Compositions and methods related to receptor pairing

Abstract

To provide an IL12 receptor binding protein.SOLUTION: Provided is an IL-12 receptor binding protein that causes multimerization of IL-12Rβ1 and IL-12Rβ2 and downstream signaling, and that comprises a single domain antibody (sdAb) that specifically binds to IL-12Rβ1 and an sdAb that specifically binds to IL-12Rβ2, in one embodiment, the anti-IL-12Rβ1 sdAb being a VHH antibody, and / or the anti-IL-12Rβ2 sdAb being a VHH antibody.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Cross-reference to related patent applications This application claims priority to U.S. Provisional Patent Application No. 63 / 061,562, filed August 5, 2020, U.S. Provisional Patent Application No. 63 / 078,745, filed September 15, 2020, and U.S. Provisional Patent Application No. 63 / 135,884, filed January 11, 2021, the disclosures of which are incorporated herein by reference in their entireties for all purposes. [Background technology]

[0002] Background to the disclosure Cytokine and growth factor ligands typically signal through homodimeric or heterodimeric cell surface receptors via transphosphorylation via Janus kinases (JAKs / TYKs) or receptor tyrosine kinases (RTKs). However, the number of naturally occurring receptor dimer pairings is limited by the number of naturally occurring ligands encoded within the genome.

[0003] In some cases, cytokines act as multispecific (e.g., bispecific or trispecific) ligands. By binding to the extracellular domains of each of the two receptors, cytokines determine which receptors are included in the dimer. In this way, cytokines act to bridge or bridge receptors in signaling complexes. Association of cytokine receptor domains or subunits results in, inter alia, activation of the intracellular JAK / STAT signaling pathway, which involves one or more of the four Janus kinases (JAK1-3 and TYK2) (Ihle, Nature 377(6550):591-4, 1995; O'Shea and Plenge, Immunity 36(4):542-50, 2012) and activation of several signal transducers and activators of transcription (STAT 1-6) proteins (Delgoffe, et al., Curr Opin Immunol. 23(5):632-8, 2011; Levy and Darnell, Nat Rev Mol Cell Biol. 3(9):651-62, 2002; Murray, J Immunol. 178(5):2623-9, 2007). Cytokines typically bind specifically to the extracellular domain of cell surface receptors, and the JAK / TYK / STAT signaling module is found in many combinations in endogenous cytokine receptor signaling complexes.

[0004] Given that ligands determine the composition of receptor domains or subunits in receptor complexes and that intracellular JAK / TYK and RTK enzymes are degenerate, the number of naturally occurring cytokine and growth factor receptor dimerizations is only a fraction of the total number of receptor pairings theoretically permitted by this system. For example, the human genome encodes approximately 40 different JAK / STAT cytokine receptors. In principle, approximately 1,600 unique homodimeric and heterodimeric cytokine receptor pairs could be generated with the potential to signal through different JAK / TYK / STAT combinations (Bazan, Proc Natl Acad Sci US A. 87(18):6934-8, 1990; Huising et al., J Endocrinol. 189(1):1-25, 2006). However, current knowledge suggests that the human genome encodes fewer than 50 different cytokine ligands (Bazan, Proc Natl Acad Sci US A. 87(18):6934-8, 1990; Huising et al., J Endocrinol. 189(1):1-25, 2006), limiting the scope of cytokine receptor complex signaling to those that can be assembled by natural ligands. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Ihle, Nature 377(6550):591-4, 1995 [Non-patent document 2] O'Shea and Plenge, Immunity 36(4):542-50, 2012 [Non-patent document 3] Delgoffe, et al., Curr Opin Immunol. 23(5):632-8, 2011 [Non-patent document 4] Levy and Darnell, Nat Rev Mol Cell Biol. 3(9):651-62, 2002 [Non-patent document 5] Murray, J Immunol. 178(5):2623-9, 2007 [Non-patent document 6] Bazan, Proc Natl Acad Sci US A. 87(18):6934-8, 1990 [Non-Patent Document 7] Huising et al., J Endocrinol. 189(1):1-25, 2006 Summary of the Invention

[0006] Disclosure Overview In one aspect, provided herein is an IL12 receptor (IL12R) binding protein that specifically binds to IL12Rβ1 and IL12Rβ2, wherein the binding protein causes multimerization of IL12Rβ1 and IL12Rβ2, which multimerization results in association of the intracellular domains of IL12Rβ1 and IL12Rβ2 and intracellular signaling, and the binding protein comprises a single domain antibody (sdAb) that specifically binds to IL12Rβ1 (anti-IL12Rβ1 sdAb) and an sdAb that specifically binds to IL12Rβ2 (anti-IL12Rβ2 sdAb).

[0007] In some embodiments, the anti-IL12Rβ1 sdAb is V H H antibody (anti-IL12Rβ1 V H H antibody) and / or the anti-IL12Rβ2 sdAb is V H H antibody (anti-IL12Rβ2 V H In some embodiments, the anti-IL12Rβ1 sdAb and anti-IL12Rβ2 sdAb are joined directly or by a peptide linker. In some embodiments, the peptide linker comprises 1-50 amino acids. In some embodiments, the IL12R binding protein has a reduced E compared to IL12. maxIn some embodiments, the IL12R binding protein has an increased E compared to IL12. max In some embodiments, the IL12R binding protein has a similar potency compared to that of IL12.

[0008] In another aspect, the present disclosure provides a method for treating a neoplastic disease, such as cancer, in a subject in need thereof, comprising administering to a subject a natural killer, CD4 + T cells and / or CD8 + The method includes administering to the subject an IL12R binding protein described herein that binds to and activates T cells. In some embodiments, the cancer is a solid tumor cancer.

[0009] In another aspect, the disclosure provides an IL27 receptor (IL27R) binding protein that specifically binds to the IL27Rα subunit (IL27Rα) and glycoprotein 130 subunit (gp130), wherein the binding protein causes multimerization of IL27Rα and gp130, which multimerization results in association of the intracellular domains of IL27Rα and gp130 and intracellular signaling, and the binding protein comprises a single domain antibody (sdAb) that specifically binds to IL27Rα (anti-IL27Rα sdAb) and an sdAb that specifically binds to gp130 (anti-gp130 sdAb).

[0010] In some embodiments, the anti-IL27Rα sdAb is V H H antibody (anti-IL27Rα V H H antibody) and / or the anti-gp130 sdAb is V H H antibody (anti-gp130 V H In some embodiments, the anti-IL27Rα sdAb and the anti-gp130 sdAb are joined directly or by a peptide linker. In some embodiments, the peptide linker comprises 1 to 50 amino acids.

[0011] In another aspect, the present disclosure provides a method for treating a neoplastic disease, such as cancer, in a subject in need thereof, comprising administering to a subject a CD8 + T cells, CD4 + The methods include administering to the subject an IL27R binding protein described herein that binds to and activates T cells and / or T regulatory (Treg) cells. In some embodiments, the IL27R binding protein binds to and activates CD8 + In some embodiments, the IL27R binding protein binds to and activates T cells. + CD8 + It binds to and activates T cells. In some embodiments, the cancer is a solid tumor cancer.

[0012] In another aspect, the present disclosure provides IL10 receptor (IL10R) binding proteins that specifically bind to the IL10Rα subunit (IL10Rα, also referred to herein as IL10R1) and IL10Rβ (also referred to herein as IL10R2), wherein the binding proteins cause multimerization of IL10Rα and IL10Rβ, which multimerization results in association of the intracellular domains of IL10Rα and IL10Rβ and intracellular signaling, and the binding proteins comprise a single domain antibody (sdAb) that specifically binds to IL10Rα (anti-IL10Rα sdAb) and an sdAb that specifically binds to IL10Rβ (anti-IL10Rβ sdAb).

[0013] In some embodiments, the anti-IL10Rα sdAb is V H H antibody (anti-IL10Rα V H H antibody) and / or the anti-IL10Rβ sdAb is V H H antibody (anti-IL10Rβ V H In some embodiments, the anti-IL10Rα sdAb and the anti-IL10Rβ sdAb are joined by a peptide linker. In some embodiments, the peptide linker comprises 1 to 50 amino acids.

[0014] In another aspect, the present disclosure provides a method for treating a neoplastic disease, such as cancer, in a subject in need thereof, comprising administering to a subject a CD8 + T cells, CD4 + The method comprises administering to the subject an IL10R binding protein described herein, which binds to and activates T cells, macrophages and / or Treg cells. In some embodiments, the IL10R binding protein provides a longer therapeutic effect than pegylated IL10. In some embodiments, the cancer is a solid tumor cancer.

[0015] In other aspects, the IL10R binding proteins described herein can also be used to treat inflammatory diseases such as Crohn's disease and ulcerative colitis, and autoimmune diseases such as psoriasis, rheumatoid arthritis, and multiple sclerosis.

[0016] In another aspect, the disclosure provides interferon (IFN) lambda receptor (IFNλR) binding proteins that specifically bind to IL10Rβ and the IL28 receptor (IL28R) α subunit (IL28Rα), which cause multimerization of IL10Rβ and IL28Rα and downstream signaling, and include a single domain antibody (sdAb) that specifically binds to IL10Rβ (anti-IL10Rβ sdAb) and an sdAb that specifically binds to IL28Rα (anti-IL28Rα sdAb).

[0017] In some embodiments, the anti-IL10Rβ sdAb is V H H antibody (anti-IL10Rβ V H H antibody) and / or the anti-IL28Rα sdAb is V H H antibody (anti-IL28Rα V H In some embodiments, the anti-IL10Rβ sdAb and the anti-IL28Rα sdAb are joined directly or by a peptide linker. In some embodiments, the peptide linker comprises 1 to 50 amino acids.

[0018] In another aspect, the present disclosure provides a method for treating an infectious disease in a subject in need thereof, comprising: inducing macrophages, CD8 + T cells, CD4 + The method includes administering to the subject an IFNλR-binding protein described herein that binds to and activates T cells, Treg cells, dendritic cells, and / or epithelial cells. In some embodiments, the IFNλR-binding protein binds to and activates macrophages. In some embodiments, the infectious disease is influenza, hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection.

[0019] In another aspect, the present disclosure provides binding proteins that specifically bind to IL10Rα and IL2Rγ, the binding proteins causing multimerization of IL10Rα and IL2Rγ and downstream signaling, and comprising an sdAb that specifically binds to IL10Rα (anti-IL10Rα sdAb) and an sdAb that specifically binds to IL2Rγ (anti-IL2Rγ sdAb).

[0020] In some embodiments, the anti-IL10Rα sdAb is V H H antibody (anti-IL10Rα V H H antibody) and / or the anti-IL2Rγ sdAb is V H H antibody (anti-IL2Rγ V H In some embodiments, the anti-IL10Rα sdAb and anti-IL2Rγ sdAb are joined directly or via a peptide linker. In some embodiments, the peptide linker comprises 1 to 50 amino acids.

[0021] In another aspect, the present disclosure provides a method for treating a neoplastic disease, such as cancer, in a subject in need thereof, comprising administering to a subject a CD8 + T cells and / or CD4 +The method includes administering to the subject a binding protein that specifically binds to IL10Rα and IL2Rγ as described herein, which binds to and activates T cells. In some embodiments, the method does not cause anemia.

[0022] In another aspect, the present disclosure provides a binding protein that specifically binds to a first receptor and a second receptor, wherein the first receptor is interferon gamma receptor 1 (IFNγR1) or IL28Rα, and the second receptor is preferentially expressed on myeloid cells and / or T cells, the binding protein causing multimerization of the first receptor and the second receptor and their downstream signaling, and comprising a single domain antibody (sdAb) that specifically binds to the first receptor and an sdAb that specifically binds to the second receptor.

[0023] In some embodiments, the sdAb that specifically binds to the first receptor is anti-IFNγR1 V H In some embodiments, the sdAb that specifically binds to the first receptor is an anti-IL28Rα V H antibody. H In some embodiments, the first receptor is IFNγR1 and the second receptor is IL2Rγ. In some embodiments, the first receptor is IL28Rα and the second receptor is IL2Rγ. In some embodiments, the sdAb that specifically binds to the first receptor and the sdAb that specifically binds to the second receptor are connected directly or by a peptide linker. In some embodiments, the peptide linker comprises 1 to 50 amino acids.

[0024] In another aspect, the present disclosure provides a method for treating a neoplastic disease, such as cancer, in a subject in need thereof, comprising administering to the subject a binding protein that specifically binds to a first receptor (e.g., IFNγR1 or IL28Rα) and a second receptor (e.g., a receptor preferentially expressed on myeloid cells and / or T cells) described herein, and that binds to and activates myeloid cells and / or T cells. In some embodiments, the binding protein binds to and activates macrophages. In some embodiments, the binding protein binds to and activates CD8 + T cells and / or CD4 + It binds to and activates T cells. [The present invention 1001] An IL12 receptor (IL12R) binding protein that specifically binds to IL12Rβ1 and IL12Rβ2, IL12Rβ1 and IL12Rβ2 multimerization and downstream signaling; and a single domain antibody (sdAb) that specifically binds to IL12Rβ1 (anti-IL12Rβ1 sdAb) and a sdAb that specifically binds to IL12Rβ2 (anti-IL12Rβ2 sdAb); The binding protein. [The present invention 1002] Anti-IL12Rβ1 sdAb V H H antibody (anti-IL12Rβ1 V H H antibody) and / or the anti-IL12Rβ2 sdAb is V H H antibody (anti-IL12Rβ2 V H 1001. The IL12R binding protein of the present invention, which is an IL12R-binding .... [The present invention 1003] The IL12R binding protein of the invention 1001 or 1002, wherein the anti-IL12Rβ1 sdAb and the anti-IL12Rβ2 sdAb are joined by a peptide linker. [The present invention 1004] 1003. An IL12R binding protein of the invention, wherein the peptide linker comprises 1 to 50 amino acids. [The present invention 1005] Reduced E compared to IL12 max IL12R binding protein according to any one of claims 1001 to 1004, comprising: [The present invention 1006] 1006. An IL12R binding protein according to any one of claims 1001 to 1005, which has a similar potency compared to that of IL12. [The present invention 1007] 1. A method for treating cancer in a subject in need thereof, comprising administering to a subject a natural killer, CD4 + T cells and / or CD8 + The method comprises the step of administering to the subject an IL12R-binding protein of any one of claims 1001 to 1006, which binds to and activates T cells. [The present invention 1008] The method of claim 1007, wherein the cancer is a solid tumor cancer. [The present invention 1009] 1. An IL27 receptor (IL27R) binding protein that specifically binds to the IL27R alpha subunit (IL27Rα) and glycoprotein 130 subunit (gp130), IL27Rα and gp130 multimerization and downstream signaling; and a single domain antibody (sdAb) that specifically binds to IL27Rα (anti-IL27Rα sdAb) and an sdAb that specifically binds to gp130 (anti-gp130 sdAb); The binding protein. [The present invention 1010] Anti-IL27Rα sdAb V H H antibody (anti-IL27Rα V H H antibody) and / or anti-gp130 sdAb is V H H antibody (anti-gp130 V H 1009. The IL27R-binding protein of the present invention, which is an IL27R-binding protein (H antibody). [The present invention 1011] 1010. The IL27R-binding protein of any one of claims 1009 to 1010, wherein the anti-IL27Rα sdAb and the anti-gp130 sdAb are connected by a peptide linker. [The present invention 1012] 1011. The IL27R-binding protein of the present invention, wherein the peptide linker comprises 1 to 50 amino acids. [The present invention 1013] 1. A method for treating cancer in a subject in need thereof, comprising administering to a subject a CD8 + T cells, CD4 + The method comprises administering to the subject an IL27R-binding protein of any of claims 1009 to 1012 that binds to and activates T cells and / or T regulatory (Treg) cells. [The present invention 1014] IL27R binding protein is CD8 + The method of the present invention 1013, which binds to and activates T cells. [The present invention 1015] IL27R binding protein is CXCR5 + CD8 + 1015. The method of claim 1013 or 1014, wherein the method binds to and activates a T cell. [The present invention 1016] Any of the methods of claims 1013 to 1015, wherein the cancer is a solid tumor cancer. [The present invention 1017] An IL10 receptor (IL10R) binding protein that specifically binds to the IL10Rα subunit (IL10Rα) and IL10Rβ, IL10Rα and IL10Rβ multimerization and downstream signaling; and single domain antibodies (sdAbs) that specifically bind to IL10Rα (anti-IL10Rα sdAb) and sdAbs that specifically bind to IL10Rβ (anti-IL10Rβ sdAb), The binding protein. [The present invention 1018] Anti-IL10Rα sdAb V H H antibody (anti-IL10Rα V H H antibody) and / or the anti-IL10Rβ sdAb is V H H antibody (anti-IL10Rβ V H 1017 IL10R-binding proteins of the present invention, which are IL10R-binding proteins of the present invention. [The present invention 1019] IL10R-binding protein of any of claims 1017 to 1018, wherein the anti-IL10Rα sdAb and the anti-IL10Rβ sdAb are connected by a peptide linker. [The present invention 1020] 1019. The IL10R binding protein of the invention, wherein the peptide linker comprises 1 to 50 amino acids. [The present invention 1021] 1. A method for treating cancer in a subject in need thereof, comprising administering to a subject a CD8 + T cells, CD4 + The method comprises the step of administering to the subject an IL10R-binding protein of any one of inventions 1017 to 1020 that binds to and activates T cells, macrophages and / or Treg cells. [The present invention 1022] The method of the present invention 1021, wherein the IL10R binding protein provides a longer therapeutic effect than pegylated IL10. [The present invention 1023] The method of claim 1021 or 1022, wherein the cancer is a solid tumor cancer. [The present invention 1024] An interferon (IFN) lambda receptor (IFNλR) binding protein that specifically binds to IL10Rβ and the IL28 receptor (IL28R) alpha subunit (IL28Rα), IL10Rβ and IL28Rα multimerization and downstream signaling; and a single domain antibody (sdAb) that specifically binds to IL10Rβ (anti-IL10Rβ sdAb) and an sdAb that specifically binds to IL28Rα (anti-IL28Rα sdAb); The binding protein. [The present invention 1025] Anti-IL10Rβ sdAb V H H antibody (anti-IL10Rβ V H H antibody) and / or the anti-IL28Rα sdAb is V H H antibody (anti-IL28Rα V H 1024 IFNλR-binding proteins of the present invention, which are IFNλR-binding proteins of the present invention. [The present invention 1026] IFNλR-binding protein of any of claims 1024 to 1025, wherein the anti-IL10Rβ sdAb and the anti-IL28Rα sdAb are connected by a peptide linker. [The present invention 1027] 1026. An IFNλR binding protein of the invention, wherein the peptide linker comprises 1 to 50 amino acids. [The present invention 1028] 1. A method for treating an infectious disease in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of macrophages, CD8 + T cells, CD4 + The method comprises administering to the subject an IFNλR-binding protein of any one of claims 1024 to 1027 that binds to and activates T cells, Treg cells, dendritic cells and / or epithelial cells. [The present invention 1029] The method of claim 1028, wherein the IFNλR binding protein binds to and activates macrophages. [The present invention 1030] 1029. The method of claim 1028 or 1029, wherein the infectious disease is influenza, hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection. [The present invention 1031] A binding protein that specifically binds to IL10Rα and IL2Rγ, IL10Rα and IL2Rγ multimerization and downstream signaling; and an sdAb that specifically binds to IL10Rα (anti-IL10Rα sdAb) and an sdAb that specifically binds to IL2Rγ (anti-IL2Rγ sdAb); The binding protein. [The present invention 1032] Anti-IL10Rα sdAb V H H antibody (anti-IL10Rα V H H antibody) and / or the anti-IL2Rγ sdAb is V H H antibody (anti-IL2Rγ V H The binding protein of the present invention 1031 is an H antibody. [The present invention 1033] The binding protein of any of claims 1031 to 1032, wherein the anti-IL10Rα sdAb and the anti-IL2Rγ sdAb are connected by a peptide linker. [The present invention 1034] The binding protein of the present invention 1033, wherein the peptide linker comprises 1 to 50 amino acids. [This invention 1035] 1. A method for treating cancer in a subject in need thereof, comprising administering to a subject a CD8 + T cells and / or CD4 + The method comprises the step of administering to the subject any of the binding proteins of the present inventions 1031 to 1034 that bind to and activate T cells. [The present invention 1036] The method of the present invention 1035 does not cause anemia. [This invention 1037] A binding protein that specifically binds to a first receptor and a second receptor, wherein the first receptor is interferon gamma receptor 1 (IFNγR1) or IL28Rα, and the second receptor is preferentially expressed on myeloid cells and / or T cells; causing multimerization of the first receptor and the second receptor and their downstream signaling; and a single domain antibody (sdAb) that specifically binds to a first receptor and an sdAb that specifically binds to a second receptor, The binding protein. [The present invention 1038] The sdAb that specifically binds to the first receptor is anti-IFNγR1 V H The binding protein of the present invention 1037 is an H antibody. [This invention 1039] The sdAb that specifically binds to the first receptor is anti-IL28Rα V H The binding protein of the present invention 1037 is an H antibody. [The present invention 1040] The binding protein of any of claims 1037 to 1039, wherein the first receptor is IFNγR1 and the second receptor is IL2Rγ. [This invention 1041] The binding protein of any of claims 1037 to 1039, wherein the first receptor is IL28Rα and the second receptor is IL2Rγ. [The present invention 1042] The binding protein of any of claims 1037 to 1041, wherein an sdAb that specifically binds to a first receptor and an sdAb that specifically binds to a second receptor are connected by a peptide linker. [This invention 1043] The binding protein of the present invention 1042, wherein the peptide linker comprises 5 to 50 amino acids. [This invention 1044] A method for treating cancer in a subject in need thereof, comprising administering to the subject a binding protein of any of claims 1037 to 1043 that binds to and activates myeloid cells and / or T cells. [This invention 1045] The method of claim 1044, wherein the binding protein binds to and activates macrophages. [The present invention 1046] Binding protein is CD8 + T cells and / or CD4 + The method of the present invention 1044, which binds to and activates T cells. [This invention 1047] IL10R-binding protein of any one of claims 1017 to 1020, wherein the anti-IL10Rα sdAb is selected from the group consisting of SEQ ID NOs: 44 to 50, and the anti-IL10Rβ sdAb is selected from the group consisting of SEQ ID Nos: 51 to 57. [This invention 1048] 1047. An IL10R binding protein of the invention, wherein the anti-IL10Rα sdAb is joined to the anti-IL10Rβ sdAb by a linker selected from the group consisting of SEQ ID Nos: 1-23. [This invention 1049] The IL10R binding protein has, in the amino to carboxy direction: a first anti-IL10R sdAb, a second anti-IL10R sdAb linked by a linker according to TIFF2025069262000001.tif154128; The linker is selected from the group consisting of SEQ ID Nos: 1 to 23. The ILR-binding protein of the present invention 1047. [The present invention 1050] 1017. An IL-10 receptor binding protein of the present invention selected from the group consisting of SEQ ID Nos: 194, 209, 210, 211, 213, 218, 226, 233, 238, 244, 250, 203, 205, 207, 269, 212, 217, 219, 224, 227, 237, 239 and 249. DETAILED DESCRIPTION OF THE INVENTION

[0025] Detailed Description of Disclosure I. Introduction The present disclosure provides a composition useful in cell receptor pairing to produce a desired effect useful in disease treatment.Generally, a binding protein is provided, comprising at least a first domain that binds to a first receptor and a second domain that binds to a second receptor, wherein the binding protein causes the functional association of the first and second receptors upon contact with cells that express the first and second receptors, thereby inducing their interaction and resulting in downstream signal transduction.In some embodiments, the first and second receptors are generated in close proximity in response to specific cytokine binding, and are herein referred to as a "natural" cytokine receptor pair.In other embodiments, the binding protein described herein binds to two receptors that do not naturally interact through binding to naturally occurring cytokines, and are herein referred to as a "non-natural" cytokine receptor pair.

[0026] Several advantages are derived from the binding proteins described herein. In the case of natural cytokine receptor pairs, the natural cytokine brings the natural cytokine receptor pair into close proximity (i.e., by its simultaneous binding with the cytokine). However, when some of these natural cytokines are used as therapeutic substances in mammalian, particularly human, subjects, they may also induce several harmful and undesirable effects through various mechanisms, including the presence of natural cytokine receptors on other cell types and binding to those same receptor pairs on other cell types, causing undesired effects or inducing undesired signal transduction. The present disclosure is directed to manipulating the multiple effects of cytokines so that desired therapeutic signal transduction occurs, particularly in desired cell or tissue subtypes, while minimizing undesired activity and / or intracellular signal transduction.

[0027] In some embodiments, the binding proteins described herein are designed so that the binding protein provides maximum desired signaling from a natural cytokine receptor pair on a desired cell type, while signaling weakly from receptors on other undesired cell types, resulting in low or no toxic effects from other undesired cell types. This can be, for example, because the binding protein has a different affinity for the target receptor or a different E compared to the affinity of the natural cytokine for the same receptor. maxThis can be achieved by selecting a binding protein that triggers the binding of a ligand to its cognate receptor. Because different cell types respond with different sensitivities to the binding of a ligand to its cognate receptor, modulating the affinity of the ligand for the receptor relative to the natural cytokine binding facilitates stimulation of the desired activity while reducing undesired activity on non-target cells. Several methods are available for measuring downstream signaling activity. For example, in some embodiments, JAK / STAT signaling can be measured by the presence of phosphorylated receptor and / or phosphorylated STAT. In other embodiments, the expression of one or more downstream genes, whose expression levels can be affected by the level of downstream signaling triggered by the binding protein, can also be measured.

[0028] In other embodiments, the binding proteins described herein provide novel signal transduction by, but not limited to, bringing two receptors into close proximity that do not generally interact significantly or measurably under natural conditions, or by signaling in a particular target cell type by binding to a non-natural cytokine receptor pair. As an example of the latter, beneficial signaling can be achieved by binding to interferon gamma receptor 1 (IFNγR1) or IL28Rα and a second receptor that is uniquely or preferentially expressed on myeloid cells or T cells, while simultaneously targeting activation of IFNγR1 or IL28Rα by contacting the target cells with a binding protein comprising a first domain that specifically binds to IFNγR1 or IL28Rα and a second domain that specifically binds to a receptor uniquely or preferentially expressed on myeloid cells or T cells, thereby targeting the binding protein to these target cells (myeloid cells or T cells) and limiting binding to other cells, thereby avoiding or reducing binding of the same receptor (e.g., IFNγR1 or IL28Rα) expressed on other cells in humans. The various receptor binding proteins described herein can be designed and tailored to bind to specific receptors, or domains or subunits thereof, that are highly expressed on the cell surface of different cell types. By binding to two separate receptors, these receptor binding proteins provide a method for selectively activating or inhibiting specific cell types, resulting in therapeutic and / or prophylactic activity useful in the treatment and / or prevention of diseases such as neoplastic and infectious diseases, including cancer.

[0029] II. Definition As used herein, the term "antibody" refers collectively to: (a) glycosylated and non-glycosylated immunoglobulins (including, but not limited to, mammalian immunoglobulin classes IgG1, IgG2, IgG3, and IgG4) that specifically bind to a target molecule, and (b) IgG(1-4) delta C, which competes with the immunoglobulin from which it was derived for binding to the target molecule. H 2, F(ab')2, Fab, ScFv, V H , V L The term "antibody" refers to immunoglobulin derivatives, including, but not limited to, tetrabodies, triabodies, diabodies, dsFv, F(ab')3, scFv-Fc, and (scFv)2. The term antibody is not limited to immunoglobulins derived from any particular mammalian species, and includes murine, human, equine, and camelid antibodies (e.g., human antibodies).

[0030] The term antibody includes so-called "single domain antibodies" or "sdAbs", as well as "heavy chain antibodies" or "V H H", which are further defined herein. H H has been derived from immunization of camelids (including camels, llamas, and alpacas) (see, e.g., Hamers-Casterman, et al. (1993) Nature 363:446-448), or V H Antibodies with a given specificity can be obtained by screening libraries (e.g., phage libraries) constructed with the H framework. Antibodies with a given specificity can be obtained by screening libraries (e.g., phage libraries) constructed with the V framework obtained from immunization of cartilaginous fish, including but not limited to sharks. HThe antibody may be derived from a non-mammalian source, such as H. The term "antibody" encompasses not only antibodies isolable from natural sources or from animals after immunization with an antigen, but also engineered antibodies, including monoclonal, bispecific, trispecific, chimeric, humanized, human, CDR-grafted, veneered, or deimmunized (e.g., to remove T-cell epitopes) antibodies. The term "human antibody" encompasses not only antibodies obtained from humans, but also antibodies obtained from transgenic mammals containing human immunoglobulin genes, such that, upon stimulation with an antigen, the transgenic animal produces antibodies containing amino acid sequences characteristic of antibodies produced by humans.

[0031] The term antibody refers to the parent antibody and any subsequent modifications that have been made, such as affinity matured, veneered, CDR grafted, humanized, or camelized (V H H), or derivatives thereof, such as binding molecules comprising the binding domains (e.g., CDRs) of an antibody in a non-immunoglobulin scaffold.

[0032] The term "antibody" should not be construed as limited to any particular synthetic means and includes not only naturally occurring antibodies isolatable from natural sources, but also engineered antibody molecules prepared by "recombinant" means, including antibodies isolated from transgenic animals transgenic for human immunoglobulin genes or hybridomas prepared therefrom, antibodies isolated from host cells transformed with nucleic acid constructs that result in the expression of antibodies, and antibodies isolated from combinatorial antibody libraries, including phage display libraries. In one embodiment, the "antibody" is a mammalian immunoglobulin. In some embodiments, the antibody is a "full-length antibody," comprising variable and constant domains that provide binding and effector functions.

[0033] The term antibody includes antibody conjugates that contain modifications to extend their duration of action, such as fusion proteins or conjugation to polymers (eg, PEGylation).

[0034] As used herein, the term "binding protein" refers to a protein that can bind to one or more cell surface receptors or domains or subunits thereof. In some embodiments, the binding protein specifically binds to two different receptors (or domains or subunits thereof), such that the receptors (or domains or subunits) are maintained in close proximity to each other such that the receptors (or domains or subunits), including their domains (e.g., intracellular domains), interact with each other to effect downstream signal transduction.

