Methods and Compositions for Treating Autoimmune and Inflammatory Conditions - Patent application

Abstract

Compositions and methods for inhibiting inflammatory or autoimmune responses and for inducing immune tolerance are provided. [Solution] A pharmaceutical composition for inducing immune tolerance in a subject, inhibiting an inflammatory or autoimmune response in a subject, suppressing a T cell response in a subject having or at risk of developing an inflammatory response, or preventing or treating an autoimmune disease or inflammatory condition, comprising an anti-DC-ASGPR antibody functionally linked to IL-10, wherein the pharmaceutical composition does not contain an antigen associated with the autoimmune disease or inflammatory condition.

Description

[Technical Field]

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 61 / 994,239, filed May 16, 2014, and U.S. Provisional Patent Application No. 62 / 014,504, filed June 19, 2014, both of which are incorporated by reference in their entireties.

[0002] This invention was made with government support under Grant No. 1R56AI105066-01 and Grant No. 2.1R01AI105066-01A1 awarded by the National Institute of Allergy and Infectious Diseases / National Institutes of Health. The U.S. Government has certain rights in this invention.

[0003] 1. Field of the Invention The present invention relates generally to the field of medicine. More particularly, the present invention relates to pharmaceutical compositions for enhancing tolerance to antigens and for treating inflammatory and autoimmune disorders. [Background technology]

[0004] 2.Background Autoimmune and inflammatory diseases result from the body's abnormal immune response to substances and tissues normally present in the body. This may be limited to a particular organ (e.g., in the case of autoimmune thyroiditis) or may affect specific tissues in various locations (e.g., Goodpasture's disease, which can affect the basement membrane in both the lungs and kidneys). Autoimmune and autoinflammatory diseases affect up to 50 million people in the United States alone, yet the causes of autoimmunity remain unknown.

[0005] These diseases are typically treated using immunosuppression, i.e., drug therapy that reduces the immune response. Conventional immunotherapy using immunosuppressants such as cyclosporine, tacrolimus, methotrexate, or anti-TNFα / IL-6 nonspecifically suppresses the function of T cells, including non-pathogenic T cells, in the host. As a result, treatment with these immunosuppressants often results in the development of severe infections, sometimes leading to fatal outcomes. There is a need in the art for therapeutic agents that treat autoimmune responses without global immunosuppression. Summary of the Invention

[0006] The present disclosure addresses a need in the art by providing methods and compositions for delivering the anti-inflammatory cytokine IL-10 to antigen-presenting cells (APCs) to suppress and alter the pathophysiological function of APCs in a subject using an APC-targeting antibody operably linked to IL-10 or a fragment thereof. Targeted delivery of anti-inflammatory cytokines to APCs in a patient is expected to result in more effective and long-lasting immune tolerance in the patient. Accordingly, an aspect of the present disclosure relates to a method for inhibiting an inflammatory or autoimmune response in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an antigen-presenting cell (APC)-targeting antibody operably linked to IL-10 or a fragment thereof.

[0007] In some embodiments, the present disclosure relates to a method for preventing or treating graft-versus-host disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of DC-ASGPR operably linked to IL-10 or a fragment thereof.

[0008] A further aspect relates to a method of inducing immune tolerance in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an APC-targeting antibody operably linked to IL-10 or a fragment thereof. Another aspect relates to a method of suppressing a T cell response in a subject by administering to a subject having or at risk of developing an inflammatory response a therapeutically effective amount of an APC-targeting antibody operably linked to IL-10 or a fragment thereof.

[0009] The term "operably linked" refers to the situation in which two components combine to form an active complex prior to binding at a target site. For example, an antibody conjugated to one of the two components of a cohesin-dockerin complex and a cytokine (e.g., IL-10) or other molecule (e.g., an antigen) complexed to the other component of the cohesin-dockerin complex are operably linked through the complexation of the cohesin molecule and the dockerin molecule. The term "operably linked" also refers to a covalent or chemical bond that conjugates the two molecules together.

[0010] Yet another aspect relates to methods and compositions for treating unwanted and / or aberrant immune responses without nonspecific suppression of the host immune system. In particular, anti-DC-ASGPR antibodies or antigen-binding fragments thereof can be used in the compositions and methods described herein to generate anti-pathogen antigen-specific regulatory T cells and / or reduce pathogenic T cell responses.

[0011] The term "anti-pathogen antigen-specific regulatory T cells" refers to T cells that have beneficial and therapeutic properties. In one embodiment, the anti-pathogen antigen-specific regulatory T cells are alloantigen-specific regulatory T cells. In another embodiment, the anti-pathogen antigen-specific regulatory T cells produce IL-10. The anti-pathogen antigen-specific regulatory T cells may be CD4+ T cells.

[0012] The term pathogenic T cell response refers to an abnormal or unwanted T cell response that contributes to the pathology of autoimmune disease or graft-versus-host disease (GVHD) or transplant rejection. In one embodiment, the pathogenic T cell response is an allogeneic T cell response. In a further embodiment, the pathogenic T cell response comprises allogeneic CD4+ T cells and CD8+ T cells. In one embodiment, the pathogenic T cell response comprises immune cells of a tissue transplant.

[0013] A further aspect of the present disclosure relates to a method for preventing or treating GVHD in a subject in need thereof, comprising administering to the subject an anti-DC-ASGPR antibody or antigen-binding fragment thereof.

[0014] Graft-versus-host disease (GVHD) is a common complication after allogeneic tissue transplantation. It is most commonly seen with stem cell or bone marrow transplantation, although the term also applies to other forms of tissue transplantation. Immune cells (white blood cells) in the tissue (graft) recognize the recipient (host) as "foreign." The transplanted immune cells then attack the host's somatic cells. GVHD can also occur after blood transfusions if the blood products used are not irradiated.

[0015] In another aspect, the present disclosure describes a method for preventing or treating transplant rejection in a subject in need thereof, comprising administering to the subject an anti-DC-ASGPR antibody or an antigen-binding fragment thereof.

[0016] Graft rejection occurs when transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue. Graft rejection is sometimes called transplant rejection or host-versus-graft disease.

[0017] In certain embodiments, the antibody or antigen-binding fragment specifically binds to DC-ASGPR and activates DC-ASGPR. DC-asialoglycoprotein receptor (DC-ASGPR) is a scavenger receptor that possesses an immunoreceptor tyrosine-based activation motif-like motif. ASGPR is also known as ASGR1, ASGPR1, CLEC4H1, and HL-1. In one embodiment, the antibody or antigen-binding fragment thereof binds to human DC-ASGPR.

[0018] In some embodiments, the APC targeting antibody targets APCs from one or more of the following group: Langerhans cells, macrophages, dendritic cells, B cells, and peripheral blood mononuclear cells. In further embodiments, the APC targeting antibody is selected from antibodies that specifically bind to MHC class I, MHC class II, CD1d, CD2, CD3, CD4, CD8, CD11b, CD14, CD15, CD16, CD19, CD20, CD29, CD31, CD40, CD43, CD44, CD45, CD54, CD56, CD57, CD58, CD83, CD86, CMRF-44, CMRF-56, DCIR, DC-ASGPR, CLEC-6, CD40, BDCA-2, MARCO, DEC-205, mannose receptor, langerin, DECTIN-1, B7-1, B7-2, IFN-γ receptor, IL-2 receptor, ICAM-1, Fcγ receptor, LOX-1, and ASPGR.

[0019] In another embodiment, the APC targeting antibody targets Langerhans cells. An example of an APC targeting antibody for Langerhans cells is anti-Langerin. In a further embodiment, the APC targeting antibody targets macrophages. For example, the APC targeting antibody can be anti-MARCO.

