embodiment, the antigen-binding molecules of the invention are affinity-matured antibodies. In one embodiment, the antigen-binding molecules of the invention are humanized affinity-matured antibodies.

[0273] Any known method can be used to increase the affinity of the antigen-binding molecules of the present invention to produce affinity-matured antibodies or humanized affinity-matured antibodies with enhanced affinity for BDCA-2 (CLEC4C).

[0274] The present invention provides affinity matured variants of the provided antigen-binding agents. The affinity matured variants have a higher binding affinity for BDCA-2 (CLEC4C) than the parent antibody. Preferably, the resulting antibody has a binding affinity for BDCA-2 (CLEC4C) that is at least 20%, at least 30%, at least 40%, and more preferably at least 50% higher than the binding affinity of the parent antibody for BDCA-2 (CLEC4C), for example, as measured by Kd.

[0275] In some embodiments, the present invention provides a method for preparing an antigen-binding molecule of the present invention, comprising providing an antigen-binding molecule as 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 a greater affinity than the parent antibody. Preferably, the resulting antibody binds to BDCA-2 (CLEC4C) with an affinity that is at least 20%, at least 30%, at least 40%, and more preferably at least 50% greater than the binding affinity of the parent antibody 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.

[0276] Affinity maturation can be carried out according to any suitable method known to the skilled person.For example, in vitro antibody display system is widely used in producing the specific antibody with high affinity.In these systems, phenotype (i.e. antibody fragment) is combined with genotype (i.e. antibody gene), thereby allows directly measuring antibody sequence. Developed several systems to realize the display of antibody library, to allow to select binding substances subsequently, and by increasing the stringency of selection, allow to select variants with higher and higher affinity. Antibody fragment can be expressed in yeast, ribosome, phage display particles, or by directly being combined with DNA to express.

[0277] Current antibody affinity maturation methods fall into two categories of mutagenesis: random and non-random. Error-prone polymerase chain reaction (PCR), mutant strains, and saturation mutagenesis are typical examples of random mutagenesis methods. Non-random techniques typically use alanine scanning or site-directed mutagenesis to generate a limited set of specific variants. In addition, shuffling methods to obtain mixed variants of the parent antibody can also be used to further improve the affinity of the antibody.

[0278] Thus, in one embodiment of the invention, the affinity maturation method is selected from the group consisting of random mutagenesis (e.g., error-prone polymerase chain reaction (PCR), mutant strains, or saturation mutagenesis), non-random mutagenesis (e.g., alanine scanning or site-directed mutagenesis), shuffling (e.g., DNA shuffling, chain shuffling, or CDR shuffling), and introduction of modifications using the CRISPR-Cas9 system.

[0279] 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 (pp. 115-140).

[0280] In some embodiments, a method for preparing a pharmaceutical composition is provided, the method comprising providing an antibody prepared according to the above method (i.e., generating 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, 3E05_var13, 3E05_var15, or 3E05_var16. The pharmaceutical compositions produced by such methods can be used in the therapeutic methods of the invention as described herein for other anti-BDCA-2 (CLEC4C) binding molecules.

[0281] Thus, provided are antigen-binding molecules that are affinity-matured mutants or variants of the antigen-binding molecules of the present invention. For example, in one embodiment, provided are affinity-matured variants 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. Generally, the affinity-matured mutants have a higher affinity for BDCA-2 (CLEC4C), particularly human BDCA-2 (CLEC4C), than the parent antibody (the antibody from which the mutant was 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.

[0282] Other variants

[0283] The antigen binding molecules of the present invention are typically antibodies, more typically monoclonal antibodies. In a preferred embodiment, 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.

[0284] Methods for producing monoclonal antibodies are well known to those skilled in the art, as described, for example, in Frenzel et al., “Expression of Recombinant Antibodies”, Front Immunol, 2013, 4:217, the contents of which are incorporated herein by reference.

[0285] The monoclonal antibodies of the present invention can be humanized by modifying the amino acid sequence of the antibody. Methods for reducing the immunogenicity of the antigen-binding molecules of the present invention include transplanting the CDRs to a suitable antibody framework scaffold or remodeling the variable surface residues, for example, by site-directed mutagenesis or other commonly used molecular biology techniques (Roguska et al Protein Eng. 9895-904 (1996)).

[0286] Other applicable methods can include potential T cell epitopes in the identification molecule, and then for example, these epitopes are removed subsequently by site-directed mutagenesis (deimmunization). In the case where antigen binding molecules are used as therapeutic agents, it may be necessary to carry out humanization of antigen binding molecules. Humanization of CDR regions or surrounding framework sequences can be carried out as required.

[0287] Monoclonal and other antibodies can be used to produce additional antibodies or chimeric molecules that retain the specificity of the original antibody using recombinant DNA technology. Such technology may involve introducing DNA encoding the immunoglobulin variable region or complementarity determining region (CDR) of an antibody into the constant region or constant region plus framework region of a different immunoglobulin. Hybridomas or other antibody-producing cells may undergo genetic mutations or other changes that may or may not alter the binding specificity of the produced antibody.

[0288] 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 conservatively humanized, for example, to retain better antigen binding. In such conservative humanized antibodies, fewer antibody substitutions can be made compared to humanized antibodies.

[0289] In some embodiments, the antigen binding molecules of the invention are deimmunized, for example using the method described in Jones et al., "Deimmunization of monoclonal antibodies", Methods Mol Biol, 2009, 525: 405-23, the contents of which are incorporated herein by reference. Deimmunization uses a combination of immunological and molecular biological techniques to remove T cell epitopes from a sequence.

[0290] Thus, in some embodiments of the present invention, a deimmunized anti-BDCA-2 (CLEC4C) antigen binding molecule or antigen-binding fragment thereof is provided, wherein the anti-BDCA-2 (CLEC4C) antigen binding molecule or antigen-binding fragment thereof comprises a deimmunized variant of six CDR regions of an antibody selected from the group consisting of 3E05_var12, 3E05_var6, 3E05_var14, 3E05, 3E05_var1, 3E05_var2, 3E05_var3, 3E05_var4, 3E05_var5, 3E05_var7, 3E05_var8, 3E05_var9, 3E05_var10, 3E05_var11, 3E05_var13, 3E05_var15, 3E05_var16, 21E06, 25E06, and 28B01. In another embodiment of the present invention, a deimmunized anti-BDCA-2 (CLEC4C) antigen binding molecule or antigen-binding fragment thereof is provided, wherein the anti-BDCA-2 (CLEC4C) antigen binding molecule or antigen-binding fragment thereof comprises a deimmunized variant of the VH and / or VL sequence of an antibody selected from the group consisting of 3E05_var12, 3E05_var6, 3E05_var14, 3E05, 3E05_var1, 3E05_var2, 3E05_var3, 3E05_var4, 3E05_var5, 3E05_var7, 3E05_var8, 3E05_var9, 3E05_var10, 3E05_var11, 3E05_var13, 3E05_var15, 3E05_var16, 21E06, 25E06, and 28B01. In another embodiment of the present invention, a deimmunized anti-BDCA-2 (CLEC4C) antibody is provided, wherein the anti-BDCA-2 (CLEC4C) antibody is an antibody selected from the group consisting of 3E05_var12, 3E05_var6, 3E05_var14, 3E05, 3E05_var1, 3E05_var2, 3E05_var3, 3E05_var4, 3E05_var5, 3E05_var7, 3E05_var8, 3E05_var9, 3E05_var10, 3E05_var11, 3E05_var13, 3E05_var15, 3E05_var16, 21E06, 25E06 and 28B01.

[0291] The antigen binding molecules and antigen binding fragments thereof are based on 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 preferred embodiments, the present invention particularly relates to humanized and deimmunized derivatives of 3E05, including 3E05_var12, 3E05_var6, and 3E05_var14. However, humanized and deimmunized derivatives of the remaining three parent antibodies are also provided. The present invention is also based on antibody fragments comprising one or more antigen-binding domains from a parent or humanized / deimmunized antibody of the present invention, as well as additional variants, such as antigen-binding domains of the antigen-binding molecules of the present invention comprising one or more conservative amino acid substitutions (e.g., 1 to 10 substitutions, or preferably 1 to 5 substitutions) and affinity-matured variants. All antigen-binding molecules of the present invention specifically bind to BDCA-2 (CLEC4C).

[0292] Humanized and deimmunized variants of the antibodies provided herein can have at least 90% sequence identity, such as at least 95% sequence identity, to the original parent sequence from which they were humanized or deimmunized.

[0293] Antigen binding molecules of the present invention, particularly antibodies, can be of any suitable type, including IgA, IgD, IgE, IgG, IgM, and IgY, although IgG may be preferred. The IgG1 backbone may be most preferred. In a related embodiment, the constant region of the antibodies of the present invention can be modified to obtain beneficial effects, such as increasing stability and reducing Fcγ receptor interactions. Such modifications include S241P and L248E substitutions in the Fc region. Other suitable modifications are known to those skilled in the art.

[0294] "Specifically binds," "specifically binds," and "specific binding" are understood to mean that an anti-BDCA-2 (CLEC4C) antigen binding molecule has less than about 10 -6 M, 10 -7 M, 10 -8 M, 10 -9 M, 10 -10 M, 10 -11 M or 10 -12 The dissociation constant (K d In a preferred embodiment, the dissociation constant is less than 10 -8 M, for example, in 10 -9 M, 10 - 10 M, 10 -11 M or 10 -12 According to some embodiments of the present invention, "specific binding", "specifically binds" and "specific binding" may refer to affinity and / or activity. In some embodiments, the affinity of the anti-BDCA-2 (CLEC4C) antigen binding molecule is 10 -8 M to 10 -6 M (e.g. about 10 -7 In some embodiments of the invention, the anti-BDCA-2 (CLEC4C) antigen binding molecule has an avidity of about 10 -10 M to 10 -8 M (e.g. about 10 -9 In some embodiments of the invention, the affinity and / or activity of the anti-BDCA-2 (CLEC4C) antigen binding molecule is about 1 nM to 700 nM, or about 1 to 600 nM, or about 1 to 500 nM, or about 1 to 400 nM, or about 1 to 300 nM.

[0295] Creating instability

[0296] Therapeutic proteins such as antibodies are inherently heterogeneous and complex due to chemical modifications and post-translational modifications (PTMs). Modifications can be caused by many factors, such as the host cell system, the processes used in manufacturing, or the conditions during storage or manufacturing. Modifications may involve the chemical stability or aggregation potential of the molecule itself and the impact this has on the intrinsic physical stability of the antibody. The spontaneous modification of amino acid motifs or residues in a given antibody sequence during manufacturing or storage may occur is called instability. Therefore, the antibody sequence can be mutated to address instability, thereby reducing the susceptibility of the antibody to modification and degradation.

[0297] Such modifications, which arise due to instability in the antibody sequence, may include glycosylation, deamidation, oxidation, and changes in the C- and N-termini. Such modifications may occur during the manufacturing process. Certain residues and structural or sequence motifs are more susceptible to certain modifications. Examples of such modifications that may contribute to instability include Asn N-linked glycosylation, Ser / Thr O-linked glycosylation, Asn deamidation, Asp isomerization / fragmentation, Lys glycosylation, Met / Trp oxidation, free thiol groups, pyroglutamate, and C-terminal Lys.

[0298] Those skilled in the art are aware that computational tools can be used to predict and identify structural and sequence instabilities that could potentially lead to modifications. To minimize the occurrence of modifications, changes can be made to the manufacturing process. Protein engineering is also being considered to mitigate risk. For example, selective mutagenesis of these destabilizing factors can help identify and mitigate the risk of modifications that compromise antibody stability.

[0299] Aspartic acid residues (Asp) may undergo spontaneous modification. Aspartic acid-containing motifs, such as Asp-Gly sequences, may undergo spontaneous isomerization to form isoaspartic acid. The formation of isoaspartate salts may weaken or completely eliminate antibody binding. This is particularly important if the Asp residue is present in the CDRs of the antibody.

[0300] In another embodiment, the present invention provides the amino acid residue of the present invention.Therefore, aspartic acid residue (Asp) can be replaced by any naturally occurring amino acid to reduce the instability that can cause modification.Alternatively, aspartic acid residue (Asp) can be replaced by alanine (Ala), glutamine (Gln) or glutamic acid (Glu) to reduce the instability that can cause modification.Can also study the optimization of production / preparation to reduce isomerization.As an alternative, the Asp-Gly motif can be modified by replacing the glycine residue with another naturally occurring amino acid to suppress deamidation rather than by replacing the Asp residue.

[0301] Methionine residues (Met) may undergo spontaneous modification. The presence of Met in CDRs, especially when exposed to solvents, may cause problems if the Met is oxidized and interferes with binding. Therefore, the Met residue can be replaced by any other naturally occurring amino acid to reduce the instability that can lead to modification. The Met residue can preferably be replaced with Ala or Leu. Optimization of production / formulation can also be studied to reduce oxidation.

[0302] 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 comprising one or more amino acid substitutions to address one or more of any potential instabilities as described above.

[0303] For example, for any antigen binding molecules defined herein by one or more amino acid sequences, if there are one or more Met residues, then one or more Met residues can be replaced by Ala residues or Leu residues independently of one another.If there are one or more Asp residues, then one or more Asp residues can be replaced by Ala residues, Gln residues or Glu residues independently of one another.