[0035] As used herein, the term "CDR" or "complementarity-determining region" is intended to mean the non-contiguous antigen-binding sites found in the variable regions of both heavy and light chain immunoglobulin polypeptides. CDRs are described by Kabat et al., J. Biol. Chem. 252:6609-6616 (1977); Kabat et al., US Dept. of Health and Human Services, "Sequences of proteins of immunological interest" (1991) (also referred to herein as Kabat 1991); Chothia et al., J. Mol. Biol. 196:901-917 (1987) (also referred to herein as Chothia 1987); and MacCallum et al., J. Mol. Biol. 262:732-745 (1996), where these definitions include overlapping or subsets of amino acid residues when compared with each other. Nevertheless, the application of either definition to refer to the CDR of an antibody or grafted antibody or variants thereof is intended to be within the scope of this term as defined and used herein. For the purposes of this disclosure, unless otherwise specified, the positioning of CDR2 and CDR3 in the variable region of an antibody follows Kabat numbering or simply "Kabat". The positioning of CDR1 in the variable region of an antibody follows a hybrid of Kabat and Chothia numbering schemes.

[0036] As used herein, the term "conservative amino acid substitution" refers to the amino acid substitution that changes a given amino acid into a different amino acid with similar biochemical properties (for example, charge, hydrophobicity and size).For example, the following groups of amino acids can be considered as each other's conservative amino acid: (1) hydrophobic amino acids: alanine, isoleucine, leucine, tryptophan, phenylalanine, valine, proline and glycine; (2) polar amino acids: glutamine, asparagine, histidine, serine, threonine, tyrosine, methionine and cysteine; (3) basic amino acids: lysine and arginine; and (4) acidic amino acids: aspartic acid and glutamic acid.

[0037] As used herein, the term "interferon lambda receptor" or "IFNλR" refers to the heterodimeric receptor formed by the IL10Rβ receptor and the IL28 receptor alpha (IL28Rα) and bound by the ligand IFNλ. The subunit IL28Rα is also referred to as IFNLR1 (IFNλ receptor 1). The human sequence of IL10Rβ is listed as UniProt ID NO. Q08334. The human sequence of IL28Rα is listed as UniProt ID NO. Q8IU57.

[0038] As used herein, the term "interferon gamma receptor 1" or "IFNγR1" refers to a subunit of the heterodimeric IFNγR formed by the subunit IFNγR1 and the subunit IFNγR2 and bound by the ligand IFNγ. The amino acid sequence of the human IFNγR1 polypeptide is known and is set forth as UniProt ID NO. P15260.

[0039] As used herein, the term "interleukin-12 receptor" or "IL12R" refers to a heterodimeric receptor formed by the subunit IL12R β1 (IL12Rβ1) and the subunit IL12R β2 (IL12Rβ2), which is bound by its cognate ligand, IL12. The amino acid sequence of human IL12Rβ1 is known and is set forth as UniProt ID NO. P42701. The amino acid sequence of human IL12Rβ2 is known and is set forth as UniProt ID NO. Q99665.

[0040] As used herein, the term "interleukin-27 receptor" or "IL27R" refers to the heterodimeric receptor formed by the subunits IL27R alpha (IL27Rα) and glycoprotein 130 (gp130) and bound by the ligand IL27. The human sequence of IL27Rα is set forth as UniProt ID NO. Q6UWB1. The human sequence of gp130 is set forth as UniProt ID NO. Q13514.

[0041] As used herein, the term "interleukin-10 receptor" or "IL10R" refers to a tetrameric receptor formed by two IL10R α subunits (IL10Rα) and two IL10R β subunits (IL10Rβ) and bound by the ligand IL10. The amino acid sequence of human IL10Rα is set forth as UniProt ID NO. Q13651. The amino acid sequence of human IL10Rβ is set forth as UniProt ID NO. Q08334.

[0042] As used herein, the term "interleukin-2 receptor gamma" or "IL2Rγ" refers to the gamma subunit of the trimeric IL2R. IL2Rγ is also known as CD132. The amino acid sequence of human IL2Rγ is set forth as UniProt ID NO. P31785.

[0043] As used herein, the term "linker" refers to a link between two elements, such as protein domains. The linker can be a covalent bond or a peptide linker. The term "bond" refers to a chemical bond, such as an amide bond or a disulfide bond, or any type of bond resulting from a chemical reaction, such as chemical conjugation. The term "peptide linker" refers to an amino acid or polypeptide that can be used to link two protein domains to provide space and / or flexibility between the two protein domains.

[0044] As used herein, the term "multimerization" refers to the bringing into close proximity of two or more cell surface receptors, or domains or subunits thereof, such that the receptors, or domains or subunits thereof, can interact with each other to cause downstream signaling.

[0045] As used herein, the term "proximity" refers to the spatial proximity or physical distance between two cell surface receptors, or domains or subunits thereof, after a binding protein described herein binds to the two cell surface receptors, or domains or subunits thereof. In some embodiments, after a binding protein binds to the cell surface receptors, or domains or subunits thereof, the spatial proximity between the cell surface receptors, or domains or subunits thereof, can be, for example, less than about 500 angstroms, such as a distance of about 5 angstroms to about 500 angstroms. In some embodiments, the spatial proximity will be less than about 5 angstroms, less than about 20 angstroms, less than about 50 angstroms, less than about 75 angstroms, less than about 100 angstroms, less than about 150 angstroms, less than about 250 angstroms, less than about 300 angstroms, less than about 350 angstroms, less than about 400 angstroms, less than about 450 angstroms, or less than about 500 angstroms. In some embodiments, the spatial proximity will be less than about 100 Angstroms. In some embodiments, the spatial proximity will be less than about 50 Angstroms. In some embodiments, the spatial proximity will be less than about 20 Angstroms. In some embodiments, the spatial proximity will be less than about 10 Angstroms. In some embodiments, the spatial proximity will range from about 10-100 Angstroms, about 50-150 Angstroms, about 100-200 Angstroms, about 150-250 Angstroms, about 200-300 Angstroms, about 250-350 Angstroms, about 300-400 Angstroms, about 350-450 Angstroms, or about 400-500 Angstroms. In some embodiments, the spatial proximity will be less than about 250 angstroms, alternatively less than about 200 angstroms, alternatively less than about 150 angstroms, alternatively less than about 120 angstroms, alternatively less than about 100 angstroms, alternatively less than about 80 angstroms, alternatively less than about 70 angstroms, or alternatively less than about 50 angstroms.

[0046] As used herein, the term "downstream signaling" refers to an intracellular signaling process that is triggered by the interaction of two or more cell surface receptors that are brought into close proximity to one another.

[0047] As used herein, the term "percent (%) sequence identity" when used in the context of a nucleic acid or polypeptide refers to a sequence having at least 50% sequence identity with a reference sequence. Alternatively, the percent sequence identity can be any integer between 50% and 100%. In some embodiments, a sequence has at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with a reference sequence as determined by BLAST using standard parameters, as described below.

[0048] In sequence comparison, usually, one sequence serves as reference sequence, and test sequence is compared to it.When using sequence comparison algorithm, test sequence and reference sequence are input into computer, and if necessary, coordinates of subsequence are designated, and program parameters of sequence algorithm are designated.Default program parameters can be used, or other parameters can be designated.Sequence comparison algorithm then calculates the percent sequence identity of test sequence with reference sequence according to program parameters.

[0049] The comparison window includes reference to any one segment of any number of contiguous positions, e.g., a segment of at least 10 residues. In some embodiments, the comparison window has 10 to 600 residues, e.g., about 10 to about 30 residues, about 10 to about 20 residues, about 50 to about 200 residues, or about 100 to about 150 residues, within which a sequence can be compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned.

[0050] Suitable algorithms for determining percent sequence identity and sequence similarity are the BLAST and BLAST 2.0 algorithms described in Altschul et al. (1990) J. Mol. Biol. 215: 403-410 and Altschul, et al. (1977) Nucleic Acids Res. 25: 3389-3402, respectively. Software for performing BLAST analysis is publicly available through the website of the National Center for Biotechnology Information (NCBI). This algorithm involves first identifying high-scoring sequence pairs (HSPs) by identifying short words of length W in a query sequence that match or meet a certain positive threshold score T when aligned with words of the same length in a database sequence. T is referred to as the neighborhood word score threshold (Altschul et al., supra). These initial neighborhood word hits serve as seeds for initiating searches to find longer HSPs containing them. The word hits are then extended in both directions for each sequence as far as the total alignment score can be increased. For nucleotide sequences, the total score is calculated using the parameters M (reward score for a pair of matching residues; always >0) and N (penalty score for mismatching residues; always <0). For amino acid sequences, a scoring matrix is ​​used to calculate the total score. Extension of the word hit in each direction is stopped until the total alignment score is reduced by an amount X from its maximum achieved value; the accumulation of alignment of one or more negatively scoring residues causes the total score to fall below zero; or the end of either sequence is reached. The BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment. The BLASTN program (for nucleotide sequences) works similarly, but uses as defaults a word size (W) of 28, an expectation (E) of 10, M=1, N=-2, and a comparison of both strands.For amino acid sequences, the BLASTP program uses as defaults a word size (W) of 3, an expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff & Henikoff, Proc. Natl. Acad. Sci. USA 89:10915 (1989)).

[0051] The BLAST algorithm also performs a statistical analysis of the similarity between two sequences (see, e.g., Karlin & Altschul, Proc. Nat'l. Acad. Sci. USA 90:5873-5787 (1993)). One measure of similarity provided by the BLAST algorithm is the smallest sum probability (P(N)), which provides an indication of the probability that a match between two nucleotide or amino acid sequences would occur by chance. For example, amino acid sequences are selected based on the smallest sum probability of less than about 0.01, more preferably less than about 10, in comparing the test amino acid sequence with the reference amino acid sequence. -5 less than, most preferably about 10 -20 If the sequence is less than 1, it is considered similar to the reference sequence.

[0052] As used herein, the term "single domain antibody" or "sdAb" refers to an antibody having a single monomeric variable antibody domain. An sdAb is capable of selectively binding to a specific antigen. V, as further defined below, H The H antibody is an example of an sdAb.

[0053] As used herein, the term "specifically bind" refers to the degree of selectivity or affinity with which one molecule binds to another molecule. In relation to a binding pair (e.g., a binding protein / receptor, ligand / receptor, antibody / antigen, antibody / ligand, or antibody / receptor binding pair described herein), if the first molecule of the binding pair does not bind significantly to other components present in the sample, the first molecule of the binding pair is said to specifically bind to the second molecule of the binding pair. If the affinity of the first molecule for the second molecule is at least 2 times greater, alternatively at least 5 times greater, alternatively at least 10 times greater, alternatively at least 20 times greater, or alternatively at least 100 times greater than the affinity of the first molecule for other components present in the sample, the first molecule of the binding pair is said to specifically bind to the second molecule.

[0054] In certain embodiments, the bispecific V H H 2 V in binding proteins H H is V H The equilibrium dissociation constant between H and the receptor, as determined by, for example, Scatchard analysis (Munsen, et al. 1980 Analyt. Biochem. 107:220-239), is approximately 10 6 Larger than M, alternatively about 10 8 Larger than M, alternatively about 10 10 Larger than M, alternatively about 10 11 Larger than M, alternatively about 10 10 Larger than M, about 10 12 If M is greater than M, it binds to a receptor (e.g., the first or second receptor of a natural or non-natural receptor pair). Specific binding can be assessed using techniques known in the art, including, but not limited to, competitive ELISA, BIACORE® assay, and / or KINEXA® assay.

[0055] As used herein, the terms "subject," "recipient," "individual," or "patient" refer to any mammalian subject, particularly humans, for whom diagnosis, treatment, or therapy is desired. These terms may also be used interchangeably herein. For purposes of treatment, "mammal" refers to any animal classified as a mammal, including humans, domestic and farm animals, and exhibition, sport, or pet animals, such as dogs, horses, cats, cows, sheep, goats, pigs, etc. In some embodiments, the mammal is a human.

[0056] The terms "treat," "treating," "treatment," and the like refer to an action initiated with respect to a subject after a disease, disorder, or condition, or a symptom thereof, has been diagnosed, observed, or otherwise, in a subject, to temporarily or permanently eliminate, reduce, inhibit, alleviate, or ameliorate at least one underlying cause of, or at least one symptom associated with, the disease, disorder, or condition afflicting the subject (e.g., administering a binding protein described herein, or a pharmaceutical composition comprising same). Treatment includes an action taken with respect to a subject suffering from a disease, which action results in the inhibition of the disease in the subject (e.g., halting the progression of, or ameliorating one or more symptoms associated with, the disease, disorder, or condition).

[0057] As used herein, the terms "prevent," "preventing," "prevention," and the like generally refer to actions initiated in a subject prior to the onset of a disease, disorder, condition, or symptoms thereof, such that the subject temporarily or permanently prevents, suppresses, inhibits, or reduces the risk of, or delays the onset of, a disease, disorder, condition, or other (e.g., as determined by the absence of clinical symptoms) predisposed to having a particular disease, disorder, or condition due to genetic, experiential, or environmental factors. In certain instances, the terms "prevent," "preventing," and "prevention" are also used to refer to slowing the progression of a disease, disorder, or condition from its current state to a more deleterious state.

[0058] As used herein, "V H The term "H" refers to a type of sdAb that has a single monomeric heavy chain variable antibody domain. Such antibodies can be found in or produced from camelid mammals (e.g., camels, llamas), which naturally lack light chains.

[0059] As used herein, "V H H 2 " refers to two V groups joined together by a linker (e.g., a covalent bond or a peptide linker). H H. "Bispecific V H H 2 " refers to a first V that binds to a first receptor, or a domain or subunit thereof. H H and a second V that binds to a second receptor, or a domain or subunit thereof. H H and V H H 2 This refers to

[0060] III. Compositions and Methods The present disclosure describes a variety of receptor binding proteins that bind to either natural cytokine receptor pairs or domains or subunits thereof, or non-natural cytokine receptor pairs or domains or subunits thereof, to create signaling diversity not observed with natural receptor pairings. A variety of receptor binding proteins can be screened for binding to the receptor pairs or domains or subunits thereof, and for signaling in therapeutically relevant cell types.

[0061] Receptor-binding proteins that bind to natural receptor pairs IL-12 receptor binding protein The IL12 receptor (IL12R) comprises the subunits IL12Rβ1 and IL12Rβ2. Provided herein are IL12R binding proteins that specifically bind to IL12Rβ1 and IL12Rβ2. In some embodiments, the IL12R binding protein binds to mammalian cells that express both IL12Rβ1 and IL12Rβ2. In some embodiments, the IL12R binding protein is a bispecific V-binding protein described below. H H 2 In other embodiments, the IL12R binding protein can be V H It may comprise a first domain which is H and a second domain which may be a fragment of IL12 or for example an scFv.

[0062] The IL12R binding protein is the first V that binds to IL12Rβ1. H H (anti-IL12 Rβ1 V H H antibody) and a second V that binds to IL12Rβ2. H H (anti-IL12Rβ2 V H H antibody) and expressing IL12Rβ1 and IL12Rβ2, e.g., natural killer or T cells (e.g., CD4 + T cells and / or CD8 + Bispecific V receptors that upon binding to T cells trigger dimerization of the two receptor subunits and downstream signaling H H2 It can be.

[0063] Anti-IL12Rβ1 V H H antibody and anti-IL12Rβ2 V H The anti-IL12Rβ1 V antibody can be linked to the IL12Rβ1 V antibody. For example, the linker can be a simple covalent bond or a peptide linker. The peptide linker can contain 1 to 50 amino acids (e.g., 2 to 50, 5 to 50, 10 to 50, 15 to 50, 20 to 50, 25 to 50, 30 to 50, 35 to 50, 40 to 50, 45 to 50, 2 to 45, 2 to 40, 2 to 35, 2 to 30, 2 to 25, 2 to 20, 2 to 15, 2 to 10, or 2 to 5 amino acids). H H antibody and anti-IL12Rβ2 V H The peptide linker linking the H antibodies can be a flexible glycine-serine linker. The linker can also be a chemical linker, such as a synthetic polymer, e.g., a polyethylene glycol (PEG) polymer.

[0064] Anti-IL12Rβ1 V H The H antibody can have a sequence that has at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) sequence identity to any one of SEQ ID NOs:105-111.

[0065] Anti-IL12Rβ2 V H The H antibody can have a sequence that has at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) sequence identity to any one of SEQ ID NOs:58-63.

[0066] Anti-IL12Rβ2 V HThe H antibody can have a sequence that has at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) sequence identity to any one of SEQ ID NOs:112-117.

[0067] In some embodiments, the IL12 receptor binding proteins described herein are selected from the group consisting of anti-IL12Rβ1 V, ... H H, linker, and anti-IL12Rβ2 V H It can have H.

[0068] Table 1. IL12 receptor binding protein constructs TIFF2025069262000002.tif91150TIFF2025069262000003.tif225150TIFF2025069262000004.tif34150

[0069] In some embodiments, the IL12R binding protein is an E max Reduced E compared to max E max reflects the maximal response level in a cell type that can be obtained by a ligand (e.g., a binding protein described herein or a natural cytokine (e.g., IL12)). In some embodiments, the IL12R binding proteins described herein inhibit the E1 response caused by IL12. max In some embodiments, the E of the IL12R binding protein is at least 1% (e.g., 1% to 100%, 10% to 100%, 20% to 100%, 30% to 100%, 40% to 100%, 50% to 100%, 60% to 100%, 70% to 100%, 80% to 100%, 90% to 100%, 1% to 90%, 1% to 80%, 1% to 70%, 1% to 60%, 1% to 50%, 1% to 40%, 1% to 30%, 1% to 20%, or 1% to 10%). maxThe IL12R binding protein can be used to target the most desirable cell types (e.g., CD8 + T cells) in max , and reduced E in other cell types (e.g., natural killer cells) max In some embodiments, the E in natural killer cells caused by the IL12R binding proteins described herein can be max is a T cell (e.g., CD8 + T cells) max In other embodiments, the E of an IL12R binding protein described herein is 1% to 100% (e.g., 10% to 100%, 20% to 100%, 30% to 100%, 40% to 100%, 50% to 100%, 60% to 100%, 70% to 100%, 80% to 100%, 90% to 100%, 1% to 90%, 1% to 80%, 1% to 70%, 1% to 60%, 1% to 50%, 1% to 40%, 1% to 30%, 1% to 20%, or 1% to 10%). max is the E of IL-12, the natural ligand max greater than (e.g., at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% greater).

[0070] The IL12R binding proteins described herein are useful in treating neoplastic diseases, such as cancer (e.g., solid tumor cancer; e.g., non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), or melanoma) in a subject in need thereof. IL12R binding proteins bind to natural killer, CD4 + T cells and / or CD8 + IL12R-binding proteins bind to and activate T cells. IL12R-binding proteins can induce different levels of downstream signaling in different cell types. For example, anti-IL12Rβ1 V in IL12R-binding proteins H H antibody and anti-IL12Rβ2 V HBy varying the length of the linker between the H antibody, the IL12R binding protein can induce higher levels of downstream signaling in desirable cell types compared to undesirable cell types. In some embodiments, by varying the linker length, the IL12R binding protein induces higher levels of downstream signaling in T cells (e.g., CD8) compared to the level of downstream signaling in natural killer cells, a cell type that expresses both the IL12Rβ1 and IL12Rβ2 receptors but can become toxic if activated too strongly. + In other embodiments, different anti-IL12Rβ1 V / T antibodies with different binding affinities can induce higher levels of downstream signaling in the target T cell. H H antibodies and different anti-IL12Rβ2 V antibodies with different binding affinities H H antibodies can be combined to create different IL12R binding proteins. Additionally, the orientation of the two antibodies in the binding protein can be changed to create different binding proteins (i.e., anti-IL12Rβ1 V H antibodies). H H antibody-linker-anti-IL12Rβ2 V H H antibody, or anti-IL12Rβ2 V H H antibody-linker-anti-IL12Rβ1 V H H antibodies). Different IL12R binding proteins can be screened to find the ideal binding protein that causes higher levels of downstream signaling in desirable cell types compared to undesirable cell types. In some embodiments, the IL12R binding protein can be a partial agonist that exerts different activities on different cell types, e.g., T cells vs. natural killer cells. For example, selective activation of T cells versus natural killer cells is desirable to avoid toxicity associated with IL12-activated natural killer cells. In some embodiments, the IL12R binding protein is a partial agonist, where the partial agonist selectively activates T cells over NK cells. In some embodiments, T cells (e.g., CD8 +The level of downstream signaling in T cells is at least 1.1, 1.5, 2, 3, 5, or 10 times the level of downstream signaling in natural killer cells.

[0071] IL-27 receptor binding protein The IL27 receptor (IL27R) comprises an IL27Rα subunit (IL27Rα) and a glycoprotein 130 subunit (gp130). Provided herein are IL27R binding proteins that specifically bind to IL27Rα and gp130. In some embodiments, the IL27R binding protein binds to mammalian cells that express both IL27Rα and gp130. In some embodiments, the IL27R binding protein is a bispecific V-type IL27R binding protein, as described below. H H 2 In other embodiments, the IL27R binding protein can be V H The antibody may comprise a first domain which is H and a second domain which may be a fragment of IL27 or, for example, an scFv.

[0072] The IL27R-binding protein is a first V that binds to IL27Rα. H H (anti-IL27Rα V H H antibody) and a second V that binds to gp130 H H (anti-gp130 V H H antibody) and expressing IL27Rα and gp130, e.g., CD8 + T cells, CD4 + Bispecific V, which upon binding to T cells and / or T regulatory (Treg) cells, triggers dimerization of the two receptor subunits and downstream signaling H H 2 It can be.

[0073] Anti-IL27Rα V H H antibody and anti-gp130 V HThe anti-IL27Rα V antibody can be linked to the IL27Rα V antibody. For example, the linker can be a simple covalent bond or a peptide linker. The peptide linker can contain 1 to 50 amino acids (e.g., 2 to 50, 5 to 50, 10 to 50, 15 to 50, 20 to 50, 25 to 50, 30 to 50, 35 to 50, 40 to 50, 45 to 50, 2 to 45, 2 to 40, 2 to 35, 2 to 30, 2 to 25, 2 to 20, 2 to 15, 2 to 10, or 2 to 5 amino acids). H H antibody and anti-gp130 V H The peptide linker linking the H antibodies can be a flexible glycine-serine linker. The linker can also be a chemical linker, such as a synthetic polymer, e.g., a polyethylene glycol (PEG) polymer.

[0074] Anti-IL27Rα V H The H antibody can have a sequence that has at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) sequence identity to any one of SEQ ID NOs:70-75.

[0075] Anti-IL27Rα V H The H antibody can have a sequence that has at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) sequence identity to any one of SEQ ID NOs:125-130.

[0076] anti-gp130v H The H antibody can have a sequence that has at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) sequence identity to any one of SEQ ID NOs:24-29.

[0077] anti-gp130v HThe H antibody can have a sequence that has at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) sequence identity to any one of SEQ ID NOs:83-89.

[0078] In some embodiments, the IL27R binding protein is a IL27-induced E max Reduced E compared to max E max reflects the maximal response level in a cell type that can be obtained by a ligand (e.g., a binding protein described herein or a natural cytokine (e.g., IL27)). In some embodiments, the IL27R binding proteins described herein inhibit the E1 response caused by IL27. max In other embodiments, the E of an IL27R-binding protein described herein is at least 1% (e.g., 1% to 100%, 10% to 100%, 20% to 100%, 30% to 100%, 40% to 100%, 50% to 100%, 60% to 100%, 70% to 100%, 80% to 100%, 90% to 100%, 1% to 90%, 1% to 80%, 1% to 70%, 1% to 60%, 1% to 50%, 1% to 40%, 1% to 30%, 1% to 20%, or 1% to 10%). max is the E of the natural ligand IL27 max In some embodiments, the E of the IL27R binding protein is increased by varying the linker length of the IL27R binding protein. max IL27R binding proteins can alter E in the most desirable cell types. max , and reduced E in other cell types max can cause.

[0079] The IL27R-binding proteins described herein are useful in treating neoplastic diseases, such as cancer (e.g., solid tumor cancer; e.g., non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC) or melanoma), and / or infectious diseases (e.g., bacterial infections and viral infections (e.g., viral infections caused by hepatitis C virus (HCV), human papillomavirus (HPV) or human immunodeficiency virus (HIV)) in a subject in need thereof. The IL27R-binding proteins are useful in treating neoplastic diseases, such as cancer (e.g., solid tumor cancer; e.g., non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC) or melanoma), and / or infectious diseases (e.g., bacterial infections and viral infections caused by hepatitis C virus (HCV), human papillomavirus (HPV) or human immunodeficiency virus (HIV)). The IL27R-binding proteins are useful in treating CD8 + T cells, CD4 + IL27R-binding proteins bind to and activate T cells and / or T regulatory (Treg) cells. IL27R-binding proteins can induce different levels of downstream signaling in different cell types. For example, anti-IL27Rα V in IL27R-binding proteins H H antibody and anti-gp130 V H By varying the length of the linker between the H antibody, the IL27R binding protein can induce higher levels of downstream signaling in desirable cell types compared to undesirable cell types. In some embodiments, by varying the linker length, the IL27R binding protein induces higher levels of downstream signaling in T cells (e.g., CD8 T cells) compared to the level of downstream signaling in other cells. + In other embodiments, different anti-IL27Rα V receptors with different binding affinities can induce higher levels of downstream signaling in the target T cell. H H antibodies and different anti-gp130 V antibodies with different binding affinities H H antibodies can be combined to create different IL27R binding proteins. Additionally, the orientation of the two antibodies in the binding protein can be changed to create different binding proteins (i.e., anti-IL27Rα V H H antibody-linker-anti-gp130 V H H antibody, or anti-gp130 V H H antibody-linker-anti-IL27Rα V HIn some embodiments, T cells (e.g., CD8 H antibodies) can be generated. Different IL27R binding proteins can be screened to find the ideal binding protein that induces higher levels of downstream signaling in desirable cell types compared to undesirable cell types. + The level of downstream signaling in the T cell) is at least 1.1, 1.5, 2, 3, 5, or 10 times the level of downstream signaling in the other cell.

[0080] In particular, IL27R-binding proteins bind to CD8 + In some embodiments, the IL27R binding protein binds to and activates T cells. + CD8 + IL27 binds to and activates T cells. For example, during viral infection, IL27 binds to memory-like CXCR5 + CD8 + It is known to promote and maintain the rapid division of T cells. CXCR5 + CD8 + T cells maintain T cell responses during persistent infection or cancer and CD8 + The IL27R binding proteins described herein can promote a proliferative burst of T cells. Thus, the IL27R binding proteins described herein are useful for maintaining and enhancing self-renewing T cells in chronic infections and neoplastic diseases such as cancer.

[0081] IL10 receptor binding protein The IL10 receptor (IL10R) comprises an IL10Rα subunit (IL10Rα) and an IL10Rβ subunit (IL10Rβ). Provided herein are IL10R binding proteins that specifically bind to IL10Rα and IL10Rβ. In some embodiments, the IL10R binding protein binds to mammalian cells that express both IL10Rα and IL10Rβ. In some embodiments, the IL10R binding protein is a bispecific V-type IL10R binding protein, as described below. H H 2 In other embodiments, the IL10R binding protein can be VH It may comprise a first domain which is H and a second domain which may be a fragment of IL10 or, for example, an scFv.

[0082] The IL10R binding protein is the first V that binds to IL10Rα. H H (anti-IL10Rα V H H antibody) and a second V that binds to IL10Rβ. H H (anti-IL10Rβ V H H antibody) and expressing IL10Rα and IL10Rβ, e.g., T cells (e.g., CD8 + T cells or CD4 + Bispecific V, which triggers dimerization of the two receptor subunits and downstream signaling upon binding to T cells, macrophages, and / or Treg cells H H 2 It can be.

[0083] Anti-IL10Rα V H H antibody and anti-IL10Rβ V H The anti-IL10Rα V antibody can be linked to the IL10Rα V antibody. For example, the linker can be a simple covalent bond or a peptide linker. The peptide linker can contain 1 to 50 amino acids (e.g., 2 to 50, 5 to 50, 10 to 50, 15 to 50, 20 to 50, 25 to 50, 30 to 50, 35 to 50, 40 to 50, 45 to 50, 2 to 45, 2 to 40, 2 to 35, 2 to 30, 2 to 25, 2 to 20, 2 to 15, 2 to 10, or 2 to 5 amino acids). H H antibody and anti-IL10Rβ V H The peptide linker linking the H antibodies can be a flexible glycine-serine linker. The linker can also be a chemical linker, such as a synthetic polymer, e.g., a polyethylene glycol (PEG) polymer.

[0084] Anti-IL10Rα V HThe H antibody can have a sequence that has at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) sequence identity to any one of SEQ ID NOs:44-50.

[0085] Anti-IL10Rα V H The H antibody has a CDR1 that has at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) sequence identity to any one of SEQ ID NOs: 388, 391, 394, 397, 400, 403 and 406, or has 0, 1, 2 or 3 amino acid changes, optionally conservative amino acid changes, relative to any one of SEQ ID NOs: 388, 391, 394, 397, 400, 403 and 406; a CDR2 that has at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) sequence identity to, or has 0, 1, 2 or 3 amino acid changes, optionally conservative amino acid changes, to, the sequence of any one of SEQ ID NOs: 389, 392, 395, 398, 401, 404 and 407; and a CDR2 that has at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) sequence identity to, or has 0, 1, 2 or 3 amino acid changes, optionally conservative amino acid changes, to, the sequence of any one of SEQ ID NOs: 390, 393, 396, 399, 402, 405 and 408. It is possible to have a sequence containing a CDR3 with 0, 1, 2 or 3 amino acid changes, optionally conservative amino acid changes, relative to the sequence of any one of 390, 393, 396, 399, 402, 405 and 408.

[0086] Anti-IL10Rβ V HThe H antibody can have a sequence that has at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) sequence identity to any one of SEQ ID NOs:51-57.

[0087] Anti-IL10Rβ V H The H antibody has a CDR1 that has at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) sequence identity to any one of SEQ ID NOs: 409, 412, 415, 418, 421, 424 and 427, or has 0, 1, 2 or 3 amino acid changes, optionally conservative amino acid changes, relative to any one of SEQ ID NOs: 409, 412, 415, 418, 421, 424 and 427; a CDR2 that has at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) sequence identity to, or has 0, 1, 2 or 3 amino acid changes, optionally conservative amino acid changes, to, the sequence of any one of SEQ ID NOs: 410, 413, 416, 419, 422, 425 and 428; and a CDR2 that has at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) sequence identity to, or has 0, 1, 2 or 3 amino acid changes, optionally conservative amino acid changes, to, the sequence of any one of SEQ ID NOs: 411, 414, 417, 420, 423, 426 and 429. It is possible to have a sequence containing a CDR3 with 0, 1, 2 or 3 amino acid changes, optionally conservative amino acid changes, relative to any one of sequences 411, 414, 417, 420, 423, 426 and 429.