[0020] In yet another embodiment, the APC-targeting antibody targets one or more APCs from the group consisting of dendritic cells, B cells, and macrophages. In a specific embodiment, the APC-targeting antibody targets dendritic cells. In some embodiments, the APC-targeting antibody comprises anti-CD40. In a further embodiment, the anti-CD40 antibody comprises anti-CD40 clone 12E12 or a fragment thereof. As shown in Example 1, anti-CD40 (12E12)-IL-10 suppressed CD86 expression. In some embodiments, the anti-CD40 antibody comprises one or more CDRs having the sequences of SEQ ID NOs: 31-33 and 37-39. In other embodiments, the anti-CD40 antibody comprises a heavy chain comprising one or more CDRs of SEQ ID NOs: 31-33. In further embodiments, the anti-CD40 antibody comprises a light chain comprising one or more CDRs of SEQ ID NOs: 37-39.

[0021] In a specific embodiment, the anti-CD40 antibody is a humanized antibody comprising a heavy chain comprising three CDRs, CDR1 comprising SEQ ID NO: 31, CDR2 comprising SEQ ID NO: 32, and CDR3 comprising SEQ ID NO: 33. In a further embodiment, the anti-CD40 antibody is a humanized antibody comprising a light chain comprising three CDRs, CDR1 comprising SEQ ID NO: 37, CDR2 comprising SEQ ID NO: 38, and CDR3 comprising SEQ ID NO: 39.

[0022] In some embodiments, the APC-targeting antibody comprises anti-DC-ASGPR or anti-Dectin-1. The anti-DC-ASGPR or anti-Dectin-1 can be one known in the art or described herein. In some embodiments, the antibody comprises a variable region comprising an amino acid sequence selected from the sequence of SEQ ID NO:3, 8, 62, 64, 66, or 68. In some embodiments, the antibody comprises a heavy chain or light chain having an amino acid sequence selected from the sequence of SEQ ID NO:1, 7, 61, 63, 65, 67, or 69-72. In some embodiments, the antibody comprises one or more CDRs from the variable region, heavy chain, or light chain of SEQ ID NO:1, 3, 7, 8, 61, 62, 63, 64, 65, 66, 67, or 68-72.

[0023] In some embodiments, the APC-targeting antibody comprises anti-DCIR. In specific embodiments, the anti-DCIR antibody comprises anti-DCIR clone 9E8 or a fragment thereof. In further embodiments, the anti-DCIR antibody comprises one or more CDRs having the sequence of SEQ ID NOs: 18-20 or 24-26. In other embodiments, the anti-DCIR antibody comprises a heavy chain comprising one or more CDRs of SEQ ID NOs: 18-20. In yet other embodiments, the anti-CD40 antibody comprises a light chain comprising one or more CDRs of SEQ ID NOs: 24-26.

[0024] Certain aspects of the present disclosure relate to a method for inhibiting an inflammatory or autoimmune response or inducing tolerance in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an anti-CD40 antibody operably linked to IL-10 or a fragment thereof, wherein the anti-CD40 is a humanized antibody having three heavy chain CDRs comprising the amino acid sequences of SEQ ID NO:31 (CDR1), SEQ ID NO:32 (CDR2), and SEQ ID NO:33 (CDR3) and three light chain CDRs comprising the amino acid sequences of SEQ ID NO:37 (CDR1), SEQ ID NO:38 (CDR2), and SEQ ID NO:39 (CDR3).

[0025] A further aspect relates to a method for inhibiting an inflammatory or autoimmune response or inducing tolerance in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an anti-DCIR antibody operably linked to IL-10 or a fragment thereof, wherein the anti-DCIR is a humanized antibody having three heavy chain CDRs derived from the variable region of the anti-DCIR 9E8 heavy chain (SEQ ID NO: 17) and three light chain CDRs derived from the variable region of the anti-DCIR 9E8 light chain (SEQ ID NO: 23).

[0026] A further aspect relates to a method for inhibiting an inflammatory response or an autoimmune response in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an anti-DC-ASGPR antibody operably linked to IL-10 or a fragment thereof, wherein the anti-DC-ASGPR antibody is a humanized antibody having three heavy chain CDRs and three light chain CDRs derived from the variable region of an anti-DC-ASGPR heavy chain and anti-DC-ASGPR light chain pair selected from SEQ ID NOs: 3 and 8, SEQ ID NOs: 58 and 60, SEQ ID NOs: 62 and 64, or SEQ ID NOs: 66 and 68; or a humanized antibody having three heavy chain CDRs and three light chain CDRs derived from the heavy chain and light chain of an anti-DC-ASGPR heavy chain and anti-DC-ASGPR light chain pair selected from SEQ ID NOs: 69 and 70 and SEQ ID NOs: 71 and 72.

[0027] In some embodiments, the APC targeting antibody or antibody conjugate or antigen-binding fragment thereof comprises an amino acid sequence that is at least or up to 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% (or any range derivable therein) identical or similar to the APC targeting antibody or antigen-binding fragment of any of SEQ ID NOs: 1, 2, 3, 7, 8, 10, 11, 13, 15-20, 22-26, 28-33, 35-39, or 45-114 (or any range derivable therein). In further embodiments, the APC targeting antibody conjugate, or antigen-binding fragment thereof, comprises a variable region comprising an amino acid sequence that is at least or at most 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical or similar (or any range derivable therein) to the APC targeting antibody variable regions set forth herein as SEQ ID NOs: 3, 8, 17, 23, 30, 36, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 79, 81, 83, 85, 87, 89, 108, 110, 112, and 114. In further embodiments, the antibody comprises a CDR having an amino acid sequence corresponding to a CDR in any one of SEQ ID NOs: 2, 3, 7, 8, 11, 13, 16, 17-20, 22-26, 29-33, 35-39, or 45-114 (or any range derivable therein). In some embodiments, the antibody comprises a CDR of SEQ ID NOs: 18-20, 24-26, 31-33, or 37-39.In further embodiments, the APC targeting antibody, or antigen-binding fragment thereof, comprises a heavy or light chain amino acid sequence that is at least or at most 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical or similar to an APC targeting antibody or antigen-binding fragment of any of SEQ ID NOs: 1, 2, 7, 10, 11, 13, 15, 16, 22, 28, 29, 35, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69-78, 80, 82, 84, 86, 88, 90-107, 109, 111, or 113 (or any range derivable therein). In certain embodiments, the antibody conjugate, or antigen-binding fragment thereof, comprises CDR1, CDR2, and / or CDR3 from the heavy chain variable region and / or the light chain variable region of an APC-targeting antibody described herein. In certain embodiments, the antibody conjugate, or antigen-binding fragment thereof, comprises all three CDRs from the light chain variable region and / or all three CDRs from the heavy chain variable region of an APC-targeting antibody described herein.

[0028] In certain embodiments, the antibody or antigen-binding fragment specifically binds to DC-ASGPR and activates DC-ASGPR. DC-asialoglycoprotein receptor (DC-ASGPR) is a scavenger receptor that possesses an immunoreceptor tyrosine-based activation motif-like motif. ASGPR may also be known as ASGR1, ASGPR1, CLEC4H1, and HL-1. In one embodiment, the antibody or antigen-binding fragment thereof binds to human DC-ASGPR.