[0304] Provides an overview of antigen-binding molecules

[0305] The following provides an overview of the antigen binding molecules provided by the present invention, wherein the designated SEQ ID NO. is identified in the accompanying sequence listing. Antigen binding variants, derivatives and fragments thereof are also provided as part of the present invention:

[0306] Table 1. Overview of the parental mouse antibody and conservatively humanized, humanized, and deimmunized versions of the two parental antibodies

[0307]

[0308] Table 2 - Combinations of humanized / deimmunized heavy and light chain variable regions generated 16 antibodies derived from the 3E05 parent antibody

[0309]

[0310]

[0311] Various embodiments of the present invention will now be discussed in greater detail.

[0312] Antigen binding molecules comprising VHCDR3 and / or VLCDR3 regions

[0313] In one embodiment, an antibody, fragment or variant thereof is provided, comprising: 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; and / or 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. Certain amino acids may be substituted to provide one or more variant antibodies as described herein.

[0314] 3E05

[0315] 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 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 8); and / or a light chain variable region comprising an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 4). In one embodiment, an antigen binding molecule is provided, such as an antibody, fragment or variant thereof, comprising: a heavy chain variable region comprising an amino acid sequence that is at least 90% identical to the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 8); and / or a light chain variable region comprising an amino acid sequence that is at least 90% identical to the amino acid sequence QQTNEDPPT (SEQ ID NO: 4).

[0316] In one embodiment, an antigen-binding molecule is provided, such as an antibody, fragment or variant thereof, 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).

[0317] Amino acid substitutions can be made to provide variant antibodies derived from 3E05, for example, an antibody, fragment, or variant thereof comprising: a heavy chain variable region comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 8), optionally comprising 1 or 2 amino acid substitutions; and / or a light chain variable region comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 4), optionally comprising 1 or 2 amino acid substitutions. The amino acid substitutions can be conservative amino acid substitutions.

[0318] In one embodiment, the antigen binding molecule is an antibody or 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 the Met residues are each independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or the Asp residues are each independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0319] 3E05_var1, 5, 9, and 13

[0320] 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 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 18); and / or a light chain variable region comprising an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 14). In one embodiment, the heavy chain variable region comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 18) and / or the light chain variable region comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 14).

[0321] 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, fragment or variant thereof is HDYYDGGLYYAMDY (SEQ ID NO: 18) and / or the VLCDR3 region of the antibody, fragment or variant thereof is QQTNEDPPT (SEQ ID NO: 14).

[0322] Amino acid substitutions can be made to provide variant antibodies derived from 3E05 var 1, 5, 9, or 13, for example, to provide an antibody, fragment, or variant thereof comprising: a heavy chain variable region comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18), optionally comprising 1 or 2 amino acid substitutions; and / or a light chain variable region comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14), optionally comprising 1 or 2 amino acid substitutions. The amino acid substitutions can be conservative amino acid substitutions.

[0323] In one embodiment, the antigen binding molecule is an antibody or fragment or variant thereof, 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), optionally wherein the Met residues are each independently replaced by an amino acid selected from the group consisting of Ala and Leu and / or the Asp residues are each independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0324] 3E05_var2, 6, 10, and 14

[0325] 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 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 28); and / or a light chain variable region comprising an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 14). In one embodiment, the heavy chain variable region comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 28) and / or the light chain variable region comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 14).

[0326] 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, fragment or variant thereof is HDYYDGGLYYAMDY (SEQ ID NO: 28) and / or the VLCDR3 region of the antibody, fragment or variant thereof is QQTNEDPPT (SEQ ID NO: 14).

[0327] Amino acid substitutions can be made to provide variant antibodies derived from 3E05 var 2, 6, 10, or 14, for example, an antibody, fragment, or variant thereof comprising: a heavy chain variable region comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28), optionally comprising 1 or 2 amino acid substitutions; and / or a light chain variable region comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14), optionally comprising 1 or 2 amino acid substitutions. The amino acid substitutions can be conservative amino acid substitutions.

[0328] 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 1 or 2 amino acid substitutions, and / or a light chain variable region comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14), optionally wherein the Met residues are each independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or the Asp residues are each independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0329] 3E05_var3, 7, 11, and 15

[0330] 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 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 38); and / or a light chain variable region comprising an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 14). In one embodiment, the heavy chain variable region comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 38) and / or the light chain variable region comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 14).

[0331] 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 VHCDR3 region of the antibody, fragment or variant thereof is HDYYDGGLYYAMDY (SEQ ID NO: 38) and / or the VLCDR3 region of the antibody, fragment or variant thereof is QQTNEDPPT (SEQ ID NO: 14).

[0332] Amino acid substitutions can be made to provide variant antibodies derived from 3E05 var 3, 7, 11, or 15, for example, an antibody, fragment, or variant thereof comprising: a heavy chain variable region comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38), optionally comprising 1 or 2 amino acid substitutions; and / or a light chain variable region comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14), optionally comprising 1 or 2 amino acid substitutions. The amino acid substitutions can be conservative amino acid substitutions.

[0333] 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 1 or 2 amino acid substitutions, and / or a light chain variable region comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14), optionally wherein the Met residues are each independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or the Asp residues are each independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0334] 3E05_var4, 8, 12, and 16

[0335] 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 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of HDYYEGGLYYAMDY (SEQ ID NO: 48); and / or a light chain variable region comprising an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 14). In one embodiment, the heavy chain variable region comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of HDYYEGGLYYAMDY (SEQ ID NO: 48) and / or the light chain variable region comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 14).

[0336] 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 VHCDR3 region of the antibody, fragment or variant thereof is HDYYEGGLYYAMDY (SEQ ID NO: 48) and / or the VLCDR3 region of the antibody, fragment or variant thereof is QQTNEDPPT (SEQ ID NO: 14).

[0337] Amino acid substitutions can be made to provide variant antibodies derived from 3E05 var 4, 8, 12, or 16, for example, an antibody, fragment, or variant thereof comprising: a heavy chain variable region comprising the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48), optionally comprising 1 or 2 amino acid substitutions; and / or a light chain variable region comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14), optionally comprising 1 or 2 amino acid substitutions. The amino acid substitutions can be conservative amino acid substitutions.

[0338] In one embodiment, the antigen binding molecule is an antibody or 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 the Met residues are each independently replaced by an amino acid selected from the group consisting of Ala and Leu and / or the Asp residues are each independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0339] 21E06

[0340] 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 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of HLYYGDYFYVMDY (SEQ ID NO: 58); and / or a light chain variable region comprising an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of QQSNEDPPT (SEQ ID NO: 54). In one embodiment, an antigen binding molecule is provided, such as an antibody, fragment or variant thereof, comprising: a heavy chain variable region comprising an amino acid sequence that is at least 90% identical to the amino acid sequence HLYYGDYFYVMDY (SEQ ID NO: 58); and / or a light chain variable region comprising an amino acid sequence that is at least 90% identical to the amino acid sequence QQSNEDPPT (SEQ ID NO: 54).

[0341] In one embodiment, an antigen-binding molecule is provided, such as an antibody, fragment or variant thereof, comprising: a heavy chain variable region comprising the amino acid sequence HLYYGDYFYVMDY (SEQ ID NO: 58); and / or a light chain variable region comprising the amino acid sequence QQSNEDPPT (SEQ ID NO: 54). In a specific embodiment, the antigen-binding molecule is an antibody or a fragment 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).

[0342] Amino acid substitutions can be made to provide variant antibodies derived from 21E06, for example, an antibody, fragment, or variant thereof comprising: a heavy chain variable region comprising the amino acid sequence HLYYGDYFYVMDY (SEQ ID NO: 58), optionally comprising 1 or 2 amino acid substitutions; and / or a light chain variable region comprising the amino acid sequence QQSNEDPPT (SEQ ID NO: 54), optionally comprising 1 or 2 amino acid substitutions. The amino acid substitutions can be conservative amino acid substitutions.

[0343] In one embodiment, the antigen binding molecule is an antibody or 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 the Met residues are each independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or the Asp residues are each independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0344] 25E06

[0345] 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 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence HHYSHYFWYFDV (SEQ ID NO: 68); and / or a light chain variable region comprising an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence QQSNEDPPT (SEQ ID NO: 64). 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 that is at least 90% identical to the amino acid sequence HHYSHYFWYFDV (SEQ ID NO: 68); and / or a light chain variable region comprising an amino acid sequence that is at least 90% identical to the amino acid sequence QQSNEDPPT (SEQ ID NO: 64).

[0346] In one embodiment, an antigen-binding molecule is provided, such as an antibody, fragment or variant thereof, comprising: a heavy chain variable region comprising the amino acid sequence HHYSHYFWYFDV (SEQ ID NO: 68); and / or a light chain variable region comprising the amino acid sequence QQSNEDPPT (SEQ ID NO: 64). In a specific embodiment, the antigen-binding molecule is an antibody or a fragment 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).

[0347] Amino acid substitutions can be made to provide variant antibodies derived from 25E06, for example, an antibody, fragment, or variant thereof comprising: a heavy chain variable region comprising the amino acid sequence HHYSHYFWYFDV (SEQ ID NO: 68), optionally comprising one or two amino acid substitutions; and / or a light chain variable region comprising the amino acid sequence QQSNEDPPT (SEQ ID NO: 64), optionally comprising one or two amino acid substitutions. The amino acid substitutions can be conservative amino acid substitutions.

[0348] In one embodiment, the antigen binding molecule is an antibody or 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 the Met residues are each independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or the Asp residues are each independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0349] 28B01

[0350] 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 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence HHYSNYFWYFDV (SEQ ID NO: 78); and / or a light chain variable region comprising an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence QQSNEDPPT (SEQ ID NO: 74). In one embodiment, an antigen binding molecule is provided, such as an antibody, fragment or variant thereof, comprising: a heavy chain variable region comprising an amino acid sequence that is at least 90% identical to the amino acid sequence HHYSNYFWYFDV (SEQ ID NO: 78); and / or a light chain variable region comprising an amino acid sequence that is at least 90% identical to the amino acid sequence QQSNEDPPT (SEQ ID NO: 74).

[0351] In one embodiment, an antigen-binding molecule is provided, such as an antibody, fragment or variant thereof, comprising: a heavy chain variable region comprising the amino acid sequence HHYSNYFWYFDV (SEQ ID NO: 78); and / or a light chain variable region comprising the amino acid sequence QQSNEDPPT (SEQ ID NO: 74). In a specific embodiment, the antigen-binding molecule is an antibody or a fragment 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).

[0352] Amino acid substitutions can be made to provide variant antibodies derived from 28B01, for example, to provide an antibody, fragment, or variant thereof comprising: a heavy chain variable region comprising the amino acid sequence HHYSNYFWYFDV (SEQ ID NO: 78), optionally comprising 1 or 2 amino acid substitutions; and / or a light chain variable region comprising the amino acid sequence QQSNEDPPT (SEQ ID NO: 74), optionally comprising 1 or 2 amino acid substitutions. The amino acid substitutions can be conservative amino acid substitutions.

[0353] In one embodiment, the antigen binding molecule is an antibody or 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 the Met residues are each independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or the Asp residues are each independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0354] Heavy chain and / or light chain CDRs

[0355] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0356] A heavy chain variable region, the heavy chain variable region comprising:

[0357] VHCDR1, the VHCDR1 comprises a VHCDR1 selected from the group consisting of SEQ ID NO: 46, 49, 26, 29, 6, 9, 16, 19,

[0358] amino acid sequences from the group consisting of 36, 39, 56, 59, 66, 69, 76, and 79;

[0359] VHCDR2, the VHCDR2 comprises a VHCDR2 selected from SEQ ID NO: 47, 50, 27, 30, 7, 10, 17, 20,

[0360] The amino acid sequence of the group consisting of 37, 40, 57, 60, 67, 70, 77 and 80; and

[0361] 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; and

[0362] A light chain variable region, the light chain variable region comprising:

[0363] VLCDR1 comprising a VLCDR1 selected from the group consisting of SEQ ID NOs: 32, 22, 42, 2, 12, 52, 62, and 72

[0364] The amino acid sequence of the group consisting of;

[0365] VLCDR2 comprising a VLCDR2 selected from the group consisting of SEQ ID NOs: 33, 23, 43, 3, 13, 53, 63, and 73

[0366] The amino acid sequence of the group consisting of:

[0367] VLCDR3 comprising a member selected from the group consisting of SEQ ID NOs: 34, 24, 44, 4, 14, 54, 64, and 74

[0368] The amino acid sequence of the group consisting of.

[0369] Certain amino acid substitutions may be made to provide one or more variant antibodies as described herein.

[0370] 3E05

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

[0372] A heavy chain variable region comprising a VHCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SYTMS (SEQ ID NO: 6), a VHCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of YISSGGGNTYYPDSVKG (SEQ ID NO: 7), and a VHCDR3 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: NO:8) comprises a VHCDR3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical; and / or

[0373] A light chain variable region comprising a VLCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of KASQSVDYDGDSSMN (SEQ ID NO: 2), a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of AASTLES (SEQ ID NO: 3), and a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: NO:4) comprises a VLC R3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical.