[0088] Anti-IL10Rβ V HThe H antibody can have a sequence that has at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) sequence identity to any one of SEQ ID NOs:99-104.

[0089] In some embodiments, the IL10R binding protein is an E max Reduced E compared to max E max reflects the maximum response level in a cell type that can be obtained by a ligand (e.g., a binding protein described herein or a natural cytokine (e.g., IL10)). In some embodiments, the IL10R binding proteins described herein inhibit the E10-induced E21. max In some embodiments, the E of the IL10R binding protein is at least 1% (e.g., 1% to 100%, 10% to 100%, 20% to 100%, 30% to 100%, 40% to 100%, 50% to 100%, 60% to 100%, 70% to 100%, 80% to 100%, 90% to 100%, 1% to 90%, 1% to 80%, 1% to 70%, 1% to 60%, 1% to 50%, 1% to 40%, 1% to 30%, 1% to 20%, or 1% to 10%). max The IL10R binding protein can be used to target the most desirable cell types (e.g., CD8 + T cells) in max , and reduced E in other cell types (e.g., macrophages) max In some embodiments, the E in macrophages caused by the IL10R binding proteins described herein can be max is triggered by IL10R-binding proteins, T cells (e.g., CD8 + T cells) maxIn other embodiments, the E of an IL10R binding protein described herein is 1% to 100% (e.g., 10% to 100%, 20% to 100%, 30% to 100%, 40% to 100%, 50% to 100%, 60% to 100%, 70% to 100%, 80% to 100%, 90% to 100%, 1% to 90%, 1% to 80%, 1% to 70%, 1% to 60%, 1% to 50%, 1% to 40%, 1% to 30%, 1% to 20%, or 1% to 10%). max is the E of the natural ligand IL10 max greater than (e.g., at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% greater).

[0090] In some embodiments, the present disclosure provides an anti-IL10Rα V H H, optional linker, and anti-IL10Rβ2 V H In some embodiments, the N-terminal V of the IL-10 binding molecule is H H is anti-IL10Rα V H H and the C-terminal V of the IL-10 receptor-binding protein H H is anti-IL10Rβ V H H and V H In some embodiments, the N-terminal V of the IL-10 receptor binding protein may optionally contain a linker between the V and H. H H is anti-IL10Rβ V H H and the C-terminal V of the IL-10 receptor-binding protein H H is anti-IL10Rα V H H and V H It may optionally include a linker between the H. In some embodiments, the IL-10 receptor binding protein may be provided with a purification handle, such as, but not limited to, an Ala-Ser-His-His-His-His-His-His ("ASH6", SEQ ID NO:430) purification handle to facilitate purification of the receptor binding protein by chelating peptide-immobilized metal affinity chromatography ("CP-IMAC" as described in U.S. Pat. No. 4,569,794).

[0091] Anti-IL10Rα V H H, linker and anti-IL10Rβ2 V H A series of 98 IL-10 receptor binding proteins (SEQ ID NOs:192-289) containing the VH and ASH6 ​​(SEQ ID NO:430) purified handles were prepared substantially according to Examples 1-4 herein and evaluated for IL-10 activity substantially according to Examples 5 and 6 herein. The VH of these 98 IL-10 receptor binding proteins H The arrangement of the H, linker and purification handle elements is provided in Table 2 below.

[0092] Table 2: IL-10 receptor-binding proteins TIFF2025069262000005.tif191146TIFF2025069262000006.tif223146TIFF2025069262000007.tif223146TIFF2025069262000008.tif63146

[0093] As provided in more detail in Example 3 herein, nucleic acid sequences encoding SEQ ID Nos: 192-289 were synthesized as SEQ ID Nos: 290-387, respectively, inserted into a recombinant expression vector, expressed in HEK293 cells in a 24-well plate format, and purified substantially according to Example 4. Supernatants containing IL-10 receptor binding proteins of SEQ ID Nos: 192-298 were evaluated for activity using unstimulated and wild-type human IL-10 as controls substantially according to Examples 5 and 6 herein. The results of these experiments are provided in Table 3 below.

[0094] Table 3. IL-10 receptor binding protein activity TIFF2025069262000009.tif90146TIFF2025069262000010.tif220146TIFF2025069262000011.tif220146TIFF20250692620 00012.tif186146TIFF2025069262000013.tif240146TIFF2025069262000014.tif220146TIFF2025069262000015.tif248146

[0095] As can be seen from the data provided above, the IL-10 receptor binding protein exhibited significant IL-10 activity in the IL-10 activity assay (Example 4). In particular, the IL-10 activity was low (higher than unstimulated and A) based on absorbance readings. 630 < 1), medium (A 630 1 to 1.5), and high (A 630 >1.5). From the above data, 11 IL10R binding proteins showed high activity (SEQ ID Nos: 194, 209, 210, 211, 213, 218, 226, 233, 238, 244 and 250), 4 had moderate activity (SEQ ID Nos: 203, 205, 207 and 269), and 8 VHHs had low activity (SEQ ID Nos: 212, 217, 219, 224, 227, 237, 239 and 249). In some embodiments, the disclosure provides an IL10R binding protein, wherein the IL10R binding protein comprises a first anti-IL10R sdAb joined in the amino to carboxy direction to a second anti-IL10R sdAb by a linker according to Table 4 below.

[0096] (Table 4) TIFF2025069262000016.tif154128 wherein the IL10R binding protein may optionally further comprise a linker selected from the group consisting of SEQ ID Nos: 1 to 23.

[0097] The IL10R binding proteins described herein are useful in treating neoplastic diseases, such as cancer (e.g., solid tumor cancer; e.g., non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), or melanoma) in a subject in need thereof. The IL10R binding proteins are useful in treating neoplastic diseases, such as cancer (e.g., solid tumor cancer; e.g., non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), or melanoma), in a subject in need thereof. + T cells, CD4 + It binds to and activates T cells, macrophages, and / or Treg cells. In some embodiments, the IL10R binding proteins described herein can provide a longer therapeutic effect (e.g., lower effective dose, reduced toxicity) than wild-type or pegylated IL10. IL10R binding proteins can induce different levels of downstream signaling in different cell types. For example, anti-IL10Rα V in IL10R binding proteins H H antibody and anti-IL10Rβ V H By varying the length of the linker between the H antibody, the IL10R binding protein can induce higher levels of downstream signaling in desirable cell types compared to undesirable cell types. In some embodiments, the IL10R binding protein is more potent in T cells (e.g., CD8) than in macrophages. + In some embodiments, the IL10R binding proteins can be partial agonists that selectively activate T cells (e.g., CD8 T cells). In some embodiments, activated T cells have upregulation of IFNγ. In some embodiments, partial agonist IL10R binding proteins can suppress autoimmune inflammatory diseases such as ulcerative colitis and Crohn's disease. In some embodiments, by varying the linker length, the IL10R binding proteins suppress the level of downstream signaling in T cells (e.g., CD8 T cells) compared to the level of downstream signaling in macrophages, a cell type that expresses both IL10Rα and IL10Rβ receptors but can cause anemia if activated too strongly. +This can cause higher levels of downstream signaling in T cells (e.g., CD8 T cells). If downstream signaling in macrophages is activated to a high level, these activated macrophages can eliminate senescent red blood cells, causing anemia. IL10R-binding proteins can increase the level of downstream signaling in T cells (e.g., CD8 T cells) compared to the level of downstream signaling in macrophages, so that anemia is avoided. + In other embodiments, different anti-IL10Rα V receptors with different binding affinities can induce higher levels of downstream signaling in the target T cell. H H antibodies and different anti-IL10Rβ V antibodies with different binding affinities H H antibodies can be combined to create different IL10R binding proteins. Additionally, the orientation of the two antibodies in the binding protein can be changed to create different binding proteins (i.e., anti-IL10Rα V H H antibody-linker-anti-IL10Rβ V H H antibody, or anti-IL10Rβ V H H antibody-linker-anti-IL10Rα V H In some embodiments, T cells (e.g., CD8 H antibodies) can be generated. Different IL10R binding proteins can be screened to find the ideal binding protein that induces higher levels of downstream signaling in desirable cell types compared to undesirable cell types. + The level of downstream signaling in macrophages (T cells) is at least 1.1, 1.5, 2, 3, 5, or 10 times the level of downstream signaling in macrophages.

[0098] IFNλ receptor-binding protein Interferon (IFN) lambda receptors (IFNλR) include IL10Rβ and the IL28 receptor (IL28R) α subunit (IL28Rα). Provided herein are IFNλR binding proteins that specifically bind to IL10Rβ and IL28Rα. In some embodiments, the IFNλR binding proteins bind to mammalian cells that express both IL10Rβ and IL28Rα. In some embodiments, the IFNλR binding proteins are bispecific V-type IFNλR binding proteins, as described below. H H 2 In other embodiments, the IFNλR binding protein can be V H It may comprise a first domain which is H and a second domain which may be a fragment of IFNλ or, for example, an scFv.

[0099] The IFNλR binding protein is the first V that binds to IL10Rβ. H H (anti-IL10Rβ V H H antibody) and a second V that binds to IL28Rα H H (anti-IL28Rα V H H antibody) and express IL10Rβ and IL28R, e.g., macrophages, T cells (e.g., CD8 + T cells or CD4 + Bispecific V receptors that trigger dimerization of the two receptor subunits and downstream signaling upon binding to T cells, Treg cells, dendritic cells, and / or epithelial cells H H 2 It can be.

[0100] Anti-IL10Rβ V H H antibody and anti-IL28Rα V HThe anti-IL10Rβ V antibody can be linked to the IL10Rβ V antibody. For example, the linker can be a simple covalent bond or a peptide linker. The peptide linker can contain 1 to 50 amino acids (e.g., 2 to 50, 5 to 50, 10 to 50, 15 to 50, 20 to 50, 25 to 50, 30 to 50, 35 to 50, 40 to 50, 45 to 50, 2 to 45, 2 to 40, 2 to 35, 2 to 30, 2 to 25, 2 to 20, 2 to 15, 2 to 10, or 2 to 5 amino acids). H H antibody and anti-IL28Rα V H The peptide linker linking the H antibodies can be a flexible glycine-serine linker. The linker can also be a chemical linker, such as a synthetic polymer, e.g., a polyethylene glycol (PEG) polymer.

[0101] Anti-IL10Rβ V H The H antibody can have a sequence that has at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) sequence identity to any one of SEQ ID NOs:51-57.

[0102] Anti-IL10Rβ V H The H antibody can have a sequence that has at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) sequence identity to any one of SEQ ID NOs:99-104.

[0103] Anti-IL28Rα V H The H antibody can have a sequence that has at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) sequence identity to any one of SEQ ID NOs:76-82.

[0104] In some embodiments, the IFNλR binding protein is an E max Reduced E compared to maxE max reflects the maximal response level in a cell type that can be obtained with a ligand (e.g., a binding protein described herein or a natural cytokine (e.g., IFNλ)). In some embodiments, the IFNλR binding proteins described herein inhibit E induced by IFNλ. max In other embodiments, the E of an IFNλR binding protein described herein has at least 1% (e.g., 1% to 100%, 10% to 100%, 20% to 100%, 30% to 100%, 40% to 100%, 50% to 100%, 60% to 100%, 70% to 100%, 80% to 100%, 90% to 100%, 1% to 90%, 1% to 80%, 1% to 70%, 1% to 60%, 1% to 50%, 1% to 40%, 1% to 30%, 1% to 20%, or 1% to 10%). max is the E of the natural ligand IFNλ. max In some embodiments, the E of the IFNλR binding protein is increased by varying the linker length of the IFNλR binding protein. max The IFNλR binding proteins can alter E in the most desirable cell types (e.g., macrophages). max , and reduced E in other cell types max can cause.

[0105] The IFNλR binding proteins of the present disclosure are useful in treating infectious diseases in subjects in need thereof. + T cells, CD4 +It binds to and activates T cells, Treg cells, dendritic cells, and / or epithelial cells. In particular, IFNλR-binding proteins bind to and activate macrophages. Examples of infectious diseases include, but are not limited to, influenza, hepatitis B, hepatitis C, and human immunodeficiency virus (HIV) infection. In some embodiments, IFNλR-binding proteins can protect Kupffer cells in the liver from the effects of infectious diseases. IFNλR-binding proteins can induce different levels of downstream signaling in different cell types. For example, anti-IL10Rβ V in IFNλR-binding proteins H H antibody and anti-IL28Rα V H By varying the length of the linker between the IFNλR binding protein and the H antibody, the IFNλR binding protein can induce higher levels of downstream signaling in desirable cell types (e.g., macrophages) compared to undesirable cell types. In some embodiments, by varying the linker length, the IFNλR binding protein results in modulation of downstream signaling in macrophages compared to the level of downstream signaling in other cells. In other embodiments, different anti-IL10Rβ V antibodies with different binding affinities are used. H H antibodies and different anti-IL28Rα V antibodies with different binding affinities H H antibodies can be combined to create different IFNλR binding proteins. Additionally, the orientation of the two antibodies in the binding protein can be changed to create different binding proteins (i.e., anti-IL10Rβ V H H antibody-linker-anti-IL28Rα V H H antibody, or anti-IL28Rα V H H antibody-linker-anti-IL10Rβ V HAlternatively, a IFNλR-binding protein (H antibody) can be generated. Different IFNλR-binding proteins can be screened to find the ideal binding protein that induces higher levels of downstream signaling in desirable cell types compared to undesirable cell types. In some embodiments, the level of downstream signaling in macrophages is at least 1.1, 1.5, 2, 3, 5, or 10 times the level of downstream signaling in other cell types.

[0106] IL-23 receptor binding protein The IL23 receptor (IL23R) comprises an IL12R β1 subunit (IL12Rβ1) and an IL23R subunit. Provided herein are IL23R binding proteins that specifically bind to IL12Rβ1 and IL23R. In some embodiments, the IL23R binding protein binds to mammalian cells that express both IL12Rβ1 and IL23R. In some embodiments, the IL23R binding protein is a bispecific V-binding protein described below. H H 2 In other embodiments, the IL23R binding protein can be V H The antibody may comprise a first domain which is H and a second domain which may be a fragment of IL23 or, for example, an scFv.

[0107] The IL23R-binding protein is the first V that binds to IL12Rβ1. H H (anti-IL12Rβ1 V H H antibody) and a second V that binds to IL23R. H H (anti-IL23R V H H antibody) and expressing IL12Rβ1 and IL23R, e.g., T cells (e.g., CD8 + T cells or CD4 + Bispecific V receptors that trigger dimerization of the two receptor subunits and downstream signaling upon binding to T cells, macrophages, and / or Treg cells H H 2 It can be.

[0108] Anti-IL12Rβ1 V H H antibody and anti-IL23R V H The anti-IL12Rβ1 V antibody can be linked to the IL12Rβ1 V antibody. For example, the linker can be a simple covalent bond or a peptide linker. The peptide linker can contain 1 to 50 amino acids (e.g., 2 to 50, 5 to 50, 10 to 50, 15 to 50, 20 to 50, 25 to 50, 30 to 50, 35 to 50, 40 to 50, 45 to 50, 2 to 45, 2 to 40, 2 to 35, 2 to 30, 2 to 25, 2 to 20, 2 to 15, 2 to 10, or 2 to 5 amino acids). H H antibody and anti-IL23R V H The peptide linker linking the H antibodies can be a flexible glycine-serine linker. The linker can also be a chemical linker, such as a synthetic polymer, e.g., a polyethylene glycol (PEG) polymer.

[0109] Anti-IL12Rβ1 V H The H antibody can have a sequence that has at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) sequence identity to any one of SEQ ID NOs:105-111.

[0110] Anti-IL23R V H The H antibody can have a sequence that has at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) sequence identity to any one of SEQ ID NOs:64-69.

[0111] Anti-IL23R V H The H antibody can have a sequence that has at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) sequence identity to any one of SEQ ID NOs:118-124.

[0112] In some embodiments, the IL23R binding protein is an E max Reduced E compared to max E max reflects the maximal response level in a cell type that can be obtained by a ligand (e.g., a binding protein described herein or a natural cytokine (e.g., IL23)). In some embodiments, the IL23R binding proteins described herein inhibit the E1 response caused by IL23. max In some embodiments, the E of the IL23R binding protein is at least 1% (e.g., 1% to 100%, 10% to 100%, 20% to 100%, 30% to 100%, 40% to 100%, 50% to 100%, 60% to 100%, 70% to 100%, 80% to 100%, 90% to 100%, 1% to 90%, 1% to 80%, 1% to 70%, 1% to 60%, 1% to 50%, 1% to 40%, 1% to 30%, 1% to 20%, or 1% to 10%). max The IL23R binding protein can be used to target the most desirable cell types (e.g., CD8 + T cells) in max , and reduced E in other cell types (e.g., macrophages) max In some embodiments, the E in macrophages caused by the IL23R binding proteins described herein can be max T cells (e.g., CD8 + T cells) max In other embodiments, the E of an IL23R-binding protein described herein is 1% to 100% (e.g., 10% to 100%, 20% to 100%, 30% to 100%, 40% to 100%, 50% to 100%, 60% to 100%, 70% to 100%, 80% to 100%, 90% to 100%, 1% to 90%, 1% to 80%, 1% to 70%, 1% to 60%, 1% to 50%, 1% to 40%, 1% to 30%, 1% to 20%, or 1% to 10%). maxis the E of the natural ligand IL23 max greater than (e.g., at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% greater).

[0113] The IL23R-binding proteins described herein are useful in wound healing. In particular, the IL23R-binding proteins described herein play an important role in initiating wound healing, for example, the healing of the keratinocyte layer of the skin. The IL23R-binding proteins bind to CD8 + T cells, CD4 + IL23R-binding proteins bind to and activate T cells, macrophages, and / or Treg cells. IL23R-binding proteins can induce different levels of downstream signaling in different cell types. For example, anti-IL12Rβ1 V in IL23R-binding proteins H H antibody and anti-IL23R V H By varying the length of the linker between the H antibody, the IL23R binding protein can induce higher levels of downstream signaling in desirable cell types compared to undesirable cell types. In some embodiments, the IL23R binding protein is more potent in T cells (e.g., CD8) than in macrophages. + In other embodiments, different anti-IL12Rβ1 V receptors with different binding affinities can be partial agonists that selectively activate IL12Rβ1 V receptors (e.g., T cells). H H antibodies and different anti-IL23R V antibodies with different binding affinities H H antibodies can be combined to create different IL23R binding proteins. Additionally, the orientation of the two antibodies in the binding protein can be changed to create different binding proteins (i.e., anti-IL12Rβ1 V H H antibody-linker-anti-IL23R V H H antibody or anti-IL23R V H H antibody-linker-anti-IL12Rβ1 V HIn some embodiments, T cells (e.g., CD8 H antibodies) can be generated. Different IL23R binding proteins can be screened to find the ideal binding protein that induces higher levels of downstream signaling in desirable cell types compared to undesirable cell types. + The level of downstream signaling in macrophages (T cells) is at least 1.1, 1.5, 2, 3, 5, or 10 times the level of downstream signaling in macrophages.

[0114] IL2 receptor binding protein The IL2 receptor (IL2R) comprises a CD25 subunit (CD25; also referred to as the IL2Rα subunit), a CD122 subunit (CD122; also referred to as the IL2Rβ subunit), and a CD132 subunit (CD132; also referred to as the IL2Rγ subunit). Provided herein are IL2R binding proteins that specifically bind to CD122 and CD132. In some embodiments, the IL2R binding protein binds to mammalian cells that express both CD122 and CD132. In some embodiments, the IL2R binding protein is a bispecific V-type IL2R binding protein, as described below. H H 2 In other embodiments, the IL2R binding protein can be V H It may comprise a first domain which is H and a second domain which may be a fragment of IL2 or for example an scFv.

[0115] The IL2R-binding protein is the first V that binds to CD122. H H (anti-CD122 V H H antibody) and a second V that binds to CD132 H H (anti-CD132 V H H antibodies) and express CD122 and CD132, e.g., T cells (e.g., CD8 + T cells or CD4 +Bispecific V, which triggers dimerization of the two receptor subunits and downstream signaling upon binding to T cells, macrophages, and / or Treg cells H H 2 It can be.

[0116] Anti-CD122 V using a linker H H antibody and anti-CD132 V H The anti-CD122 VH antibody can be linked to the anti-CD122 VH antibody. For example, the linker can be a simple covalent bond or a peptide linker. The peptide linker can contain 1 to 50 amino acids (e.g., 2 to 50, 5 to 50, 10 to 50, 15 to 50, 20 to 50, 25 to 50, 30 to 50, 35 to 50, 40 to 50, 45 to 50, 2 to 45, 2 to 40, 2 to 35, 2 to 30, 2 to 25, 2 to 20, 2 to 15, 2 to 10, or 2 to 5 amino acids). H H antibody and anti-CD132 V H The peptide linker linking the H antibodies can be a flexible glycine-serine linker. The linker can also be a chemical linker, such as a synthetic polymer, e.g., a polyethylene glycol (PEG) polymer.

[0117] anti-CD122 V H The H antibody can have a sequence that has at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) sequence identity to any one of SEQ ID NOs:30-37.

[0118] anti-CD122 V H The H antibody can have a sequence that has at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) sequence identity to the sequence of any one of SEQ ID NOs:90 and 91.

[0119] anti-CD132 V HThe H antibody can have a sequence that has at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) sequence identity to any one of SEQ ID NOs:38-43.

[0120] anti-CD132 V H The H antibody can have a sequence that has at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) sequence identity to any one of SEQ ID NOs:92-98.

[0121] In some embodiments, the IL2R binding protein is an IL2-induced E max Reduced E compared to max E max reflects the maximum response level in a cell type that can be obtained by a ligand (e.g., a binding protein described herein or a natural cytokine (e.g., IL2)). In some embodiments, the IL2R binding proteins described herein inhibit the E response caused by IL2. max In some embodiments, the E of the IL2R binding protein is at least 1% (e.g., 1% to 100%, 10% to 100%, 20% to 100%, 30% to 100%, 40% to 100%, 50% to 100%, 60% to 100%, 70% to 100%, 80% to 100%, 90% to 100%, 1% to 90%, 1% to 80%, 1% to 70%, 1% to 60%, 1% to 50%, 1% to 40%, 1% to 30%, 1% to 20%, or 1% to 10%). max The IL2R binding protein can be used to target the most desirable cell types (e.g., CD8 + T cells) in max , and reduced E in other cell types (e.g., macrophages) maxIn some embodiments, the E in macrophages caused by the IL2R binding proteins described herein can be max is a T cell (e.g., CD8 + T cells) max In other embodiments, the E of the IL2R binding protein described herein is 1% to 100% (e.g., 10% to 100%, 20% to 100%, 30% to 100%, 40% to 100%, 50% to 100%, 60% to 100%, 70% to 100%, 80% to 100%, 90% to 100%, 1% to 90%, 1% to 80%, 1% to 70%, 1% to 60%, 1% to 50%, 1% to 40%, 1% to 30%, 1% to 20%, or 1% to 10%). max is the E of the natural ligand IL2 max greater than (e.g., at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% greater).

[0122] The IL2R binding proteins described herein are useful in treating neoplastic diseases, such as cancer (e.g., solid tumor cancer; e.g., non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), melanoma, kidney cancer, or lung cancer) in a subject in need thereof. The IL2R binding proteins are useful in treating neoplastic diseases, such as cancer (e.g., solid tumor cancer; e.g., non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), melanoma, kidney cancer, or lung cancer) in a subject in need thereof. + T cells, CD4 + IL2R-binding proteins bind to and activate T cells, macrophages, and / or Treg cells. IL2R-binding proteins can induce different levels of downstream signaling in different cell types. For example, anti-CD122 V in IL2R-binding proteins H H antibody and anti-CD132 V H By varying the length of the linker between the H antibody, the IL2R binding protein can induce higher levels of downstream signaling in desirable cell types compared to undesirable cell types. In some embodiments, the IL2R binding protein is more potent in T cells (e.g., CD8) than in macrophages. +In some embodiments, the IL2R binding proteins can be partial agonists that selectively activate T cells (e.g., CD8 T cells). In some embodiments, partial agonist IL2R binding proteins can suppress autoimmune inflammatory diseases such as lupus, type 2 diabetes, ulcerative colitis, and Crohn's disease. In some embodiments, by varying the linker length, the IL2R binding proteins can selectively activate T cells (e.g., CD8 T cells) compared to the level of downstream signaling in other cell types. + In other embodiments, different anti-CD122 V receptors with different binding affinities can induce higher levels of downstream signaling in T cells. H H antibodies and different anti-CD132 V antibodies with different binding affinities H H antibodies can be combined to create different IL2R binding proteins. Additionally, the orientation of the two antibodies in the binding protein can be changed to create different binding proteins (i.e., anti-CD122 VH antibodies). H H antibody-linker-anti-CD132 V H H antibody, or anti-CD132 V H H antibody-linker-anti-CD122 V H In some embodiments, T cells (e.g., CD8 H antibodies) can be generated. Different IL2R binding proteins can be screened to find the ideal binding protein that induces higher levels of downstream signaling in desirable cell types compared to undesirable cell types. + T cells) is at least 1.1, 1.5, 2, 3, 5, or 10 times the level of downstream signaling in other cell types.

[0123] IL-22 receptor binding protein The IL22 receptor (IL22R) comprises the IL22R1 subunit (IL22R1) and the IL10Rβ subunit (IL10Rβ). IL10Rβ is expressed on a wide range of cells, particularly immune cells including monocytes, T cells, B cells, and NK cells, whereas expression of the IL22R1 subunit of the IL22 receptor complex is primarily observed in non-immune tissues including skin, small intestine, liver, colon, lung, kidney, and pancreas; see, e.g., Wolk, et al. (2004) Immunity 21(2):241-254. Provided herein are IL22R binding proteins that specifically bind to IL22R1 and IL10Rβ. In some embodiments, the IL22R binding protein binds to mammalian cells expressing both IL22R1 and IL10Rβ. In some embodiments, the IL22R binding protein is a bispecific V-binding protein described below. H H 2 In other embodiments, the IL22R binding protein can be V H It may comprise a first domain which is H and a second domain which may be a fragment of IL22 or for example an scFv.

[0124] The IL22R-binding protein contains the first V that binds to IL22R1. H H (anti-IL22R1 V H H antibody) and a second V that binds to IL10Rβ. H H (anti-IL10Rβ V H and a bispecific VH antibody) which, upon binding to cells expressing IL22R1 and IL10Rβ, e.g., epithelial cells, causes dimerization of the two receptor subunits and downstream signaling. H H 2 IL22R is expressed in tissue cells but not in immune cells. IL22R1 is almost exclusively expressed in cells of non-hematopoietic origin, such as epithelial cells, renal tubular cells, and pancreatic ductal cells.

[0125] Anti-IL22R1 V H H antibody and anti-IL10Rβ V HThe anti-IL22R1 VH antibody can be linked to the IL22R1 VH antibody. For example, the linker can be a simple covalent bond or a peptide linker. The peptide linker can contain 1 to 50 amino acids (e.g., 2 to 50, 5 to 50, 10 to 50, 15 to 50, 20 to 50, 25 to 50, 30 to 50, 35 to 50, 40 to 50, 45 to 50, 2 to 45, 2 to 40, 2 to 35, 2 to 30, 2 to 25, 2 to 20, 2 to 15, 2 to 10, or 2 to 5 amino acids). H H antibody and anti-IL10Rβ V H The peptide linker linking the H antibodies can be a flexible glycine-serine linker. The linker can also be a chemical linker, such as a synthetic polymer, e.g., a polyethylene glycol (PEG) polymer.

[0126] Anti-IL10Rβ V H The H antibody can have a sequence that has at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) sequence identity to any one of SEQ ID NOs:51-57.

[0127] Anti-IL10Rβ V H The H antibody can have a sequence that has at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) sequence identity to any one of SEQ ID NOs:99-104.

[0128] In some embodiments, the IL22R binding protein is an E max Reduced E compared to max E max reflects the maximal response level in a cell type that can be obtained by a ligand (e.g., a binding protein described herein or a natural cytokine (e.g., IL22)). In some embodiments, the IL22R binding proteins described herein inhibit the E1 response caused by IL22. maxIn some embodiments, the E of the IL22R binding protein is at least 1% (e.g., 1% to 100%, 10% to 100%, 20% to 100%, 30% to 100%, 40% to 100%, 50% to 100%, 60% to 100%, 70% to 100%, 80% to 100%, 90% to 100%, 1% to 90%, 1% to 80%, 1% to 70%, 1% to 60%, 1% to 50%, 1% to 40%, 1% to 30%, 1% to 20%, or 1% to 10%). max can be varied.

[0129] IL22R binding proteins are expressed in the most desirable cell types (e.g., epithelial cells, IL22R1-expressing tumor cells). max , and reduced E in other cell types max In some embodiments, the E in macrophages caused by the IL22R binding proteins described herein can be max E1 expression in epithelial cells caused by IL22R-binding proteins max In other embodiments, the E of an IL22R-binding protein described herein is 1% to 100% (e.g., 10% to 100%, 20% to 100%, 30% to 100%, 40% to 100%, 50% to 100%, 60% to 100%, 70% to 100%, 80% to 100%, 90% to 100%, 1% to 90%, 1% to 80%, 1% to 70%, 1% to 60%, 1% to 50%, 1% to 40%, 1% to 30%, 1% to 20%, or 1% to 10%). max is the E of the natural ligand IL22 max greater than (e.g., at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% greater).

[0130] The biological activity of IL22 is regulated by a specific endogenous antagonist, IL22-binding protein (IL22BP), which is believed to be a soluble, neutralizing decoy receptor for IL22. Because wild-type IL22 possesses a higher affinity for IL22BP compared to the IL22-receptor complex, IL22BP is thought to control the biological activity of IL22 in vivo. In one embodiment, the IL22R-binding protein of the present disclosure provides selective binding to the IL22-receptor complex relative to IL22BP, and can avoid endogenous antagonism and regulation of IL22 activity resulting from the presence of endogenous IL22BP. In some embodiments, an IL22R binding protein described herein exhibits between 1% and 100% (e.g., between 10% and 100%, 20% and 100%, 30% and 100%, 40% and 100%, 50% and 100%, 60% and 100%, 70% and 100%, 80% and 100%, 90% and 100%, 1% and 90%, 1% and 80%, 1% and 70%, 1% and 60%, 1% and 50%, 1% and 40%, 1% and 30%, 1% and 20%, or 1% and 10%) of the affinity of the natural ligand, IL22, for IL22BP.