[0029] In some embodiments, the antibody or antigen-binding fragment of the methods and compositions described herein is an anti-DC-ASGPR antibody and comprises an amino acid sequence that is at least or at most 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% (or any range derivable therein) identical or similar to the DC-ASGPR antibody or antigen-binding fragment of any of SEQ ID NOs: 2, 3, 7, 8 and 61-72 (or any range derivable therein). In a further embodiment, the DC-ASGPR antibody or antigen-binding fragment thereof is an ASGPR-binding polypeptide, e.g., anti-ASGPR_49C11_7H (heavy chain), SEQ ID NO:2; anti-ASGPR_49C11_7K (light chain), SEQ ID NO:7; anti-hASGPR_6.3H9.1D11H (heavy chain), SEQ ID NO:69; anti-hASGPR_6.3H9.1D11K (light chain), SEQ ID NO:70; anti-hASGPR_5H8.1D4H (heavy chain), SEQ ID NO:71; anti-hASGPR_5H8.1D4K (light chain), SEQ ID NO:72; anti-ASGPR_4G2.2_ (heavy chain), SEQ ID NO:57; anti-ASGPR_4G2.2_ (light chain), SEQ ID NO: anti-ASGPR-5F10H (heavy chain), SEQ ID NO:61; anti-ASGPR-5F10H (light chain), SEQ ID NO:63; anti-ASGPR1H11 (heavy chain), SEQ ID NO:65; or anti-ASGPR1H11 (light chain), SEQ ID NO:67, etc. In further embodiments, the DC-ASGPR antibody or antigen-binding fragment thereof comprises a variable region comprising an amino acid sequence that is at least or at most 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical or similar to a DC-ASGPR antibody or antigen-binding fragment of any of SEQ ID NOs: 3, 8, 62, 64, 66, and 68.In some embodiments, the antibody comprises at least one, two, or all three CDRs of a variable region from a heavy chain amino acid sequence or a light chain amino acid sequence selected from SEQ ID NOs: 2, 7, 57, 59, 61, 63, 65, 67, and 69-72. In some embodiments, the antibody comprises at least one, two, or all three CDRs of a variable region from a heavy chain variable region amino acid sequence or a light chain variable region amino acid sequence selected from SEQ ID NOs: 3, 8, 58, 60, 62, 64, 66, and 68. In further embodiments, the antibody comprises at least or exactly one, two, three, four, five, or six (or any range derivable therein) CDRs from a heavy chain antibody fragment and a light chain antibody fragment selected from SEQ ID NOs:2 and 7, SEQ ID NOs:57 and 59, SEQ ID NOs:61 and 63, SEQ ID NOs:65 and 67, SEQ ID NOs:69 and 70, or SEQ ID NOs:71 and 72. In some embodiments, the antibody comprises at least or exactly one, two, three, four, five, or six (or any range derivable therein) CDRs from a heavy chain variable region antibody fragment and a light chain variable region antibody fragment selected from SEQ ID NOs:3 and 8, SEQ ID NOs:58 and 60, SEQ ID NOs:62 and 64, or SEQ ID NOs:66 and 68.

[0030] The ASGPR antibodies or antigen-binding fragments described herein may be selected from the group consisting of at least or up to 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120 3, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138 , 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240 7, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 2 12, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241 , 242, 243, 244, 245, 246, 247, 248, 249, 250, 300, 400, 500, 550, 1000 pieces,or more consecutive amino acids, or any range of consecutive amino acids derived therefrom, The variant may comprise 8, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 or more variant amino acids.

[0031] The APC targeting antibody conjugates or antigen-binding fragments described herein are those having SEQ ID NO: NO: 1-5, 7-8, 10-11, 13, 15-20, 22-26, 28-33, 35-39, or 45-114, at least or at most 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62 , 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131 , 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233 91, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250,1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, or more consecutive amino acids in a sequence of 300, 400, 500, 550, 1000, or more consecutive amino acids, or in any range of consecutive amino acids derivable therefrom , 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 or more variant amino acids (or any range derivable therein).

[0032] Embodiments are provided in which the APC-targeting antibody or antigen-binding fragment comprises one or more CDR domains derived from an antibody that specifically binds to an antigen-presenting cell surface protein. In certain embodiments, the APC-targeting antibody or antigen-binding fragment thereof comprises one, two, three, four, five, six, or more CDR domains from the VH or VL domains of the monoclonal antibodies set forth herein in SEQ ID NOs: 3, 8, 17, 23, 30, 36, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 79, 81, 83, 85, 87, 89, 108, 110, 112, and 114. In certain aspects, the APC targeting antibody or antigen-binding fragment thereof is selected from the following monoclonal antibodies: anti-Dectin-1 clones 11B6.4, 15E2.5, or 2D8.2D4; ASGPR clones 49C11, 4G2.2, 5F10, 1H11, 6.3H9.1D11, or 5H8.1D4; anti-CD40 clones 12E12, 12B4.2C10, 24A3, or 11B6.1C3. anti-Lox-1 clones 11C8, 10F9, or 15C4; anti-DCIR clones 24A5.4A5, 24E7.3H9, 29E9.2E2, 29G10.3D9, 31A6.IF5, 3C2.2D9, 6C8.1G9, 9E8, or 2C9; or anti-Langrin clones 15B10 or 2G3.In some embodiments, the APC targeting antibody or antigen-binding fragment thereof is selected from the following monoclonal antibodies: anti-Dectin-1 clones 11B6.4, 15E2.5, or 2D8.2D4; ASGPR clones 49C11, 4G2.2, 5F10, 1H11, 6.3H9.1D11, or 5H8.1D4; anti-CD40 clones 12E12, 12B4.2C10, 24A3, or 11B6.1C3; anti-Lox-1 clones 11C8, 10F9, or comprises a sequence that is at least or up to 70%, 75%, 80%, 85%, 90%, 95%, or 99% (or any range derivable therein) identical to the VH domain or VL domain of 15C4; anti-DCIR clones 24A5.4A5, 24E7.3H9, 29E9.2E2, 29G10.3D9, 31A6.IF5, 3C2.2D9, 6C8.1G9, 9E8, or 2C9; or anti-Rangrin clones 15B10 or 2G3. Embodiments are provided in which the APC targeting antibody or antigen-binding fragment thereof comprises a VH domain derived from a monoclonal antibody listed herein, and / or a VL domain derived from a monoclonal antibody listed herein. In further embodiments, the monoclonal antibody is selected from: anti-Dectin-1 clone 11B6.4, 15E2.5, or 2D8.2D4; ASGPR clone 49C11, 4G2.2, 5F10, 1H11, 6.3H9.1D11, or 5H8.1D4; anti-CD40 clone 12E12, 12B4.2C10, 24A3, or 11B6.1C3; anti-Lox-1 clone 11C8, 10F9, or 15C4; anti-DCIR clone 24A5.4A5, 24E7.3H9, 29E9.2E2, 29G10.3D9, 31A6.IF5, 3C2.2D9, 6C8.1G9, 9E8, or 2C9; or anti-Rangrin clone 15B10 or 2G3.