[0374] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0375] A heavy chain variable region comprising a VHCDR1 that comprises at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of GFTFSSY (SEQ ID NO: 9), a VHCDR2 that comprises at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SSGGGNTY (SEQ ID NO: 10), and a VHCDR3 that comprises at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 11). NO:8) comprises a VHCDR3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical; and / or

[0376] A light chain variable region comprising a VLCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of KASQSVDYDGDSSMN (SEQ ID NO: 2), a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of AASTLES (SEQ ID NO: 3), and a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: NO:4) comprises a VLC R3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical.

[0377] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0378] a heavy chain variable region comprising a VHCDR1 comprising at least 90% identity to the amino acid sequence of SYTMS (SEQ ID NO: 6), a VHCDR2 comprising at least 90% identity to the amino acid sequence of YISSGGGNTYYPDSVKG (SEQ ID NO: 7), and a VHCDR3 comprising at least 90% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 8); and / or

[0379] A light chain variable region comprising a VLCDR1 comprising at least 90% identity to the amino acid sequence of KASQSVDYDGDSSMN (SEQ ID NO: 2), a VLCDR2 comprising at least 90% identity to the amino acid sequence of AASTLES (SEQ ID NO: 3), and a VLCDR3 comprising at least 90% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 4).

[0380] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0381] a heavy chain variable region comprising a VHCDR1 comprising at least 90% identity to the amino acid sequence of GFTFSSY (SEQ ID NO: 9), a VHCDR2 comprising at least 90% identity to the amino acid sequence of SSGGGNTY (SEQ ID NO: 10), and a VHCDR3 comprising at least 90% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 8); and / or

[0382] A light chain variable region comprising a VLCDR1 comprising at least 90% identity to the amino acid sequence of KASQSVDYDGDSSMN (SEQ ID NO: 2), a VLCDR2 comprising at least 90% identity to the amino acid sequence of AASTLES (SEQ ID NO: 3), and a VLCDR3 comprising at least 90% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 4).

[0383] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0384] a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SYTMS (SEQ ID NO: 6), a VHCDR2 comprising the amino acid sequence of YISSGGGNTYYPDSVKG (SEQ ID NO: 7), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 8); and

[0385] The light chain variable region comprises a VLCDR1 comprising the amino acid sequence of KASQSVDYDGDSSMN (SEQ ID NO: 2), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 3), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 4).

[0386] Amino acid substitutions can be made to provide variant antibodies derived from 3E05, for example to provide an antibody, fragment or variant thereof comprising:

[0387] a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 6) optionally comprising 1 or 2 amino acid substitutions, a VHCDR2 comprising the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 7) optionally comprising 1 or 2 amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 8) optionally comprising 1 or 2 amino acid substitutions; and / or

[0388] A light chain variable region comprising: a VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 2), optionally comprising 1 or 2 amino acid substitutions; a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 3), optionally comprising 1 or 2 amino acid substitutions; and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 4), optionally comprising 1 or 2 amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0389] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0390] a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SYTMS (SEQ ID NO: 6), a VHCDR2 comprising the amino acid sequence of YISSGGGNTYYPDSVKG (SEQ ID NO: 7), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 8); and

[0391] a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of KASQSVDYDGDSSMN (SEQ ID NO: 2), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 3), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 4);

[0392] Optionally, wherein the Met residues are each independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or the Asp residues are each independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

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

[0394] a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 9), a VHCDR2 comprising the amino acid sequence of SSGGGNTY (SEQ ID NO: 10), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 8); and

[0395] The light chain variable region comprises a VLCDR1 comprising the amino acid sequence of KASQSVDYDGDSSMN (SEQ ID NO: 2), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 3), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 4).

[0396] Amino acid substitutions can be made to provide variant antibodies derived from 3E05, for example to provide an antibody, fragment or variant thereof comprising:

[0397] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 9) optionally comprising 1 or 2 amino acid substitutions, a VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 10) optionally comprising 1 or 2 amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 8) optionally comprising 1 or 2 amino acid substitutions; and / or

[0398] A light chain variable region comprising: a VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 2) optionally comprising one or two amino acid substitutions, a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 3) optionally comprising one or two amino acid substitutions, and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 4) optionally comprising one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

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

[0400] a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 9), a VHCDR2 comprising the amino acid sequence of SSGGGNTY (SEQ ID NO: 10), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 8); and

[0401] a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of KASQSVDYDGDSSMN (SEQ ID NO: 2), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 3), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 4);

[0402] Optionally, wherein the Met residues are each independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or the Asp residues are each independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0403] 3E05_var12

[0404] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0405] A heavy chain variable region comprising a VHCDR1 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SYTMS (SEQ ID NO: 46); a VHCDR2 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of YISSGGGQTYYPDSVKG (SEQ ID NO: 47); and a VHCDR3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of HDYYEGGLYYAMDY (SEQ ID NO: NO:48) comprises a VHCDR3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical; and / or

[0406] A light chain variable region comprising a VLCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of AASTLES (SEQ ID NO: 33), and a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: NO:34) comprises a VLC R3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical.

[0407] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0408] A heavy chain variable region comprising a VHCDR1 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of GFTFSSY (SEQ ID NO: 49), a VHCDR2 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SSGGGQTY (SEQ ID NO: 50), and a VHCDR3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of HDYYEGGLYYAMDY (SEQ ID NO: NO:48) comprises a VHCDR3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical; and / or

[0409] A light chain variable region comprising a VLCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of AASTLES (SEQ ID NO: 33), and a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: NO:34) comprises a VLC R3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical.

[0410] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0411] a heavy chain variable region comprising a VHCDR1 comprising at least 90% identity to the amino acid sequence of SYTMS (SEQ ID NO: 46), a VHCDR2 comprising at least 90% identity to the amino acid sequence of YISSGGGQTYYPDSVKG (SEQ ID NO: 47), and a VHCDR3 comprising at least 90% identity to the amino acid sequence of HDYYEGGLYYAMDY (SEQ ID NO: 48); and / or

[0412] A light chain variable region comprising a VLCDR1 comprising at least 90% identity to the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising at least 90% identity to the amino acid sequence of AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising at least 90% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 34).

[0413] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0414] a heavy chain variable region comprising a VHCDR1 comprising at least 90% identity to the amino acid sequence of GFTFSSY (SEQ ID NO: 49), a VHCDR2 comprising at least 90% identity to the amino acid sequence of SSGGGQTY (SEQ ID NO: 50), and a VHCDR3 comprising at least 90% identity to the amino acid sequence of HDYYEGGLYYAMDY (SEQ ID NO: 48); and / or

[0415] A light chain variable region comprising a VLCDR1 comprising at least 90% identity to the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising at least 90% identity to the amino acid sequence of AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising at least 90% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 34).

[0416] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0417] a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SYTMS (SEQ ID NO: 46), a VHCDR2 comprising the amino acid sequence of YISSGGGQTYYPDSVKG (SEQ ID NO: 47), and a VHCDR3 comprising the amino acid sequence of HDYYEGGLYYAMDY (SEQ ID NO: 48); and

[0418] The light chain variable region comprises a VLCDR1 comprising the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 34).

[0419] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var12, for example to provide an antibody, fragment or variant thereof comprising:

[0420] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 46) optionally comprising 1 or 2 amino acid substitutions, a VHCDR2 comprising the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 47) optionally comprising 1 or 2 amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48) optionally comprising 1 or 2 amino acid substitutions; and / or

[0421] A light chain variable region comprising: a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), optionally comprising 1 or 2 amino acid substitutions; a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33), optionally comprising 1 or 2 amino acid substitutions; and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34), optionally comprising 1 or 2 amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0422] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0423] a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SYTMS (SEQ ID NO: 46), a VHCDR2 comprising the amino acid sequence of YISSGGGQTYYPDSVKG (SEQ ID NO: 47), and a VHCDR3 comprising the amino acid sequence of HDYYEGGLYYAMDY (SEQ ID NO: 48); and

[0424] a light chain variable region comprising a VLCDR1 comprising the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 34);

[0425] Optionally, wherein the Met residues are each independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or the Asp residues are each independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0426] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0427] a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 49), a VHCDR2 comprising the amino acid sequence of SSGGGQTY (SEQ ID NO: 50), and a VHCDR3 comprising the amino acid sequence of HDYYEGGLYYAMDY (SEQ ID NO: 48); and

[0428] The light chain variable region comprises a VLCDR1 comprising the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 34).

[0429] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var12, for example to provide an antibody, fragment or variant thereof comprising:

[0430] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 49) optionally comprising 1 or 2 amino acid substitutions, a VHCDR2 comprising the amino acid sequence SSGGGQTY (SEQ ID NO: 50) optionally comprising 1 or 2 amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48) optionally comprising 1 or 2 amino acid substitutions; and / or

[0431] A light chain variable region comprising: a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), optionally comprising 1 or 2 amino acid substitutions; a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33), optionally comprising 1 or 2 amino acid substitutions; and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34), optionally comprising 1 or 2 amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0432] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0433] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 49), a VHCDR2 comprising the amino acid sequence of SSGGGQTY (SEQ ID NO: 50), and a VHCDR3 comprising the amino acid sequence of HDYYEGGLYYAMDY (SEQ ID NO: 48); and

[0434] a light chain variable region comprising: a VLCDR1 comprising the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 34);

[0435] Optionally, wherein the Met residues are each independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or the Asp residues are each independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0436] An antigen-binding molecule of 3E05_var12 or an antigen-binding molecule 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 0.5 M and / or an IC90 for IFN secretion of less than about 5 nM. In a specific embodiment, an antigen binding molecule of 3E05_var12 or an antigen binding molecule derived from 3E05_var12 (e.g., an antibody having one or more amino acid substitutions) can 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.

[0437] 3E05_var6

[0438] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0439] A heavy chain variable region comprising: a VHCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SYTMS (SEQ ID NO: 26); a VHCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of YISSGGGNTYYADSVKG (SEQ ID NO: 27); and a VHCDR3 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: NO:28) comprises a VHCDR3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical; and / or

[0440] A light chain variable region comprising: a VLCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 22); a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of AASTLES (SEQ ID NO: 23); and a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: NO:24) comprises a VLC R3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical.

[0441] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0442] A heavy chain variable region comprising: a VHCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of GFTFSSY (SEQ ID NO: 29); a VHCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SSGGGNTY (SEQ ID NO: 30); and a VHCDR3 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: NO:28) comprises a VHCDR3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical; and / or

[0443] A light chain variable region comprising: a VLCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 22); a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of AASTLES (SEQ ID NO: 23); and a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: NO:24) comprises a VLC R3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical.

[0444] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0445] a heavy chain variable region comprising: a VHCDR1 comprising at least 90% identity to the amino acid sequence of SYTMS (SEQ ID NO: 26), a VHCDR2 comprising at least 90% identity to the amino acid sequence of YISSGGGNTYYADSVKG (SEQ ID NO: 27), and a VHCDR3 comprising at least 90% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 28); and / or

[0446] A light chain variable region comprising: a VLCDR1 comprising at least 90% identity to the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 comprising at least 90% identity to the amino acid sequence of AASTLES (SEQ ID NO: 23), and a VLCDR3 comprising at least 90% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 24).

[0447] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0448] a heavy chain variable region comprising: a VHCDR1 comprising at least 90% identity to the amino acid sequence of GFTFSSY (SEQ ID NO: 29), a VHCDR2 comprising at least 90% identity to the amino acid sequence of SSGGGNTY (SEQ ID NO: 30), and a VHCDR3 comprising at least 90% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 28); and / or

[0449] A light chain variable region comprising: a VLCDR1 comprising at least 90% identity to the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 comprising at least 90% identity to the amino acid sequence of AASTLES (SEQ ID NO: 23), and a VLCDR3 comprising at least 90% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 24).

[0450] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0451] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of SYTMS (SEQ ID NO: 26), a VHCDR2 comprising the amino acid sequence of YISSGGGNTYYADSVKG (SEQ ID NO: 27), and a VHCDR comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 28); and

[0452] The light chain variable region comprises: VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23), and VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24).

[0453] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 6, for example to provide an antibody, fragment or variant thereof comprising:

[0454] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 26) optionally comprising 1 or 2 amino acid substitutions, a VHCDR2 comprising the amino acid sequence YISSGGGNTYYADSVKG (SEQ ID NO: 27) optionally comprising 1 or 2 amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28) optionally comprising 1 or 2 amino acid substitutions; and / or

[0455] A light chain variable region comprising: a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), optionally comprising 1 or 2 amino acid substitutions; a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23), optionally comprising 1 or 2 amino acid substitutions; and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24), optionally comprising 1 or 2 amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0456] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0457] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of SYTMS (SEQ ID NO: 26), a VHCDR2 comprising the amino acid sequence of YISSGGGNTYYADSVKG (SEQ ID NO: 27), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 28); and

[0458] a light chain variable region comprising: a VLCDR1 comprising the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 23), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 24);

[0459] Optionally, wherein the Met residues are each independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or the Asp residues are each independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0460] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0461] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 29), a VHCDR2 comprising the amino acid sequence of SSGGGNTY (SEQ ID NO: 30), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 28); and

[0462] The light chain variable region comprises a VLCDR1 comprising the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 23), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 24).