[0131] The IL22R binding proteins described herein are useful in treating neoplastic diseases, such as cancer (e.g., solid tumor cancer; e.g., non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), melanoma, kidney cancer, or lung cancer) in a subject in need thereof. IL22R binding proteins bind to and activate epithelial cells. IL22R binding proteins can induce different levels of downstream signaling in target cells. For example, anti-IL22R1 V in IL22R binding proteins H H antibody and anti-IL10Rβ V HBy varying the length of the linker between the IL22R binding protein and the H antibody, the IL22R binding protein can induce different (e.g., higher or lower) levels of downstream signaling in desirable cell types compared to undesirable cell types. In some embodiments, the IL22R binding protein can be a partial agonist that selectively activates epithelial cells. In some embodiments, partial agonist IL22R binding proteins are useful in treating or preventing diseases such as psoriasis, graft-versus-host disease, inflammatory diseases of the lungs and airways such as pulmonary fibrosis, ventilator-induced lung injury, neoplastic diseases (e.g., IL22R1-expressing tumors), diseases associated with liver injury such as liver fibrosis, alcohol-induced (acute or chronic) steatosis, pancreatitis, lupus, type 2 diabetes, ulcerative colitis, and Crohn's disease. In some embodiments, by varying the linker length, the IL22R binding protein can induce higher levels of downstream signaling in epithelial cells compared to the levels of downstream signaling in other cell types. In other embodiments, different anti-IL22R1 V antibodies with different binding affinities can be used. H H antibodies and different anti-IL10Rβ V antibodies with different binding affinities H H antibodies can be combined to create different IL22R binding proteins. Additionally, the orientation of the two antibodies in the binding protein can be changed to create different binding proteins (i.e., anti-IL22R1 VH antibodies). H H antibody-linker-anti-IL10Rβ V H H antibody, or anti-IL10Rβ V H H antibody-linker-anti-IL22R1 V H Alternatively, a target IL22R antibody (H antibody) can be generated. Different IL22R binding proteins can be screened to find the ideal binding protein that induces higher levels of downstream signaling in desired cell types compared to undesired cell types. In some embodiments, the level of downstream signaling in target cells is at least 1.1, 1.5, 2, 3, 5, or 10 times the level of downstream signaling in other cell types or cells derived from different tissues.

[0132] Receptor-binding proteins that bind to non-natural receptor pairs Receptor-binding proteins that bind to IL10Rα and IL2Rγ Provided herein are binding proteins that specifically bind to IL10Rα and IL2Rγ. In some embodiments, the binding proteins bind to mammalian cells that express both IL10Rα and IL2Rγ. In some embodiments, the binding proteins comprise a first V that specifically binds to the extracellular domain of IL10Rα. H H (anti-IL10Rα V H H antibody) and a second V that specifically binds to the extracellular domain of IL2Rγ. H H (anti-IL2Rγ V H H antibody) and expressing IL10Rα and IL2Rγ, e.g., T cells (e.g., CD8 + T cells and / or CD4 + Bispecific V receptors that upon binding to T cells trigger dimerization of the two receptor subunits and downstream signaling H H 2 In some embodiments, the binding protein that specifically binds to IL10Rα and IL2Rγ is a bispecific V H H 2 In other embodiments, the binding protein can be V H H and a second domain which may be a fragment of IL10Rα or IL2Rγ or an scFv, for example.

[0133] Anti-IL10Rα V H H antibody and anti-IL2Rγ V HThe anti-IL10Rα V antibody can be linked to the IL10Rα V antibody. For example, the linker can be a simple covalent bond or a peptide linker. The peptide linker can contain 1 to 50 amino acids (e.g., 2 to 50, 5 to 50, 10 to 50, 15 to 50, 20 to 50, 25 to 50, 30 to 50, 35 to 50, 40 to 50, 45 to 50, 2 to 45, 2 to 40, 2 to 35, 2 to 30, 2 to 25, 2 to 20, 2 to 15, 2 to 10, or 2 to 5 amino acids). H H antibody and anti-IL2Rγ V H The peptide linker linking the H antibodies can be a flexible glycine-serine linker. The linker can also be a chemical linker, such as a synthetic polymer, e.g., a polyethylene glycol (PEG) polymer.

[0134] Anti-IL10Rα V H The H antibody can have a sequence that has at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) sequence identity to any one of SEQ ID NOs:44-50.

[0135] Anti-IL2Rγ V H The H antibody can have a sequence that has at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) sequence identity to any one of SEQ ID NOs:38-43.

[0136] Anti-IL2Rγ V H The H antibody can have a sequence that has at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) sequence identity to any one of SEQ ID NOs:92-98.

[0137] In some embodiments, the binding protein that specifically binds IL10Rα and IL2Rγ is max Reduced E compared to maxE max reflects the maximal response level in a cell type that can be obtained with a ligand (e.g., a binding protein described herein or a natural cytokine (e.g., IL10)). In some embodiments, the binding proteins described herein that specifically bind IL10Rα and IL2Rγ suppress E responses triggered by IL10. max In some embodiments, the linker length of a binding protein that specifically binds to IL10Rα and IL2Rγ is varied to reduce the E of the binding protein. max The binding protein can be used to target the most desirable cell type, CD8 + E in T cells max In some embodiments, CD8 is induced by binding proteins that specifically bind to IL10Rα and IL2Rγ. + E in T cells max E in other T cells triggered by binding proteins max In another embodiment, the E of a binding protein that specifically binds to IL10Rα and IL2Rγ is 1% to 100% (e.g., 10% to 100%, 20% to 100%, 30% to 100%, 40% to 100%, 50% to 100%, 60% to 100%, 70% to 100%, 80% to 100%, 90% to 100%, 1% to 90%, 1% to 80%, 1% to 70%, 1% to 60%, 1% to 50%, 1% to 40%, 1% to 30%, 1% to 20%, or 1% to 10%). max is the E of the natural ligand max greater than (e.g., at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% greater).

[0138] The binding proteins that bind IL10Rα and IL2Rγ described herein are useful in treating diseases in a subject in need thereof, including, but not limited to, the treatment of neoplastic diseases such as cancer (e.g., solid tumor cancer; e.g., non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), or melanoma). + T cells and / or CD4 + It binds to and activates T cells. In certain embodiments, the method does not cause anemia. IL10 is known to have activity against macrophages and T cells. In some embodiments, the methods provided herein use binding proteins of the present disclosure that bind to IL10Rα and IL2Rγ, resulting in the selective activation of T cells over macrophages. The selective activation of T cells over macrophages is beneficial because IL10-activated macrophages can phagocytose senescent red blood cells, which manifests as anemia in patients receiving IL10. The binding proteins described herein, which provide selective, substantial activation of T cells while providing minimal activation of macrophages, result in molecules that cause fewer side effects, such as anemia, compared to the natural IL10 ligand. Other problems and toxicities associated with IL10 activation are described, for example, in Fioranelli and Grazia, J Integr Cardiol 1(1):2-6, 2014. Such problems can be circumvented by using the binding proteins of the present disclosure that specifically bind to IL10Rα and IL2Rγ.

[0139] In some embodiments, binding proteins that bind to IL10Rα and IL2Rγ can induce different levels of downstream signaling in different cell types. For example, anti-IL10Rα V in binding proteins H H antibody and anti-IL2Rγ V H By varying the length of the linker between the H antibody and the binding protein, downstream signaling was significantly enhanced in CD8 T cells compared to other T cells. +In other embodiments, different anti-IL10Rα V antibodies with different binding affinities are regulated in T cells. H H antibodies and different anti-IL2Rγ V antibodies with different binding affinities H H antibodies can be combined to create different binding proteins. Additionally, the orientation of the two antibodies in the binding protein can be changed to create different binding proteins (i.e., anti-IL10Rα V H H antibody-linker-anti-IL2Rγ V H H antibody, or anti-IL2Rγ V H H antibody-linker-anti-IL10Rα V H Different binding proteins can be screened to find the ideal binding protein that induces higher levels of downstream signaling in desirable cell types compared to undesirable cell types. In some embodiments, CD8 + The level of downstream signaling in the T cell is at least 1.1, 1.5, 2, 3, 5 or 10 times the level of downstream signaling in other T cells.

[0140] IFNγR1 or IL28Rα and receptor-binding proteins that bind to myeloid cells and / or T cells Also provided herein are binding proteins that specifically bind to a first receptor and a second receptor, wherein the first receptor is interferon gamma receptor 1 (IFNγR1) or IL28Rα, and the second receptor is preferentially expressed on myeloid cells and / or T cells. In some embodiments, the binding protein binds to mammalian cells that express both the first receptor and the second receptor. For example, the binding protein can selectively induce downstream signaling in T cells if it binds to IFNγR1 as the first receptor and IL2Rγ as the second receptor expressed on T cells. In some embodiments, the binding protein is a bispecific V-binding protein described below. H H 2 In other embodiments, the binding protein can be V HThe antibody may comprise a first domain which is H and a second domain which may be a fragment of IFNγR1 or IL28Rα or an scFv, for example.

[0141] In one embodiment, the binding protein comprises a first V that specifically binds to a first receptor. H H (e.g., anti-IFNγR1 V H H antibody or anti-IL28Rα V H H antibody) and a second V that specifically binds to a second receptor. H and H, which upon binding to a cell expressing IFNγR1 or IL28Rα and a cell expressing a second receptor, e.g., a myeloid cell and / or a T cell, causes dimerization of the two receptors and downstream signaling. H H 2 is.

[0142] Using a linker, two V H H can be bonded. For example, the linker can be a simple covalent bond or a peptide linker. The peptide linker can contain 1 to 50 amino acids (e.g., 2 to 50, 5 to 50, 10 to 50, 15 to 50, 20 to 50, 25 to 50, 30 to 50, 35 to 50, 40 to 50, 45 to 50, 2 to 45, 2 to 40, 2 to 35, 2 to 30, 2 to 25, 2 to 20, 2 to 15, 2 to 10, or 2 to 5 amino acids). Two V H The peptide linker linking the H can be a flexible glycine-serine linker. The linker can also be a chemical linker, such as a synthetic polymer, e.g., a polyethylene glycol (PEG) polymer.

[0143] Anti-IL28Rα V H The H antibody can have a sequence that has at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) sequence identity to any one of SEQ ID NOs:76-82.

[0144] In certain embodiments of the binding proteins described herein, the binding protein binds to a first receptor, IFNγR1, and a second receptor, IL2Rγ. In certain embodiments, the binding protein may activate T cells and avoid activating macrophages. In other embodiments, different antibodies with different binding affinities for a first receptor and different antibodies with different binding affinities for a second receptor can be combined to create different binding proteins. Additionally, the orientation of the two antibodies in the binding protein can be changed to create different binding proteins (i.e., V for the first receptor). H H antibody-linker-V against second receptor H H antibodies, or V against a second receptor H H antibody-linker-V against the first receptor H It is also possible to generate a binding protein that induces a higher level of downstream signaling in desirable cell types compared to undesirable cell types. In some embodiments, the level of downstream signaling in T cells is at least 1.1, 1.5, 2, 3, 5, or 10 times the level of downstream signaling in macrophages.

[0145] In certain embodiments of the binding proteins described herein, the binding protein binds to a first receptor, IL28Rα, and a second receptor, IL2Rγ.

[0146] The binding proteins described herein are useful in treating neoplastic diseases, such as cancer (e.g., solid tumor cancer; e.g., non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), or melanoma) in a subject in need thereof. In some embodiments, the binding proteins bind to and activate myeloid cells and / or T cells. In certain embodiments, the binding proteins bind to and activate macrophages. In certain embodiments, the binding proteins bind to and activate CD8 + T cells and / or CD4 + It binds to and activates T cells.

[0147] IV. Single Domain Antibodies and V H H A single domain antibody (sdAb) is an antibody that contains a single monomeric variable antibody domain. Like a full-length antibody, it can selectively bind to a specific antigen. The complementarity-determining regions (CDRs) of an sdAb are located within a single domain polypeptide. Single domain antibodies are characterized by a V H These antibodies can be designed from the heavy chain antibodies found in camelids, called H. Cartilaginous fish also have heavy chain antibodies (IgNAR, "immunoglobulin new antigen receptor"), from which V NAR Single-domain antibodies, also known as sdAbs, can be obtained. The dimeric variable domain from human or mouse common immunoglobulin G (IgG) can also be split into monomers to create sdAbs. While most research on sdAbs is currently based on heavy chain variable domains, sdAbs derived from light chains have also been shown to specifically bind to targets; see, e.g., Moller et al., J Biol Chem. 285(49):38348-38361, 2010. In some embodiments, sdAbs are composed of a single monomeric light chain variable antibody domain.

[0148] sdAb is a heavy chain antibody (V H H). V H H is a type of sdAb that has a single monomeric heavy chain variable antibody domain. Like conventional antibodies, V H H is capable of selectively binding to a specific antigen. The binding proteins described herein comprise two V that are linked together by a linker (e.g., a peptide linker). H H (e.g., V H H 2 The binding protein can include a first V that binds to a first receptor or a domain or subunit thereof. H H and a second V that binds to a second receptor or a domain or subunit thereof. H Bispecific V, including H and H H 2where the two V H H is attached by a linker.

[0149] Exemplary V H H has a molecular weight of approximately 12-15 kDa, which is much smaller than conventional mammalian antibodies (150-160 kDa), which are composed of two heavy chains and two light chains. H H can be found in or produced by mammals of the Camelidae family (e.g., camels, llamas, dromedaries, alpacas, and guanacos), which naturally lack light chains. H Descriptions of H can be found, for example, in De Greve et al., Curr Opin Biotechnol. 61:96-101, 2019; Ciccarese, et al., Front Genet. 10:997, 2019; Chanier and Chames, Antibodies (Basel) 8(1), 2019; and De Vlieger et al., Antibodies (Basel) 8(1), 2018.

[0150] Bispecific V H H 2 In some embodiments, two V H The H can be synthesized separately and then linked together by a linker. Alternatively, the bispecific V H H 2 V with different binding activities and receptor targets can be synthesized as fusion proteins. H Pairing of Hs to form bispecific V H H 2 Binding proteins can be screened for signaling on cells bearing one or both of the relevant receptors.

[0151] V. Linker As previously described, the binding domains of the binding proteins of the present disclosure may be contiguously linked (e.g., from the first V H The C-terminal amino acid of H binds the second V in the protein H The binding domains of the binding protein may be optionally joined by a linker. A linker is a link between two elements, e.g., protein domains. The bispecific V described herein H H 2 In the binding protein, the linker is a linker between two V H The linker can be a covalent bond or a peptide linker. In some embodiments, two V in a binding protein H The H is directly (i.e., via a covalent bond) linked to two V in the binding protein. H The length of the linker between the H and the two V of the binding protein H The linker can be used to adjust the proximity of H. By varying the length of the linker, the overall size and length of the binding protein can be tailored to bind to a specific cellular receptor or its domains or subunits. For example, if the binding protein is designed to bind to two receptors or their domains or subunits located near each other on the same cell, a short linker can be used. In another example, if the binding protein is designed to bind to two receptors or their domains or subunits located on two different cells, a long linker can be used.

[0152] In some embodiments, the linker is a peptide linker. The peptide linker can contain 1 to 50 amino acids (e.g., 2 to 50, 5 to 50, 10 to 50, 15 to 50, 20 to 50, 25 to 50, 30 to 50, 35 to 50, 40 to 50, 45 to 50, 2 to 45, 2 to 40, 2 to 35, 2 to 30, 2 to 25, 2 to 20, 2 to 15, 2 to 10, or 2 to 5 amino acids). The linker can also be a chemical linker such as a synthetic polymer, for example, a polyethylene glycol (PEG) polymer.

[0153] In some embodiments, the linker is located between the first V in the binding protein H The C-terminus of H is linked to a second V in the binding protein. H In other embodiments, the linker is attached to the N-terminus of the second V in the binding protein. H The C-terminus of H is linked to the first V in the binding protein. H Link to the N-terminus of H.

[0154] Suitable peptide linkers are known in the art and include, for example, peptide linkers containing flexible amino acid residues, such as glycine and serine. In certain embodiments, the peptide linker can include a motif, e.g., multiple or repeated motifs, of GS, GGS, GGGGS (SEQ ID NO:1), GGGGGS (SEQ ID NO:2), GGSG (SEQ ID NO:3), or SGGG (SEQ ID NO:4). In certain embodiments, the peptide linker can include 2 to 12 amino acids containing a GS motif, e.g., TIFF2025069262000017.tif11138. In certain other embodiments, the peptide linker can comprise 3 to 12 amino acids containing a GGS motif, e.g., GGS, GGSGGS (SEQ ID NO:9), GGSGGSGGS (SEQ ID NO:10), and GGSGGSGGSGGS (SEQ ID NO:11). In yet other embodiments, the peptide linker can comprise 4 to 20 amino acids containing a GGSG (SEQ ID NO:3) motif, e.g., TIFF2025069262000018.tif18150. In other embodiments, the peptide linker can include a GGGGS (SEQ ID NO:1) motif, e.g., GGGGSGGGGS (SEQ ID NO:16) or GGGGSGGGSGGGGS (SEQ ID NO:17).

[0155] VI. Modifications to Extend Duration of Action In Vivo The binding proteins described herein can be modified to provide extended in vivo lifespan and / or extended duration of action in subjects.In some embodiments, binding proteins can be conjugated to carrier molecules to provide desired pharmacological properties such as extended half-life.In some embodiments, binding proteins can be covalently bound to the Fc domain of IgG, albumin, or other molecules, for example, by PEGylation, glycosylation, etc., as known in the art, to extend half-life.

[0156] In some embodiments, the binding protein is conjugated to a functional domain of an Fc-fusion chimeric polypeptide molecule. Fc fusion conjugates have been shown to increase the systemic half-life of biologics, thus allowing biologic products to require less frequent administration. Fc binds to the neonatal Fc receptor (FcRn) in endothelial cells lining blood vessels. Upon binding, the Fc fusion molecule is protected from degradation and re-released into the circulation, maintaining the molecule in circulation for a longer period. This Fc binding is thought to be the mechanism by which endogenous IgG maintains its long plasma half-life. Recent Fc-fusion technology links a single copy of a biologic to the Fc region of an antibody, optimizing the pharmacokinetic and pharmacodynamic properties of the biologic compared with conventional Fc-fusion conjugates. The "Fc region" useful for preparing Fc fusions can be a natural or synthetic polypeptide homologous to the IgG C-terminal domain produced by digestion of IgG with papain. IgG Fc has a molecular weight of approximately 50 kDa. The binding proteins described herein can be conjugated to the entire Fc region or smaller portions that retain the ability to extend the circulating half-life of the chimeric polypeptide of which they are a part. In addition, the full-length or fragmented Fc region can be a variant of the wild-type molecule. In a typical presentation, each monomer of the dimeric Fc can carry a heterologous polypeptide, which can be the same or different.

[0157] In some embodiments, when the binding proteins described herein are to be administered in the form of an Fc fusion, particularly in situations where the polypeptide chains conjugated to each subunit of the Fc dimer are different, the Fc fusion can be engineered to have a "knob-into-hole modification." Knob-into-hole modifications are more fully described in Ridgway, et al. (1996) Protein Engineering 9(7):617-621 and U.S. Patent No. 5,731,168, issued March 24, 1998. A knob-into-hole modification refers to a modification at the interface between two immunoglobulin heavy chains in the CH3 domain, in which: i) an amino acid residue in the CH3 domain of a first heavy chain is replaced with an amino acid residue having a larger side chain (e.g., tyrosine or tryptophan) to create a protrusion ("knob") from the surface; and ii) an amino acid residue in the CH3 domain of a second heavy chain is replaced with an amino acid residue having a smaller side chain (e.g., alanine or threonine), thereby creating a cavity ("hole") at the interface in the second CH3 domain, into which the protruding side chain ("knob") of the first CH3 domain is accommodated by the cavity in the second CH3 domain. In one embodiment, the "knob-into-hole modification" comprises the amino acid substitution T366W and, optionally, the amino acid substitution S354C in one of the antibody heavy chains, and the amino acid substitutions T366S, L368A, Y407V, and, optionally, Y349C in the other antibody heavy chain. Additionally, the Fc domain may be modified by the introduction of cysteine ​​residues at positions S354 and Y349, which result in stabilizing disulfide bridges between the two antibody heavy chains in the Fe region (Carter, et al. (2001) Immunol Methods 248, 7-15). The knob-into-hole format is used to facilitate expression of a first polypeptide on a first Fc monomer bearing a "knob" modification and a second polypeptide on a second Fc monomer bearing a "hole" modification to facilitate expression of a heterodimeric polypeptide conjugate.

[0158] In some embodiments, the binding protein may be conjugated to one or more water-soluble polymers. Examples of water-soluble polymers useful in the practice of the present disclosure include polyethylene glycol (PEG), polypropylene glycol (PPG), polysaccharides (polyvinylpyrrolidone, copolymers of ethylene glycol and propylene glycol, poly(oxyethylated polyols), polyolefin alcohols), polysaccharides), poly-alpha-hydroxy acids), polyvinyl alcohol (PVA), polyphosphazenes, polyoxazolines (POZ), poly(N-acryloylmorpholine), or combinations thereof.

[0159] In some embodiments, the binding protein may be conjugated with one or more polyethylene glycol molecules, or "PEGylated." While the method or site of attachment of PEG to the binding protein can vary, in certain embodiments, PEGylation does not alter, or only minimally alters, the activity of the binding protein.

[0160] In some embodiments, selective PEGylation of binding proteins can be utilized, for example, by incorporating unnatural amino acids with side chains that facilitate selective PEG conjugation. The specific PEGylation site can be selected so that PEGylation of the binding protein does not affect its binding to the target receptor.

[0161] In certain embodiments, the increase in half-life is greater than any decrease in biological activity. PEG suitable for conjugation to polypeptide sequences is generally water soluble at room temperature and has the general formula R(O-CH-CH), where R is hydrogen or a protecting group such as an alkyl or alkanol group, and n is an integer between 1 and 1000. n The PEG conjugated to the polypeptide sequence can be linear or branched. Branched PEG derivatives, "star PEGs," and multi-armed PEGs are contemplated by the present disclosure.

[0162] The molecular weight of PEG used in the present disclosure is not limited to any particular range. The PEG component of the binding protein can have a molecular mass greater than about 5 kDa, greater than about 10 kDa, greater than about 15 kDa, greater than about 20 kDa, greater than about 30 kDa, greater than about 40 kDa, or greater than about 50 kDa. In some embodiments, the molecular mass is about 5 kDa to about 10 kDa, about 5 kDa to about 15 kDa, about 5 kDa to about 20 kDa, about 10 kDa to about 15 kDa, about 10 kDa to about 20 kDa, about 10 kDa to about 25 kDa, or about 10 kDa to about 30 kDa. The linear or branched PEG molecule has a molecular weight of about 2,000 to about 80,000 daltons, alternatively about 2,000 to about 70,000 daltons, alternatively about 5,000 to about 50,000 daltons, alternatively about 10,000 to about 50,000 daltons, alternatively about 20,000 to about 50,000 daltons, alternatively about 30,000 to about 50,000 daltons, alternatively about 20,000 to about 40,000 daltons, or alternatively about 30,000 to about 40,000 daltons. In one embodiment of the present disclosure, the PEG is a 40 kD branched PEG comprising two 20 kD arms.

[0163] The present disclosure also contemplates compositions of conjugates in which the PEG has different n values, and thus the various different PEGs are present in specific ratios. For example, some compositions contain a mixture of conjugates where n = 1, 2, 3, and 4. In some compositions, the proportion of conjugates where n = 1 is 18-25%, the proportion of conjugates where n = 2 is 50-66%, the proportion of conjugates where n = 3 is 12-16%, and the proportion of conjugates where n = 4 is up to 5%. Such compositions can be produced using reaction conditions and purification methods known in the art. Chromatography can be used to separate fractions of conjugates, and then, for example, fractions containing conjugates with a desired number of PEGs attached can be identified and purified to remove unmodified protein sequences and conjugates with other numbers of PEGs.

[0164] PEG suitable for conjugation to polypeptide sequences is generally water soluble at room temperature and has the general formula R(O-CH-CH), where R is hydrogen or a protecting group such as an alkyl or alkanol group, and n is an integer between 1 and 1000. n It has OR. When R is a protecting group, it generally has 1 to 8 carbons.

[0165] Two widely used first-generation activated monomethoxy PEGs (mPEGs) are succinimidyl carbonate PEG (SC-PEG; see, e.g., Zalipsky, et al. (1992) Biotehnol. Appl. Biochem 15:100-114) and benzotriazole carbonate PEG (BTC-PEG; see, e.g., Dolence et al., U.S. Pat. No. 5,650,234), which react preferentially with lysine residues to form carbamate bonds but are also known to react with histidine and tyrosine residues. The use of PEG-aldehyde linkers targets a single site at the N-terminus of a polypeptide through reductive amination.

[0166] PEGylation most often occurs at the α-amino group at the N-terminus of a polypeptide, the epsilon-amino group at the side chain of a lysine residue, and the imidazole group at the side chain of a histidine residue. Most recombinant polypeptides have a single α-amino group and several ε-amino groups and imidazole groups, so multiple positional isomers can be generated depending on the chemical nature of the linker. General PEGylation strategies known in the art can be applied herein.

[0167] PEG can be attached to the binding proteins of the present disclosure through a terminal reactive group ("spacer") that mediates a bond between a free amino or carboxyl group of one or more polypeptide sequences and polyethylene glycol. PEGs having a spacer that can be attached to a free amino group include N-hydroxysuccinylimide polyethylene glycol, which can be prepared by activating the succinate ester of polyethylene glycol with N-hydroxysuccinylimide.

[0168] In some embodiments, the PEGylation of binding protein is promoted by incorporating unnatural amino acids with unique side chains to facilitate site-specific PEGylation.The incorporation of unnatural amino acids into polypeptides to provide functional moieties for achieving site-specific PEGylation of such polypeptides is known in the art.See, for example, Ptacin et al., PCT International Application No. PCT / US2018 / 045257, filed on August 3, 2018, and published on February 7, 2019, as International Publication No. WO 2019 / 028419A1.

[0169] The PEG conjugated to the polypeptide sequence can be linear or branched. Branched PEG derivatives, "star PEGs," and multi-armed PEGs are contemplated by the present disclosure. In certain embodiments, the PEG useful in the practice of the present disclosure is a 10 kDa linear PEG-aldehyde (e.g., Sunbright® ME-100AL, NOF America Corporation, One North Broadway, White Plains,NY 10601 USA), 10 kDa linear PEG-NHS ester (e.g., Sunbright® ME-100CS, Sunbright® ME-100AS, Sunbright® ME-100GS, Sunbright® ME-100HS, NOF), 20 kDa linear PEG-aldehyde (e.g., Sunbright® ME-200AL, NOF), 20 kDa linear PEG-NHS ester (e.g., Sunbright® ME-200CS, Sunbright® ME-200AS, Sunbright® ME-200GS, Sunbright® ME-200HS, NOF), 20 kDa two-arm branched PEG-aldehyde, which comprises two 10 kDa linear PEG molecules (e.g., Sunbright® ME-200AL, NOF), GL2-200AL3, NOF), 20 kDa two-arm branched PEG-NHS ester comprising two 10 kDa linear PEG molecules (e.g., Sunbright® GL2-200TS, Sunbright® GL200GS2, NOF), 40 kDa two-arm branched PEG-aldehyde comprising two 20 kDa linear PEG molecules (e.g., Sunbright® GL2-400AL3), 40 kDa two-arm branched PEG-NHS ester comprising two 20 kDa linear PEG molecules (e.g., Sunbright® GL2-400AL3, Sunbright® GL2-400GS2, NOF), linear 30 kDa These include PEG-aldehydes (e.g., Sunbright® ME-300AL) and linear 30 kDa PEG-NHS esters.

[0170] In some embodiments, a linker can be used to connect the binding protein and the PEG molecule. Suitable linkers generally include "flexible linkers" of sufficient length to allow some movement between the modified polypeptide sequence and the linked components and molecules. Linker molecules are generally about 6 to 50 atoms in length. Linker molecules can be, for example, arylacetylene, ethylene glycol oligomers containing 2 to 10 monomer units, diamines, diacids, amino acids, or combinations thereof. Suitable linkers can be readily selected and can be of any suitable length, for example, 1 amino acid (e.g., Gly), 2, 3, 4, 5, 6, 7, 8, 9, 10, 10-20, 20-30, 30-50, or more than 50 amino acids in length.

[0171] Examples of flexible linkers include glycine polymers (G)n, glycine-alanine polymers, alanine-serine polymers, glycine-serine polymers (e.g., (GmSo)n (SEQ ID NO: 431), (GSGGS)n (SEQ ID NO: 432), (GmSoGm)n (SEQ ID NO: 433), (GmSoGmSoGm)n (SEQ ID NO: 434), (GSGGSm)n (SEQ ID NO: 435), (GSGSmG)n (SEQ ID NO: 436), and (GGGSm)n (SEQ ID NO: 437), and combinations thereof, where m, n, and o are each independently selected from integers of at least 1-20, e.g., 1-18, 216, 3-14, 4-12, 5-10, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, as well as other flexible linkers. Glycine and glycine-serine polymers are relatively unstructured and can therefore function as neutral tethers between components. Examples of flexible linkers include, but are not limited to, GGSG (SEQ ID NO:3), GGSGG (SEQ ID NO:18), GSGSG (SEQ ID NO:19), GSGGG (SEQ ID NO:20), GGGSG (SEQ ID NO:21), and GSSSG (SEQ ID NO:22). Other examples of flexible linkers are described in Section V.

[0172] Further examples of flexible linkers include glycine polymers (G)n or glycine-serine polymers (e.g., (GS)n (SEQ ID NO: 438), (GSGGS)n (SEQ ID NO: 439), (GGGS)n (SEQ ID NO: 440) and (GGGGS)n (SEQ ID NO: 441), where n=1-50, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 10-20, 20-30, 30-50). Exemplary flexible linkers include, but are not limited to, GGGS (SEQ ID NO:23), GGGGS (SEQ ID NO:1), GGSG (SEQ ID NO:3), GGSGG (SEQ ID NO:18), GSGSG (SEQ ID NO:19), GSGGG (SEQ ID NO:20), GGGSG (SEQ ID NO:21), and GSSSG (SEQ ID NO:22). Multimers (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 10-20, 20-30, or 30-50) of these linker sequences may be linked together to provide a flexible linker that can be used to conjugate two molecules. Instead of a polypeptide linker, the linker can be a chemical linker, such as a PEG-aldehyde linker. In some embodiments, the binding protein is acetylated at the N-terminus by enzymatic reaction with an N-terminal acetyltransferase and, for example, acetyl-CoA. Alternatively, or in addition to N-terminal acetylation, the binding protein may be acetylated at one or more lysine residues, for example, by enzymatic reaction with a lysine acetyltransferase. See, e.g., Choudhary et al. (2009) Science 325 (5942):834-840.