[0033] In certain embodiments, the APC targeting antibody or antigen-binding fragment thereof is recombinant. In certain aspects, the recombinant polypeptide is selected from the group consisting of anti-Dectin-1 clones 11B6.4, 15E2.5, or 2D8.2D4; ASGPR clones 49C11, 4G2.2, 5F10, 1H11, 6.3H9.1D11, or 5H8.1D4; anti-CD40 clones 12E12, 12B4.2C10, 24A3, or 11B6.1C3; anti-Lox-1 clones 11C8, 10F9, or 15 C4; comprising at least 90%, 95%, or 99% of one or more CDR domains derived from the VH domain or VL domain of anti-DCIR clones 24A5.4A5, 24E7.3H9, 29E9.2E2, 29G10.3D9, 31A6.IF5, 3C2.2D9, 6C8.1G9, 9E8, or 2C9; or anti-Rangrin clones 15B10 or 2G3 monoclonal antibodies. In some embodiments, the recombinant polypeptide is selected from the group consisting of anti-Dectin-1 clones 11B6.4, 15E2.5, or 2D8.2D4; ASGPR clones 49C11, 4G2.2, 5F10, 1H11, 6.3H9.1D11, or 5H8.1D4; anti-CD40 clones 12E12, 12B4.2C10, 24A3, or 11B6.1C3; anti-Lox-1 clones 11C8, 10F9, or comprises two, three, four, five, six, or more CDR domains from the VH domain or VL domain of 15C4; anti-DCIR clones 24A5.4A5, 24E7.3H9, 29E9.2E2, 29G10.3D9, 31A6.IF5, 3C2.2D9, 6C8.1G9, 9E8, or 2C9; or anti-Rangrin clones 15B10 or 2G3 monoclonal antibodies.

[0034] In some embodiments, the recombinant polypeptide comprises (i) CDR1 (SEQ ID NO:37), CDR2 (SEQ ID NO:38), and / or CDR3 (SEQ ID NO:39) from the variable light chain of anti-CD40 12E12; and / or (ii) CDR1 (SEQ ID NO:31), CDR2 (SEQ ID NO:32), and / or CDR3 (SEQ ID NO:33) from the variable heavy chain of 12E12. In some embodiments, the recombinant polypeptide comprises (i) CDR1, CDR2, and / or CDR3 from the variable light chain of anti-DCIR 9E8; and / or (ii) CDR1, CDR2, and / or CDR3 from the variable heavy chain of 9E8.

[0035] One particular aspect is directed to a method of inhibiting an inflammatory response or inducing tolerance in a subject in need thereof, comprising administering to the subject an effective amount of one or more APC-targeting antibodies or antigen-binding fragments thereof operably linked to IL-10. The antibody may be a purified polyclonal antibody, a purified monoclonal antibody, a recombinant polypeptide, or a fragment thereof. In one aspect, the antibody is humanized or human. In yet another aspect, the antibody is a recombinant antibody segment. In some aspects, the monoclonal antibodies include one or more of anti-Dectin-1 clones 11B6.4, 15E2.5, or 2D8.2D4; ASGPR clones 49C11, 4G2.2, 5F10, 1H11, 6.3H9.1D11, or 5H8.1D4; anti-CD40 clones 12E12, 12B4.2C10, 24A3, or 11B6.1C3; anti-Lox-1 clones 11C8, 10F9, or 15C4; anti-DCIR clones 24A5.4A5, 24E7.3H9, 29E9.2E2, 29G10.3D9, 31A6.IF5, 3C2.2D9, 6C8.1G9, 9E8, or 2C9; or anti-Rangrin clones 15B10 or 2G3. The antibody is administered at a dose of 0.1, 0.5, 1, 5, 10, 50, 100 mg / kg or 0.1, 0.5, 1, 5, 10, 50, 100 μg / kg to 5, 10, 50, 100, 500 mg / kg or 5, 10, 50, 100, 500 μg / kg, or any range derivable therein.

[0036] The methods described herein result in a dose-sparing effect, in that targeted delivery of IL-10 requires a smaller amount or dose to achieve the same effect as non-targeted IL-10. In certain embodiments, the therapeutically effective amount of an APC-targeting antibody operably linked to IL-10 is at least 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, 500-fold, or 1000-fold less than the dose of non-targeted IL-10. In further embodiments, the therapeutically effective amount of an APC-targeting antibody operably linked to IL-10 is more than 50%, more than 75%, more than 80%, more than 90%, or more than 99% less than the effective dose of non-targeted IL-10. Therapeutically effective amounts of non-targeted IL-10 are known in the art and may vary depending on the disease to be treated. In certain embodiments, the effective amount of non-targeted IL-10 is 1, 5, 10, or 20 μg / kg. In one embodiment, the effective amount of non-targeted IL-10 is 5 μg / kg. In another embodiment, the therapeutically effective amount of an APC-targeting antibody operably linked to IL-10 is at least 5-fold less than the dose of non-targeted IL-10.

[0037] In certain embodiments, the antibody is a human antibody, a humanized antibody, a recombinant antibody, a bispecific antibody, a chimeric antibody, a nanobody, a DARPin, an antibody derivative, a veneered antibody, a diabody, a monoclonal antibody, or a polyclonal antibody. In one specific embodiment, the antibody is a humanized antibody.

[0038] In certain embodiments, the antibody is a non-naturally occurring antibody. In some embodiments, the antibody is non-naturally occurring because it comprises at least two polypeptide segments derived from different sources. The different sources may be, for example, different mammals, such as a human and a mouse.

[0039] In some embodiments of the methods described herein, the subject is a human subject. The terms "subject," "individual," or "patient" are used interchangeably herein and refer to a vertebrate, such as a primate, a mammal, or preferably a human. Mammals include, but are not limited to, equines, canines, bovines, ovines, murines, rats, monkeys, humans, farm animals, sport animals, and pets.

[0040] In some embodiments, the subject is a subject with an autoimmune disease or inflammatory disorder.The autoimmune disease or inflammatory disorder can be known in the art and / or described herein.In some embodiments, the autoimmune disease or inflammatory disorder is selected from rheumatoid arthritis, allergy, asthma, systemic juvenile arthritis, inflammatory bowel disease, systemic lupus erythematosus, multiple sclerosis, type 1 diabetes, transplant rejection, graft-versus-host disease, colitis, and Crohn's disease.

[0041] In some embodiments, the subject is at risk of developing the disease mediated by pathogenic T cell response.In further embodiments, the subject is suffering from autoimmune disease or autoinflammatory disease, or is at risk of suffering from autoimmune disease or autoinflammatory disease.In one specific embodiment, the autoimmune disease or autoinflammatory disease is selected from rheumatoid arthritis, allergy, asthma, systemic juvenile arthritis, inflammatory bowel disease, systemic lupus erythematosus, multiple sclerosis, type 1 diabetes, transplant rejection, graft-versus-host disease, colitis and Crohn's disease.

[0042] In some embodiments, the subject is the subject that will receive or has received transplanted tissue.In a related embodiment, the transplanted tissue is an allograft.Allograft (allograft, allogeneic transplant, or homograft) refers to the transplantation of cells, tissues, or organs from a donor of the same species that is not genetically identical to the recipient.In a related embodiment, the subject is the subject that has complications due to transplanted tissue, and the complications are graft rejection or GVHD.

[0043] In some embodiments, the APC-targeting antibody is administered prior to tissue transplantation. When the antibody or antigen-binding fragment thereof is administered prior to tissue transplantation, the method may further include preventing complications associated with the transplanted tissue, including GVHD or graft rejection.

[0044] In some embodiments, the APC-targeting antibody is administered after tissue transplantation. When the antibody or antigen-binding fragment thereof is administered after tissue transplantation, the method may further include treating complications from the transplanted tissue, including GVHD or graft rejection.

[0045] The tissue used for transplantation can be any tissue that is known in the art to be therapeutically useful for transplantation.Non-limiting examples of tissue transplantation include anterior cruciate ligament (ACL); knee and ankle joint reconstruction; meniscus replacement; reconstruction due to cancer or trauma; gum augmentation in dental treatment; shoulder joint repair; spinal fusion; urinary tissue; skin transplant; corneal transplant; heart transplant; heart valve; lung transplant; intestinal transplant, such as isolated small intestine, intestine, or multiple organs; liver transplant; kidney transplant; bone marrow transplant; bone allograft; and ligament or tendon allograft.