[0463] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 6, for example to provide an antibody, fragment or variant thereof comprising:

[0464] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 29) optionally comprising 1 or 2 amino acid substitutions, a VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 30) optionally comprising 1 or 2 amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28) optionally comprising 1 or 2 amino acid substitutions; and / or

[0465] A light chain variable region comprising: a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), optionally comprising 1 or 2 amino acid substitutions; a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23), optionally comprising 1 or 2 amino acid substitutions; and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24), optionally comprising 1 or 2 amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0466] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0467] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 29), a VHCDR2 comprising the amino acid sequence of SSGGGNTY (SEQ ID NO: 30), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 28); and

[0468] a light chain variable region comprising: a VLCDR1 comprising the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 23), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 24);

[0469] Optionally, wherein the Met residues are each independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or the Asp residues are each independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0470] An antigen-binding molecule of 3E05_var 6 or an antigen-binding molecule derived from 3E05_var 6 (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 0.5 M and / or an IC90 for IFN secretion of less than about 5 nM. In a specific embodiment, the antigen binding molecule of 3E05_var 6 or an antigen binding molecule derived from 3E05_var 6 (e.g., an antibody having one or more amino acid substitutions) can 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.

[0471] 3E05_var14

[0472] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0473] A heavy chain variable region comprising: a VHCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SYTMS (SEQ ID NO: 26); a VHCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of YISSGGGNTYYADSVKG (SEQ ID NO: 27); and a VHCDR3 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: NO:28) comprises a VHCDR3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical; and / or

[0474] A light chain variable region comprising: a VLCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of KASQSVDYEGDSSMN (SEQ ID NO: 42); a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of AASTLES (SEQ ID NO: 43); and a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: NO:44) comprises a VLC R3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical.

[0475] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0476] A heavy chain variable region comprising: a VHCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of GFTFSSY (SEQ ID NO: 29); a VHCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SSGGGNTY (SEQ ID NO: 30); and a VHCDR3 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: NO:28) comprises a VHCDR3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical; and / or

[0477] A light chain variable region comprising: a VLCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of KASQSVDYEGDSSMN (SEQ ID NO: 42); a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of AASTLES (SEQ ID NO: 43); and a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: NO:44) comprises a VLC R3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical.

[0478] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0479] a heavy chain variable region comprising: a VHCDR1 comprising at least 90% identity to the amino acid sequence of SYTMS (SEQ ID NO: 26), a VHCDR2 comprising at least 90% identity to the amino acid sequence of YISSGGGNTYYADSVKG (SEQ ID NO: 27), and a VHCDR3 comprising at least 90% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 28); and / or

[0480] A light chain variable region comprising: a VLCDR1 comprising at least 90% identity to the amino acid sequence of KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 comprising at least 90% identity to the amino acid sequence of AASTLES (SEQ ID NO: 43), and a VLCDR3 comprising at least 90% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 44).

[0481] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0482] a heavy chain variable region comprising: a VHCDR1 comprising at least 90% identity to the amino acid sequence of GFTFSSY (SEQ ID NO: 29), a VHCDR2 comprising at least 90% identity to the amino acid sequence of SSGGGNTY (SEQ ID NO: 30), and a VHCDR3 comprising at least 90% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 28); and / or

[0483] A light chain variable region comprising: a VLCDR1 comprising at least 90% identity to the amino acid sequence of KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 comprising at least 90% identity to the amino acid sequence of AASTLES (SEQ ID NO: 43), and a VLCDR3 comprising at least 90% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 44).

[0484] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0485] 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); and / or

[0486] The light chain variable region comprises: VLCDR1 comprising the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 43), and VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44).

[0487] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 14, for example to provide an antibody, fragment or variant thereof comprising:

[0488] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 26) optionally comprising 1 or 2 amino acid substitutions, a VHCDR2 comprising the amino acid sequence YISSGGGNTYYADSVKG (SEQ ID NO: 27) optionally comprising 1 or 2 amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28) optionally comprising 1 or 2 amino acid substitutions; and / or

[0489] A light chain variable region comprising: a VLCDR comprising the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), optionally comprising 1 or 2 amino acid substitutions; a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 43), optionally comprising 1 or 2 amino acid substitutions; and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44), optionally comprising 1 or 2 amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0490] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0491] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of SYTMS (SEQ ID NO: 26), a VHCDR2 comprising the amino acid sequence of YISSGGGNTYYADSVKG (SEQ ID NO: 27), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 28); and

[0492] a light chain variable region comprising: a VLCDR1 comprising the amino acid sequence of KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 43), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 44);

[0493] Optionally, wherein the Met residues are each independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or the Asp residues are each independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0494] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0495] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 29), a VHCDR2 comprising the amino acid sequence of SSGGGNTY (SEQ ID NO: 30), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 28); and

[0496] The light chain variable region comprises: VLCDR1 comprising the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 43), and VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44).

[0497] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 14, for example to provide an antibody, fragment or variant thereof comprising:

[0498] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 29) optionally comprising 1 or 2 amino acid substitutions, a VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 30) optionally comprising 1 or 2 amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28) optionally comprising 1 or 2 amino acid substitutions; and / or

[0499] A light chain variable region comprising: a VLCDR1 comprising the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), optionally comprising one or two amino acid substitutions; a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 43), optionally comprising one or two amino acid substitutions; and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44), optionally comprising one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0500] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0501] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 29), a VHCDR2 comprising the amino acid sequence of SSGGGNTY (SEQ ID NO: 30), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 28); and

[0502] a light chain variable region comprising: a VLCDR1 comprising the amino acid sequence of KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 43), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 44);

[0503] Optionally, wherein the Met residues are each independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or the Asp residues are each independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0504] An antigen-binding molecule of or derived from 3E05_var14 (e.g., an antibody having one or more amino acid substitutions) can 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 a specific embodiment, an antigen binding molecule of 3E05_var14 or an antigen binding molecule derived from 3E05_var14 (e.g., an antibody having one or more amino acid substitutions) can 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.

[0505] 3E05_var1

[0506] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0507] A heavy chain variable region comprising: a VHCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SYTMS (SEQ ID NO: 16); a VHCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of YISSGGGNTYYPDSVKG (SEQ ID NO: 17); and a VHCDR3 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 18). NO:18) comprises a VHCDR3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical; and / or

[0508] A light chain variable region comprising: a VLCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of KASQSVDYDGDSSMN (SEQ ID NO: 12); a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of AASTLES (SEQ ID NO: 13); and a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 14). NO: 14) comprises a VLC R3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical.

[0509] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0510] A heavy chain variable region comprising: a VHCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of GFTFSSY (SEQ ID NO: 19); a VHCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SSGGGNTY (SEQ ID NO: 20); and a VHCDR3 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: NO:18) comprises a VHCDR3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical; and / or

[0511] A light chain variable region comprising: a VLCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of KASQSVDYDGDSSMN (SEQ ID NO: 12); a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of AASTLES (SEQ ID NO: 13); and a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 14). NO: 14) comprises a VLC R3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical.

[0512] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0513] a heavy chain variable region comprising: a VHCDR1 comprising at least 90% identity to the amino acid sequence of SYTMS (SEQ ID NO: 16), a VHCDR2 comprising at least 90% identity to the amino acid sequence of YISSGGGNTYYPDSVKG (SEQ ID NO: 17), and a VHCDR3 comprising at least 90% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 18); and / or

[0514] A light chain variable region comprising: a VLCDR1 comprising at least 90% identity to the amino acid sequence of KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 comprising at least 90% identity to the amino acid sequence of AASTLES (SEQ ID NO: 13), and a VLCDR3 comprising at least 90% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 14).

[0515] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0516] a heavy chain variable region comprising: a VHCDR1 comprising at least 90% identity to the amino acid sequence of GFTFSSY (SEQ ID NO: 19), a VHCDR2 comprising at least 90% identity to the amino acid sequence of SSGGGNTY (SEQ ID NO: 20), and a VHCDR3 comprising at least 90% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 18); and

[0517] A light chain variable region comprising: a VLCDR1 comprising at least 90% identity to the amino acid sequence of KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 comprising at least 90% identity to the amino acid sequence of AASTLES (SEQ ID NO: 13), and a VLCDR3 comprising at least 90% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 14).

[0518] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0519] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of SYTMS (SEQ ID NO: 16), a VHCDR2 comprising the amino acid sequence of YISSGGGNTYYPDSVKG (SEQ ID NO: 17), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 18); and / or

[0520] The light chain variable region comprises: 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).

[0521] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 1, for example to provide an antibody, fragment or variant comprising:

[0522] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 16) optionally comprising 1 or 2 amino acid substitutions, a VHCDR2 comprising the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 17) optionally comprising 1 or 2 amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18) optionally comprising 1 or 2 amino acid substitutions; and / or

[0523] A light chain variable region comprising: a VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), optionally comprising one or two amino acid substitutions; a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 13), optionally comprising one or two amino acid substitutions; and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14), optionally comprising one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0524] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0525] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of SYTMS (SEQ ID NO: 16), a VHCDR2 comprising the amino acid sequence of YISSGGGNTYYPDSVKG (SEQ ID NO: 17), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 18); and

[0526] a light chain variable region comprising: a VLCDR1 comprising the amino acid sequence of KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 13), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 14);

[0527] Optionally, wherein the Met residues are each independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or the Asp residues are each independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0528] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0529] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 19), a VHCDR2 comprising the amino acid sequence of SSGGGNTY (SEQ ID NO: 20), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 18); and

[0530] The light chain variable region comprises: 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).

[0531] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 1, for example to provide an antibody, fragment or variant comprising:

[0532] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 19) optionally comprising 1 or 2 amino acid substitutions, a VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 20) optionally comprising 1 or 2 amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18) optionally comprising 1 or 2 amino acid substitutions; and / or

[0533] A light chain variable region comprising: a VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), optionally comprising one or two amino acid substitutions; a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 13), optionally comprising one or two amino acid substitutions; and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14), optionally comprising one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0534] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0535] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 19), a VHCDR2 comprising the amino acid sequence of SSGGGNTY (SEQ ID NO: 20), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 18); and

[0536] a light chain variable region comprising: a VLCDR1 comprising the amino acid sequence of KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 13), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 14);

[0537] Optionally, wherein the Met residues are each independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or the Asp residues are each independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0538] An antigen-binding molecule of 3E05_var1 or an antigen-binding molecule derived from 3E05_var1 (eg, an antibody having one or more amino acid substitutions) may 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.

[0539] 3E05_var2

[0540] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0541] A heavy chain variable region comprising: a VHCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SYTMS (SEQ ID NO: 26); a VHCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of YISSGGGNTYYADSVKG (SEQ ID NO: 27); and a VHCDR3 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: NO:28) comprises a VHCDR3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical; and / or

[0542] A light chain variable region comprising: a VLCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of KASQSVDYDGDSSMN (SEQ ID NO: 12); a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of AASTLES (SEQ ID NO: 13); and a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 14). NO: 14) comprises a VLC R3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical.

[0543] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0544] A heavy chain variable region comprising: a VHCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of GFTFSSY (SEQ ID NO: 29); a VHCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SSGGGNTY (SEQ ID NO: 30); and a VHCDR3 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: NO:28) comprises a VHCDR3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical; and / or

[0545] A light chain variable region comprising: a VLCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of KASQSVDYDGDSSMN (SEQ ID NO: 12); a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of AASTLES (SEQ ID NO: 13); and a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 14). NO: 14) comprises a VLC R3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical.

[0546] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0547] a heavy chain variable region comprising: a VHCDR1 comprising at least 90% identity to the amino acid sequence of SYTMS (SEQ ID NO: 26), a VHCDR2 comprising at least 90% identity to the amino acid sequence of YISSGGGNTYYADSVKG (SEQ ID NO: 27), and a VHCDR3 comprising at least 90% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 28); and / or

[0548] A light chain variable region comprising: a VLCDR1 comprising at least 90% identity to the amino acid sequence of KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 comprising at least 90% identity to the amino acid sequence of AASTLES (SEQ ID NO: 13), and a VLCDR3 comprising at least 90% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 14).

[0549] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0550] a heavy chain variable region comprising: a VHCDR1 comprising at least 90% identity to the amino acid sequence of GFTFSSY (SEQ ID NO: 29), a VHCDR2 comprising at least 90% identity to the amino acid sequence of SSGGGNTY (SEQ ID NO: 30), and a VHCDR3 comprising at least 90% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 28); and / or

[0551] A light chain variable region comprising: a VLCDR1 comprising at least 90% identity to the amino acid sequence of KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 comprising at least 90% identity to the amino acid sequence of AASTLES (SEQ ID NO: 13), and a VLCDR3 comprising at least 90% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 14).

[0552] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0553] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of SYTMS (SEQ ID NO: 26), a VHCDR2 comprising the amino acid sequence of YISSGGGNTYYADSVKG (SEQ ID NO: 27), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 28); and

[0554] The light chain variable region comprises: 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).

[0555] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 2, for example to provide an antibody, fragment or variant comprising:

[0556] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 26) optionally comprising 1 or 2 amino acid substitutions, a VHCDR2 comprising the amino acid sequence YISSGGGNTYYADSVKG (SEQ ID NO: 27) optionally comprising 1 or 2 amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28) optionally comprising 1 or 2 amino acid substitutions; and / or

[0557] A light chain variable region comprising: a VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), optionally comprising one or two amino acid substitutions; a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 13), optionally comprising one or two amino acid substitutions; and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14), optionally comprising one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0558] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0559] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of SYTMS (SEQ ID NO: 26), a VHCDR2 comprising the amino acid sequence of YISSGGGNTYYADSVKG (SEQ ID NO: 27), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 28); and

[0560] The light chain variable region comprises: 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).