[0173] In other embodiments, the binding protein can be modified to include an additional polypeptide sequence that functions as an antigenic tag, such as a FLAG sequence. The FLAG sequence is recognized by a biotinylated, highly specific anti-FLAG antibody as described herein (see, for example, Blanar et al. (1992) Science 256:1014 and LeClair, et al. (1992) PNAS-USA 89:8145). In some embodiments, the binding protein further includes a C-terminal c-myc epitope tag.

[0174] In some embodiments, the binding protein is expressed as a fusion protein with an albumin molecule known in the art (eg, human serum albumin) to facilitate long-term exposure in vivo.

[0175] In some embodiments, binding proteins (including fusion proteins of binding proteins) of the present disclosure are expressed as fusion proteins with one or more transition metal chelating polypeptide sequences. The incorporation of such transition metal chelating domains facilitates purification by immobilized metal affinity chromatography (IMAC), as described in Smith et al., U.S. Pat. No. 4,569,794, issued Feb. 11, 1986. Examples of transition metal chelating polypeptides useful in the practice of the present disclosure are described in Smith et al., supra, and in Dobeli et al., U.S. Pat. No. 5,320,663, issued May 10, 1995, the entire teachings of which are incorporated herein by reference. A particular transition metal chelating polypeptide useful in the practice of the present disclosure is a peptide containing three to six consecutive histidine residues (SEQ ID NO: 443), e.g., the 6-histidine peptide (His)6 (SEQ ID NO: 442), often referred to in the art as a "His tag."

[0176] The above-described fusion proteins may be readily produced by recombinant DNA methods according to techniques known in the art by constructing a recombinant vector containing a nucleic acid sequence encoding the binding protein, either N-terminal or C-terminal to the binding protein, in frame with a nucleic acid sequence encoding a fusion partner, which may optionally further comprise a nucleic acid sequence encoding a linker or spacer polypeptide in frame.

[0177] VII. Pharmaceutical Compositions The binding proteins of the present disclosure can be administered to a subject in a pharmaceutically acceptable dosage form. Preferred formulations depend on the intended method of administration and therapeutic use. Pharmaceutical dosage forms of the binding proteins described herein include physiologically acceptable carriers that are essentially non-toxic and non-therapeutic. Examples of such carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, and PEG. Carriers for topical or gel-based forms of polypeptides include polysaccharides such as sodium carboxymethylcellulose or methylcellulose, polyvinylpyrrolidone, polyacrylates, polyoxyethylene-polyoxypropylene block polymers, PEG, polymeric amino acids, amino acid copolymers, and lipid aggregates (such as oil droplets or liposomes).

[0178] The pharmaceutical composition may contain a pharmaceutically acceptable, non-toxic carrier, excipient, stabilizer, or diluent, which are defined as vehicles commonly used to formulate pharmaceutical compositions for administration to animals or humans. The diluent is selected so as not to affect the biological activity of the combination. Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (e.g., octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl, or benzyl alcohol; alkyl parabens, such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (fewer than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, asparagine, histidine, arginine, or lysine; Monosaccharides, disaccharides, and other sugars including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or non-ionic surfactants such as TWEEN™, PLURONICS™, or polyethylene glycol (PEG).

[0179] Formulations to be used for in vivo administration are typically sterile. Sterilization of the compositions of the present disclosure can be readily accomplished by filtration through sterile filtration membranes.

[0180] Typically, compositions are prepared as injections, either as liquid solutions or suspensions; solid forms suitable for solution or suspension in liquid vehicles before injection can also be prepared.As discussed above, preparations can also be emulsified or encapsulated in liposomes or microparticles such as polylactide, polyglycolide or copolymers to enhance adjuvant effect (Langer, Science 249: 1527, 1990 and Hanes, Advanced Drug Delivery Reviews 28: 97-119, 1997).The active substance of the present disclosure can be administered in the form of a depot injection or implant preparation, which can be formulated in a way that allows sustained or pulsed release of active ingredients.The pharmaceutical compositions are generally sterile, substantially isotonic, and formulated in full compliance with all Good Manufacturing Practice (GMP) regulations of the US Food and Drug Administration.

[0181] Administration of the binding proteins described herein can be achieved through any of a variety of art-recognized methods, including, but not limited to, topical, intravascular injection (including intravenous or intra-arterial infusion), intradermal injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, intracranial injection, intratumoral injection, intranodal injection, transdermal, transmucosal, iontophoretic delivery, intralymphatic injection (Senti and Kundig (2009) Current Opinions in Allergy and Clinical Immunology 9(6):537-543), intragastric injection, intraprostatic injection, intracisternal injection (e.g., bladder), respiratory inhaler including nebulizer, intraocular injection, intraperitoneal injection, intralesional injection, intraovarian injection, intracerebral infusion or injection, intracerebroventricular injection (ICVI), etc. In some embodiments, administration includes (e.g., parenteral) administration of the binding protein itself, as well as administration of a recombinant vector (e.g., viral or non-viral vector) to cause in situ expression of the binding protein in a subject. Alternatively, cells, such as cells isolated from a subject, can be recombinantly modified to express a binding protein of the present disclosure.

[0182] The dosage of the pharmaceutical composition will depend on factors including the route of administration, the disease being treated, and the subject's physical characteristics, such as age, weight, and general health. Typically, the amount of binding protein contained in a single dose will be that amount that effectively prevents, delays, or treats the disease without inducing significant toxicity. The pharmaceutical compositions of the present disclosure may be administered in a dose range of 0.01 to 500 mg / kg (e.g., 0.01 to 450 mg, 0.01 to 400 mg, 0.01 to 350 mg, 0.01 to 300 mg, 0.01 to 250 mg, 0.01 to 200 mg, 0.01 to 150 mg, 0.01 to 100 mg, 0.01 to 50 mg, 0.01 to 10 mg, 0.01 to 1 mg, 0.1 to 500 mg / kg, 1 to 500 mg / kg, 5 to 500 mg / kg, 10 to 500 mg / kg, 50 to 500 mg / kg, 100 to 500 mg / kg, 150 to 500 mg / kg, 200 to 500 mg / kg, 250 to 500 mg / kg, 300 to 500 mg / kg, 350 to 500 mg / kg, 400 to 500 mg / kg, 500 to 500 mg / kg, 600 to 600 mg / kg, 700 to 700 mg / kg, 800 to 800 mg / kg, 900 to 900 mg / kg, 1000 to 1000 mg / kg, 1500 to 1000 mg / kg, 2000 to 500 mg / kg, 2500 to 500 mg / kg, 3000 to 500 mg / kg, 3500 to 500 mg / kg, 4000 to 4000 mg / kg, 5000 to 500 mg / kg, 6000 to 7000 mg / kg, 700 mg / kg, 400 to 500 mg / kg, or 450 to 500 mg / kg), and in a more specific embodiment, about 1 to about 100 mg / kg (e.g., about 1 to about 90 mg / kg, about 1 to about 80 mg / kg, about 1 to about 70 mg / kg, about 1 to about 60 mg / kg, about 1 to about 50 mg / kg, about 1 to about 40 mg / kg, about 1 to about 30 mg / kg, about 1 to about 20 mg / kg, about 1 to about 10 mg / kg, about 10 to about 100 mg / kg, about 20 to about 100 mg / kg, about 30 to about 100 mg / kg, about 40 to about 100 mg / kg, about 50 to about 100 mg / kg, about 60 to about 100 mg / kg, about 70 to about 100 mg / kg, about 80 to about 100 mg / kg, or about 90 to about 100 The dosage may include a dose of the binding proteins described herein in the range of 0.1 mg / kg (mg / kg).In some embodiments, a pharmaceutical composition of the present disclosure may comprise a dosage of a binding protein described herein in the range of 0.01 to 20 mg / kg (e.g., 0.01 to 15 mg / kg, 0.01 to 10 mg / kg, 0.01 to 8 mg / kg, 0.01 to 6 mg / kg, 0.01 to 4 mg / kg, 0.01 to 2 mg / kg, 0.01 to 1 mg / kg, 0.01 to 0.1 mg / kg, 0.01 to 0.05 mg / kg, 0.05 to 20 mg / kg, 0.1 to 20 mg / kg, 1 to 20 mg / kg, 2 to 20 mg / kg, 4 to 20 mg / kg, 6 to 20 mg / kg, 8 to 20 mg / kg, 10 to 20 mg / kg, 15 to 20 mg / kg). The dosage may be adapted by a physician according to conventional factors such as the extent of the disease and different parameters of the subject.

[0183] Pharmaceutical compositions containing the binding proteins described herein can be administered to a subject in need thereof, for example, one or more times (e.g., 1 to 10 or more times) daily, weekly, monthly, twice-yearly, yearly, or as medically necessary. Doses can be provided in either a single or multiple dosage regimen. The timing between doses can decrease as the medical condition improves or increase as the patient's health condition declines. A course of treatment can be a single dose or multiple doses over a period of time. In some embodiments, a single dose is used. In some embodiments, two or more split doses administered over a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 28, 30, 60, 90, 120, or 180 days are used. Each dose administered in such a split dosing protocol can be the same or different in each administration. A multi-day dosing protocol over a period of time can be provided by one skilled in the art (e.g., a physician) monitoring the administration, taking into account the subject's response to treatment, including side effects of the treatment and adjustments thereof, as discussed above.

[0184] VIII. Indications Neoplastic disease The present disclosure provides methods of use of the binding proteins described herein in treating subjects suffering from neoplastic diseases by administration of a therapeutically effective amount of the binding proteins (or nucleic acids encoding the binding proteins, including recombinant vectors encoding the binding proteins).

[0185] The compositions and methods of the present disclosure are useful in treating subjects suffering from neoplastic diseases characterized by the presence of a neoplasm, including benign and malignant neoplasms and neoplastic diseases. Examples of benign neoplasms suitable for treatment using the compositions and methods of the present disclosure include, but are not limited to, adenomas, fibromas, hemangiomas, and lipomas. Examples of premalignant neoplasms suitable for treatment using the compositions and methods of the present disclosure include, but are not limited to, hyperplasia, atypia, metaplasia, and dysplasia. Examples of malignant neoplasms suitable for treatment using the compositions and methods of the present disclosure include, but are not limited to, carcinomas (cancers arising from epithelial tissues such as skin or tissues covering internal organs), leukemia, lymphoma, and sarcomas, which typically originate from bone, fat, muscle, blood vessels, or connective tissue. The term neoplasm also includes virally induced neoplasms such as warts and EBV-induced diseases (i.e., infectious mononucleosis), hyperproliferative vascular diseases including scar formation, intimal smooth muscle cell hyperplasia, restenosis, vascular occlusion, and the like.

[0186] The term "neoplastic disease" includes cancers characterized by solid and non-solid tumors, including, but not limited to, breast cancer, sarcoma (including, but not limited to, osteosarcoma and angiosarcoma and fibrosarcoma), leukemia, lymphoma, genitourinary cancer (including, but not limited to, ovarian, urethral, ​​bladder, and prostate cancer), gastrointestinal cancer (including, but not limited to, colon, esophageal, and stomach cancer), lung cancer, myeloma, pancreatic cancer, liver cancer, kidney cancer, endocrine cancer, skin cancer, and tumors of the brain or central nervous system (CNS) and peripheral nervous system, including glioma and neuroblastoma, astrocytoma, myelodysplastic disorders, malignant or benign, cervical intraepithelial neoplasia, intestinal polyposis, oral leukoplakia, histiocytosis, hyperproliferative scars including keloid scars, hemangiomas, hyperproliferative arterial stenosis, psoriasis, inflammatory arthritis, hyperkeratosis and papular-scaling eruptions including arthritis.

[0187] The term neoplastic disease includes cancer. The term "cancer" refers to malignant diseases of epithelial or endocrine tissue, including cancers of the respiratory system, digestive system, genitourinary system, testicular cancer, breast cancer, prostate cancer, endocrine system cancer, and melanoma. The term neoplastic disease includes adenocarcinoma. "Adenocarcinoma" refers to cancers that originate in glandular tissue or in which the tumor cells form recognizable glandular structures.

[0188] The term "hematopoietic neoplastic disorder" refers to a neoplastic disease involving hyperplastic / neoplastic cells arising from hematopoietic origin, e.g., myeloid, lymphoid, or erythroid lineages, or their precursor cells. Myeloid neoplasms include, but are not limited to, myeloproliferative neoplasms, myeloid and lymphoid disorders with eosinophilia, myeloproliferative / myelodysplastic neoplasms, myelodysplastic syndromes, acute myeloid leukemia and related progenitor neoplasms, and acute leukemia of ambiguous lineage. Exemplary myeloid disorders amenable to treatment according to the present disclosure include, but are not limited to, acute promyelocytic leukemia (APML), acute myeloid leukemia (AML), and chronic myeloid leukemia (CML). Lymphoid neoplasms include, but are not limited to, precursor lymphoid neoplasms, mature B-cell neoplasms, mature T-cell neoplasms, Hodgkin's lymphoma, and immunodeficiency-associated lymphoproliferative disorders. Exemplary lymphoid disorders amenable to treatment according to the present disclosure include, but are not limited to, acute lymphoblastic leukemia (ALL), including B-cell acute lymphoblastic leukemia (ALL) and T-cell ALL, chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), hairy cell leukemia (HLL), and Waldenstrom's hypergammaglobulinemia (WM).

[0189] In some cases, hematopoietic neoplastic disorders result from poorly differentiated acute leukemias (e.g., erythroblastic leukemia and acute megakaryoblastic leukemia). As used herein, the term "hematopoietic neoplastic disorder" refers to malignant lymphomas, including, but not limited to, non-Hodgkin's lymphoma and its variants, peripheral T-cell lymphoma, adult T-cell leukemia / lymphoma (ATL), cutaneous T-cell lymphoma (CTCL), large granular lymphocytic leukemia (LGF), Hodgkin's disease, and Reed-Sternberg disease.

[0190] A determination of whether a subject "has a neoplastic disease" refers to a determination made by a physician about a subject that the subject requires or would benefit from treatment based on available information accepted in the art for identifying a disease, disorder, or condition, including, but not limited to, x-rays, CT scans, conventional clinical diagnostic tests (e.g., blood counts), genomic data, protein expression data, and immunohistochemistry.

[0191] Determining the effectiveness of the disclosed methods in treating cancer generally relates to achieving one or more parameters recognized in the art, such as reduction in lesions, particularly reduction in metastatic lesions, reduction in metastasis, reduction in tumor volume, improvement in ECOG score, etc. Determining response to treatment can be assessed through the measurement of biomarkers that can provide reproducible information useful in any aspect of binding protein therapy, including the presence and degree of subject response to such therapy and the presence and degree of adverse effects caused by such therapy. Treatment response may be characterized by improvements in traditional measures of clinical efficacy, such as complete response (CR), partial response (PR), and stable disease (SD) for target lesions, including complete response (CR), incomplete response / stable disease (SD) as defined by RECIST, as well as immune-related complete response (irCR), immune-related partial response (irPR), and immune-related stable disease (irSD) as defined by immune-related response criteria (irRC), which are considered by those skilled in the art to evidence efficacy in treating neoplastic disease in mammalian (e.g., human) subjects.

[0192] infectious disease The present disclosure provides methods of use of the binding proteins described herein in treating a subject suffering from an infectious disease by administration of a therapeutically effective amount of the binding proteins (or nucleic acids encoding the binding proteins, including recombinant vectors encoding the binding proteins).

[0193] In some embodiments, the infection is a chronic infection, i.e., an infection that is not eliminated by the host immune system within a period of up to one week, two weeks, etc. In some cases, chronic infection involves the integration of pathogen genetic elements into the host genome, such as retroviruses, lentiviruses, hepatitis B viruses, etc. In other cases, chronic infections, such as certain intracellular bacterial or protozoan pathogens, arise from pathogen cells present within host cells. Furthermore, in some embodiments, the infection is in a latent stage, such as herpesvirus or human papillomavirus.

[0194] Viral pathogens of interest include, but are not limited to, retroviruses, hepatitis B, lentiviruses, and the like, such as HIV-1; HIV-2, HTLV, FIV, SIV, and the like, hepatitis A, B, C, D, and E viruses. In some embodiments, the methods of the present invention involve diagnosing a patient with an infectious disease or selecting a patient previously diagnosed with an infectious disease; treating the patient with a modified type III interferon therapy regimen, optionally in combination with additional therapy; and monitoring the patient for the effectiveness of the treatment. Monitoring may involve measuring clinical indicators of infection, such as fever, white blood cell count, and / or directly monitoring the presence of pathogens. Treatment may be combined with other active agents. Cytokines, such as interferon gamma, tumor necrosis factor alpha, interleukin-12, and the like, may also be included. Antiviral agents, such as acyclovir and ganciclovir, may also be used in treatment. Subjects suspected of having an infectious disease, including HCV infection, may be screened prior to treatment. Furthermore, subjects undergoing therapy can be tested to assess the activity and effectiveness of the treatment. Significant improvement in one or more parameters indicates efficacy. Adjusting the administration regimen and dosage to optimally benefit the patient, depending on various factors (e.g., patient-dependent factors such as the severity of the disease, the administered compound, etc.), is well within the skill of a medical professional (e.g., a clinician). For example, HCV infection in an individual can be detected and / or monitored by the presence of HCV RNA in the blood and / or the presence of anti-HCV antibodies in the serum. Other clinical signs and symptoms that may be useful in diagnosis and / or treatment monitoring include assessment of liver function and assessment of liver fibrosis (e.g., that may accompany chronic viral infection).

[0195] Subjects who can be administered the therapies described herein include treatment-naive individuals (e.g., individuals who have been diagnosed with an infection but have not previously received treatment) and individuals who have failed previous treatments ("treatment failure" patients). In the case of HCV therapy, previous treatments include, for example, treatment with IFN-α monotherapy (e.g., IFN-α and / or PEGylated IFN-α) or IFN-α combination therapy, which may include administration of IFN-α and an antiviral agent such as ribavirin. Treatment failure patients include non-responders (i.e., individuals whose HCV titer was not significantly or sufficiently reduced by previous treatment for HCV, e.g., previous IFN-α monotherapy, previous IFN-α and ribavirin combination therapy, or previous pegylated IFN-α and ribavirin combination therapy, to provide a clinically significant response); and relapsers (i.e., individuals who have previously received treatment for HCV (e.g., previous IFN-α monotherapy, previous IFN-α and ribavirin combination therapy, or previous pegylated IFN-α and ribavirin combination therapy) and demonstrated a clinically significant response with a decrease in HCV titer, but the decrease in HCV titer was not maintained due to a subsequent increase in HCV titer).

[0196] Other subjects of interest for the treatment methods disclosed herein include those who are "difficult to treat" due to the nature of their HCV infection. "Difficult to treat" subjects are those who: 1) have a serum concentration of at least about 10 per milliliter of serum; 5 , at least about 5 × 10 5 Or at least about 10 6 1) have a high-titer HCV infection, typically defined as an HCV titer of 1 or more HCV genome copies; 2) are infected with an HCV genotype recognized in the art as being associated with treatment failure (e.g., HCV genotype 1, its subtypes (e.g., 1a, 1b, etc.) and quasi-species); or 3) both.

[0197] In another embodiment, a method is provided for treating or reducing primary or metastatic cancer in a regimen comprising contacting a subject in need of treatment with a therapeutically effective amount or effective dose of an IFN λ synthekine or IFN λ variant polypeptide. The effective dose for cancer treatment will vary depending on many different factors, including the means of administration, the target site, the patient's physiological condition, whether the patient is human or animal, other medications administered, and whether the treatment is prophylactic or therapeutic. Typically, the patient is a human, but non-human mammals, such as companion animals such as dogs, cats, and horses, and experimental mammals such as rabbits, mice, and rats, can also be treated. Treatment dosages can be titrated to optimize safety and efficacy.

[0198] In prophylactic applications, relatively low dosages may be administered at relatively infrequent intervals over a long period of time. Some patients may continue to receive treatment for the rest of their lives. Other therapeutic applications may require relatively high dosages at relatively short intervals until the progression of the disease is reduced or terminated, preferably until the patient shows partial or complete improvement in the symptoms of the disease. Thereafter, the patient can be administered a prophylactic regimen.

[0199] In still other embodiments, methods of the invention include treating, reducing, or preventing tumor growth, tumor metastasis, or tumor invasion of cancers, including hematological cancers, melanomas, sarcomas, and gliomas, particularly cancers of epithelial origin, that express IFNλR1 and IFNAR1 or IFNAR2, or IL-10Rβ and IFNAR1 or IFNAR2. In some embodiments, a cancer is assessed for responsiveness to an IFNλ synthekine by determining whether the cancer expresses a cognate receptor that the synthekine activates, e.g., by determining expression of IFNλR1 and IFNAR1 or IFNAR2. Tissues known to express IFNλR1 include, for example, lung, heart, liver (hepatocytes), prostate, keratinocytes, and melanocytes. Cancers that respond to IFNλ and IFNλ synthekines can include, but are not limited to, melanoma, fibrosarcoma, hepatocellular carcinoma, bladder cancer, Burkitt's lymphoma, colorectal cancer, glioblastoma, non-small cell lung cancer, esophageal cancer, and osteosarcoma, among others.

[0200] For prophylactic applications, pharmaceutical compositions or drugs are administered to a patient susceptible to or otherwise at risk of a disease in an amount sufficient to eliminate or reduce the risk of, lessen the severity of, or delay the onset of, the disease, including the biochemical, histological, and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes manifesting during the development of the disease. [Example]

[0201] Example 1. V h Generation of H: Camels were allowed to acclimate in the laboratory for at least 7 days prior to immunization. Antigen was diluted in 1x PBS (approximately 1 mg total antigen). Antigen quality was assessed by SDS-PAGE to ensure purity (e.g., greater than 80%). For the first immunization, 10 mL of CFA (followed by six doses of IFA) was added to a mortar, and 10 mL of the antigen in 1x PBS was slowly added to the mortar and crushed with a pestle. The antigen and CFA / IFA were crushed until the components appeared milky white and difficult to disperse. Camels were injected subcutaneously with CFA-emulsified antigen at at least six sites on their bodies, with approximately 2 mL injected at each site (10 mL total per camel). Injecting larger volumes at more sites resulted in stronger immune responses. Immunizations were performed seven times, one week apart (7 days apart). To avoid emulsion leakage, the needle was inserted into the subcutaneous space for 10–15 seconds after each injection. Alternatively, leakage was prevented by gently pulling the syringe plunger. Blood samples were collected 3 days after the seventh immunization.

[0202] After immunization, libraries were constructed. Briefly, RNA was extracted from blood and transcribed into cDNA. H The H region was obtained by two-step PCR, fragmenting approximately 400 bp. The PCR product and the pMECS phagemid vector were digested with PstI and NotI and then ligated into the pMECS / Nb recombinant. After ligation, the product was transformed into Escherichia coli (E. coli) TG1 cells by electroporation. The transformants were then enriched in growth medium and plated. Finally, the library size was estimated by counting the number of colonies.

[0203] After library construction, library biopanning was performed to screen candidates against the antigen. Phage display technology was applied in this procedure. Positive colonies were identified by PE-ELISA.

[0204] Example 2. Generation of anti-hIL10R VHH Camelian human IL10Rα extracellular domain (amino acids 22–235, UniProtKB Q13651, hIL-10Rα ecd ) and the IL10Rβ extracellular domain (amino acids 20–220, UniProtKB Q08334, hIL-10Rβ ecd ) weekly for 7 weeks, and PBMCs were collected on day 52. ​​Phage display libraries were constructed and biopanned as described in Example 1 above. 50 VHH sequences were obtained after selection on hIL10-R1, and 47 VHH sequences were obtained after selection on hIL10-R2. Sequences were clonotyped using germline assignment and CDR3 sequence similarity.

[0205] Example 3. Synthesis of DNA encoding synthekines Seven unique anti-hIL-10Rα antibodies from each cohort ecd Sequences (SEQ ID No: 44-50) and seven unique anti-hIL-10Rβ ecd Sequences (SEQ ID Nos. 51-57) were selected, and DNAs were synthesized consisting of one IL-10Rα VHH-encoding DNA and one IL-10Rβ VHH-encoding DNA separated by a linker sequence consisting of GGGS (SEQ ID NO:23)-encoding DNA. DNAs were prepared for 7 x 7 x 2 = 98 VHH dimers, for each possible VHH combination and in both orientations, for a total of 98. His-6 (SEQ ID NO:442) DNA (ASH6, SEQ ID NO:430) followed by an Ala-Ser ("AS") linker was added to the 3' end of each DNA construct. The codon-optimized DNA sequences encoding these constructs are provided as SEQ ID Nos. 290-237, and the orientations of the components are described in Table 2 of the above specification.

[0206] Example 4. Recombinant production and purification Codon-optimized DNA inserts (SEQ ID Nos. 290-237) were cloned into modified pcDNA3.4 (Genscript) for small-scale expression in HEK293 cells in 24-well plates. Supernatant IL2R-binding proteins were purified essentially according to the following procedure: 96 x 4 ml of supernatant from 4 x 24-well blocks was rearrayed into 4 x 96-well, 1 mL blocks using a Hamilton Star automation system. PhyNexus micropipette tips (Biotage, San Jose, CA) containing 80 μL of Ni-Excel IMAC resin (Cytiva) were equilibrated with wash buffer: PBS pH 7.4, 30 mM imidazole. The PhyNexus tips were immersed and pipetted 1 mL across all 4 x 96-well blocks for 14 cycles. The PhyNexus tips were washed in 2 x 1 mL blocks containing wash buffer. PhyNexus chips were eluted in 3 x 0.36 mL blocks containing elution buffer: PBS pH 7.4, 400 mM imidazole. PhyNexus chips were regenerated in 3 x 1 mL blocks of 0.5 M sodium hydroxide.

[0207] Purified protein eluates were quantified using a Biacore® T200 essentially according to the following procedure: 10 μL of the initial 96 × 0.36 mL eluates were transferred to a Biacore® 96-well microplate and diluted to 60 μL in HBS-EP+ buffer (10 mM Hepes pH 7.4, 150 mM NaCl, 1 mM EDTA, 0.05% Tween 20). Each of the 96 samples was injected onto a CM5 Series S chip pre-functionalized with an anti-histidine capture antibody (Cytiva): injections were performed at 5 μL / min for 18 seconds. Capture levels were recorded 60 seconds after a buffer wash. To eliminate cell-to-cell surface variations, a standard curve of known VHH concentrations (270, 90, 30, 10, 3.3, 1.1 μg / mL) was acquired on each of the four Biacore chip flow cells. The 96 captures were interpolated against the standard curve using a nonlinear model including specific and nonspecific single-site binding. The concentration of the first elution block varied from 12 to 452 μg / mL, corresponding to 4 to 149 μg. SDS-PAGE analysis of five randomly selected samples was performed to confirm that the molecular weight of the eluate corresponded to the expected value (approximately 30 kDa).

[0208] Protein concentrations were normalized using a Hamilton Star automated system essentially according to the following procedure: Concentration values ​​were imported into an Excel spreadsheet, and pipetting volumes were calculated to perform a dilution to 50 μg / mL in 0.22 mL. The spreadsheet was imported into a dedicated Hamilton Star method to perform dilution pipetting using the initial elution block and elution buffer as diluents. The final normalized plate was sterile filtered using a 0.22 μm filter plate (Corning) and was used as material for the following in vitro assays.

[0209] Example 5. IL10 Activity Assay: The HEK-Blue™ IL-10 reporter cell line (Invivogen, San Diego, CA) was used to screen IL10R1 / R2 VHHs. HEK-Blue™ IL-10 cells were generated by stable transfection of the human embryonic kidney HEK293 cell line with genes encoding the hIL-10Rα and β chains, human STAT3, and a STAT3-inducible SEAP (secreted embryonic alkaline phosphatase) reporter. Binding of IL-10 to its receptor on the surface of HEK-Blue™ IL-10 cells induces JAK1 / STAT3 signaling and subsequent SEAP production. Signals were then detected by quantifying SEAP activity in the cell culture supernatant using QUANTI-Blue™ color development solution (Invivogen, San Diego, CA), and absorbance was measured spectrophotometrically at 630 nm. Because STAT3 is also involved in signaling cytokines such as IFN-α / β and IL-6, HEK-Blue™ IL-10 cells are knocked out for expression of hIFNAR2 and hIL-6R.

[0210] Example 6. Screening of SEQ ID NOs: 192-289: To screen IL10R1 / R2 VHHs, HEK-Blue™ IL-10 cells were seeded at 50,000 cells per well in 96-well plates and treated with 25 nM or 100 nM protein (in triplicate) for 24 hours. Animal-free recombinant human IL-10 (Shenandoah Biotechnology, Inc. Warwick, PA, catalog number 100-83AF) was used as a positive control, and unstimulated cells were used as a negative control. After 24 hours of treatment, 20 μl of cell supernatant was transferred to a flat-bottom 96-well plate, and the assay was developed by adding 180 μl of QUANTI-Blue™ (Invivogen) for 2 hours. Absorbance values ​​were measured at 630 nm using an Envision® (PerkinElmer, Waltham MA) multilabel plate reader. The results of this screening are presented in Table 3 herein.