[0046] In one embodiment, the transplant tissue comprises immune cells. The term immune cells includes cells of the immune system that are involved in the body's defense against both infections and foreign substances. Immune cells can include, for example, neutrophils, eosinophils, basophils, lymphocytes, such as B cells and T cells, and monocytes. T cells can include, for example, CD4+, CD8+, helper T cells, cytotoxic T cells, γδ T cells, regulatory T cells, suppressor T cells, and natural killer cells.

[0047] In another embodiment, the transplant tissue comprises stem cells. Various stem cells are known in the art. Non-limiting examples of stem cells include hematopoietic stem cells, neural stem cells, and embryonic stem cells. In one embodiment, the stem cells are hematopoietic stem cells. In a further embodiment, the transplant tissue comprises bone marrow. In yet another embodiment, the transplant tissue comprises blood. In another embodiment, the transplant tissue comprises skin cells.

[0048] In some embodiments, the APC-targeting antibody operably linked to IL-10 or a fragment thereof is administered in an amount that results in the maintenance of pathogen-specific immunity in the subject.

[0049] The IL-10 polypeptide may be a polypeptide or fragment of an IL-10 protein known in the art or described herein under Accession No. NP_000563.1. In some embodiments, the IL-10 polypeptide comprises SEQ ID NO:5. In some embodiments, the IL-10 is covalently linked to the antibody. In some embodiments, the covalent linkage is by a peptide bond. The IL-10 polypeptide may also be linked to the antibody via a binding polypeptide. In one embodiment, the binding polypeptide is dockerin or cohesin.

[0050] In some embodiments, the method further comprises administering an antigen or allergen. The antigen or allergen may be functionally linked to an APC targeting antibody or IL-10. In some embodiments, the antigen or allergen is covalently linked to the APC targeting antibody, its antigen-binding fragment, or IL-10 (i.e., by peptide bond). When the antigen or allergen is functionally linked to the APC targeting antibody, its antigen-binding fragment, or IL-10, it may be linked via a binding polypeptide. Examples of binding peptides include dockerin and cohesin.

[0051] In further embodiments, the composition or method does not include an antigen or allergen or administration of an allergen or antigen. For example, the antigen or allergen is not functionally (directly or indirectly) linked to an APC targeting antibody. In some embodiments, the composition consists essentially of an antigen-presenting cell (APC) targeting antibody functionally linked to IL-10 or a fragment thereof.

[0052] In further embodiments, the composition or method does not include a TLR molecule or administration of a TLR molecule.

[0053] In some embodiments, the antibody may comprise a γ4 constant region. In a related embodiment, the γ4 constant region comprises a leucine to glutamic acid substitution at residue 235. In another embodiment, the γ4 constant region comprises a serine to proline substitution at residue 228 in the hinge region.

[0054] In certain embodiments, the method includes multiple administrations of the composition. The administrations may be spaced apart by days, weeks, months, years, or decades. The compositions comprising the conjugates described herein can be administered orally, intravenously, subcutaneously, intradermally, intramuscularly, intranasally, by injection, by inhalation, mucosally, and / or by using a nebulizer.

[0055] In certain embodiments of the methods described herein, the anti-DC-ASGPR antibody or antigen-binding fragment is administered in a therapeutically effective amount.In certain embodiments, the antibody or antigen-binding fragment is administered in an amount that increases the production of IL-10 in the subject.In a further embodiment, the antibody or antigen-binding fragment is administered in an amount that allows the subject to maintain pathogen-specific immunity after administration of the antibody or antigen-binding fragment.

[0056] In some embodiments, the anti-DC-ASGPR antibody or its antigen-binding fragment may be administered in the form of a pharmaceutical composition. In some embodiments, the pharmaceutical composition does not contain an antigen or does not contain a detectable amount of antigen. In a further embodiment, the pharmaceutical composition consists essentially of an anti-DC-ASGPR antibody. In a further embodiment, the antibody or its antigen-binding fragment is not conjugated to an antigen, or is not conjugated to a dockerin molecule or a cohesin molecule. In another further embodiment, the antibody is not covalently or functionally linked to an antigen.

[0057] The term "operably linked" refers to the situation in which two components combine to form an active complex prior to binding at a target site. For example, an antibody conjugated to one of the two components of a cohesin-docerin complex and an antigen conjugated to the other component of the cohesin-docerin complex are operably linked through the complexation of the cohesin molecule and the doserin.

[0058] Also disclosed herein are compositions comprising the antibodies and antibody conjugates as described herein.

[0059] Aspects of the present disclosure relate to APC targeting antibodies and APC targeting antibodies conjugated to IL-10 in pharmaceutical compositions and for use in preparing medicaments for treating autoimmune and / or inflammatory conditions as described herein.

[0060] Aspects also relate to an APC targeting antibody or an APC targeting antibody conjugated to IL-10 in a pharmaceutical composition and for use in the preparation of a medicament for inducing immune tolerance or suppressing a T cell response in a subject having or at risk of developing an autoimmune or inflammatory response, wherein the autoimmune or inflammatory response is caused by an autoimmune or inflammatory disease as described herein.

[0061] As used herein, "a" or "an" can mean one or more. In the claims, when used with the word "comprising," "a" or "an" can mean one or more. A composition with the words "consisting essentially of" is intended to exclude any active ingredients not specifically recited in the composition. Examples of active ingredients include cytokines, TLRs, antigens, adjuvants, etc. In any of the embodiments described herein, embodiments consisting essentially of the recited elements are also contemplated.

[0062] Although the present disclosure supports definitions that refer to alternatives only and "and / or," use of the term "or" in the claims is used to mean "and / or" unless expressly stated to refer to only that alternative or the alternatives are mutually exclusive. As used herein, "another" can mean at least a second or more.

[0063] Throughout this application, the term "about" is used to indicate that a value includes the inherent variation of error for the method being employed to determine the value, the device, or the variation that exists in the study.