[0561] Optionally, wherein the Met residues are each independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or the Asp residues are each independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0562] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0563] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 29), a VHCDR2 comprising the amino acid sequence of SSGGGNTY (SEQ ID NO: 30), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 28); and

[0564] The light chain variable region comprises: 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).

[0565] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 2, for example to provide an antibody, fragment or variant comprising:

[0566] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 29) optionally comprising 1 or 2 amino acid substitutions, a VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 30) optionally comprising 1 or 2 amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28) optionally comprising 1 or 2 amino acid substitutions; and / or

[0567] A light chain variable region comprising: a VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), optionally comprising one or two amino acid substitutions; a VLCDR3 comprising the amino acid sequence AASTLES (SEQ ID NO: 13), optionally comprising one or two amino acid substitutions; and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14), optionally comprising one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0568] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0569] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 29), a VHCDR2 comprising the amino acid sequence of SSGGGNTY (SEQ ID NO: 30), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 28); and

[0570] a light chain variable region comprising: a VLCDR1 comprising the amino acid sequence of KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 13), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 14);

[0571] Optionally, wherein the Met residues are each independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or the Asp residues are each independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0572] An antigen-binding molecule of 3E05_var2 or an antigen-binding molecule derived from 3E05_var2 (e.g., an antibody having one or more amino acid substitutions) can 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.

[0573] 3E05_var3

[0574] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0575] A heavy chain variable region comprising: a VHCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SYTMS (SEQ ID NO: 36); a VHCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of YISSGGGQTYYPDSVKG (SEQ ID NO: 37); and a VHCDR3 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: NO:38) comprises a VHCDR3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical; and / or

[0576] A light chain variable region comprising: a VLCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of KASQSVDYDGDSSMN (SEQ ID NO: 12); a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of AASTLES (SEQ ID NO: 13); and a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 14). NO: 14) comprises a VLC R3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical.

[0577] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0578] A heavy chain variable region comprising: a VHCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of GFTFSSY (SEQ ID NO: 39); a VHCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SSGGGQTY (SEQ ID NO: 40); and a VHCDR3 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: NO:38) comprises a VHCDR3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical; and / or

[0579] A light chain variable region comprising: a VLCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of KASQSVDYDGDSSMN (SEQ ID NO: 12); a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of AASTLES (SEQ ID NO: 13); and a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 14). NO: 14) comprises a VLC R3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical.

[0580] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0581] a heavy chain variable region comprising: a VHCDR1 comprising at least 90% identity to the amino acid sequence of SYTMS (SEQ ID NO: 36), a VHCDR2 comprising at least 90% identity to the amino acid sequence of YISSGGGQTYYPDSVKG (SEQ ID NO: 37), and a VHCDR3 comprising at least 90% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 38); and / or

[0582] A light chain variable region comprising: a VLCDR1 comprising at least 90% identity to the amino acid sequence of KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 comprising at least 90% identity to the amino acid sequence of AASTLES (SEQ ID NO: 13), and a VLCDR3 comprising at least 90% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 14).

[0583] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0584] a heavy chain variable region comprising: a VHCDR1 comprising at least 90% identity to the amino acid sequence of GFTFSSY (SEQ ID NO: 39), a VHCDR2 comprising at least 90% identity to the amino acid sequence of SSGGGQTY (SEQ ID NO: 40), and a VHCDR3 comprising at least 90% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 38); and / or

[0585] A light chain variable region comprising: a VLCDR1 comprising at least 90% identity to the amino acid sequence of KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 comprising at least 90% identity to the amino acid sequence of AASTLES (SEQ ID NO: 13), and a VLCDR3 comprising at least 90% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 14).

[0586] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0587] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of SYTMS (SEQ ID NO: 36), a VHCDR2 comprising the amino acid sequence of YISSGGGQTYYPDSVKG (SEQ ID NO: 37), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 38); and

[0588] The light chain variable region comprises: 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).

[0589] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 3, for example to provide an antibody, fragment or variant comprising:

[0590] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 36) optionally comprising 1 or 2 amino acid substitutions, a VHCDR2 comprising the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 37) optionally comprising 1 or 2 amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38) optionally comprising 1 or 2 amino acid substitutions; and / or

[0591] A light chain variable region comprising: a VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), optionally comprising one or two amino acid substitutions; a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 13), optionally comprising one or two amino acid substitutions; and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14), optionally comprising one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0592] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0593] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of SYTMS (SEQ ID NO: 36), a VHCDR2 comprising the amino acid sequence of YISSGGGQTYYPDSVKG (SEQ ID NO: 37), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 38); and

[0594] a light chain variable region comprising: a VLCDR1 comprising the amino acid sequence of KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 13), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 14);

[0595] Optionally, wherein the Met residues are each independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or the Asp residues are each independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0596] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0597] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 39), a VHCDR2 comprising the amino acid sequence of SSGGGQTY (SEQ ID NO: 40), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 38); and

[0598] The light chain variable region comprises: 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).

[0599] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 3, for example to provide an antibody, fragment or variant comprising:

[0600] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 39) optionally comprising 1 or 2 amino acid substitutions, a VHCDR2 comprising the amino acid sequence SSGGGQTY (SEQ ID NO: 40) optionally comprising 1 or 2 amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38) optionally comprising 1 or 2 amino acid substitutions; and / or

[0601] A light chain variable region comprising: a VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), optionally comprising one or two amino acid substitutions; a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 13), optionally comprising one or two amino acid substitutions; and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14), optionally comprising one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0602] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0603] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 39), a VHCDR2 comprising the amino acid sequence of SSGGGQTY (SEQ ID NO: 40), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 38); and

[0604] a light chain variable region comprising: a VLCDR1 comprising the amino acid sequence of KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 13), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 14);

[0605] Optionally, wherein the Met residues are each independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or the Asp residues are each independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0606] An antigen-binding molecule of 3E05_var3 or an antigen-binding molecule derived from 3E05_var3 (eg, an antibody having one or more amino acid substitutions) may 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.

[0607] 3E05_var4

[0608] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0609] A heavy chain variable region comprising: a VHCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SYTMS (SEQ ID NO: 46); a VHCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of YISSGGGQTYYPDSVKG (SEQ ID NO: 47); and a VHCDR3 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of HDYYEGGLYYAMDY (SEQ ID NO: NO:48) comprises a VHCDR3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical; and / or

[0610] A light chain variable region comprising: a VLCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of KASQSVDYDGDSSMN (SEQ ID NO: 12); a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of AASTLES (SEQ ID NO: 13); and a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 14). NO: 14) comprises a VLC R3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical.

[0611] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0612] A heavy chain variable region comprising: a VHCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of GFTFSSY (SEQ ID NO: 49); a VHCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SSGGGQTY (SEQ ID NO: 50); and a VHCDR3 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of HDYYEGGLYYAMDY (SEQ ID NO: NO:48) comprises a VHCDR3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical; and / or

[0613] A light chain variable region comprising: a VLCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of KASQSVDYDGDSSMN (SEQ ID NO: 12); a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of AASTLES (SEQ ID NO: 13); and a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 14). NO: 14) comprises a VLC R3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical.

[0614] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0615] a heavy chain variable region comprising: a VHCDR1 comprising at least 90% identity to the amino acid sequence of SYTMS (SEQ ID NO: 46), a VHCDR2 comprising at least 90% identity to the amino acid sequence of YISSGGGQTYYPDSVKG (SEQ ID NO: 47), and a VHCDR3 comprising at least 90% identity to the amino acid sequence of HDYYEGGLYYAMDY (SEQ ID NO: 48); and / or

[0616] A light chain variable region comprising: a VLCDR1 comprising at least 90% identity to the amino acid sequence of KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 comprising at least 90% identity to the amino acid sequence of AASTLES (SEQ ID NO: 13), and a VLCDR3 comprising at least 90% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 14).

[0617] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0618] a heavy chain variable region comprising: a VHCDR1 comprising at least 90% identity to the amino acid sequence of GFTFSSY (SEQ ID NO: 49), a VHCDR2 comprising at least 90% identity to the amino acid sequence of SSGGGQTY (SEQ ID NO: 50), and a VHCDR3 comprising at least 90% identity to the amino acid sequence of HDYYEGGLYYAMDY (SEQ ID NO: 48); and / or

[0619] A light chain variable region comprising: a VLCDR1 comprising at least 90% identity to the amino acid sequence of KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 comprising at least 90% identity to the amino acid sequence of AASTLES (SEQ ID NO: 13), and a VLCDR3 comprising at least 90% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 14).

[0620] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0621] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of SYTMS (SEQ ID NO: 46), a VHCDR2 comprising the amino acid sequence of YISSGGGQTYYPDSVKG (SEQ ID NO: 47), and a VHCDR3 comprising the amino acid sequence of HDYYEGGLYYAMDY (SEQ ID NO: 48); and

[0622] The light chain variable region comprises: 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).

[0623] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 4, for example to provide an antibody, fragment or variant comprising:

[0624] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 46) optionally comprising 1 or 2 amino acid substitutions, a VHCDR2 comprising the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 47) optionally comprising 1 or 2 amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48) optionally comprising 1 or 2 amino acid substitutions; and / or

[0625] A light chain variable region comprising: a VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), optionally comprising one or two amino acid substitutions; a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 13), optionally comprising one or two amino acid substitutions; and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14), optionally comprising one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0626] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0627] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of SYTMS (SEQ ID NO: 46), a VHCDR2 comprising the amino acid sequence of YISSGGGQTYYPDSVKG (SEQ ID NO: 47), and a VHCDR3 comprising the amino acid sequence of HDYYEGGLYYAMDY (SEQ ID NO: 48); and

[0628] a light chain variable region comprising: a VLCDR1 comprising the amino acid sequence of KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 13), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 14);

[0629] Optionally, wherein the Met residues are each independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or the Asp residues are each independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0630] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0631] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 49), a VHCDR2 comprising the amino acid sequence of SSGGGQTY (SEQ ID NO: 50), and a VHCDR3 comprising the amino acid sequence of HDYYEGGLYYAMDY (SEQ ID NO: 48); and

[0632] The light chain variable region comprises: 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).

[0633] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 4, for example to provide an antibody, fragment or variant thereof comprising:

[0634] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 49) optionally comprising 1 or 2 amino acid substitutions, a VHCDR2 comprising the amino acid sequence SSGGGQTY (SEQ ID NO: 50) optionally comprising 1 or 2 amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48); and / or

[0635] A light chain variable region comprising: a VLCDR1 comprising the amino acid sequence KASQSVDYDGDSSMN (SEQ ID NO: 12), optionally comprising one or two amino acid substitutions; a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 13), optionally comprising one or two amino acid substitutions; and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 14), optionally comprising one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0636] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0637] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 49), a VHCDR2 comprising the amino acid sequence of SSGGGQTY (SEQ ID NO: 50), and a VHCDR3 comprising the amino acid sequence of HDYYEGGLYYAMDY (SEQ ID NO: 48); and

[0638] a light chain variable region comprising: a VLCDR1 comprising the amino acid sequence of KASQSVDYDGDSSMN (SEQ ID NO: 12), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 13), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 14);

[0639] Optionally, wherein the Met residues are each independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or the Asp residues are each independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0640] An antigen-binding molecule of 3E05_var4 or an antigen-binding molecule derived from 3E05_var4 (e.g., an antibody having one or more amino acid substitutions) can 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.

[0641] 3E05_var5

[0642] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0643] A heavy chain variable region comprising: a VHCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SYTMS (SEQ ID NO: 16); a VHCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of YISSGGGNTYYPDSVKG (SEQ ID NO: 17); and a VHCDR3 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 18). NO:18) comprises a VHCDR3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical; and / or

[0644] A light chain variable region comprising: a VLCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 22); a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of AASTLES (SEQ ID NO: 23); and a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: NO:24) comprises a VLC R3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical.

[0645] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0646] A heavy chain variable region comprising: a VHCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of GFTFSSY (SEQ ID NO: 19); a VHCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SSGGGNTY (SEQ ID NO: 20); and a VHCDR3 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: NO:18) comprises a VHCDR3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical; and / or

[0647] A light chain variable region comprising: a VLCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 22); a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of AASTLES (SEQ ID NO: 23); and a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: NO:24) comprises a VLC R3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical.

[0648] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0649] a heavy chain variable region comprising: a VHCDR1 comprising at least 90% identity to the amino acid sequence of SYTMS (SEQ ID NO: 16), a VHCDR2 comprising at least 90% identity to the amino acid sequence of YISSGGGNTYYPDSVKG (SEQ ID NO: 17), and a VHCDR3 comprising at least 90% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 18); and / or

[0650] A light chain variable region comprising: a VLCDR1 comprising at least 90% identity to the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 comprising at least 90% identity to the amino acid sequence of AASTLES (SEQ ID NO: 23), and a VLCDR3 comprising at least 90% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 24).

[0651] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0652] a heavy chain variable region comprising: a VHCDR1 comprising at least 90% identity to the amino acid sequence of GFTFSSY (SEQ ID NO: 19), a VHCDR2 comprising at least 90% identity to the amino acid sequence of SSGGGNTY (SEQ ID NO: 20), and a VHCDR3 comprising at least 90% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 18); and / or

[0653] A light chain variable region comprising: a VLCDR1 comprising at least 90% identity to the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 comprising at least 90% identity to the amino acid sequence of AASTLES (SEQ ID NO: 23), and a VLCDR3 comprising at least 90% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 24).