[0211] Unofficial sequence listing TIFF2025069262000019.tif215156TIFF2025069262000020.tif229156TIFF2025069262000021.tif229156TIFF2025069262000022.tif229156TIFF2025069262000023.tif221156TIFF2025069262000024.tif229156TIFF2025069262000025.tif228156TIFF2025069262000026.tif232156TIFF2025069262000027.tif224156TIFF2025069262000028.tif232156TIFF2025069262000029.tif224156TIFF2025069262000030.tif232156TIFF2025069262000031.tif210156TIFF2025069262000032.tif216156TIFF2025069262000033.tif216156TIFF2025069262000034.tif216156TIFF2025069262000035.tif216156TIFF2025069262000036.tif216156TIFF2025069262000037.tif216156TIFF2025069262000038.tif212156TIFF2025069262000039.tif216156TIFF2025069262000040.tif216156TIFF2025069262000041.tif216156TIFF2025069262000042.tif208156TIFF2025069262000043.tif192156TIFF2025069262000044.tif192156TIFF2025069262000045.tif200156TIFF2025069262000046.tif204156TIFF2025069262000047.tif200156TIFF2025069262000048.tif200156TIFF2025069262000049.tif204156TIFF2025069262000050.tif204156TIFF2025069262000051.tif204156TIFF2025069262000052.tif196156TIFF2025069262000053.tif196156TIFF2025069262000054.tif19 2156TIFF2025069262000055.tif196156TIFF2025069262000056.tif196156TIFF2025069262000057.tif192156T IFF2025069262000058.tif196156TIFF2025069262000059.tif200156TIFF2025069262000060.tif200156TIFF20 25069262000061.tif196156TIFF2025069262000062.tif200156TIFF2025069262000063.tif192156TIFF2025069 262000064.tif196156TIFF2025069262000065.tif192156TIFF2025069262000066.tif200156TIFF202506926200 0067.tif196156TIFF2025069262000068.tif196156TIFF2025069262000069.tif204156TIFF2025069262000070. tif196156TIFF2025069262000071.tif204156TIFF2025069262000072.tif192156TIFF2025069262000073.tif19 6156TIFF2025069262000074.tif196156TIFF2025069262000075.tif226156TIFF2025069262000076.tif192156.

[0212] It is understood that the embodiments described herein are for illustrative purposes only, and that various modifications or changes will be suggested to those skilled in the art in light thereof and are to be included within the spirit and scope of this application and the appended claims. Sequences of sequence accession numbers cited herein are incorporated herein by reference.