[0064] Other objects, features, and advantages of the present invention will be apparent from the following detailed description. It should be understood, however, that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of example only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. [The present invention 1001] A method for inducing immune tolerance in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an APC-targeting antibody functionally linked to IL-10 or a fragment thereof. [The present invention 1002] A method for preventing or treating graft-versus-host disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of DC-ASGPR linked to IL-10 or a fragment thereof. [The present invention 1003] The method of the present invention 1002, wherein the anti-DC-ASGPR antibody is a humanized antibody having three heavy chain CDRs and three light chain CDRs derived from the variable region of a pair of anti-DC-ASGPR heavy chain variable region and anti-DC-ASGPR light chain variable region selected from SEQ ID NOs:3 and 8, SEQ ID NOs:58 and 60, SEQ ID NOs:62 and 64, or SEQ ID NOs:66 and 68; or a humanized antibody having three heavy chain CDRs and three light chain CDRs derived from the heavy chain and light chain of a pair of anti-DC-ASGPR heavy chain and anti-DC-ASGPR light chain selected from SEQ ID NOs:69 and 70 and SEQ ID NOs:71 and 72. [The present invention 1004] A method for inhibiting an inflammatory or autoimmune response in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an antigen-presenting cell (APC) targeting antibody functionally linked to IL-10 or a fragment thereof. [The present invention 1005] A method for suppressing a T cell response in a subject having or at risk of developing an inflammatory response by administering to the subject a therapeutically effective amount of an APC targeting antibody functionally linked to IL-10 or a fragment thereof. [The present invention 1006] The method of any of claims 1001 to 1005, wherein said APC targeting antibody targets one or more APCs from the group consisting of Langerhans cells, macrophages, dendritic cells, B cells, and peripheral blood mononuclear cells. [The present invention 1007] 1006. The method of any one of claims 1001 to 1006, wherein the APC targeting antibody is selected from antibodies that specifically bind to MHC class I, MHC class II, CD1d, CD2, CD3, CD4, CD8, CD11b, CD14, CD15, CD16, CD19, CD20, CD29, CD31, CD40, CD43, CD44, CD45, CD54, CD56, CD57, CD58, CD83, CD86, CMRF-44, CMRF-56, DCIR, DC-ASGPR, CLEC-6, CD40, BDCA-2, MARCO, DEC-205, mannose receptor, Langerin, DECTIN-1, B7-1, B7-2, IFN-γ receptor, IL-2 receptor, ICAM-1, Fcγ receptor, LOX-1, and ASPGR. [The present invention 1008] The method of any one of claims 1001 to 1007, wherein said APC targeting antibody targets Langerhans cells. [The present invention 1009] 1008. The method of claim 10, wherein said APC targeting antibody comprises anti-Langerin. [The present invention 1010] The method of any one of claims 1001 to 1007, wherein said APC targeting antibody targets macrophages. [The present invention 1011] 1010. The method of claim 10, wherein said APC targeting antibody comprises anti-MARCO. [The present invention 1012] The method of any of claims 1001 to 1007, wherein said APC targeting antibody targets one or more APCs from the group of dendritic cells, B cells, and macrophages. [The present invention 1013] The method of claim 1012, wherein said APC targeting antibody targets dendritic cells. [The present invention 1014] 1014. The method of claim 1012 or 1013, wherein said APC targeting antibody comprises anti-CD40. [The present invention 1015] 1015. The method of claim 1014, wherein said anti-CD40 antibody comprises anti-CD40 clone 12E12 or a fragment thereof. [The present invention 1016] 1015. The method of claim 1015, wherein said anti-CD40 antibody comprises one or more CDRs having the sequence of SEQ ID NO: 31-33 or 37-39. [The present invention 1017] 1017. The method of any of claims 1014 to 1016, wherein said anti-CD40 antibody comprises a heavy chain comprising one or more CDRs of SEQ ID NOs: 31 to 33. [The present invention 1018] 1018. The method of any of claims 1014 to 1017, wherein said anti-CD40 antibody comprises a light chain comprising one or more CDRs of SEQ ID NOs: 37 to 39. [The present invention 1019] Any of the methods of claims 1014 to 1018, wherein the anti-CD40 antibody is a humanized antibody comprising a heavy chain comprising three CDRs, wherein CDR1 comprises SEQ ID NO: 31, CDR2 comprises SEQ ID NO: 32, and CDR3 comprises SEQ ID NO: 33. [The present invention 1020] Any of the methods of claims 1014 to 1019, wherein the anti-CD40 antibody is a humanized antibody comprising a light chain comprising three CDRs, wherein CDR1 comprises SEQ ID NO:37, CDR2 comprises SEQ ID NO:38, and CDR3 comprises SEQ ID NO:39. [The present invention 1021] 1014. The method of claim 1012 or 1013, wherein the APC targeting antibody comprises anti-DC-ASGPR. [The present invention 1022] The method of claim 1021, wherein the antibody comprises a variable region comprising an amino acid sequence selected from the sequence of SEQ ID NO: 3, 8, 62, 64, 66, or 68. [The present invention 1023] 1023. The method of claim 1021 or 1022, wherein the antibody comprises a heavy chain or a light chain having an amino acid sequence selected from the sequences of SEQ ID NOs: 1, 7, 61, 63, 65, 67, or 69-72. [The present invention 1024] 1021. The method of claim 1021, wherein the antibody comprises one or more CDRs from the variable region, heavy chain, or light chain of SEQ ID NO: 1, 3, 7, 8, 61, 62, 63, 64, 65, 66, 67, or 68-72. [The present invention 1025] 1014. The method of claim 1012 or 1013, wherein said APC targeting antibody comprises anti-Dectin-1. [The present invention 1026] 1014. The method of claim 1012 or 1013, wherein said APC targeting antibody comprises anti-DCIR. [The present invention 1027] 1027. The method of claim 1026, wherein said anti-DCIR antibody comprises anti-DCIR clone 9E8 or a fragment thereof. [The present invention 1028] 1027. The method of claim 1027, wherein said anti-DCIR antibody comprises one or more CDRs having the sequences of SEQ ID NOs: 18-20 or 24-26. [The present invention 1029] 1029. The method of any of claims 1026 to 1028, wherein said anti-DCIR antibody comprises a heavy chain comprising one or more CDRs of SEQ ID NOs: 18-20. [The present invention 1030] 1029. The method of any of claims 1026 to 1029, wherein said anti-DCIR antibody comprises a light chain comprising one or more CDRs of SEQ ID NOs:24 to 26. [The present invention 1031] The method of any one of claims 1026 to 1030, wherein the anti-DCIR antibody is a humanized antibody comprising a heavy chain comprising three CDRs derived from the variable region of the anti-DCIR 9E8 heavy chain (SEQ ID NO: 17). [The present invention 1032] The method of any one of claims 1026 to 1031, wherein the anti-DCIR antibody is a humanized antibody comprising a light chain comprising three CDRs derived from the variable region of the anti-DCIR 9E8 light chain (SEQ ID NO: 23). [The present invention 1033] 1033. The method of any of claims 1001 to 1032, wherein said antibody is a human antibody, a humanized antibody, a recombinant antibody, a bispecific antibody, a chimeric antibody, a nanobody, a DARPin, an antibody derivative, a veneered antibody, a diabody, a monoclonal antibody, or a polyclonal antibody. [The present invention 1034] The method of claim 1033, wherein the antibody is a humanized antibody. [This invention 1035] The method of any one of claims 1001 to 1034, wherein said subject is a human subject. [The present invention 1036] The method of any of claims 1003 to 1035, wherein said subject has an autoimmune disease or an inflammatory disorder. [This invention 1037] The method of any one of claims 1001 to 1036, wherein the subject is suffering from inflammation. [The present invention 1038] The method of claim 1037, wherein the inflammation is acute. [This invention 1039] The method of claim 1037, wherein the inflammation is chronic. [The present invention 1040] 1036. The method of claim 1036, wherein said autoimmune disease or said inflammatory disorder is selected from rheumatoid arthritis, allergy, asthma, systemic juvenile arthritis, inflammatory bowel disease, systemic lupus erythematosus, multiple sclerosis, type 1 diabetes, transplant rejection, graft-versus-host disease, colitis, and Crohn's