[0654] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0655] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of SYTMS (SEQ ID NO: 16), a VHCDR2 comprising the amino acid sequence of YISSGGGNTYYPDSVKG (SEQ ID NO: 17), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 18); and

[0656] The light chain variable region comprises: VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23), and VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24).

[0657] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 5, for example to provide an antibody, fragment or variant thereof comprising:

[0658] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 16) optionally comprising 1 or 2 amino acid substitutions, a VHCDR2 comprising the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 17) optionally comprising 1 or 2 amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18) optionally comprising 1 or 2 amino acid substitutions; and / or

[0659] A light chain variable region comprising: a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), optionally comprising 1 or 2 amino acid substitutions; a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23), optionally comprising 1 or 2 amino acid substitutions; and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24), optionally comprising 1 or 2 amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0660] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0661] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of SYTMS (SEQ ID NO: 16), a VHCDR2 comprising the amino acid sequence of YISSGGGNTYYPDSVKG (SEQ ID NO: 17), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 18); and

[0662] a light chain variable region comprising: a VLCDR1 comprising the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 23), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 24);

[0663] Optionally, wherein the Met residues are each independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or the Asp residues are each independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0664] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0665] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 19), a VHCDR2 comprising the amino acid sequence of SSGGGNTY (SEQ ID NO: 20), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 18); and

[0666] The light chain variable region comprises: VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23), and VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24).

[0667] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 5, for example to provide an antibody, fragment or variant thereof comprising:

[0668] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 19) optionally comprising 1 or 2 amino acid substitutions, a VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 20) optionally comprising 1 or 2 amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18) optionally comprising 1 or 2 amino acid substitutions; and / or

[0669] A light chain variable region comprising: a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), optionally comprising 1 or 2 amino acid substitutions; a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23), optionally comprising 1 or 2 amino acid substitutions; and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24), optionally comprising 1 or 2 amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0670] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0671] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 19), a VHCDR2 comprising the amino acid sequence of SSGGGNTY (SEQ ID NO: 20), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 18); and

[0672] a light chain variable region comprising: a VLCDR1 comprising the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 23), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 24);

[0673] Optionally, wherein the Met residues are each independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or the Asp residues are each independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0674] An antigen-binding molecule of 3E05_var5 or an antigen-binding molecule derived from 3E05_var5 (e.g., an antibody having one or more amino acid substitutions) can 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.

[0675] 3E05_var7

[0676] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0677] A heavy chain variable region comprising: a VHCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SYTMS (SEQ ID NO: 36); a VHCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of YISSGGGQTYYPDSVKG (SEQ ID NO: 37); and a VHCDR3 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: NO:38) comprises a VHCDR3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical; and / or

[0678] A light chain variable region comprising: a VLCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 22); a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of AASTLES (SEQ ID NO: 23); and a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: NO:24) comprises a VLC R3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical.

[0679] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0680] A heavy chain variable region comprising: a VHCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of GFTFSSY (SEQ ID NO: 39); a VHCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SSGGGQTY (SEQ ID NO: 40); and a VHCDR3 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: NO:38) comprises a VHCDR3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical; and / or

[0681] A light chain variable region comprising: a VLCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 22); a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of AASTLES (SEQ ID NO: 23); and a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: NO:24) comprises a VLC R3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical.

[0682] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0683] a heavy chain variable region comprising: a VHCDR1 comprising at least 90% identity to the amino acid sequence of SYTMS (SEQ ID NO: 36), a VHCDR2 comprising at least 90% identity to the amino acid sequence of YISSGGGQTYYPDSVKG (SEQ ID NO: 37), and a VHCDR3 comprising at least 90% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 38); and / or

[0684] A light chain variable region comprising: a VLCDR1 comprising at least 90% identity to the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 comprising at least 90% identity to the amino acid sequence of AASTLES (SEQ ID NO: 23), and a VLCDR3 comprising at least 90% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 24).

[0685] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0686] a heavy chain variable region comprising: a VHCDR1 comprising at least 90% identity to the amino acid sequence of GFTFSSY (SEQ ID NO: 39), a VHCDR2 comprising at least 90% identity to the amino acid sequence of SSGGGQTY (SEQ ID NO: 40), and a VHCDR3 comprising at least 90% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 38); and / or

[0687] A light chain variable region comprising: a VLCDR1 comprising at least 90% identity to the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 comprising at least 90% identity to the amino acid sequence of AASTLES (SEQ ID NO: 23), and a VLCDR3 comprising at least 90% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 24).

[0688] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0689] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of SYTMS (SEQ ID NO: 36), a VHCDR2 comprising the amino acid sequence of YISSGGGQTYYPDSVKG (SEQ ID NO: 37), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 38); and

[0690] The light chain variable region comprises: VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23), and VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24).

[0691] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 7, for example to provide an antibody, fragment or variant thereof comprising:

[0692] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 36) optionally comprising 1 or 2 amino acid substitutions, a VHCDR2 comprising the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 37) optionally comprising 1 or 2 amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38) optionally comprising 1 or 2 amino acid substitutions; and / or

[0693] A light chain variable region comprising: a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), optionally comprising 1 or 2 amino acid substitutions; a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23), optionally comprising 1 or 2 amino acid substitutions; and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24), optionally comprising 1 or 2 amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0694] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0695] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of SYTMS (SEQ ID NO: 36), a VHCDR2 comprising the amino acid sequence of YISSGGGQTYYPDSVKG (SEQ ID NO: 37), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 38); and

[0696] a light chain variable region comprising: a VLCDR1 comprising the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 23), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 24);

[0697] Optionally, wherein the Met residues are each independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or the Asp residues are each independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0698] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0699] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 39), a VHCDR2 comprising the amino acid sequence of SSGGGQTY (SEQ ID NO: 40), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 38); and

[0700] The light chain variable region comprises: VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23), and VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24).

[0701] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 7, for example to provide an antibody, fragment or variant thereof comprising:

[0702] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 39) optionally comprising 1 or 2 amino acid substitutions, a VHCDR2 comprising the amino acid sequence SSGGGQTY (SEQ ID NO: 40) optionally comprising 1 or 2 amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38) optionally comprising 1 or 2 amino acid substitutions; and / or

[0703] A light chain variable region comprising: a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), optionally comprising 1 or 2 amino acid substitutions; a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23), optionally comprising 1 or 2 amino acid substitutions; and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24), optionally comprising 1 or 2 amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0704] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0705] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 39), a VHCDR2 comprising the amino acid sequence of SSGGGQTY (SEQ ID NO: 40), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 38); and

[0706] a light chain variable region comprising: a VLCDR1 comprising the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 23), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 24);

[0707] Optionally, wherein the Met residues are each independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or the Asp residues are each independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0708] An antigen-binding molecule of 3E05_var7 or an antigen-binding molecule derived from 3E05_var7 (e.g., an antibody having one or more amino acid substitutions) can 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.

[0709] 3E05_var8

[0710] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0711] A heavy chain variable region comprising: a VHCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SYTMS (SEQ ID NO: 46); a VHCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of YISSGGGQTYYPDSVKG (SEQ ID NO: 47); and a VHCDR3 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of HDYYEGGLYYAMDY (SEQ ID NO: NO:48) comprises a VHCDR3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical; and / or

[0712] A light chain variable region comprising: a VLCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 22); a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of AASTLES (SEQ ID NO: 23); and a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: NO:24) comprises a VLC R3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical.

[0713] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0714] A heavy chain variable region comprising: a VHCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of GFTFSSY (SEQ ID NO: 49); a VHCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SSGGGQTY (SEQ ID NO: 50); and a VHCDR3 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of HDYYEGGLYYAMDY (SEQ ID NO: NO:48) comprises a VHCDR3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical; and / or

[0715] A light chain variable region comprising: a VLCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 22); a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of AASTLES (SEQ ID NO: 23); and a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: NO:24) comprises a VLC R3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical.

[0716] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0717] a heavy chain variable region comprising: a VHCDR1 comprising at least 90% identity to the amino acid sequence of SYTMS (SEQ ID NO: 46), a VHCDR2 comprising at least 90% identity to the amino acid sequence of YISSGGGQTYYPDSVKG (SEQ ID NO: 47), and a VHCDR3 comprising at least 90% identity to the amino acid sequence of HDYYEGGLYYAMDY (SEQ ID NO: 48); and / or

[0718] A light chain variable region comprising: a VLCDR1 comprising at least 90% identity to the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 comprising at least 90% identity to the amino acid sequence of AASTLES (SEQ ID NO: 23), and a VLCDR3 comprising at least 90% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 24).

[0719] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0720] a heavy chain variable region comprising: a VHCDR1 comprising at least 90% identity to the amino acid sequence of GFTFSSY (SEQ ID NO: 49), a VHCDR2 comprising at least 90% identity to the amino acid sequence of SSGGGQTY (SEQ ID NO: 50), and a VHCDR3 comprising at least 90% identity to the amino acid sequence of HDYYEGGLYYAMDY (SEQ ID NO: 48); and / or

[0721] A light chain variable region comprising: a VLCDR1 comprising at least 90% identity to the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 comprising at least 90% identity to the amino acid sequence of AASTLES (SEQ ID NO: 23), and a VLCDR3 comprising at least 90% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 24).

[0722] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0723] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of SYTMS (SEQ ID NO: 46), a VHCDR2 comprising the amino acid sequence of YISSGGGQTYYPDSVKG (SEQ ID NO: 47), and a VHCDR3 comprising the amino acid sequence of HDYYEGGLYYAMDY (SEQ ID NO: 48); and

[0724] The light chain variable region comprises: VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23), and VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24).

[0725] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 8, for example to provide an antibody, fragment or variant thereof comprising:

[0726] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 46) optionally comprising 1 or 2 amino acid substitutions, a VHCDR2 comprising the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 47) optionally comprising 1 or 2 amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48) optionally comprising 1 or 2 amino acid substitutions; and / or

[0727] A light chain variable region comprising: a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), optionally comprising 1 or 2 amino acid substitutions; a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23), optionally comprising 1 or 2 amino acid substitutions; and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24), optionally comprising 1 or 2 amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0728] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0729] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of SYTMS (SEQ ID NO: 46), a VHCDR2 comprising the amino acid sequence of YISSGGGQTYYPDSVKG (SEQ ID NO: 47), and a VHCDR3 comprising the amino acid sequence of HDYYEGGLYYAMDY (SEQ ID NO: 48); and

[0730] a light chain variable region comprising: a VLCDR1 comprising the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 23), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 24);

[0731] Optionally, wherein the Met residues are each independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or the Asp residues are each independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0732] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0733] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 49), a VHCDR2 comprising the amino acid sequence of SSGGGQTY (SEQ ID NO: 50), and a VHCDR3 comprising the amino acid sequence of HDYYEGGLYYAMDY (SEQ ID NO: 48); and

[0734] The light chain variable region comprises: VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23), and VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24).

[0735] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 8, for example to provide an antibody, fragment or variant thereof comprising:

[0736] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 49) optionally comprising 1 or 2 amino acid substitutions, a VHCDR2 comprising the amino acid sequence SSGGGQTY (SEQ ID NO: 50) optionally comprising 1 or 2 amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HDYYEGGLYYAMDY (SEQ ID NO: 48) optionally comprising 1 or 2 amino acid substitutions; and / or

[0737] A light chain variable region comprising: a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 22), optionally comprising 1 or 2 amino acid substitutions; a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 23), optionally comprising 1 or 2 amino acid substitutions; and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 24), optionally comprising 1 or 2 amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0738] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0739] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 49), a VHCDR2 comprising the amino acid sequence of SSGGGQTY (SEQ ID NO: 50), and a VHCDR3 comprising the amino acid sequence of HDYYEGGLYYAMDY (SEQ ID NO: 48); and

[0740] a light chain variable region comprising: a VLCDR1 comprising the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 22), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 23), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 24);

[0741] Optionally, wherein the Met residues are each independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or the Asp residues are each independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0742] An antigen-binding molecule of 3E05_var 8 or an antigen-binding molecule derived from 3E05_var 8 (e.g., an antibody having one or more amino acid substitutions) may 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.

[0743] 3E05_var9

[0744] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0745] A heavy chain variable region comprising: a VHCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SYTMS (SEQ ID NO: 16); a VHCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of YISSGGGNTYYPDSVKG (SEQ ID NO: 17); and a VHCDR3 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 18). NO:18) comprises a VHCDR3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical; and / or

[0746] A light chain variable region comprising: a VLCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 32); a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of AASTLES (SEQ ID NO: 33); and a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: NO:34) comprises a VLC R3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical.

[0747] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0748] A heavy chain variable region comprising: a VHCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of GFTFSSY (SEQ ID NO: 19); a VHCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SSGGGNTY (SEQ ID NO: 20); and a VHCDR3 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: NO:18) comprises a VHCDR3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical; and / or

[0749] A light chain variable region comprising: a VLCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 32); a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of AASTLES (SEQ ID NO: 33); and a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: NO:34) comprises a VLC R3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical.