[0213] Sequence information SEQUENCE LISTING <110> SYNTHEKINE, INC. <120> COMPOSITIONS AND METHODS RELATED TO RECEPTOR PAIRINGS <150> US 63 / 135,884 <151> 2021-01-11 <150> US 63 / 078,745 <151> 2020-09-15 <150> US 63 / 061,562 <151> 2020-08-05 <160> 443 <170> PatentIn version 3.5 <210> 1 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 1 Gly Gly Gly Gly Ser 1 5 <210> 2 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 2 Gly Gly Gly Gly Gly Ser 1 5 <210> 3 <211> 4 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 3 Gly Gly Ser Gly 1 <210> 4 <211> 4 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 4 Ser Gly Gly Gly 1 <210> 5 <211> 4 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 5 Gly Ser Gly Ser 1 <210> 6 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 6 Gly Ser Gly Ser Gly Ser 1 5 <210> 7 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 7 Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser 1 5 10 <210> 8 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 8 Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser 1 5 10 <210> 9 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 9 Gly Gly Ser Gly Gly Ser 1 5 <210> 10 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 10 Gly Gly Ser Gly Gly Ser Gly Gly Ser 1 5 <210> 11 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 11 Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser 1 5 10 <210> 12 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 12 Gly Gly Ser Gly Gly Gly Ser Gly 1 5 <210> 13 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 13 Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly 1 5 10 <210> 14 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 14 Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly 1 5 10 15 <210> 15 <211> 20 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 15 Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly 1 5 10 15 Gly Gly Ser Gly 20 <210> 16 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 16 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1 5 10 <210> 17 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 17 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1 5 10 15 <210> 18 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 18 Gly Gly Ser Gly Gly 1 5 <210> 19 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 19 Gly Ser Gly Ser Gly 1 5 <210> 20 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 20 Gly Ser Gly Gly Gly 1 5 <210> 21 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 21 Gly Gly Gly Ser Gly 1 5 <210> 22 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 22 Gly Ser Ser Ser Gly 1 5 <210> 23 <211> 4 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 23 Gly Gly Gly Ser 1 <210> 24 <211> 129 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 24 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Ala Ile Ala Ser Gly Tyr 20 25 30 Ile Asp Ser Arg Trp Cys Met Ala Trp Phe Arg Gln Ala Pro Gly Lys 35 40 45 Glu Arg Glu Gly Val Ala Ala Ile Trp Pro Gly Gly Gly Leu Thr Val 50 55 60 Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp His Ala 65 70 75 80 Lys Asn Thr Leu Tyr Leu Gln Met Asn Asn Leu Lys Pro Glu Asp Thr 85 90 95 Ala Met Tyr Tyr Cys Ala Ala Gly Ser Pro Arg Met Cys Pro Ser Leu 100 105 110 Glu Phe Gly Phe Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser 115 120 125 Ser <210> 25 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 25 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Ala Ser Ala Ser Thr Tyr Cys Thr Tyr 20 25 30 Asp Met His Trp Tyr Arg Gln Ala Pro Gly Lys Gly Arg Glu Phe Val 35 40 45 Ser Ala Ile Asp Ser Asp Gly Thr Thr Arg Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Gln Gly Thr Ala Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Gln Pro Glu Asp Thr Ala Met Tyr Tyr Cys Lys 85 90 95 Thr Val Cys Val Val Gly Ser Arg Trp Ser Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Gln Val Thr Val Ser Ser 115 <210> 26 <211> 123 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 26 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Pro Gly Phe Thr Ser Asn Ser Cys 20 25 30 Gly Met Asp Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val 35 40 45 Ser Ser Ile Ser Thr Asp Gly Thr Thr Gly Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Lys Asp Lys Ala Lys Asp Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Gly Met Tyr Ser Cys Lys 85 90 95 Thr Lys Asp Gly Thr Ile Ala Thr Met Glu Leu Cys Asp Phe Gly Tyr 100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 27 <211> 128 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 27 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Pro Tyr Ser Asn Gly 20 25 30 Tyr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val 35 40 45 Ala Thr Ile Tyr Thr Gly Asp Gly Arg Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Asp 65 70 75 80 Leu Gln Met Ser Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Ala Arg Ala Ala Pro Leu Tyr Ser Ser Gly Ser Pro Leu Thr Arg 100 105 110 Ala Arg Tyr Asn Val Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 125 <210> 28 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 28 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Thr Leu Ser Cys Ala Ala Ser Glu Tyr Ala Tyr Ser Thr Cys 20 25 30 Asn Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val 35 40 45 Ser Ala Phe Ile Ser Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Thr Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Ile Tyr Tyr Cys Ser 85 90 95 Ala Asn Cys Tyr Arg Arg Leu Arg Asn Tyr Trp Gly Gln Gly Thr Gln 100 105 110 Val Thr Val Ser Ser 115 <210> 29 <211> 124 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 29 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Leu Thr Phe Asp Asp Ser 20 25 30 Val Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Ala Val 35 40 45 Ser Cys Ile Ser Ser Ser Gly Ala Asn Ala Phe Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Thr Tyr Tyr Cys 85 90 95 Lys Arg Gly His Ala Cys Ala Gly Tyr Tyr Pro Ile Pro Tyr Asp Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 30 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 30 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Glu Tyr Cys Arg Ile 20 25 30 His Met Thr Trp Tyr Arg Gln Gly Pro Gly Lys Glu Arg Glu Phe Val 35 40 45 Ser Ser Ile Gly Ser Asp Gly Arg Lys Thr Tyr Ala Asn Ser Val Thr 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Asn His Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Ser Pro Glu Asp Thr Ala Met Tyr Tyr Cys Lys 85 90 95 Thr Glu Tyr Leu Tyr Gly Leu Gly Cys Pro Asp Gly Ser Ala Tyr Trp 100 105 110 Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 31 <211> 124 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 31 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Glu Tyr Thr Ala Ser Arg Tyr 20 25 30 Cys Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val 35 40 45 Ala Ala Ile His Pro Gly Gly Gly Thr Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Ser Ile Ser Gln Asp Ser Ala Asp Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Ala Gly Ser Leu Trp Val Pro Phe Gly Asp Arg Cys Ala Ala Asn 100 105 110 Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 32 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 32 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30 Trp Ile Phe Trp Val Arg Gln Ala Ala Gly Lys Gly Leu Glu Trp Leu 35 40 45 Ser Thr Ser Asn Thr Gly Gly Asp Thr Thr Lys Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Ser Ala Lys Asn Thr Glu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Glu Thr Gly Arg Cys Ala Arg Ser Gly Gly Tyr Gln Gly Thr Gln Val 100 105 110 Thr Val Ser Ser 115 <210> 33 <211> 124 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 33 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Val Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Thr Ser Gly Asp Thr Lys Ser Ile Arg 20 25 30 Cys Met Gly Trp Phe Arg Gln Thr Pro Gly Lys Glu Arg Glu Gly Ile 35 40 45 Ala Ala Ile Asp Arg Glu Gly Phe Ala Thr Tyr Ala Asp Ser Val Tyr 50 55 60 Asp Arg Phe Thr Ile Ala Gln Asp Asn Ala Gln Asn Thr Leu Tyr Leu 65 70 75 80 Glu Met Asn Ala Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Ala 85 90 95 Ala Gln Asn Met Cys Arg Val Val Arg Gly Ala Met Thr Gly Val Asp 100 105 110 Tyr Trp Gly Lys Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 34 <211> 125 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 34 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Val Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Tyr Thr Tyr Ser Ser Tyr 20 25 30 Tyr Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly 35 40 45 Val Ala Ala Ile Asp Ser Asp Gly Ser Thr Ser Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Gln Asp Asp Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Ala Ser Tyr Glu Val Val Asp Cys Tyr Pro Ser Gly Tyr Gly Gln 100 105 110 Asp Tyr Trp Gly Lys Gly Thr Gln Val Thr Val Ser Ser 115 120 125 <210> 35 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 35 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Gly Ser Gly Tyr Thr Tyr Asp Thr Ser 20 25 30 Asp Met Ser Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val 35 40 45 Ser Asp Ile Asp Ser Gly Asp Trp Ala Ala Tyr Ala Asp Ala Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Lys Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Glu Pro Glu Asp Thr Ala Met Tyr Tyr Cys Lys 85 90 95 Ala Ser Tyr Trp Lys Trp Gly Lys Leu Asn Asn Phe Trp Gly Pro Gly 100 105 110 Thr Gln Val Thr Val Ser Ser 115 <210> 36 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 36 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Arg Phe Ser Asn Tyr 20 25 30 Gly Met Ser Trp Val Arg Gln Ala Pro Gly Glu Gly Leu Glu Trp Val 35 40 45 Ser Tyr Ile Asn Gly Asp Gly Ser Arg Thr His Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Leu Asn Ser Leu Lys Thr Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Glu Lys Gly Leu Ser Arg Asp Gly Trp Ser Leu Ser Ala Ala Ser Arg 100 105 110 Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 37 <211> 125 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 37 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Thr Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Tyr Thr Thr Tyr Ser Phe 20 25 30 Asn Tyr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly 35 40 45 Val Ala Val Ile Tyr Thr Gly Gly Gly Ser Thr Leu Tyr Ala Asp Ser 50 55 60 Val Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Val 65 70 75 80 Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr 85 90 95 Cys Ala Ala Asp Asp Gln Arg Phe Ala Ser Pro Leu Tyr Ala Tyr Phe 100 105 110 Gly Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 125 <210> 38 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 38 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Ser Phe Ser Ser Tyr 20 25 30 Pro Met Thr Trp Ala Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Thr Ile Ala Ser Asp Gly Gly Ser Thr Ala Tyr Ala Ala Ser Val 50 55 60 Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Ser Thr Leu Tyr 65 70 75 80 Leu Gln Leu Asn Ser Leu Lys Thr Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Thr Lys Gly Tyr Gly Asp Gly Thr Pro Ala Pro Gly Gln Gly Thr Gln 100 105 110 Val Thr Val Ser Ser 115 <210> 39 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 39 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Ala 20 25 30 His Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Arg Glu Trp Ile 35 40 45 Ala Ser Ile Tyr Ser Gly Gly Gly Thr Phe Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Leu Asn Ser Leu Lys Ala Glu Asp Thr Ala Met Tyr Tyr Cys Ala 85 90 95 Thr Asn Arg Leu His Tyr Tyr Ser Asp Asp Asp Ser Leu Arg Gly Gln 100 105 110 Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 40 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 40 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Asp Asp Arg 20 25 30 Glu Met Asn Trp Tyr Arg Gln Ala Pro Gly Asn Glu Cys Glu Leu Val 35 40 45 Ser Thr Ile Ser Ser Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asp Ser Val Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Ala Asp Phe Met Ile Ala Ile Gln Ala Pro Gly Ala Gly Cys Trp Gly 100 105 110 Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 41 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 41 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Tyr Thr Ser Cys Met Gly 20 25 30 Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Ala Val Ala Thr Ile 35 40 45 Tyr Thr Arg Gly Arg Ser Ile Tyr Tyr Ala Asp Ser Val Lys Gly Arg 50 55 60 Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met 65 70 75 80 Asn Ser Leu Lys Pro Glu Asp Ile Ala Met Tyr Ser Cys Ala Ala Gly 85 90 95 Gly Tyr Ser Trp Ser Ala Gly Cys Glu Phe Asn Tyr Trp Gly Gln Gly 100 105 110 Thr Gln Val Thr Val Ser Ser 115 <210> 42 <211> 125 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 42 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Asp Asp Ser 20 25 30 Asp Met Gly Trp Tyr Arg Gln Ala Pro Gly Asn Glu Cys Glu Leu Val 35 40 45 Ser Thr Ile Ser Ser Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Ala Glu Pro Arg Gly Tyr Tyr Ser Asn Tyr Gly Gly Arg Arg Glu Cys 100 105 110 Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 125 <210> 43 <211> 127 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 43 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Tyr Thr Phe Ser Ser Tyr 20 25 30 Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val 35 40 45 Ala Ala Leu Gly Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly 50 55 60 Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln 65 70 75 80 Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Ala Ala 85 90 95 Ala Trp Val Ala Cys Leu Glu Phe Gly Gly Ser Trp Tyr Asp Leu Ala 100 105 110 Arg Tyr Lys His Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 125 <210> 44 <211> 125 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 44 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Tyr Leu Tyr Ser Ile Asp 20 25 30 Tyr Met Ala Trp Phe Arg Gln Ser Pro Gly Lys Glu Arg Glu Pro Val 35 40 45 Ala Val Ile Tyr Thr Ala Ser Gly Ala Thr Phe Tyr Pro Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Met Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Ala Val Arg Lys Thr Asp Ser Tyr Leu Phe Asp Ala Gln Ser Phe 100 105 110 Thr Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 125 <210> 45 <211> 129 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 45 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Phe Thr Tyr Ser Ser Tyr 20 25 30 Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val 35 40 45 Ala Ser Ile Asp Ser Asp Gly Ser Thr Ser Tyr Thr Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Lys Asp Asn Ala Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Ala 85 90 95 Leu Asp Leu Met Ser Thr Val Val Pro Gly Phe Cys Gly Phe Leu Leu 100 105 110 Ser Ala Gly Met Asp Tyr Trp Gly Lys Gly Thr Gln Val Thr Val Ser 115 120 125 Ser <210> 46 <211> 131 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 46 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Tyr Ser Met Tyr 20 25 30 Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val 35 40 45 Ala Gln Ile Asn Ser Asp Gly Ser Thr Ser Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Lys Asp Asn Ala Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Ala 85 90 95 Ala Asp Ser Arg Val Tyr Gly Gly Ser Trp Tyr Glu Arg Leu Cys Gly 100 105 110 Pro Tyr Thr Tyr Glu Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr 115 120 125 Val Ser Ser 130 <210> 47 <211> 134 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 47 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Tyr Ala Tyr Ser Thr Tyr 20 25 30 Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val 35 40 45 Ala Ala Ile Asp Ser Gly Gly Ser Thr Ser Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Lys Asp Asn Ala Lys Asn Thr Leu Tyr Leu 65 70 75 80 Arg Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Ala 85 90 95 Ala Val Pro Pro Pro Pro Asp Gly Gly Ser Cys Leu Phe Leu Gly Pro 100 105 110 Glu Ile Lys Val Ser Lys Ala Asp Phe Arg Tyr Trp Gly Gln Gly Thr 115 120 125 Gln Val Thr Val Ser Ser 130 <210> 48 <211> 127 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 48 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Val Ser Gly Tyr Thr Tyr Ser Ser Asn 20 25 30 Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val 35 40 45 Ala Thr Ile Tyr Thr Gly Gly Gly Asn Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Asn Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Ala Glu Pro Leu Ser Arg Val Tyr Gly Gly Ser Cys Pro Thr Pro 100 105 110 Thr Phe Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 125 <210> 49 <211> 126 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 49 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Gly Ala Ser Gly Tyr Thr Tyr Ser Ser Tyr 20 25 30 Cys Met Gly Trp Phe Arg Gln Val Pro Gly Lys Glu Arg Glu Gly Val 35 40 45 Ala Val Ile Asp Ser Asp Gly Ser Thr Ser Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Lys Asp Asn Gly Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Ala 85 90 95 Ala Asp Leu Gly His Tyr Arg Pro Pro Cys Gly Val Leu Tyr Leu Gly 100 105 110 Met Asp Tyr Trp Gly Lys Gly Thr Gln Val Thr Val Ser Ser 115 120 125 <210> 50 <211> 127 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 50 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ser Asn Cys Ser Tyr 20 25 30 Asp Met Thr Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val 35 40 45 Ser Ala Ile His Ser Asp Gly Ser Thr Arg Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Phe Ile Ser Gln Asp Asn Ala Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Lys 85 90 95 Thr Asp Pro Leu His Cys Arg Ala His Gly Gly Ser Trp Tyr Ser Val 100 105 110 Arg Ala Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 125 <210> 51 <211> 126 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 51 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Tyr Ser Ser Gly 20 25 30 Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Ala Val 35 40 45 Ala Ala Ile Asn Ser Asp Gly Ser Thr Ser Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Lys Asp Asn Ala Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Ala 85 90 95 Ala Glu Pro Tyr Cys Ser Gly Gly Tyr Pro Arg Trp Ser Val Ala Glu 100 105 110 Phe Gly Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 125 <210> 52 <211> 124 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 52 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Tyr Ser Ser Tyr 20 25 30 Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val 35 40 45 Ala His Ile Asp Ser Asp Gly Ser Thr Ser Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Lys Asp Asn Ala Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Ala 85 90 95 Ala Asp Pro Ile Pro Gly Pro Gly Tyr Cys Asp Gly Gly Pro Asn Lys 100 105 110 Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 53 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 53 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Tyr Thr Tyr Asn Ser Tyr 20 25 30 Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val 35 40 45 Ala Thr Ile Asp Ser Asp Gly Met Thr Arg Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Lys Asp Asn Ala Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Ala 85 90 95 Ala Asp Ala Asp Cys Thr Ile Ala Ala Met Thr Thr Asn Pro Leu Gly 100 105 110 Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 54 <211> 125 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 54 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Val Ser Arg Tyr Thr Ala Ser Val Asn 20 25 30 Tyr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val 35 40 45 Ala Thr Ile Phe Thr Gly Ala Gly Thr Thr Tyr Tyr Ala Asn Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Ile Tyr Tyr Cys 85 90 95 Ala Val Asp Phe Arg Gly Gly Leu Leu Tyr Arg Pro Ala Tyr Glu Tyr 100 105 110 Thr Tyr Arg Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 125 <210> 55 <211> 126 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 55 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Glu Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr His Ser Ser Tyr 20 25 30 Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val 35 40 45 Ala Ala Ile Asp Val Asp Gly Ser Thr Thr Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Lys Asp Asn Ala Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Gly Met Tyr Tyr Cys Ala 85 90 95 Ala Glu Phe Ala Asp Cys Ser Ser Asn Tyr Phe Leu Pro Pro Gly Ala 100 105 110 Val Arg Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 125 <210> 56 <211> 124 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 56 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ser Tyr Ser Ser Tyr 20 25 30 Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val 35 40 45 Ala Thr Ile Asp Ser Asp Gly Met Thr Arg Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Lys Asp Asn Ala Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Ala 85 90 95 Ala Pro Leu Tyr Asp Cys Asp Ser Gly Ala Val Gly Arg Asn Pro Pro 100 105 110 Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 57 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 57 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Thr Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Tyr Leu Arg Gly 20 25 30 Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val 35 40 45 Ala Val Met Asp Val Val Gly Asp Arg Arg Ser Tyr Ile Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Ala Asn Ser Val Tyr 65 70 75 80 Leu Gln Met Asp Asn Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Thr Ala Gly Pro Asn Cys Val Gly Trp Arg Ser Gly Leu Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 58 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 58 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Thr Arg Tyr 20 25 30 Cys Met Gly Trp Leu Arg Gln Ala Pro Gly Lys Gln Arg Glu Gly Val 35 40 45 Ala Ile Ile Glu Arg Asp Gly Arg Thr Gly Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Lys Asp Asn Ala Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Gly 85 90 95 Ala Ile Glu Gly Ser Cys Arg Pro Asp Phe Gly Tyr Arg Gly Gln Gly 100 105 110 Thr Gln Val Thr Val Ser Ser 115 <210> 59 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 59 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Leu Thr Phe Asp Asp Val 20 25 30 Glu Met Ala Trp Tyr Arg Gln Gly Pro Gly Asp Asp Tyr Asp Leu Val 35 40 45 Ser Ser Ile Asn Thr Asp Ser Arg Val Tyr Tyr Val Asp Ser Val Lys 50 55 60 Asp Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Asn Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Ala Asp Pro Trp Gly Gly Asp Leu Arg Gly Tyr Pro Asn Tyr Trp Gly 100 105 110 Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 60 <211> 124 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 60 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Gln Ala Ser Gly Tyr Thr Tyr Gly Leu Phe 20 25 30 Cys Met Gly Trp Phe Arg Gln Val Ser Gly Lys Lys Arg Glu Gly Val 35 40 45 Ala Val Val Asp Ser Pro Gly Gly Arg His Val Ala Asp Ser Leu Lys 50 55 60 Gly Arg Phe Thr Ile Ser Lys Asp Asn Ala Asn Asn Ile Leu Tyr Leu 65 70 75 80 Asp Met Thr Asn Leu Lys Ser Glu Asp Thr Ala Thr Tyr Tyr Cys Ala 85 90 95 Ala Asp Pro Glu Lys Tyr Cys Phe Leu Phe Ser Asp Ala Gly Tyr Gln 100 105 110 Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 61 <211> 128 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 61 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Val Thr Tyr Ser Arg Tyr 20 25 30 Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Leu Glu Arg Glu Arg Val 35 40 45 Ala His Ile Tyr Ser Arg Gly Ile Ile Thr Tyr Tyr Thr Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Gln Asp Ser Ala Lys Lys Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Ala Thr Arg Glu Thr Tyr Gly Gly Ser Gly Asp Cys Gly Tyr Glu 100 105 110 Ser Val Tyr Asn Tyr Trp Ala Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 125 <210> 62 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 62 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu Pro Glu Trp Ile 35 40 45 Ser Arg Ile Ser Ser Gly Gly Gly Asn Thr Tyr Tyr Ala Asp Ala Val 50 55 60 Lys Gly Arg Phe Ala Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Leu Asn Ser Leu Lys Thr Glu Asp Thr Ala Ile Tyr Val Cys 85 90 95 Thr Met Asp Asp Tyr Tyr Gly Gly Ser Trp His Pro Ile Ser Arg Gly 100 105 110 His Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 63 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 63 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Phe Thr Val Asp Asp Phe 20 25 30 Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Asn Glu Cys Glu Leu Val 35 40 45 Ser Thr Ile Ser Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Gln Asp Ser Ala Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Pro Ser Ser Val Gly Cys Pro Leu Gly Tyr Trp Gly Gln Gly Thr Gln 100 105 110 Val Thr Val Ser Ser 115 <210> 64 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 64 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Thr Arg Tyr 20 25 30 Cys Met Gly Trp Leu Arg Gln Ala Pro Gly Lys Gln Arg Glu Gly Val 35 40 45 Ala Ile Ile Glu Arg Asp Gly Arg Thr Gly Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Lys Asp Asn Ala Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Gly 85 90 95 Ala Ile Glu Gly Ser Cys Arg Pro Asp Phe Gly Tyr Arg Gly Gln Gly 100 105 110 Thr Gln Val Thr Val Ser Ser 115 <210> 65 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 65 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Leu Thr Phe Asp Asp Val 20 25 30 Glu Met Ala Trp Tyr Arg Gln Gly Pro Gly Asp Asp Tyr Asp Leu Val 35 40 45 Ser Ser Ile Asn Thr Asp Ser Arg Val Tyr Tyr Val Asp Ser Val Lys 50 55 60 Asp Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Asn Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Ala Asp Pro Trp Gly Gly Asp Leu Arg Gly Tyr Pro Asn Tyr Trp Gly 100 105 110 Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 66 <211> 124 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 66 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Gln Ala Ser Gly Tyr Thr Tyr Gly Leu Phe 20 25 30 Cys Met Gly Trp Phe Arg Gln Val Ser Gly Lys Lys Arg Glu Gly Val 35 40 45 Ala Val Val Asp Ser Pro Gly Gly Arg His Val Ala Asp Ser Leu Lys 50 55 60 Gly Arg Phe Thr Ile Ser Lys Asp Asn Ala Asn Asn Ile Leu Tyr Leu 65 70 75 80 Asp Met Thr Asn Leu Lys Ser Glu Asp Thr Ala Thr Tyr Tyr Cys Ala 85 90 95 Ala Asp Pro Glu Lys Tyr Cys Phe Leu Phe Ser Asp Ala Gly Tyr Gln 100 105 110 Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 67 <211> 128 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 67 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Val Thr Tyr Ser Arg Tyr 20 25 30 Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Leu Glu Arg Glu Arg Val 35 40 45 Ala His Ile Tyr Ser Arg Gly Ile Ile Thr Tyr Tyr Thr Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Gln Asp Ser Ala Lys Lys Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Ala Thr Arg Glu Thr Tyr Gly Gly Ser Gly Asp Cys Gly Tyr Glu 100 105 110 Ser Val Tyr Asn Tyr Trp Ala Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 125 <210> 68 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 68 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu Pro Glu Trp Ile 35 40 45 Ser Arg Ile Ser Ser Gly Gly Gly Asn Thr Tyr Tyr Ala Asp Ala Val 50 55 60 Lys Gly Arg Phe Ala Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Leu Asn Ser Leu Lys Thr Glu Asp Thr Ala Ile Tyr Val Cys 85 90 95 Thr Met Asp Asp Tyr Tyr Gly Gly Ser Trp His Pro Ile Ser Arg Gly 100 105 110 His Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 69 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 69 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Phe Thr Val Asp Asp Phe 20 25 30 Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Asn Glu Cys Glu Leu Val 35 40 45 Ser Thr Ile Ser Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Gln Asp Ser Ala Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Pro Ser Ser Val Gly Cys Pro Leu Gly Tyr Trp Gly Gln Gly Thr Gln 100 105 110 Val Thr Val Ser Ser 115 <210> 70 <211> 124 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 70 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Glu 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Asn Val Ala Tyr Gly Ile Thr Ser Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Thr Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Leu Asn Ser Leu Lys Thr Glu Asp Thr Ala Ile Tyr Tyr Cys 85 90 95 Val Lys His Ser Gly Thr Thr Ile Pro Arg Gly Phe Ile Ser Tyr Thr 100 105 110 Lys Arg Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 71 <211> 123 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 71 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Val Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Pro Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Ser Thr Ile Ser Ala Gly Gly Asp Thr Thr Leu Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ser Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Leu Asn Ser Leu Lys Thr Glu Asp Thr Ala Ile Tyr Tyr Cys 85 90 95 Ala Lys Arg Ile Asp Cys Asn Ser Gly Tyr Cys Tyr Arg Arg Asn Tyr 100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 72 <211> 129 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 72 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Arg Ala Ser Gly Ser Thr Tyr Ser Asn Tyr 20 25 30 Cys Leu Gly Trp Phe Arg Gln Ile Thr Gly Lys Glu Arg Glu Gly Val 35 40 45 Ala Val Ile Asn Trp Val Gly Gly Met Leu Tyr Phe Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Val Ser Gln Asp Gln Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Ala Glu Ser Val Ser Ser Phe Ser Cys Gly Gly Trp Leu Thr Arg 100 105 110 Pro Asp Arg Val Pro Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser 115 120 125 Ser <210> 73 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 73 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Tyr Val Ser Cys Asp Tyr 20 25 30 Phe Leu Pro Ser Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe 35 40 45 Val Ser Ile Ile Asp Gly Thr Gly Ser Thr Ser Tyr Ala Ala Ser Val 50 55 60 Lys Gly Arg Phe Thr Ala Ser Gln Asp Lys Gly Lys Asn Ile Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Lys Ala Ser Cys Val Arg Gly Arg Gly Ile Ser Glu Tyr Trp Gly Gln 100 105 110 Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 74 <211> 128 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 74 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ser Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Tyr Ser Thr Ser 20 25 30 Asn Ser Trp Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu 35 40 45 Gly Val Ala Ala Ile Tyr Thr Val Gly Gly Ser Ile Phe Tyr Ala Asp 50 55 60 Ser Val Arg Gly Arg Phe Thr Ile Ser Gln Asp Ala Thr Lys Asn Met 65 70 75 80 Phe Tyr Leu Gln Met Asn Thr Leu Lys Pro Glu Asp Thr Ala Met Tyr 85 90 95 Tyr Cys Ala Ala Ala Ser Gly Arg Leu Arg Gly Lys Trp Phe Trp Pro 100 105 110 Tyr Glu Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 125 <210> 75 <211> 123 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 75 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser His Ser 20 25 30 Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Thr Ile Asn Ser Gly Gly Ala Ser Thr Tyr Tyr Thr Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Met Leu Tyr 65 70 75 80 Leu Gln Leu Asn Ser Leu Lys Thr Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Lys Gly Gly Ser Gly Tyr Gly Asp Ala Ser Arg Met Thr Ser Pro 100 105 110 Gly Ser Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 76 <211> 124 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 76 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ser Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Tyr Ser Ser Tyr 20 25 30 Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val 35 40 45 Ala Ala Ile Asp Ser Asp Gly Ser Thr Ser Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Lys Asp Asn Ala Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Met Tyr Tyr Cys Ala 85 90 95 Ala Asp Gly Glu Tyr Asn Asp Tyr Val Cys Trp Ser Thr Gly Leu Arg 100 105 110 Tyr Arg Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 77 <211> 115 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 77 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Met Gly Leu Glu Arg Val 35 40 45 Ser Ala Ile Gly Arg Asp Gly Ser Thr Phe Tyr Pro Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Leu Asn Ser Leu Lys Thr Glu Asp Thr Ala Met Tyr Tyr Cys Ala 85 90 95 Lys Glu Glu Pro Gly Ser Ser Ser Arg Gly Gln Gly Thr Gln Val Thr 100 105 110 Val Ser Ser 115 <210> 78 <211> 129 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 78 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Val Ser Arg Tyr Thr Ile Ser Arg Ser 20 25 30 Asp Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly 35 40 45 Val Ala Arg Ile Gly Ser Asp Gly Thr Thr Ser Tyr Ala Asp Ser Val 50 55 60 Lys Glu Arg Phe Thr Ile Ser Lys Asp Asn Ala Lys Asn Ile Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Arg Tyr Tyr Cys 85 90 95 Ala Ala Thr Ala Leu Leu Leu Gly Arg Gly Ser Ala Cys His Lys Glu 100 105 110 Val Ser Val Phe Ser Trp Trp Gly Gln Gly Thr Gln Val Thr Val Ser 115 120 125 Ser <210> 79 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 79 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30 Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Asn Ser Gly Gly Asp Asp Thr Phe Tyr Thr Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Met Gly Ala Ser Gly Met Ile Pro Arg Gly Gln Gly Thr Gln Ile 100 105 110 Thr Val Ser Ser 115 <210> 80 <211> 127 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 80 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Leu Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Leu Val Ser Gly Ser Thr Asp Asn Ile Lys 20 25 30 Tyr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val 35 40 45 Ala Ala Val Tyr Thr Ser Gly Gly Ala Val Val Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Gln Asp Asp Ala Lys Asn Thr Met Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Ala Ser Arg Ala Pro Ala Pro Pro Arg Leu Leu Leu Gln Arg Ala 100 105 110 Leu Val Glu Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 125 <210> 81 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 81 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala 20 25 30 Thr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Glu Ile Glu Trp Val 35 40 45 Ser Ala Ile Ser Asn Ser Arg Gly Thr Lys Tyr Tyr Ala Ala Phe Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Leu Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Thr Lys Asp Trp Lys Thr Ser Tyr Ser Asp Tyr Asp Leu Ser Asp Gly 100 105 110 Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 82 <211> 127 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 82 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ser Ser Gly Tyr Ile Ser Ser Ser Tyr 20 25 30 Cys Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Ala 35 40 45 Ala Gly Val Thr Arg Asp Gly Lys Thr Tyr Tyr Gly Asp Ser Val Lys 50 55 60 Gly Arg Phe Ala Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Ala 85 90 95 Ala Gly Pro Pro Pro Cys Ile Thr Ser Met Pro Ala Gly Gly Asp Tyr 100 105 110 Gly Tyr Arg Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 125 <210> 83 <211> 114 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 83 Gln Val Gln Leu Gln Glu Ser Gly Gly Ala Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Tyr 20 25 30 Ala Met Lys Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser Gly Gly Gly Gly Ala Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Thr Asn Asp Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Gln Asn Leu Asp Tyr Arg Gly Gln Gly Thr Gln Val Thr Val 100 105 110 Ser Ser <210> 84 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 84 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Asn Ser Ala 20 25 30 His Leu Lys Trp Glu Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Phe Ile Thr Asn Gly Gly Ala Ser Thr Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Thr Gly Gly Leu Arg Gly Gln Gly Thr Gln Val Thr Val Ser Ser 100 105 110 <210> 85 <211> 124 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 85 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Ser Thr Tyr 20 25 30 Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Pro Glu Trp Val 35 40 45 Ser Ala Val Ser Arg Gly Gly Phe Asn Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Met Ser Ser Val Ser Phe Tyr Gly Trp Pro Pro Asp Arg Val Pro Ser 100 105 110 Pro Thr Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 86 <211> 124 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 86 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr 20 25 30 Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Thr Ile Asn Tyr Ser Gly Ser Ser Thr Tyr Tyr Val Asp Ser Val 50 55 60 Leu Gly Arg Phe Thr Ile Ala Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Asn Leu Gln Thr Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ser Val Lys Glu Arg Arg Ser Asn Gly His Pro Ile Val Phe Gly 100 105 110 Asp Arg Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 87 <211> 125 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 87 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Asn Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Asn Ser Gly Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Lys His Val Thr Gly Asp Tyr Asp Pro Ser Leu Arg Tyr Glu Tyr 100 105 110 Asn Tyr Trp Ser Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 125 <210> 88 <211> 125 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 88 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Ile Ser Gly Phe Thr Tyr Arg Gln Thr 20 25 30 Phe Met Gly Trp Phe Arg Gln Val Val Gly Lys Glu Arg Glu Gly Val 35 40 45 Ala Ala Ile Ser Thr Gly Gly Gly Ser Thr Ile Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Gln Asp Ser Ser Lys Asp Thr Val Tyr 65 70 75 80 Leu Glu Met Asn Gly Leu Lys Leu Glu Asp Thr Gly Met Tyr Tyr Cys 85 90 95 Ala Ala Ser Thr Val Ile Thr Ser Glu Ser Ile Asn Arg Asn Leu Tyr 100 105 110 Gln Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 125 <210> 89 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 89 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Phe Leu Arg Leu Ser Cys Ala Phe Ser Gly Tyr Thr Gly Cys Met Gly 20 25 30 Trp Phe Arg Gln Gly Pro Gly Gln Glu Arg Glu Gly Val Ala Ser Ile 35 40 45 Asn Asp Gly Gly Ser Leu Thr Tyr Ala Asp Ser Val Lys Gly Arg Phe 50 55 60 Thr Ile Ser Lys Asp Asn Ala Lys Lys Thr Leu Asp Leu Gln Met Asn 65 70 75 80 Thr Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Ala Ala Ser Leu 85 90 95 Ser Tyr Cys Leu Asn Pro Thr Leu Arg Val Asp Gly Tyr Asn Tyr Trp 100 105 110 Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 90 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 90 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Leu Tyr 20 25 30 Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Asn Ser Gly Gly Tyr Ser Thr Tyr Tyr Ala Ala Ser Ala 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Leu Ser Ser Val Lys Thr Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Gln Arg Gly Leu Thr Ser Pro Tyr Val Ile Pro Asn Ile Arg Leu 100 105 110 Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 91 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 91 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Glu Phe Thr Phe Ser Asn Asn 20 25 30 Trp Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Phe Glu Trp Val 35 40 45 Ser Ser Ile His Ser Gly Met Ala Ile Thr His Tyr Arg Gly Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ser Asp Ile Ala Lys Asn Ile Val Ser 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Gly Glu Gly Asn Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 100 105 110 <210> 92 <211> 127 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 92 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Leu Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Tyr Gly Tyr Asn Tyr Ile 20 25 30 Gly Trp Phe Arg Gln Thr Pro Gly Lys Glu Arg Glu Gly Val Ala Val 35 40 45 Ile Tyr Thr Gly Gly Gly Asp Thr Tyr Tyr Ala Asp Ser Val Lys Gly 50 55 60 Arg Phe Thr Ala Ser Arg Asp Asn Ala Lys Ser Thr Leu Tyr Leu Gln 65 70 75 80 Met Asn Ser Leu Glu Pro Glu Asp Thr Ala Met Tyr Tyr Gly Val Ala 85 90 95 Arg Tyr Cys Val Gly Ser Val Tyr Ala Cys Leu Arg Gly Gly His Asp 100 105 110 Glu Tyr Ala His Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 125 <210> 93 <211> 134 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 93 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Tyr Ala Asn Tyr 20 25 30 Leu Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val 35 40 45 Ala Ala Ile Tyr Ser Gly Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Ala Ala Ser Ala Val Lys Gly Asp Lys Gly Asp Ile Val Val Val 100 105 110 Val Thr Gly Thr Gln Arg Met Glu Tyr Asp Tyr Trp Gly His Gly Thr 115 120 125 Gln Val Thr Val Ser Ser 130 <210> 94 <211> 132 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 94 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Ala 1 5 10 15 Ser Leu Arg Leu Ser Cys Ser Val Ser Gly Phe Thr Phe Asp Glu Ser 20 25 30 Val Met Ser Trp Leu Arg Gln Gly Pro Gly Asn Glu Cys Asp Ala Val 35 40 45 Ala Ile Ile Ser Ser Asp Asp Asn Thr Tyr Tyr Asp Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Glu Asp Asn Ala Lys Asn Met Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Ala Arg Arg Arg Arg Pro Val Tyr Asp Ser Asp Tyr Glu Leu Arg Pro 100 105 110 Arg Pro Leu Cys Gly Asp Phe Gly Val Trp Gly Gln Gly Thr Gln Val 115 120 125 Thr Val Ser Ser 130 <210> 95 <211> 129 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 95 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ile Gly Ser Gly Leu Pro Phe Asp Glu Asp 20 25 30 Asp Met Gly Trp Tyr Arg Gln Ala Pro Gly Asn Glu Cys Glu Leu Val 35 40 45 Ser Ser Ile Ser Ser Asp Gly Thr Ala Tyr Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Leu Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Ala Gly Val His Arg Gln Phe Gly Gly Ser Ser Ser Cys Gly Asp Ala 100 105 110 Phe Tyr Gly Met Asp Tyr Trp Gly Lys Gly Thr Gln Val Thr Val Ser 115 120 125 Ser <210> 96 <211> 124 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 96 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Asp Val Tyr Gly Arg Asn 20 25 30 Ser Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val 35 40 45 Ala Val Gly Tyr Ser Val Val Thr Thr Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Glu Asp Asn Asp Lys Asn Thr Val Tyr 65 70 75 80 Leu Glu Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Ala Asp Gly Asn Leu Trp Arg Gly Leu Arg Pro Ser Glu Tyr Thr 100 105 110 Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 97 <211> 126 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 97 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Asp Asp Phe 20 25 30 Asp Met Gly Trp Tyr Arg Gln Ala Pro Gly Asn Glu Cys Glu Leu Val 35 40 45 Ser Thr Ile Ser Asp Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Ser Ser Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Arg Leu Lys Pro Glu Asp Thr Gly Val Tyr Tyr Cys Ala 85 90 95 Ala Glu Gly Ala Leu Gly Ser Lys Met Asn Cys Gly Trp Val Gly Asn 100 105 110 Phe Gly Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 125 <210> 98 <211> 128 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 98 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Thr Ser Gly Phe Pro Tyr Ser Arg Tyr 20 25 30 Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val 35 40 45 Ala Ala Ile Glu Pro Asp Gly Ser Thr Ser Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Val Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Asn Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Ala 85 90 95 Ala Asp Glu Arg Cys Phe Tyr Leu Lys Asp Tyr Asp Leu Arg Arg Pro 100 105 110 Ala Gln Tyr Arg Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 125 <210> 99 <211> 125 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 99 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Tyr Asn Arg Arg 20 25 30 Phe Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Leu 35 40 45 Ala Ile Ile Tyr Thr Pro Asn Ser Ser Thr Phe Tyr Ala Asp Ser Val 50 55 60 Thr Gly Arg Phe Thr Ile Ser Gln Asp Ser Ala Arg Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Ala Ala Arg Ile Ala Ser Met Thr Glu Leu Ser Val Arg Asp Met 100 105 110 Asp Tyr Trp Gly Lys Gly Thr Gln Val Thr Val Ser Ser 115 120 125 <210> 100 <211> 126 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 100 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Arg Tyr Ile Ala Leu Asn Ala 20 25 30 Cys Met Ala Trp Ile Arg Gln Ala Pro Gly Ser Glu Arg Glu Val Val 35 40 45 Ala Thr Ile Val Thr Asp Gly Ser Arg Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Met Tyr 65 70 75 80 Leu Gln Met Asn Gly Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Ala Asp Arg Arg Cys Pro Val Ser Arg Ala Pro Tyr Glu Tyr Glu 100 105 110 Leu Arg Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 125 <210> 101 <211> 123 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 101 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Asp Thr Tyr Ser Arg Lys 20 25 30 Tyr Ile Ala Trp Val Arg Gln Val Pro Gly Lys Glu Arg Glu Gly Val 35 40 45 Ala Val Met Tyr Thr Pro Gly Ser Ala Thr Tyr Tyr Thr Asp Thr Val 50 55 60 Met Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Phe Cys 85 90 95 Ala Ala Lys Ala Ser Gly Ser Met Phe Asn Phe Arg Asp Tyr Thr Tyr 100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 102 <211> 127 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 102 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ala Leu Arg Leu Ser Cys Thr Ala Ser Gly Tyr Thr Ala Ser Ser Ile 20 25 30 Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Arg Val 35 40 45 Ala Val Ile Thr Thr Ala Ala Ser Gly Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Asn Gly Arg Phe Ser Ile Ser Gln Asn Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Asp Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Ala Thr Arg Arg Gly Gly Asp Cys Leu Asp Pro Leu Gln Thr Pro 100 105 110 Ala Tyr Asn Thr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 125 <210> 103 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 103 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Thr Ser Gly Tyr Ala Ser Cys Ser Arg 20 25 30 Ala Met Arg Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val 35 40 45 Ala Tyr Ile Asp Gly Val Gly Ser Thr Gly Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Tyr Thr Ala Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Asn 85 90 95 Arg Gly Cys Arg Ala Asp Gly Ser Asn Ser Leu Asp Asn Tyr Trp Gly 100 105 110 Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 104 <211> 123 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 104 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Tyr Asn Gly Lys 20 25 30 Cys Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Val Val 35 40 45 Ala Gly Ile Tyr Thr Gly Gly Ser Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asp Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Thr Ser Arg Ser Cys Ser Asp Leu Arg Arg Arg Ser Ile Ala Tyr 100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 105 <211> 127 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 105 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Tyr Thr Tyr Ser Ser Ala 20 25 30 Phe Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val 35 40 45 Ala Ala Ile Tyr Thr Arg Asp Gly Gly Thr Val Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Ala Lys Ile Pro Gln Pro Gly Arg Ala Ser Leu Leu Asp Ser Gln 100 105 110 Thr Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 125 <210> 106 <211> 126 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 106 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Tyr Asp Tyr Cys Gly Tyr 20 25 30 Asp Val Arg Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val 35 40 45 Ser Gly Ile Asp Ser Asp Gly Ser Thr Ser Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Glu Asn Thr Ser Tyr Leu 65 70 75 80 His Met Phe Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Lys 85 90 95 Thr Glu Ser Pro Ala Gly Glu Ser Ala Trp Cys Arg Asn Phe Arg Gly 100 105 110 Met Asp Tyr Trp Gly Lys Gly Thr Gln Val Thr Val Ser Ser 115 120 125 <210> 107 <211> 126 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 107 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Tyr Ser Tyr Cys Gly Tyr 20 25 30 Asp Met Met Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val 35 40 45 Ala Leu Ile Thr Ser Asp Tyr Ser Ile Arg Tyr Glu Asp Ser Val Glu 50 55 60 Gly Arg Phe Ser Ile Ser Arg Asp Asn Ala Lys Asn Thr Gly Tyr Leu 65 70 75 80 Leu Met Ser Asn Leu Thr Pro Ala Asp Thr Ala Ile Tyr Tyr Cys Lys 85 90 95 Thr Ser Thr Ala Ala Arg Glu Ser Ser Trp Cys Arg Ser Arg Tyr Arg 100 105 110 Val Ala Ser Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 125 <210> 108 <211> 127 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 108 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Tyr Thr Tyr Thr Asn Asn 20 25 30 Phe Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val 35 40 45 Ala Ala Ile Tyr Thr Gly Asp Gly Tyr Ala Tyr Tyr Phe Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Asp Lys Asn Met Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Ala Met Glu Arg Arg Ser Gly Arg Arg Arg Met Thr Glu Asn Ala 100 105 110 Glu Tyr Lys Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 125 <210> 109 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 109 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Glu 1 5 10 15 Thr Leu Arg Leu Ser Cys Thr Val Ser Gly Phe Thr Ile Asp Asp Ser 20 25 30 Glu Met Gly Trp Tyr Arg Gln Ala Pro Gly His Glu Cys Glu Leu Val 35 40 45 Ala Ser Gly Ser Ser Asp Asp Asp Thr Tyr Tyr Val Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Leu Asp Asn Ala Lys Asn Met Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Thr Gly Pro Thr Tyr Pro Pro Lys Asp Gly Asp Cys Ala His Trp Gly 100 105 110 Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 110 <211> 127 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 110 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Tyr Thr Tyr Ser Ser Ala 20 25 30 Phe Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val 35 40 45 Ala Ala Ile Tyr Thr Arg Asp Gly Ser Pro Val Tyr Ala Asp Ser Leu 50 55 60 Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Leu His 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Ala Lys Ile Pro Glu Pro Gly Arg Ile Ser Leu Leu Asp Ser Gln 100 105 110 Thr Tyr Asp Tyr Trp Gly His Gly Thr Gln Val Thr Val Ser Ser 115 120 125 <210> 111 <211> 126 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 111 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Tyr Asp Tyr Cys Gly Tyr 20 25 30 Asp Val Arg Trp Tyr Arg Arg Ala Pro Gly Lys Glu Arg Glu Phe Val 35 40 45 Ser Gly Ile Asp Ser Asp Gly Ser Thr Ser Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Glu Asn Thr Ser Tyr Leu 65 70 75 80 His Met Phe Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Lys 85 90 95 Thr Glu Ser Pro Ala Gly Glu Ser Ala Trp Cys Arg Asn Phe Arg Gly 100 105 110 Met Asp Tyr Trp Gly Lys Gly Thr Gln Val Thr Val Ser Ser 115 120 125 <210> 112 <211> 126 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 112 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Tyr Ser Asn Arg 20 25 30 His Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val 35 40 45 Ala Ala Ile Tyr Thr Gly Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Asp Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Thr Pro Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Ala Asp Leu Thr Arg Trp Tyr Ser Gly Gly Trp Arg Asp Pro Arg 100 105 110 Gly Tyr Lys Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser 115 120 125 <210> 113 <211> 128 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 113 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Val Thr Tyr Gly Ser Tyr 20 25 30 Tyr Met Ala Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly 35 40 45 Val Ala Ser Ile Tyr Gly Gly Ser Asp Ser Thr Tyr Tyr Ala Asp Ser 50 55 60 Val Leu Gly Arg Phe Thr Ile Ser Gln Asp Asn Gly Lys Asn Thr Leu 65 70 75 80 Tyr Leu Gln Met Asn Ser Leu Lys Pro Asp Asp Thr Ala Met Tyr Tyr 85 90 95 Cys Ala Ala Ala Pro Pro Gly Lys Trp Phe Leu Lys Arg Leu Glu Gly 100 105 110 His Asn Tyr Ser Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 125 <210> 114 <211> 131 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 114 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Val Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Tyr Ser Ser Ser 20 25 30 Cys Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val 35 40 45 Ala Thr Ile Tyr Pro Ala Gly Gly Asn Ile Phe Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asp Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Ala Arg Gly Gly Gln Thr Trp Gly Ser Gly Gly Asn Arg Cys Ser 100 105 110 Leu Trp Leu Pro Ala Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr 115 120 125 Val Ser Ser 130 <210> 115 <211> 123 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 115 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Val Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Lys Leu Tyr Gly Gly Ala 20 25 30 Trp Phe Arg Gln Ala Gln Gly Lys Gly Arg Glu Gly Val Ala Ala Ile 35 40 45 Trp Ile Gly Thr Gly Thr Thr Phe Tyr Ala Asp Ser Val Lys Gly Arg 50 55 60 Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met 65 70 75 80 Asp Gly Leu Lys Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Ala Asp 85 90 95 Asp Arg Pro Gly Tyr Arg Asp Pro Leu Ala Pro Val Ser Tyr Asn His 100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 116 <211> 126 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 116 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ile Thr Tyr Arg Gly Val 20 25 30 Trp Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val 35 40 45 Ala Thr Ile Tyr Thr Gly Ser Gly His Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Ala Arg Thr Val Gly Gly Thr Phe Tyr Thr Leu Ala Ala Asp Ser 100 105 110 Phe Asn Thr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 125 <210> 117 <211> 126 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 117 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Asp Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asp Ile Tyr Ala Arg Asn 20 25 30 Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Lys Ile 35 40 45 Ala Val Ala Asp Thr Gly Gly Arg Ser Pro Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Asp 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Gly Pro Leu Val Pro Val Val Asn Thr Ala Ala Arg Cys Val 100 105 110 Tyr Glu Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 125 <210> 118 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 118 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Tyr Ser Ser Cys 20 25 30 Thr Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val 35 40 45 Ser Met Leu Ile Ser Asp Gly Ser Thr Phe Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Phe Ser Gln Glu Tyr Ala Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Gly 85 90 95 Cys Ala Thr Leu Gly Ser Arg Thr Val Trp Gly Gln Gly Thr Gln Val 100 105 110 Thr Val Ser Ser 115 <210> 119 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 119 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Thr Leu Ser Cys Thr Ala Pro Gly Phe Thr Phe Arg Leu Ala 20 25 30 Ala Met Arg Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Asp Ser Arg Gly Ser Thr Ile Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Lys Asp Asn Ala Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Leu Asn Ser Leu Lys Thr Glu Asp Thr Ala Met Tyr Tyr Cys Ala 85 90 95 Gln Gly Val Tyr Gly Asp Thr Tyr Ser Gly Ser Gln Gly Thr Gln Val 100 105 110 Thr Val Ser Ser 115 <210> 120 <211> 127 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 120 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Val Asn Thr Tyr Cys Glu Tyr 20 25 30 Asn Met Ser Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val 35 40 45 Ser Gly Val Asp Ser Asp Gly Ser Thr Arg Tyr Ser Glu Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Met Tyr Leu 65 70 75 80 Gln Met Asn Gly Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Lys 85 90 95 Thr Tyr Val Cys Thr Phe Cys Ser Gly Asn Ser Cys Tyr Tyr Glu Tyr 100 105 110 Lys Tyr Tyr Tyr Glu Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 125 <210> 121 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 121 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Tyr Ser Asn Asn 20 25 30 Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Asp Arg Glu Arg Ile 35 40 45 Ala Asn Ile Tyr Thr Gly Gly Gly Arg Thr Thr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Gln Asp Ser Ala Lys Ser Thr Val Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Ala Gly Ser Cys Gly Ser Ala Arg Ser Glu Tyr Ser Tyr Trp Gly 100 105 110 Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 122 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 122 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Cys Met Ala 20 25 30 Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val Ala Arg Phe 35 40 45 Tyr Thr Arg Asp Gly Tyr Thr Tyr Tyr Ser Asp Ser Val Lys Gly Arg 50 55 60 Phe Thr Ile Ser Gln Asn Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met 65 70 75 80 Asn Ser Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys Ala Ala Asp 85 90 95 Leu Ala Arg Cys Ser Ser Asn Lys Asn Asp Phe Arg Tyr Trp Gly Gln 100 105 110 Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 123 <211> 127 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 123 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Ser Gly Asn Tyr 20 25 30 Trp Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val 35 40 45 Ala Thr Leu Trp Thr Gly Gly Ala Ser Thr Phe Tyr Gly Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Val Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Ala Asp Pro Ala Leu Arg Leu Gly Ala Asn Ile Leu Arg Pro Ala 100 105 110 Glu Tyr Lys Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 125 <210> 124 <211> 118 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 124 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Ser 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Asp Trp Val 35 40 45 Ser Gly Ile Asp Ser Gly Gly Thr Thr Val Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Ser Ala Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Ile Gly Leu Pro Trp Gly Asn Thr Trp Arg Thr Arg Gly Gln Gly Thr 100 105 110 Gln Val Thr Val Ser Ser 115 <210> 125 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 125 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Asp Ser Thr Tyr Ser Met 20 25 30 Gly Trp Phe Arg Gln Pro Pro Gly Lys Glu Arg Glu Gly Val Ala Ala 35 40 45 Ile Thr Lys Asp Ile Thr Ile His Ala Asp Ser Val Lys Gly Arg Phe 50 55 60 Thr Ile Ser Lys Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn 65 70 75 80 Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Ala Ala His Arg 85 90 95 Pro Tyr Gly Pro Pro Leu Asn Pro Arg Trp Tyr Thr Tyr Trp Gly Gln 100 105 110 Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 126 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 126 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Tyr Thr Ser Ser Arg Tyr 20 25 30 Cys Met Gly Trp Phe Arg Gln Thr Pro Gly Lys Lys Arg Glu Gly Val 35 40 45 Ala Ala Ile Tyr Thr Gly Gly Gly Thr Thr Phe Tyr His Gly Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Thr Thr Asn Thr Val Tyr 65 70 75 80 Leu Gln Met His Asn Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Ala Gly Pro Val Thr Arg Ala Cys Asp Glu Tyr Asn Tyr Trp Gly 100 105 110 Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 127 <211> 123 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 127 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ser Ile Asn Arg Met 20 25 30 Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val Ala Ala 35 40 45 Ile Ser Ile Gly Gly Gly Gln Thr Tyr Tyr Ala Asp Ser Val Lys Gly 50 55 60 Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Val Asp Leu Gln 65 70 75 80 Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Ala Ala 85 90 95 Gly Leu Val Tyr Gly Glu Ala Trp Leu Asp Ser Arg His Tyr Asn Lys 100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 128 <211> 126 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 128 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Gly Ser Gly Tyr Ser Leu Ser Asn Tyr 20 25 30 Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Gln Gly Arg Glu Gly Val 35 40 45 Ala Ser Leu Arg Phe Val Ser Gly Ala Thr Phe Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ala Gln Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Gly Ile Lys Ser Arg Gly Ile Cys Gly Gly Arg Leu Val Asp Val Asp 100 105 110 Phe Gly Asn Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 125 <210> 129 <211> 123 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 129 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Lys Asn Ser Asn Phe Met Gly 20 25 30 Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val Ala Ala Met 35 40 45 Met Thr Lys Asn Asn Asn Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg 50 55 60 Phe Thr Ile Ser His Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met 65 70 75 80 Asp Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Val 85 90 95 Tyr Arg Thr Arg Arg Leu Arg Val Leu Glu Ala Ala Asn Phe Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 130 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 130 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Tyr Ser Ser Tyr 20 25 30 Cys Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val 35 40 45 Ala Ala Ile Asp Ser Asp Gly Ser Thr Ser Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Lys Asp Asn Ala Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Ala 85 90 95 Ala Ala Ser Gly Arg Cys Leu Gly Pro Gly Ile Arg Ser Leu Ile Trp 100 105 110 Gly Gln Gly Thr Gln Val Thr Val Ser Ser 115 120 <210> 131 <211> 257 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 131 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Tyr Thr Tyr Ser Ser Ala 20 25 30 Phe Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val 35 40 45 Ala Ala Ile Tyr Thr Arg Asp Gly Gly Thr Val Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Ala Lys Ile Pro Gln Pro Gly Arg Ala Ser Leu Leu Asp Ser Gln 100 105 110 Thr Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly 115 120 125 Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln 130 135 140 Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Tyr 145 150 155 160 Ser Asn Arg His Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg 165 170 175 Glu Gly Val Ala Ala Ile Tyr Thr Gly Gly Gly Ser Thr Tyr Tyr Ala 180 185 190 Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn 195 200 205 Thr Leu Tyr Leu Gln Met Asn Ser Leu Thr Pro Glu Asp Thr Ala Met 210 215 220 Tyr Tyr Cys Ala Ala Asp Leu Thr Arg Trp Tyr Ser Gly Gly Trp Arg 225 230 235 240 Asp Pro Arg Gly Tyr Lys Tyr Trp Gly Gln Gly Thr Gln Val Thr Val 245 250 255 Ser <210> 132 <211> 259 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 132 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Tyr Thr Tyr Ser Ser Ala 20 25 30 Phe Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val 35 40 45 Ala Ala Ile Tyr Thr Arg Asp Gly Gly Thr Val Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Ala Lys Ile Pro Gln Pro Gly Arg Ala Ser Leu Leu Asp Ser Gln 100 105 110 Thr Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly 115 120 125 Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln 130 135 140 Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Val Thr Tyr 145 150 155 160 Gly Ser Tyr Tyr Met Ala Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu 165 170 175 Arg Glu Gly Val Ala Ser Ile Tyr Gly Gly Ser Asp Ser Thr Tyr Tyr 180 185 190 Ala Asp Ser Val Leu Gly Arg Phe Thr Ile Ser Gln Asp Asn Gly Lys 195 200 205 Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Lys Pro Asp Asp Thr Ala 210 215 220 Met Tyr Tyr Cys Ala Ala Ala Pro Pro Gly Lys Trp Phe Leu Lys Arg 225 230 235 240 Leu Glu Gly His Asn Tyr Ser Tyr Trp Gly Gln Gly Thr Gln Val Thr 245 250 255 Val Ser Ser <210> 133 <211> 262 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 133 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Tyr Thr Tyr Ser Ser Ala 20 25 30 Phe Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val 35 40 45 Ala Ala Ile Tyr Thr Arg Asp Gly Gly Thr Val Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Ala Lys Ile Pro Gln Pro Gly Arg Ala Ser Leu Leu Asp Ser Gln 100 105 110 Thr Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly 115 120 125 Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln 130 135 140 Val Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Tyr 145 150 155 160 Ser Ser Ser Cys Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg 165 170 175 Glu Gly Val Ala Thr Ile Tyr Pro Ala Gly Gly Asn Ile Phe Tyr Ala 180 185 190 Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn 195 200 205 Thr Val Tyr Leu Gln Met Asp Ser Leu Lys Pro Glu Asp Thr Ala Met 210 215 220 Tyr Tyr Cys Ala Ala Arg Gly Gly Gln Thr Trp Gly Ser Gly Gly Asn 225 230 235 240 Arg Cys Ser Leu Trp Leu Pro Ala Tyr Asn Tyr Trp Gly Gln Gly Thr 245 250 255 Gln Val Thr Val Ser Ser 260 <210> 134 <211> 254 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 134 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Tyr Thr Tyr Ser Ser Ala 20 25 30 Phe Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val 35 40 45 Ala Ala Ile Tyr Thr Arg Asp Gly Gly Thr Val Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Ala Lys Ile Pro Gln Pro Gly Arg Ala Ser Leu Leu Asp Ser Gln 100 105 110 Thr Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly 115 120 125 Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln 130 135 140 Val Gly Gly Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Lys Leu Tyr 145 150 155 160 Gly Gly Ala Trp Phe Arg Gln Ala Gln Gly Lys Gly Arg Glu Gly Val 165 170 175 Ala Ala Ile Trp Ile Gly Thr Gly Thr Thr Phe Tyr Ala Asp Ser Val 180 185 190 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr 195 200 205 Leu Gln Met Asp Gly Leu Lys Pro Glu Asp Thr Ala Leu Tyr Tyr Cys 210 215 220 Ala Ala Asp Asp Arg Pro Gly Tyr Arg Asp Pro Leu Ala Pro Val Ser 225 230 235 240 Tyr Asn His Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 245 250 <210> 135 <211> 257 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 135 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Tyr Thr Tyr Ser Ser Ala 20 25 30 Phe Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val 35 40 45 Ala Ala Ile Tyr Thr Arg Asp Gly Gly Thr Val Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Ala Lys Ile Pro Gln Pro Gly Arg Ala Ser Leu Leu Asp Ser Gln 100 105 110 Thr Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly 115 120 125 Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln 130 135 140 Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ile Thr Tyr 145 150 155 160 Arg Gly Val Trp Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg 165 170 175 Glu Gly Val Ala Thr Ile Tyr Thr Gly Ser Gly His Thr Tyr Tyr Ala 180 185 190 Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn 195 200 205 Thr Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met 210 215 220 Tyr Tyr Cys Ala Ala Arg Thr Val Gly Gly Thr Phe Tyr Thr Leu Ala 225 230 235 240 Ala Asp Ser Phe Asn Thr Trp Gly Gln Gly Thr Gln Val Thr Val Ser 245 250 255 Ser <210> 136 <211> 257 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 136 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Tyr Thr Tyr Ser Ser Ala 20 25 30 Phe Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val 35 40 45 Ala Ala Ile Tyr Thr Arg Asp Gly Gly Thr Val Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Ala Lys Ile Pro Gln Pro Gly Arg Ala Ser Leu Leu Asp Ser Gln 100 105 110 Thr Tyr Asp Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly 115 120 125 Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln 130 135 140 Asp Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asp Ile Tyr 145 150 155 160 Ala Arg Asn Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg 165 170 175 Glu Lys Ile Ala Val Ala Asp Thr Gly Gly Arg Ser Pro Tyr Tyr Ala 180 185 190 Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn 195 200 205 Thr Val Asp Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val 210 215 220 Tyr Tyr Cys Ala Ala Gly Pro Leu Val Pro Val Val Asn Thr Ala Ala 225 230 235 240 Arg Cys Val Tyr Glu Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser 245 250 255 Ser <210> 137 <211> 256 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 137 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Tyr Asp Tyr Cys Gly Tyr 20 25 30 Asp Val Arg Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val 35 40 45 Ser Gly Ile Asp Ser Asp Gly Ser Thr Ser Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Glu Asn Thr Ser Tyr Leu 65 70 75 80 His Met Phe Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Lys 85 90 95 Thr Glu Ser Pro Ala Gly Glu Ser Ala Trp Cys Arg Asn Phe Arg Gly 100 105 110 Met Asp Tyr Trp Gly Lys Gly Thr Gln Val Thr Val Ser Ser Gly Gly 115 120 125 Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala 130 135 140 Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Tyr Ser 145 150 155 160 Asn Arg His Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu 165 170 175 Gly Val Ala Ala Ile Tyr Thr Gly Gly Gly Ser Thr Tyr Tyr Ala Asp 180 185 190 Ser Val Lys Asp Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr 195 200 205 Leu Tyr Leu Gln Met Asn Ser Leu Thr Pro Glu Asp Thr Ala Met Tyr 210 215 220 Tyr Cys Ala Ala Asp Leu Thr Arg Trp Tyr Ser Gly Gly Trp Arg Asp 225 230 235 240 Pro Arg Gly Tyr Lys Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser 245 250 255 <210> 138 <211> 258 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 138 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Tyr Asp Tyr Cys Gly Tyr 20 25 30 Asp Val Arg Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val 35 40 45 Ser Gly Ile Asp Ser Asp Gly Ser Thr Ser Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Glu Asn Thr Ser Tyr Leu 65 70 75 80 His Met Phe Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Lys 85 90 95 Thr Glu Ser Pro Ala Gly Glu Ser Ala Trp Cys Arg Asn Phe Arg Gly 100 105 110 Met Asp Tyr Trp Gly Lys Gly Thr Gln Val Thr Val Ser Ser Gly Gly 115 120 125 Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala 130 135 140 Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Val Thr Tyr Gly 145 150 155 160 Ser Tyr Tyr Met Ala Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg 165 170 175 Glu Gly Val Ala Ser Ile Tyr Gly Gly Ser Asp Ser Thr Tyr Tyr Ala 180 185 190 Asp Ser Val Leu Gly Arg Phe Thr Ile Ser Gln Asp Asn Gly Lys Asn 195 200 205 Thr Leu Tyr Leu Gln Met Asn Ser Leu Lys Pro Asp Asp Thr Ala Met 210 215 220 Tyr Tyr Cys Ala Ala Ala Pro Pro Gly Lys Trp Phe Leu Lys Arg Leu 225 230 235 240 Glu Gly His Asn Tyr Ser Tyr Trp Gly Gln Gly Thr Gln Val Thr Val 245 250 255 Ser Ser <210> 139 <211> 261 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 139 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Tyr Asp Tyr Cys Gly Tyr 20 25 30 Asp Val Arg Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val 35 40 45 Ser Gly Ile Asp Ser Asp Gly Ser Thr Ser Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Glu Asn Thr Ser Tyr Leu 65 70 75 80 His Met Phe Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Lys 85 90 95 Thr Glu Ser Pro Ala Gly Glu Ser Ala Trp Cys Arg Asn Phe Arg Gly 100 105 110 Met Asp Tyr Trp Gly Lys Gly Thr Gln Val Thr Val Ser Ser Gly Gly 115 120 125 Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Val 130 135 140 Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Tyr Ser 145 150 155 160 Ser Ser Cys Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu 165 170 175 Gly Val Ala Thr Ile Tyr Pro Ala Gly Gly Asn Ile Phe Tyr Ala Asp 180 185 190 Ser Val Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr 195 200 205 Val Tyr Leu Gln Met Asp Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr 210 215 220 Tyr Cys Ala Ala Arg Gly Gly Gln Thr Trp Gly Ser Gly Gly Asn Arg 225 230 235 240 Cys Ser Leu Trp Leu Pro Ala Tyr Asn Tyr Trp Gly Gln Gly Thr Gln 245 250 255 Val Thr Val Ser Ser 260 <210> 140 <211> 253 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 140 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Tyr Asp Tyr Cys Gly Tyr 20 25 30 Asp Val Arg Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val 35 40 45 Ser Gly Ile Asp Ser Asp Gly Ser Thr Ser Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Glu Asn Thr Ser Tyr Leu 65 70 75 80 His Met Phe Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Lys 85 90 95 Thr Glu Ser Pro Ala Gly Glu Ser Ala Trp Cys Arg Asn Phe Arg Gly 100 105 110 Met Asp Tyr Trp Gly Lys Gly Thr Gln Val Thr Val Ser Ser Gly Gly 115 120 125 Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Val 130 135 140 Gly Gly Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Lys Leu Tyr Gly 145 150 155 160 Gly Ala Trp Phe Arg Gln Ala Gln Gly Lys Gly Arg Glu Gly Val Ala 165 170 175 Ala Ile Trp Ile Gly Thr Gly Thr Thr Phe Tyr Ala Asp Ser Val Lys 180 185 190 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu 195 200 205 Gln Met Asp Gly Leu Lys Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala 210 215 220 Ala Asp Asp Arg Pro Gly Tyr Arg Asp Pro Leu Ala Pro Val Ser Tyr 225 230 235 240 Asn His Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 245 250 <210> 141 <211> 256 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 141 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Tyr Asp Tyr Cys Gly Tyr 20 25 30 Asp Val Arg Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val 35 40 45 Ser Gly Ile Asp Ser Asp Gly Ser Thr Ser Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Glu Asn Thr Ser Tyr Leu 65 70 75 80 His Met Phe Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Lys 85 90 95 Thr Glu Ser Pro Ala Gly Glu Ser Ala Trp Cys Arg Asn Phe Arg Gly 100 105 110 Met Asp Tyr Trp Gly Lys Gly Thr Gln Val Thr Val Ser Ser Gly Gly 115 120 125 Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala 130 135 140 Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ile Thr Tyr Arg 145 150 155 160 Gly Val Trp Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu 165 170 175 Gly Val Ala Thr Ile Tyr Thr Gly Ser Gly His Thr Tyr Tyr Ala Asp 180 185 190 Ser Val Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr 195 200 205 Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr 210 215 220 Tyr Cys Ala Ala Arg Thr Val Gly Gly Thr Phe Tyr Thr Leu Ala Ala 225 230 235 240 Asp Ser Phe Asn Thr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 245 250 255 <210> 142 <211> 256 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 142 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Tyr Asp Tyr Cys Gly Tyr 20 25 30 Asp Val Arg Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val 35 40 45 Ser Gly Ile Asp Ser Asp Gly Ser Thr Ser Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Glu Asn Thr Ser Tyr Leu 65 70 75 80 His Met Phe Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Lys 85 90 95 Thr Glu Ser Pro Ala Gly Glu Ser Ala Trp Cys Arg Asn Phe Arg Gly 100 105 110 Met Asp Tyr Trp Gly Lys Gly Thr Gln Val Thr Val Ser Ser Gly Gly 115 120 125 Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Asp 130 135 140 Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asp Ile Tyr Ala 145 150 155 160 Arg Asn Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu 165 170 175 Lys Ile Ala Val Ala Asp Thr Gly Gly Arg Ser Pro Tyr Tyr Ala Asp 180 185 190 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr 195 200 205 Val Asp Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr 210 215 220 Tyr Cys Ala Ala Gly Pro Leu Val Pro Val Val Asn Thr Ala Ala Arg 225 230 235 240 Cys Val Tyr Glu Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 245 250 255 <210> 143 <211> 256 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 143 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Tyr Ser Tyr Cys Gly Tyr 20 25 30 Asp Met Met Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val 35 40 45 Ala Leu Ile Thr Ser Asp Tyr Ser Ile Arg Tyr Glu Asp Ser Val Glu 50 55 60 Gly Arg Phe Ser Ile Ser Arg Asp Asn Ala Lys Asn Thr Gly Tyr Leu 65 70 75 80 Leu Met Ser Asn Leu Thr Pro Ala Asp Thr Ala Ile Tyr Tyr Cys Lys 85 90 95 Thr Ser Thr Ala Ala Arg Glu Ser Ser Trp Cys Arg Ser Arg Tyr Arg 100 105 110 Val Ala Ser Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly 115 120 125 Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala 130 135 140 Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Tyr Ser 145 150 155 160 Asn Arg His Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu 165 170 175 Gly Val Ala Ala Ile Tyr Thr Gly Gly Gly Ser Thr Tyr Tyr Ala Asp 180 185 190 Ser Val Lys Asp Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr 195 200 205 Leu Tyr Leu Gln Met Asn Ser Leu Thr Pro Glu Asp Thr Ala Met Tyr 210 215 220 Tyr Cys Ala Ala Asp Leu Thr Arg Trp Tyr Ser Gly Gly Trp Arg Asp 225 230 235 240 Pro Arg Gly Tyr Lys Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser 245 250 255 <210> 144 <211> 258 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 144 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Tyr Ser Tyr Cys Gly Tyr 20 25 30 Asp Met Met Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val 35 40 45 Ala Leu Ile Thr Ser Asp Tyr Ser Ile Arg Tyr Glu Asp Ser Val Glu 50 55 60 Gly Arg Phe Ser Ile Ser Arg Asp Asn Ala Lys Asn Thr Gly Tyr Leu 65 70 75 80 Leu Met Ser Asn Leu Thr Pro Ala Asp Thr Ala Ile Tyr Tyr Cys Lys 85 90 95 Thr Ser Thr Ala Ala Arg Glu Ser Ser Trp Cys Arg Ser Arg Tyr Arg 100 105 110 Val Ala Ser Trp Gly Gly Gly Thr Gln Val Thr Val Ser Ser Gly Gly 115 120 125 Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala 130 135 140 Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Val Thr Tyr Gly 145 150 155 160 Ser Tyr Tyr Met Ala Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg 165 170 175 Glu Gly Val Ala Ser Ile Tyr Gly Gly Ser Asp Ser Thr Tyr Tyr Ala 180 185 190 Asp Ser Val Leu Gly Arg Phe Thr Ile Ser Gln Asp Asn Gly Lys Asn 195 200 205 Thr Leu Tyr Leu Gln Met Asn Ser Leu Lys Pro Asp Asp Thr Ala Met 210 215 220 Tyr Tyr Cys Ala Ala Ala Pro Pro Gly Lys Trp Phe Leu Lys Arg Leu 225 230 235 240 Glu Gly His Asn Tyr Ser Tyr Trp Gly Gln Gly Thr Gln Val Thr Val 245 250 255 Ser Ser <210> 145 <211> 261 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 145 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Tyr Ser Tyr Cys Gly Tyr 20 25 30 Asp Met Met Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val 35 40 45 Ala Leu Ile Thr Ser Asp Tyr Ser Ile Arg Tyr Glu Asp Ser Val Glu 50 55 60 Gly Arg Phe Ser Ile Ser Arg Asp Asn Ala Lys Asn Thr Gly Tyr Leu 65 70 75 80 Leu Met Ser Asn Leu Thr Pro Ala Asp Thr Ala Ile Tyr Tyr Cys Lys 85 90 95 Thr Ser Thr Ala Ala Arg Glu Ser Ser Trp Cys Arg Ser Arg Tyr Arg 100 105 110 Val Ala Ser Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly 115 120 125 Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Val 130 135 140 Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Tyr Ser 145 150 155 160 Ser Ser Cys Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu 165 170 175 Gly Val Ala Thr Ile Tyr Pro Ala Gly Gly Asn Ile Phe Tyr Ala Asp 180 185 190 Ser Val Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr 195 200 205 Val Tyr Leu Gln Met Asp Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr 210 215 220 Tyr Cys Ala Ala Arg Gly Gly Gln Thr Trp Gly Ser Gly Gly Asn Arg 225 230 235 240 Cys Ser Leu Trp Leu Pro Ala Tyr Asn Tyr Trp Gly Gln Gly Thr Gln 245 250 255 Val Thr Val Ser Ser 260 <210> 146 <211> 253 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 146 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Tyr Ser Tyr Cys Gly Tyr 20 25 30 Asp Met Met Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val 35 40 45 Ala Leu Ile Thr Ser Asp Tyr Ser Ile Arg Tyr Glu Asp Ser Val Glu 50 55 60 Gly Arg Phe Ser Ile Ser Arg Asp Asn Ala Lys Asn Thr Gly Tyr Leu 65 70 75 80 Leu Met Ser Asn Leu Thr Pro Ala Asp Thr Ala Ile Tyr Tyr Cys Lys 85 90 95 Thr Ser Thr Ala Ala Arg Glu Ser Ser Trp Cys Arg Ser Arg Tyr Arg 100 105 110 Val Ala Ser Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly 115 120 125 Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Val 130 135 140 Gly Gly Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Lys Leu Tyr Gly 145 150 155 160 Gly Ala Trp Phe Arg Gln Ala Gln Gly Lys Gly Arg Glu Gly Val Ala 165 170 175 Ala Ile Trp Ile Gly Thr Gly Thr Thr Phe Tyr Ala Asp Ser Val Lys 180 185 190 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu 195 200 205 Gln Met Asp Gly Leu Lys Pro Glu Asp Thr Ala Leu Tyr Tyr Cys Ala 210 215 220 Ala Asp Asp Arg Pro Gly Tyr Arg Asp Pro Leu Ala Pro Val Ser Tyr 225 230 235 240 Asn His Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 245 250 <210> 147 <211> 256 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 147 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Tyr Ser Tyr Cys Gly Tyr 20 25 30 Asp Met Met Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val 35 40 45 Ala Leu Ile Thr Ser Asp Tyr Ser Ile Arg Tyr Glu Asp Ser Val Glu 50 55 60 Gly Arg Phe Ser Ile Ser Arg Asp Asn Ala Lys Asn Thr Gly Tyr Leu 65 70 75 80 Leu Met Ser Asn Leu Thr Pro Ala Asp Thr Ala Ile Tyr Tyr Cys Lys 85 90 95 Thr Ser Thr Ala Ala Arg Glu Ser Ser Trp Cys Arg Ser Arg Tyr Arg 100 105 110 Val Ala Ser Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly 115 120 125 Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala 130 135 140 Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ile Thr Tyr Arg 145 150 155 160 Gly Val Trp Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu 165 170 175 Gly Val Ala Thr Ile Tyr Thr Gly Ser Gly His Thr Tyr Tyr Ala Asp 180 185 190 Ser Val Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr 195 200 205 Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr 210 215 220 Tyr Cys Ala Ala Arg Thr Val Gly Gly Thr Phe Tyr Thr Leu Ala Ala 225 230 235 240 Asp Ser Phe Asn Thr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 245 250 255 <210> 148 <211> 256 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 148 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Tyr Ser Tyr Cys Gly Tyr 20 25 30 Asp Met Met Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val 35 40 45 Ala Leu Ile Thr Ser Asp Tyr Ser Ile Arg Tyr Glu Asp Ser Val Glu 50 55 60 Gly Arg Phe Ser Ile Ser Arg Asp Asn Ala Lys Asn Thr Gly Tyr Leu 65 70 75 80 Leu Met Ser Asn Leu Thr Pro Ala Asp Thr Ala Ile Tyr Tyr Cys Lys 85 90 95 Thr Ser Thr Ala Ala Arg Glu Ser Ser Trp Cys Arg Ser Arg Tyr Arg 100 105 110 Val Ala Ser Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly 115 120 125 Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Asp 130 135 140 Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asp Ile Tyr Ala 145 150 155 160 Arg Asn Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu 165 170 175 Lys Ile Ala Val Ala Asp Thr Gly Gly Arg Ser Pro Tyr Tyr Ala Asp 180 185 190 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr 195 200 205 Val Asp Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr 210 215 220 Tyr Cys Ala Ala Gly Pro Leu Val Pro Val Val Asn Thr Ala Ala Arg 225 230 235 240 Cys Val Tyr Glu Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser 245 250 255 <210> 149 <211> 257 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 149 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Tyr Thr Tyr Thr Asn Asn 20 25 30 Phe Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val 35 40 45 Ala Ala Ile Tyr Thr Gly Asp Gly Tyr Ala Tyr Tyr Phe Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Asp Lys Asn Met Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Ala Met Glu Arg Arg Ser Gly Arg Arg Arg Met Thr Glu Asn Ala 100 105 110 Glu Tyr Lys Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly 115 120 125 Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln 130 135 140 Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Tyr 145 150 155 160 Ser Asn Arg His Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg 165 170 175 Glu Gly Val Ala Ala Ile Tyr Thr Gly Gly Gly Ser Thr Tyr Tyr Ala 180 185 190 Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn 195 200 205 Thr Leu Tyr Leu Gln Met Asn Ser Leu Thr Pro Glu Asp Thr Ala Met 210 215 220 Tyr Tyr Cys Ala Ala Asp Leu Thr Arg Trp Tyr Ser Gly Gly Trp Arg 225 230 235 240 Asp Pro Arg Gly Tyr Lys Tyr Trp Gly Gln Gly Thr Gln Val Thr Val 245 250 255 Ser <210> 150 <211> 259 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 150 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Tyr Thr Tyr Thr Asn Asn 20 25 30 Phe Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val 35 40 45 Ala Ala Ile Tyr Thr Gly Asp Gly Tyr Ala Tyr Tyr Phe Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Asp Lys Asn Met Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Ala Met Glu Arg Arg Ser Gly Arg Arg Arg Met Thr Glu Asn Ala 100 105 110 Glu Tyr Lys Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly 115 120 125 Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln 130 135 140 Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Val Thr Tyr 145 150 155 160 Gly Ser Tyr Tyr Met Ala Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu 165 170 175 Arg Glu Gly Val Ala Ser Ile Tyr Gly Gly Ser Asp Ser Thr Tyr Tyr 180 185 190 Ala Asp Ser Val Leu Gly Arg Phe Thr Ile Ser Gln Asp Asn Gly Lys 195 200 205 Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Lys Pro Asp Asp Thr Ala 210 215 220 Met Tyr Tyr Cys Ala Ala Ala Pro Pro Gly Lys Trp Phe Leu Lys Arg 225 230 235 240 Leu Glu Gly His Asn Tyr Ser Tyr Trp Gly Gln Gly Thr Gln Val Thr 245 250 255 Val Ser Ser <210> 151 <211> 262 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 151 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Tyr Thr Tyr Thr Asn Asn 20 25 30 Phe Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val 35 40 45 Ala Ala Ile Tyr Thr Gly Asp Gly Tyr Ala Tyr Tyr Phe Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Asp Lys Asn Met Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Ala Met Glu Arg Arg Ser Gly Arg Arg Arg Met Thr Glu Asn Ala 100 105 110 Glu Tyr Lys Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly 115 120 125 Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln 130 135 140 Val Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Tyr 145 150 155 160 Ser Ser Ser Cys Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg 165 170 175 Glu Gly Val Ala Thr Ile Tyr Pro Ala Gly Gly Asn Ile Phe Tyr Ala 180 185 190 Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn 195 200 205 Thr Val Tyr Leu Gln Met Asp Ser Leu Lys Pro Glu Asp Thr Ala Met 210 215 220 Tyr Tyr Cys Ala Ala Arg Gly Gly Gln Thr Trp Gly Ser Gly Gly Asn 225 230 235 240 Arg Cys Ser Leu Trp Leu Pro Ala Tyr Asn Tyr Trp Gly Gln Gly Thr 245 250 255 Gln Val Thr Val Ser Ser 260 <210> 152 <211> 254 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 152 Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Tyr Thr Tyr Thr Asn Asn 20 25 30 Phe Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val 35 40 45 Ala Ala Ile Tyr Thr Gly Asp Gly Tyr Ala Tyr Tyr Phe Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Asp Lys Asn Met Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Ala Met Glu Arg Arg Ser Gly Arg Arg Arg Met Thr Glu Asn Ala 100 105 110 Glu Tyr Lys Tyr Trp G...