disease. [This invention 1041] The method of any one of claims 1001 to 1040, wherein the subject is a subject who is planning to receive or has received a transplant tissue. [The present invention 1042] The method of claim 1041, wherein the subject has a complication due to the transplanted tissue, and the complication is transplant rejection. [This invention 1043] The method of claim 1041, wherein the subject has a complication due to the transplanted tissue, and the complication is GVHD. [This invention 1044] The method of any of claims 1041 to 1043, wherein said APC targeting antibody functionally linked to IL-10 or a fragment thereof is administered before tissue transplantation. [This invention 1045] 104. The method of claim 1044, further comprising the step of preventing complications associated with said transplanted tissue, said complications including GVHD or graft rejection. [The present invention 1046] The method of any of claims 1041 to 1043, wherein said APC targeting antibody functionally linked to IL-10 or a fragment thereof is administered after tissue transplantation. [This invention 1047] 1046. The method of claim 1046, further comprising treating complications due to said transplanted tissue, said complications including GVHD or graft rejection. [This invention 1048] The method of any of claims 1001 to 1047, wherein said APC targeting antibody functionally linked to IL-10 or a fragment thereof is administered in an amount that results in the maintenance of pathogen-specific immunity in said subject. [This invention 1049] The method of any of claims 1001 to 1048, wherein IL-10 is covalently linked to said antibody. [The present invention 1050] 1049. The method of any of claims 1001 to 1049, wherein IL-10 is covalently linked to said antibody via a peptide bond. [This invention 1051] The method of any of claims 1001 to 1048, wherein said antibody is functionally linked to IL-10 via a binding polypeptide. [This invention 1052] 1051. The method of claim 1051, wherein said binding polypeptides are dockerin and cohesin. [This invention 1053] The method of any of claims 1001 to 1052, further comprising administering an antigen. [This invention 1054] 1054. The method of claim 1053, wherein said antigen is operably linked to said APC targeting antibody. [This invention 1055] The method of claim 1053, wherein said antigen is operably linked to IL-10. [The present invention 1056] 1056. The method of any of claims 1053 to 1055, wherein said antigen is covalently linked to said APC targeting antibody, an antigen-binding fragment thereof, or IL-10. [This invention 1057] The method of any of claims 1053 to 1055, wherein said antigen is functionally linked to said APC targeting antibody, an antigen-binding fragment thereof, or IL-10 via a binding polypeptide. [This invention 1058] 1057. The method of claim 1057, wherein said binding polypeptides are dockerin and cohesin. [This invention 1059] Any of the methods of claims 1001 to 1058, wherein the antibody operably linked to IL-10 is administered orally, intravenously, subcutaneously, intradermally, intramuscularly, intranasally, by injection, by inhalation, mucosally, and / or by using a nebulizer. [The present invention 1060] The method of any of claims 1001 to 1059, wherein said IL-10 comprises a peptide having the amino acid sequence of SEQ ID NO:5, or a fragment thereof. [This invention 1061] The method of any of claims 1001 to 1060, wherein said antibody further comprises a modification. [This invention 1062] 1062. The method of claim 1061, wherein said modifications are conservative amino acid mutations within the CDR1, CDR2, and / or CDR3 regions of VH and / or VL. [The present invention 1063] 1062. The method of claim 1061, wherein said modification is a conservative amino acid mutation within the Fc hinge region. [The present invention 1064] The method of claim 1061, wherein said modification is pegylation. [This invention 1065] 1061. The method of claim 1061, wherein said modification is conjugation with a serum protein. [The present invention 1066] 1062. The method of claim 1061, wherein said modification is conjugation with human serum albumin. [This invention 1067] 1061. The method of claim 1061, wherein said modification is conjugation with a detectable label. [The present invention 1068] 1062. The method of claim 1061, wherein said modification is conjugation with a diagnostic agent. [The present invention 1069] 1062. The method of claim 1061, wherein said modification is conjugation with an enzyme. [The present invention 1070] 1061. The method of claim 1061, wherein said modification is conjugation with a fluorescent, luminescent, or bioluminescent substance. [This invention 1071] 1062. The method of claim 1061, wherein said modification is conjugation with a radioactive substance. [This invention 1072] 1061. The method of claim 1061, wherein said modification is conjugation with a therapeutic agent. [This invention 1073] A method for inhibiting an inflammatory or autoimmune response in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an anti-CD40 antibody functionally linked to IL-10 or a fragment thereof, wherein the anti-CD40 is a humanized antibody having three heavy chain CDRs comprising the amino acid sequences of SEQ ID NO:31 (CDR1), SEQ ID NO:32 (CDR2), and SEQ ID NO:33 (CDR3) and three light chain CDRs comprising the amino acid sequences of SEQ ID NO:37 (CDR1), SEQ ID NO:38 (CDR2), and SEQ ID NO:39 (CDR3). [This invention 1074] A method for inhibiting an inflammatory or autoimmune response in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an anti-DCIR antibody functionally linked to IL-10 or a fragment thereof, wherein the anti-DCIR is a humanized antibody having three heavy chain CDRs derived from the anti-DCIR 9E8 heavy chain variable region (SEQ ID NO: 17) and three light chain CDRs derived from the anti-DCIR 9E8 light chain variable region (SEQ ID NO: 23). [This invention 1075] A method for inhibiting an inflammatory response or an autoimmune response in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an anti-DC-ASGPR antibody functionally linked to IL-10 or a fragment thereof, wherein the anti-DC-ASGPR antibody is a humanized antibody having three heavy chain CDRs and three light chain CDRs derived from the variable region of a pair of anti-DC-ASGPR heavy chain variable region and anti-DC-ASGPR light chain variable region selected from SEQ ID NOs: 3 and 8, SEQ ID NOs: 58 and 60, SEQ ID NOs: 62 and 64, or SEQ ID NOs: 66 and 68; or a humanized antibody having three heavy chain CDRs and three light chain CDRs derived from the heavy chain and light chain of a pair of anti-DC-ASGPR heavy chain and anti-DC-ASGPR light chain selected from SEQ ID NOs: 69 and 70 and SEQ ID NOs: 71 and 72. [This invention 1076] A pharmaceutical composition comprising an antigen-presenting cell (APC) targeting antibody operably linked to IL-10 or a fragment thereof. [This invention 1077] 1076. The pharmaceutical composition of claim 1076, wherein said APC targeting antibody targets one or more APCs from the group consisting of Langerhans cells, macrophages, dendritic cells, B cells, and peripheral blood mononuclear cells. [This invention 1078] 1078. The pharmaceutical composition of claim 1076 or 1077, wherein said APC targeting antibody is selected from antibodies that specifically bind to MHC class I, MHC class II, CD1d, CD2, CD3, CD4, CD8, CD11b, CD14, CD15, CD16, CD19, CD20, CD29, CD31, CD40, CD43, CD44, CD45, CD54, CD56, CD57, CD58, CD83, CD86, CMRF-44, CMRF-56, DCIR, DC-ASGPR, CLEC-6, CD40, BDCA-2, MARCO, DEC-205, mannose receptor, Langerin, DECTIN-1, B7-1, B7-2, IFN-γ receptor, IL-2 receptor, ICAM-1, Fcγ receptor, LOX-1, and ASPGR. [This invention 1079] 19. The pharmaceutical composition of any one of claims 1076 to 1078, wherein said APC targeting antibody targets Langerhans cells. [The present invention 1080] 1079. The pharmaceutical composition of claim 1079, wherein said APC targeting antibody comprises anti-Langerin. [This invention 1081] 19. The pharmaceutical composition of any one of claims 1076 to 1078, wherein said APC targeting antibody targets macrophages. [This invention 1082] 1081. The pharmaceutical composition of claim 1081, wherein said APC targeting antibody comprises anti-MARCO. [This invention 1083] 1079. The pharmaceutical composition of any of claims 1076 to 1078, wherein said APC targeting antibody targets one or more APCs from the group