[0750] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0751] a heavy chain variable region comprising: a VHCDR1 comprising at least 90% identity to the amino acid sequence of SYTMS (SEQ ID NO: 16), a VHCDR2 comprising at least 90% identity to the amino acid sequence of YISSGGGNTYYPDSVKG (SEQ ID NO: 17), and a VHCDR3 comprising at least 90% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 18); and / or

[0752] A light chain variable region comprising: a VLCDR1 comprising at least 90% identity to the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising at least 90% identity to the amino acid sequence of AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising at least 90% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 34).

[0753] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0754] a heavy chain variable region comprising: a VHCDR1 comprising at least 90% identity to the amino acid sequence of GFTFSSY (SEQ ID NO: 19), a VHCDR2 comprising at least 90% identity to the amino acid sequence of SSGGGNTY (SEQ ID NO: 20), and a VHCDR3 comprising at least 90% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 18); and / or

[0755] A light chain variable region comprising: a VLCDR1 comprising at least 90% identity to the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising at least 90% identity to the amino acid sequence of AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising at least 90% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 34).

[0756] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0757] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of SYTMS (SEQ ID NO: 16), a VHCDR2 comprising the amino acid sequence of YISSGGGNTYYPDSVKG (SEQ ID NO: 17), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 18); and

[0758] The light chain variable region comprises: VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33), and VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34).

[0759] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 9, for example to provide an antibody, fragment or variant thereof comprising:

[0760] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 16) optionally comprising 1 or 2 amino acid substitutions, a VHCDR2 comprising the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 17) optionally comprising 1 or 2 amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18) optionally comprising 1 or 2 amino acid substitutions; and / or

[0761] A light chain variable region comprising: a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), optionally comprising one or two amino acid substitutions; a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33), optionally comprising one or two amino acid substitutions; and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34), optionally comprising one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0762] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0763] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of SYTMS (SEQ ID NO: 16), a VHCDR2 comprising the amino acid sequence of YISSGGGNTYYPDSVKG (SEQ ID NO: 17), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 18); and

[0764] a light chain variable region comprising: a VLCDR1 comprising the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 34);

[0765] Optionally, wherein the Met residues are each independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or the Asp residues are each independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0766] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0767] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 19), a VHCDR2 comprising the amino acid sequence of SSGGGNTY (SEQ ID NO: 20), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 18); and

[0768] The light chain variable region comprises: VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33), and VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34).

[0769] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 9, for example to provide an antibody, fragment or variant thereof comprising:

[0770] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 19) optionally comprising 1 or 2 amino acid substitutions, a VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 20) optionally comprising 1 or 2 amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18) optionally comprising 1 or 2 amino acid substitutions; and / or

[0771] A light chain variable region comprising: a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), optionally comprising one or two amino acid substitutions; a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33), optionally comprising one or two amino acid substitutions; and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34), optionally comprising one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0772] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0773] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 19), a VHCDR2 comprising the amino acid sequence of SSGGGNTY (SEQ ID NO: 20), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 18); and

[0774] a light chain variable region comprising: a VLCDR1 comprising the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 34);

[0775] Optionally, wherein the Met residues are each independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or the Asp residues are each independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0776] An antigen-binding molecule of 3E05_var9 or an antigen-binding molecule derived from 3E05_var9 (eg, an antibody having one or more amino acid substitutions) may 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.

[0777] 3E05_var10

[0778] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0779] A heavy chain variable region comprising: a VHCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SYTMS (SEQ ID NO: 26); a VHCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of YISSGGGNTYYADSVKG (SEQ ID NO: 27); and a VHCDR3 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: NO:28) comprises a VHCDR3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical; and / or

[0780] A light chain variable region comprising: a VLCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 32); a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of AASTLES (SEQ ID NO: 33); and a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: NO:34) comprises a VLC R3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical.

[0781] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0782] A heavy chain variable region comprising: a VHCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of GFTFSSY (SEQ ID NO: 29); a VHCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SSGGGNTY (SEQ ID NO: 30); and a VHCDR3 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: NO:28) comprises a VHCDR3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical; and / or

[0783] A light chain variable region comprising: a VLCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 32); a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of AASTLES (SEQ ID NO: 33); and a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: NO:34) comprises a VLC R3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical.

[0784] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0785] a heavy chain variable region comprising: a VHCDR1 comprising at least 90% identity to the amino acid sequence of SYTMS (SEQ ID NO: 26), a VHCDR2 comprising at least 90% identity to the amino acid sequence of YISSGGGNTYYADSVKG (SEQ ID NO: 27), and a VHCDR3 comprising at least 90% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 28); and / or

[0786] A light chain variable region comprising: a VLCDR1 comprising at least 90% identity to the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising at least 90% identity to the amino acid sequence of AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising at least 90% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 34).

[0787] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0788] a heavy chain variable region comprising: a VHCDR1 comprising at least 90% identity to the amino acid sequence of GFTFSSY (SEQ ID NO: 29), a VHCDR2 comprising at least 90% identity to the amino acid sequence of SSGGGNTY (SEQ ID NO: 30), and a VHCDR3 comprising at least 90% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 28); and / or

[0789] A light chain variable region comprising: a VLCDR1 comprising at least 90% identity to the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising at least 90% identity to the amino acid sequence of AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising at least 90% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 34).

[0790] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0791] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of SYTMS (SEQ ID NO: 26), a VHCDR2 comprising the amino acid sequence of YISSGGGNTYYADSVKG (SEQ ID NO: 27), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 28); and

[0792] The light chain variable region comprises: VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33), and VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34).

[0793] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 10, for example to provide an antibody, fragment or variant thereof comprising:

[0794] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 26) optionally comprising 1 or 2 amino acid substitutions, a VHCDR2 comprising the amino acid sequence YISSGGGNTYYADSVKG (SEQ ID NO: 27) optionally comprising 1 or 2 amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28) optionally comprising 1 or 2 amino acid substitutions; and / or

[0795] A light chain variable region comprising: a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), optionally comprising one or two amino acid substitutions; a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33), optionally comprising one or two amino acid substitutions; and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34), optionally comprising one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0796] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0797] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of SYTMS (SEQ ID NO: 26), a VHCDR2 comprising the amino acid sequence of YISSGGGNTYYADSVKG (SEQ ID NO: 27), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 28); and

[0798] a light chain variable region comprising: a VLCDR1 comprising the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 34);

[0799] Optionally, wherein the Met residues are each independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or the Asp residues are each independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

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

[0801] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 29), a VHCDR2 comprising the amino acid sequence of SSGGGNTY (SEQ ID NO: 30), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 28); and

[0802] The light chain variable region comprises: VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33), and VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34).

[0803] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 10, for example to provide an antibody, fragment or variant thereof comprising:

[0804] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 29) optionally comprising 1 or 2 amino acid substitutions, a VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 30) optionally comprising 1 or 2 amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 28) optionally comprising 1 or 2 amino acid substitutions; and / or

[0805] A light chain variable region comprising: a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), optionally comprising one or two amino acid substitutions; a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33), optionally comprising one or two amino acid substitutions; and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34), optionally comprising one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

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

[0807] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 29), a VHCDR2 comprising the amino acid sequence of SSGGGNTY (SEQ ID NO: 30), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 28); and

[0808] a light chain variable region comprising: a VLCDR1 comprising the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 34);

[0809] Optionally, wherein the Met residues are each independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or the Asp residues are each independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0810] An antigen-binding molecule of 3E05_var 10 or an antigen-binding molecule derived from 3E05_var 10 (e.g., an antibody having one or more amino acid substitutions) may 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.

[0811] 3E05_var11

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

[0813] A heavy chain variable region comprising: a VHCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SYTMS (SEQ ID NO: 36); a VHCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of YISSGGGQTYYPDSVKG (SEQ ID NO: 37); and a VHCDR3 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: NO:38) comprises a VHCDR3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical; and / or

[0814] A light chain variable region comprising: a VLCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 32); a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of AASTLES (SEQ ID NO: 33); and a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: NO:34) comprises a VLC R3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical.

[0815] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0816] A heavy chain variable region comprising: a VHCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of GFTFSSY (SEQ ID NO: 39); a VHCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SSGGGQTY (SEQ ID NO: 40); and a VHCDR3 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: NO:38) comprises a VHCDR3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical; and / or

[0817] A light chain variable region comprising: a VLCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 32); a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of AASTLES (SEQ ID NO: 33); and a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: NO:34) comprises a VLC R3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical.

[0818] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0819] a heavy chain variable region comprising: a VHCDR1 comprising at least 90% identity to the amino acid sequence of SYTMS (SEQ ID NO: 36), a VHCDR2 comprising at least 90% identity to the amino acid sequence of YISSGGGQTYYPDSVKG (SEQ ID NO: 37), and a VHCDR3 comprising at least 90% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 38); and / or

[0820] A light chain variable region comprising: a VLCDR1 comprising at least 90% identity to the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising at least 90% identity to the amino acid sequence of AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising at least 90% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 34).

[0821] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0822] a heavy chain variable region comprising: a VHCDR1 comprising at least 90% identity to the amino acid sequence of GFTFSSY (SEQ ID NO: 39), a VHCDR2 comprising at least 90% identity to the amino acid sequence of SSGGGQTY (SEQ ID NO: 40), and a VHCDR3 comprising at least 90% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 38); and / or

[0823] A light chain variable region comprising: a VLCDR1 comprising at least 90% identity to the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising at least 90% identity to the amino acid sequence of AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising at least 90% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 34).

[0824] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0825] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of SYTMS (SEQ ID NO: 36), a VHCDR2 comprising the amino acid sequence of YISSGGGQTYYPDSVKG (SEQ ID NO: 37), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 38); and

[0826] The light chain variable region comprises: VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33), and VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34).

[0827] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 11, for example to provide an antibody, fragment or variant thereof comprising:

[0828] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 36) optionally comprising 1 or 2 amino acid substitutions, a VHCDR2 comprising the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 37) optionally comprising 1 or 2 amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38) optionally comprising 1 or 2 amino acid substitutions; and / or

[0829] A light chain variable region comprising: a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), optionally comprising one or two amino acid substitutions; a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33), optionally comprising one or two amino acid substitutions; and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34), optionally comprising one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

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

[0831] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of SYTMS (SEQ ID NO: 36), a VHCDR2 comprising the amino acid sequence of YISSGGGQTYYPDSVKG (SEQ ID NO: 37), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 38); and

[0832] a light chain variable region comprising: a VLCDR1 comprising the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 34);

[0833] Optionally, wherein the Met residues are each independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or the Asp residues are each independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0834] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0835] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 39), a VHCDR2 comprising the amino acid sequence of SSGGGQTY (SEQ ID NO: 40), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 38); and

[0836] The light chain variable region comprises: VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33), and VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34).

[0837] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 11, for example to provide an antibody, fragment or variant thereof comprising:

[0838] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 39) optionally comprising 1 or 2 amino acid substitutions, a VHCDR2 comprising the amino acid sequence SSGGGQTY (SEQ ID NO: 40) optionally comprising 1 or 2 amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38) optionally comprising 1 or 2 amino acid substitutions; and / or

[0839] A light chain variable region comprising: a VLCDR1 comprising the amino acid sequence KSSQSVDYDGDSSMN (SEQ ID NO: 32), optionally comprising one or two amino acid substitutions; a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 33), optionally comprising one or two amino acid substitutions; and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 34), optionally comprising one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0840] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0841] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 39), a VHCDR2 comprising the amino acid sequence of SSGGGQTY (SEQ ID NO: 40), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 38); and

[0842] a light chain variable region comprising: a VLCDR1 comprising the amino acid sequence of KSSQSVDYDGDSSMN (SEQ ID NO: 32), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 33), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 34);

[0843] Optionally, wherein the Met residues are each independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or the Asp residues are each independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0844] An antigen-binding molecule of 3E05_var11 or an antigen-binding molecule derived from 3E05_var11 (eg, an antibody having one or more amino acid substitutions) may 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.

[0845] 3E05_var13

[0846] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0847] A heavy chain variable region comprising: a VHCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SYTMS (SEQ ID NO: 16); a VHCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of YISSGGGNTYYPDSVKG (SEQ ID NO: 17); and a VHCDR3 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 18). NO:18) comprises a VHCDR3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical; and / or

[0848] A light chain variable region comprising: a VLCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of KASQSVDYEGDSSMN (SEQ ID NO: 42); a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of AASTLES (SEQ ID NO: 43); and a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: NO:44) comprises a VLC R3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical.

[0849] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0850] A heavy chain variable region comprising: a VHCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of GFTFSSY (SEQ ID NO: 19); a VHCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SSGGGNTY (SEQ ID NO: 20); and a VHCDR3 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: NO:18) comprises a VHCDR3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical; and / or

[0851] A light chain variable region comprising: a VLCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of KASQSVDYEGDSSMN (SEQ ID NO: 42); a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of AASTLES (SEQ ID NO: 43); and a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: NO:44) comprises a VLC R3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical.

[0852] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0853] a heavy chain variable region comprising: a VHCDR1 comprising at least 90% identity to the amino acid sequence of SYTMS (SEQ ID NO: 16), a VHCDR2 comprising at least 90% identity to the amino acid sequence of YISSGGGNTYYPDSVKG (SEQ ID NO: 17), and a VHCDR3 comprising at least 90% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 18); and / or

[0854] A light chain variable region comprising: a VLCDR1 comprising at least 90% identity to the amino acid sequence of KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 comprising at least 90% identity to the amino acid sequence of AASTLES (SEQ ID NO: 43), and a VLCDR3 comprising at least 90% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 44).