Claims

1. 1. An IL12 receptor (IL12R) binding protein that specifically binds to IL12Rβ1 and IL12Rβ2, Causes multimerization of IL12Rβ1 and IL12Rβ2 and downstream signaling, and including single domain antibodies (sdAbs) that specifically bind to IL12Rβ1 (anti-IL12Rβ1 sdAb) and sdAbs that specifically bind to IL12Rβ2 (anti-IL12Rβ2 sdAb); The binding protein.

2. Anti-IL12Rβ1 sdAb V H H antibody (anti-IL12Rβ1 V H H antibody) and / or the anti-IL12Rβ2 sdAb is V H H antibody (anti-IL12Rβ2 V H 2. The IL12R binding protein of claim 1, which is an IL12R-binding protein (H antibody).

3. 3. The IL12R binding protein of claim 1 or 2, wherein the anti-IL12Rβ1 sdAb and the anti-IL12Rβ2 sdAb are joined by a peptide linker.

4. 4. The IL12R binding protein of claim 3, wherein the peptide linker comprises 1 to 50 amino acids.

5. Reduced E compared to IL12 max 5. The IL12R binding protein of any one of claims 1 to 4, having the following structure:

6. 6. The IL12R binding protein of any one of claims 1 to 5, which has a similar potency compared to that of IL12.

7. 1. A method for treating cancer in a subject in need thereof, comprising administering to a subject a natural killer, CD4 + T cells and / or CD8 + The method comprises administering to the subject an IL12R binding protein according to any one of claims 1 to 6, which binds to and activates T cells.

8. 8. The method of claim 7, wherein the cancer is a solid tumor cancer.

9. 1. An IL27 receptor (IL27R) binding protein that specifically binds to the IL27R alpha subunit (IL27Rα) and glycoprotein 130 subunit (gp130), Causes multimerization of IL27Rα and gp130 and downstream signaling; and a single domain antibody (sdAb) that specifically binds to IL27Rα (anti-IL27Rα sdAb) and a sdAb that specifically binds to gp130 (anti-gp130 sdAb); The binding protein.

10. Anti-IL27Rα sdAb V H H antibody (anti-IL27Rα V H H antibody) and / or the anti-gp130 sdAb is V H H antibody (anti-gp130 V H 10. The IL27R binding protein of claim 9, which is an H antibody.

11. 11. The IL27R binding protein of any one of claims 9 to 10, wherein the anti-IL27Rα sdAb and the anti-gp130 sdAb are joined by a peptide linker.

12. 12. The IL27R binding protein of claim 11, wherein the peptide linker comprises 1 to 50 amino acids.

13. 1. A method for treating cancer in a subject in need thereof, comprising administering to a subject a CD8 + T cells, CD4 + The method comprises administering to the subject an IL27R binding protein according to any one of claims 9 to 12 that binds to and activates T cells and / or T regulatory (Treg) cells.

14. IL27R binding protein is CD8 + The method of claim 13, which binds to and activates T cells.

15. IL27R binding protein is CXCR5 + CD8 + 15. The method of claim 13 or 14, which binds to and activates T cells.

16. The method of any one of claims 13 to 15, wherein the cancer is a solid tumor cancer.

17. 1. An IL10 receptor (IL10R) binding protein that specifically binds to the IL10Rα subunit (IL10Rα) and IL10Rβ, Causes multimerization of IL10Rα and IL10Rβ and downstream signaling; and including single domain antibodies (sdAbs) that specifically bind to IL10Rα (anti-IL10Rα sdAb) and sdAbs that specifically bind to IL10Rβ (anti-IL10Rβ sdAb); The binding protein.

18. Anti-IL10Rα sdAb V H H antibody (anti-IL10Rα V H H antibody) and / or the anti-IL10Rβ sdAb is V H H antibody (anti-IL10Rβ V H 18. The IL10R binding protein of claim 17, which is an IL10R binding protein (H antibody).

19. 19. The IL10R binding protein of any one of claims 17 to 18, wherein the anti-IL10Rα sdAb and the anti-IL10Rβ sdAb are joined by a peptide linker.

20. 20. The IL10R binding protein of claim 19, wherein the peptide linker comprises 1 to 50 amino acids.

21. 1. A method for treating cancer in a subject in need thereof, comprising administering to a subject a CD8 + T cells, CD4 + The method comprises administering to the subject an IL10R binding protein according to any one of claims 17 to 20 which binds to and activates T cells, macrophages and / or Treg cells.

22. 22. The method of claim 21, wherein the IL10R binding protein provides a longer therapeutic effect than pegylated IL10.

23. 23. The method of claim 21 or 22, wherein the cancer is a solid tumor cancer.

24. An interferon (IFN) lambda receptor (IFNλR) binding protein that specifically binds to IL10Rβ and the IL28 receptor (IL28R) alpha subunit (IL28Rα), Causes multimerization of IL10Rβ and IL28Rα and downstream signaling; and a single domain antibody (sdAb) that specifically binds to IL10Rβ (anti-IL10Rβ sdAb) and a sdAb that specifically binds to IL28Rα (anti-IL28Rα sdAb); The binding protein.

25. Anti-IL10Rβ sdAb V H H antibody (anti-IL10Rβ V H H antibody) and / or the anti-IL28Rα sdAb is V H H antibody (anti-IL28Rα V H 25. The IFNλR binding protein of claim 24, which is an H antibody.

26. 26. The IFNλR binding protein of any one of claims 24 to 25, wherein the anti-IL10Rβ sdAb and the anti-IL28Rα sdAb are joined by a peptide linker.

27. 27. The IFNλR binding protein of claim 26, wherein the peptide linker comprises 1 to 50 amino acids.

28. A method for treating an infectious disease in a subject in need thereof, comprising administering to a subject a cell line comprising macrophages, CD8 + T cells, CD4 + The method comprises administering to the subject an IFNλR binding protein according to any one of claims 24 to 27 which binds to and activates T cells, Treg cells, dendritic cells and / or epithelial cells.

29. 30. The method of claim 28, wherein the IFNλR binding protein binds to and activates macrophages.

30. 30. The method of claim 28 or 29, wherein the infectious disease is influenza, hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection.

31. A binding protein that specifically binds to IL10Rα and IL2Rγ, Causes multimerization of IL10Rα and IL2Rγ and downstream signaling; and including an sdAb that specifically binds to IL10Rα (anti-IL10Rα sdAb) and an sdAb that specifically binds to IL2Rγ (anti-IL2Rγ sdAb), The binding protein.

32. Anti-IL10Rα sdAb V H H antibody (anti-IL10Rα V H H antibody) and / or the anti-IL2Rγ sdAb is V H H antibody (anti-IL2Rγ V H 32. The binding protein of claim 31 , which is a IgG antibody (H antibody).

33. 33. The binding protein of any one of claims 31-32, wherein the anti-IL10Rα sdAb and the anti-IL2Rγ sdAb are joined by a peptide linker.

34. 34. The binding protein of claim 33, wherein the peptide linker comprises 1 to 50 amino acids.

35. 1. A method for treating cancer in a subject in need thereof, comprising administering to a subject a CD8 + T cells and / or CD4 + The method comprises administering to the subject a binding protein of any one of claims 31-34 that binds to and activates T cells.

36. 36. The method of claim 35, which does not cause anemia.

37. A binding protein that specifically binds to a first receptor and a second receptor, wherein the first receptor is interferon gamma receptor 1 (IFNγR1) or IL28Rα, and the second receptor is preferentially expressed on myeloid cells and / or T cells; Causes multimerization of the first receptor and the second receptor and their downstream signaling; and A single domain antibody (sdAb) that specifically binds to a first receptor and a single domain antibody (sdAb) that specifically binds to a second receptor, The binding protein.

38. The sdAb that specifically binds to the first receptor is anti-IFNγR1 V H 38. The binding protein of claim 37 which is an H antibody.

39. The sdAb that specifically binds to the first receptor is anti-IL28Rα V H 38. The binding protein of claim 37 which is an H antibody.

40. 40. The binding protein of any one of claims 37 to 39, wherein the first receptor is IFNγR1 and the second receptor is IL2Rγ.

41. 40. The binding protein of any one of claims 37 to 39, wherein the first receptor is IL28Rα and the second receptor is IL2Rγ.

42. 42. The binding protein of any one of claims 37 to 41, wherein the sdAb that specifically binds to the first receptor and the sdAb that specifically binds to the second receptor are joined by a peptide linker.

43. 43. The binding protein of claim 42, wherein the peptide linker comprises 5 to 50 amino acids.

44. 44. A method for treating cancer in a subject in need thereof, comprising administering to the subject a binding protein of any one of claims 37-43 that binds to and activates myeloid cells and / or T cells.

45. 45. The method of claim 44, wherein the binding protein binds to and activates macrophages.

46. Binding protein is CD8 + T cells and / or CD4 + The method of claim 44, which binds to and activates T cells.

47. 21. The IL10R binding protein of any one of claims 17 to 20, wherein the anti-IL10Rα sdAb is selected from the group consisting of SEQ ID NOs: 44 to 50 and the anti-IL10Rβ sdAb is selected from the group consisting of SEQ ID Nos: 51 to 57.

48. 48. The IL10R binding protein of claim 47, wherein the anti-IL10Rα sdAb is joined to the anti-IL10Rβ sdAb by a linker selected from the group consisting of SEQ ID No: 1-23.

49. The IL10R binding protein comprises, in the amino to carboxy direction: and comprising a first anti-IL10R sdAb, a second anti-IL10R sdAb linked by a linker according to The linker is selected from the group consisting of SEQ ID No: 1 to 23; 48. The ILR binding protein of claim 47.

50. 18. The IL-10 receptor binding protein of claim 17, selected from the group consisting of SEQ ID Nos: 194, 209, 210, 211, 213, 218, 226, 233, 238, 244, 250, 203, 205, 207, 269, 212, 217, 219, 224, 227, 237, 239 and 249.

Images