[0855] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0856] a heavy chain variable region comprising: a VHCDR1 comprising at least 90% identity to the amino acid sequence of GFTFSSY (SEQ ID NO: 19), a VHCDR2 comprising at least 90% identity to the amino acid sequence of SSGGGNTY (SEQ ID NO: 20), and a VHCDR3 comprising at least 90% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 18); and / or

[0857] A light chain variable region comprising: a VLCDR1 comprising at least 90% identity to the amino acid sequence of KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 comprising at least 90% identity to the amino acid sequence of AASTLES (SEQ ID NO: 43), and a VLCDR3 comprising at least 90% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 44).

[0858] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0859] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of SYTMS (SEQ ID NO: 16), a VHCDR2 comprising the amino acid sequence of YISSGGGNTYYPDSVKG (SEQ ID NO: 17), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 18); and

[0860] The light chain variable region comprises: VLCDR1 comprising the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 43), and VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44).

[0861] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 13, for example to provide an antibody, fragment or variant thereof comprising:

[0862] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 16) optionally comprising 1 or 2 amino acid substitutions, a VHCDR2 comprising the amino acid sequence YISSGGGNTYYPDSVKG (SEQ ID NO: 17) optionally comprising 1 or 2 amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18) optionally comprising 1 or 2 amino acid substitutions; and / or

[0863] A light chain variable region comprising: a VLCDR1 comprising the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), optionally comprising one or two amino acid substitutions; a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 43), optionally comprising one or two amino acid substitutions; and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44), optionally comprising one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0864] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0865] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of SYTMS (SEQ ID NO: 16), a VHCDR2 comprising the amino acid sequence of YISSGGGNTYYPDSVKG (SEQ ID NO: 17), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 18); and

[0866] a light chain variable region comprising: a VLCDR1 comprising the amino acid sequence of KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 43), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 44);

[0867] Optionally, wherein the Met residues are each independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or the Asp residues are each independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0868] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0869] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 19), a VHCDR2 comprising the amino acid sequence of SSGGGNTY (SEQ ID NO: 20), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 18); and

[0870] The light chain variable region comprises: VLCDR1 comprising the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 43), and VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44).

[0871] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 13, for example to provide an antibody, fragment or variant thereof comprising:

[0872] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 19) optionally comprising 1 or 2 amino acid substitutions, a VHCDR2 comprising the amino acid sequence SSGGGNTY (SEQ ID NO: 20) optionally comprising 1 or 2 amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 18) optionally comprising 1 or 2 amino acid substitutions; and / or

[0873] A light chain variable region comprising: a VLCDR1 comprising the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), optionally comprising one or two amino acid substitutions; a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 43), optionally comprising one or two amino acid substitutions; and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44), optionally comprising one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0874] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0875] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 19), a VHCDR2 comprising the amino acid sequence of SSGGGNTY (SEQ ID NO: 20), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 18); and

[0876] a light chain variable region comprising: a VLCDR1 comprising the amino acid sequence of KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 43), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 44);

[0877] Optionally, wherein the Met residues are each independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or the Asp residues are each independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0878] An antigen-binding molecule of 3E05_var13 or an antigen-binding molecule derived from 3E05_var13 (eg, an antibody having one or more amino acid substitutions) may 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.

[0879] 3E05_var15

[0880] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0881] A heavy chain variable region comprising: a VHCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SYTMS (SEQ ID NO: 36); a VHCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of YISSGGGQTYYPDSVKG (SEQ ID NO: 37); and a VHCDR3 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: NO:38) comprises a VHCDR3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical; and / or

[0882] A light chain variable region comprising: a VLCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of KASQSVDYEGDSSMN (SEQ ID NO: 42); a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of AASTLES (SEQ ID NO: 43); and a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: NO:44) comprises a VLC R3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical.

[0883] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0884] A heavy chain variable region comprising: a VHCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of GFTFSSY (SEQ ID NO: 39); a VHCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SSGGGQTY (SEQ ID NO: 40); and a VHCDR3 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: NO:38) comprises a VHCDR3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical; and / or

[0885] A light chain variable region comprising: a VLCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of KASQSVDYEGDSSMN (SEQ ID NO: 42); a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of AASTLES (SEQ ID NO: 43); and a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: NO:44) comprises a VLC R3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical.

[0886] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0887] a heavy chain variable region comprising: a VHCDR1 comprising at least 90% identity to the amino acid sequence of SYTMS (SEQ ID NO: 36), a VHCDR2 comprising at least 90% identity to the amino acid sequence of YISSGGGQTYYPDSVKG (SEQ ID NO: 37), and a VHCDR3 comprising at least 90% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 38); and / or

[0888] A light chain variable region comprising: a VLCDR1 comprising at least 90% identity to the amino acid sequence of KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 comprising at least 90% identity to the amino acid sequence of AASTLES (SEQ ID NO: 43), and a VLCDR3 comprising at least 90% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 44).

[0889] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0890] a heavy chain variable region comprising: a VHCDR1 comprising at least 90% identity to the amino acid sequence of GFTFSSY (SEQ ID NO: 39), a VHCDR2 comprising at least 90% identity to the amino acid sequence of SSGGGQTY (SEQ ID NO: 40), and a VHCDR3 comprising at least 90% identity to the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 38); and / or

[0891] A light chain variable region comprising: a VLCDR1 comprising at least 90% identity to the amino acid sequence of KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 comprising at least 90% identity to the amino acid sequence of AASTLES (SEQ ID NO: 43), and a VLCDR3 comprising at least 90% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 44).

[0892] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0893] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of SYTMS (SEQ ID NO: 36), a VHCDR2 comprising the amino acid sequence of YISSGGGQTYYPDSVKG (SEQ ID NO: 37), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 38); and

[0894] The light chain variable region comprises: VLCDR1 comprising the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 43), and VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44).

[0895] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 15, for example to provide an antibody, fragment or variant thereof comprising:

[0896] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence SYTMS (SEQ ID NO: 36) optionally comprising 1 or 2 amino acid substitutions, a VHCDR2 comprising the amino acid sequence YISSGGGQTYYPDSVKG (SEQ ID NO: 37) optionally comprising 1 or 2 amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38) optionally comprising 1 or 2 amino acid substitutions; and / or

[0897] A light chain variable region comprising: a VLCDR1 comprising the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), optionally comprising one or two amino acid substitutions; a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 43), optionally comprising one or two amino acid substitutions; and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44), optionally comprising one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0898] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0899] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of SYTMS (SEQ ID NO: 36), a VHCDR2 comprising the amino acid sequence of YISSGGGQTYYPDSVKG (SEQ ID NO: 37), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 38); and

[0900] a light chain variable region comprising: a VLCDR1 comprising the amino acid sequence of KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 43), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 44);

[0901] Optionally, wherein the Met residues are each independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or the Asp residues are each independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0902] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0903] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 39), a VHCDR2 comprising the amino acid sequence of SSGGGQTY (SEQ ID NO: 40), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 38); and

[0904] The light chain variable region comprises: VLCDR1 comprising the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 43), and VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44).

[0905] Amino acid substitutions can be made to provide variant antibodies derived from 3E05_var 15, for example to provide an antibody, fragment or variant thereof comprising:

[0906] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence GFTFSSY (SEQ ID NO: 39) optionally comprising 1 or 2 amino acid substitutions, a VHCDR2 comprising the amino acid sequence SSGGGQTY (SEQ ID NO: 40) optionally comprising 1 or 2 amino acid substitutions, and a VHCDR3 comprising the amino acid sequence HDYYDGGLYYAMDY (SEQ ID NO: 38) optionally comprising 1 or 2 amino acid substitutions; and / or

[0907] A light chain variable region comprising: a VLCDR1 comprising the amino acid sequence KASQSVDYEGDSSMN (SEQ ID NO: 42), optionally comprising one or two amino acid substitutions; a VLCDR2 comprising the amino acid sequence AASTLES (SEQ ID NO: 43), optionally comprising one or two amino acid substitutions; and a VLCDR3 comprising the amino acid sequence QQTNEDPPT (SEQ ID NO: 44), optionally comprising one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0908] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0909] a heavy chain variable region comprising: a VHCDR1 comprising the amino acid sequence of GFTFSSY (SEQ ID NO: 39), a VHCDR2 comprising the amino acid sequence of SSGGGQTY (SEQ ID NO: 40), and a VHCDR3 comprising the amino acid sequence of HDYYDGGLYYAMDY (SEQ ID NO: 38); and

[0910] a light chain variable region comprising: a VLCDR1 comprising the amino acid sequence of KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 comprising the amino acid sequence of AASTLES (SEQ ID NO: 43), and a VLCDR3 comprising the amino acid sequence of QQTNEDPPT (SEQ ID NO: 44);

[0911] Optionally, wherein the Met residues are each independently replaced by an amino acid selected from the group consisting of Ala and Leu, and / or the Asp residues are each independently replaced by an amino acid selected from the group consisting of Ala, Gln and Glu.

[0912] An antigen-binding molecule of 3E05_var15 or an antigen-binding molecule derived from 3E05_var15 (eg, an antibody having one or more amino acid substitutions) may 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.

[0913] 3E05_var16

[0914] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0915] A heavy chain variable region comprising: a VHCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SYTMS (SEQ ID NO: 46); a VHCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of YISSGGGQTYYPDSVKG (SEQ ID NO: 47); and a VHCDR3 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of HDYYEGGLYYAMDY (SEQ ID NO: NO:48) comprises a VHCDR3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical; and / or

[0916] A light chain variable region comprising: a VLCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of KASQSVDYEGDSSMN (SEQ ID NO: 42); a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of AASTLES (SEQ ID NO: 43); and a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: NO:44) comprises a VLC R3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical.

[0917] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0918] A heavy chain variable region comprising: a VHCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of GFTFSSY (SEQ ID NO: 49); a VHCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SSGGGQTY (SEQ ID NO: 50); and a VHCDR3 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of HDYYEGGLYYAMDY (SEQ ID NO: NO:48) comprises a VHCDR3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical; and / or

[0919] A light chain variable region comprising: a VLCDR1 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of KASQSVDYEGDSSMN (SEQ ID NO: 42); a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of AASTLES (SEQ ID NO: 43); and a VLCDR2 comprising at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: NO:44) comprises a VLC R3 that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical.

[0920] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0921] a heavy chain variable region comprising: a VHCDR1 comprising at least 90% identity to the amino acid sequence of SYTMS (SEQ ID NO: 46), a VHCDR2 comprising at least 90% identity to the amino acid sequence of YISSGGGQTYYPDSVKG (SEQ ID NO: 47), and a VHCDR3 comprising at least 90% identity to the amino acid sequence of HDYYEGGLYYAMDY (SEQ ID NO: 48); and / or

[0922] A light chain variable region comprising: a VLCDR1 comprising at least 90% identity to the amino acid sequence of KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 comprising at least 90% identity to the amino acid sequence of AASTLES (SEQ ID NO: 43), and a VLCDR3 comprising at least 90% identity to the amino acid sequence of QQTNEDPPT (SEQ ID NO: 44).

[0923] In one embodiment, an antibody, fragment or variant thereof is provided, comprising:

[0924] a heavy chain variable region comprising: a VHCDR1 comprising at least 90% identity to the amino acid sequence of GFTFSSY (SEQ ID NO: 49), a VHCDR2 comprising at least 90% identity to the amino acid sequence of SSGGGQTY (SEQ ID NO: 50), and a VHCDR3 comprising at least 90% identity to the amino acid sequence of HDYYEGGLYYAMDY (SEQ ID NO: 48); and / or

[0925] A light chain variable region comprising: a VLCDR1 comprising at least 90% identity to the amino acid sequence of KASQSVDYEGDSSMN (SEQ ID NO: 42), a VLCDR2 comprising at least 90% identity to the amino acid sequence of AASTLES (SEQ ID NO: 43), and a VLCDR3 comprising at least 90% identity to the amino acid sequence of QQTNEDPPT (SEQ I...

Claims

1. A nucleic acid encoding an anti-BDCA-2 (CLEC4C) antigen binding molecule, wherein the antigen binding molecule comprises: A heavy chain variable region, wherein the heavy chain variable region comprises an amino acid sequence or its CDR 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, wherein the light chain variable region comprises an amino acid sequence or its CDR 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.

2. An anti-BDCA-2 (CLEC4C) antigen-binding molecule, wherein the antigen-binding molecule comprises: 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, or a CDR thereof; 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, or a CDR thereof.

3. The anti-BDCA-2 (CLEC4C) antigen binding molecule according to claim 2, for use in treating a disease. 4 . A cell expressing the anti-BDCA-2 (CLEC4C) antigen binding agent of claim 2 .

5. A method for preparing the anti-BDCA-2 (CLEC4C) antigen binding agent of claim 2, the method comprising expressing in a cell a nucleic acid sequence encoding an immunoglobulin heavy chain of the anti-BDCA-2 (CLEC4C) binding agent of claim 2 and a nucleic acid sequence encoding an immunoglobulin light chain of the anti-BDCA-2 (CLEC4C) binding agent of claim 2. A cell expressing the nucleic acid of claim 1 .

7. A method for preparing an anti-BDCA-2 (CLEC4C) antigen binding agent, the method comprising expressing the nucleic acid sequence of claim 1 in a cell.

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