consisting of dendritic cells, B cells, and macrophages. [This invention 1084] The pharmaceutical composition of the present invention 1083, wherein said APC targeting antibody targets dendritic cells. [This invention 1085] 1083 or 1084, wherein said APC targeting antibody comprises anti-CD40. [This invention 1086] 1085. The pharmaceutical composition of claim 1085, wherein said anti-CD40 antibody comprises anti-CD40 clone 12E12 or a fragment thereof. [This invention 1087] 1086. The pharmaceutical composition of the present invention, wherein said anti-CD40 antibody comprises one or more CDRs having the sequence of SEQ ID NO: 31-33 or 37-39. [This invention 1088] 8. The pharmaceutical composition of any of claims 1085 to 1087, wherein said anti-CD40 antibody comprises a heavy chain comprising one or more CDRs of SEQ ID NOs: 31 to 33. [This invention 1089] 9. The pharmaceutical composition of any of claims 1085 to 1088, wherein said anti-CD40 antibody comprises a light chain comprising one or more CDRs of SEQ ID NOs: 37 to 39. [The present invention 1090] The pharmaceutical composition of any of claims 1085 to 1089, wherein the anti-CD40 antibody is a humanized antibody comprising a heavy chain comprising three CDRs, wherein CDR1 comprises SEQ ID NO: 31, CDR2 comprises SEQ ID NO: 32, and CDR3 comprises SEQ ID NO: 33. [This invention 1091] The pharmaceutical composition of any of claims 1085 to 1090, wherein the anti-CD40 antibody is a humanized antibody comprising a light chain comprising three CDRs, wherein CDR1 comprises SEQ ID NO: 37, CDR2 comprises SEQ ID NO: 38, and CDR3 comprises SEQ ID NO: 39. [This invention 1092] 1083 or 1084, wherein the APC targeting antibody comprises anti-DC-ASGPR. [This invention 1093] 1092. The pharmaceutical composition of the present invention, wherein the antibody comprises a variable region comprising an amino acid sequence selected from the sequences of SEQ ID NO: 3, 8, 62, 64, 66, or 68. [This invention 1094] The pharmaceutical composition of the present invention 1092 or 1093, wherein the antibody comprises a heavy chain or a light chain having an amino acid sequence selected from the sequences of SEQ ID NO: 1, 7, 61, 63, 65, 67, or 69-72. [This invention 1095] 1092. The pharmaceutical composition of the present invention, wherein the antibody comprises one or more CDRs from the variable region, heavy chain, or light chain of SEQ ID NO: 1, 3, 7, 8, 61, 62, 63, 64, 65, 66, 67, or 68-72. [This invention 1096] 1083 or 1084, wherein the APC targeting antibody comprises anti-Dectin-1. [This invention 1097] 1083 or 1084, wherein the APC targeting antibody comprises anti-DCIR. [This invention 1098] 1097. The pharmaceutical composition of the present invention, wherein said anti-DCIR antibody comprises anti-DCIR clone 9E8 or a fragment thereof. [This invention 1099] 1098. The pharmaceutical composition of the present invention, wherein said anti-DCIR antibody comprises one or more CDRs having the sequence of SEQ ID NO: 18-20 or 24-26. [The present invention 1100] 1097-1099. The pharmaceutical composition of any of claims 1097-1099, wherein said anti-DCIR antibody comprises a heavy chain comprising one or more CDRs of SEQ ID NOs: 18-20. [The present invention 1101] 1097-1100. The pharmaceutical composition of any of claims 1097-1100, wherein said anti-CD40 antibody comprises a light chain comprising one or more CDRs of SEQ ID NO:24-26. [The present invention 1102] The pharmaceutical composition of any of claims 1098 to 1101, wherein the anti-DCIR antibody is a humanized antibody comprising a heavy chain comprising three CDRs derived from the variable region of the anti-DCIR 9E8 heavy chain (SEQ ID NO: 17). [The present invention 1103] The pharmaceutical composition of any of claims 1098 to 1102, wherein the anti-DCIR antibody is a humanized antibody comprising a light chain comprising three CDRs derived from the variable region of the anti-DCIR 9E8 light chain (SEQ ID NO: 23). [The present invention 1104] The pharmaceutical composition of any of claims 1076 to 1103, wherein the antibody is a human antibody, a humanized antibody, a recombinant antibody, a bispecific antibody, a chimeric antibody, a nanobody, a DARPin, an antibody derivative, a veneered antibody, a diabody, a monoclonal antibody, or a polyclonal antibody. [This invention 1105] 1104. The pharmaceutical composition of the present invention, wherein said antibody is a humanized antibody. [The present invention 1106] 6. The pharmaceutical composition of any one of claims 1076 to 1105, wherein said IL-10 is covalently linked to said antibody. [This invention 1107] 17. The pharmaceutical composition of any of claims 1076 to 1106, wherein IL-10 is covalently linked to said antibody via a peptide bond. [This invention 1108] The pharmaceutical composition of any one of claims 1086 to 1105, wherein the antibody is functionally linked to IL-10 via a binding polypeptide. [This invention 1109] 1108. The pharmaceutical composition of claim 1108, wherein said binding polypeptides are dockerin and cohesin. [The present invention 1110] The pharmaceutical composition of any one of claims 1076 to 1109, further comprising an antigen. [The present invention 1111] 1110. The pharmaceutical composition of claim 1110, wherein said antigen is operably linked to said APC-targeting antibody. [The present invention 1112] The pharmaceutical composition of invention 1110, wherein said antigen is operably linked to IL-10. [The present invention 1113] The pharmaceutical composition of any of claims 1110 to 1112, wherein said antigen is covalently linked to said APC-targeting antibody, an antigen-binding fragment thereof, or IL-10. [This invention 1114] The pharmaceutical composition of any of claims 1110 to 1112, wherein the antigen is functionally linked to the APC-targeting antibody, its antigen-binding fragment, or IL-10 via a binding polypeptide. [This invention 1115] 1114. The pharmaceutical composition of claim 1114, wherein said binding polypeptides are dockerin and cohesin. [The present invention 1116] 1076-1115. The pharmaceutical composition of any of claims 1076-1115, which is formulated for oral, intravenous, subcutaneous, intradermal, intramuscular, mucosal, or nasal administration, or for administration by injection, inhalation, or nebulizer. [This invention 1117] The pharmaceutical composition of any one of claims 1076 to 1116, wherein the IL-10 comprises a peptide having the amino acid sequence of SEQ ID NO: 5, or a fragment thereof. [This invention 1118] 17. The pharmaceutical composition of any one of claims 1076 to 1116, wherein said APC-targeting antibody further comprises a modification. [This invention 1119] 1118. The pharmaceutical composition of the present invention, wherein said modifications are conservative amino acid mutations in the CDR1, CDR2, and / or CDR3 regions of VH and / or VL. [The present invention 1120] The pharmaceutical composition of the present invention 1118, wherein said modification is a conservative amino acid mutation within the Fc hinge region. [This invention 1121] 1118. The pharmaceutical composition of claim 1118, wherein said modification is pegylation. [This invention 1122] 1118. The pharmaceutical composition of claim 1118, wherein said modification is conjugation with a serum protein. [This invention 1123] 1118. The pharmaceutical composition of claim 1118, wherein said modification is conjugation with human serum albumin. [This invention 1124] 1118. The pharmaceutical composition of claim 1118, wherein said modification is conjugation with a detectable label. [This invention 1125] 1118. The pharmaceutical composition of claim 1118, wherein said modification is conjugation with a diagnostic agent. [Invention 1126] 1118. The pharmaceutical composition of claim 1118, wherein said modification is conjugation with an enzyme. [This invention 1127] 1118. The pharmaceutical composition of claim 1118, wherein said modification is conjugation with a fluorescent substance, a luminescent substance, or a bioluminescent substance. [This invention 1128] 1118. The pharmaceutical composition of claim 1118, wherein said modification is conjugation with a radioactive substance. [This invention 1129] The pharmaceutical composition of claim 1118, wherein said modification is conjugation with a therapeutic agent. [The present invention 1130] A pharmaceutical composition comprising an anti-CD40 antibody functionally linked to IL-10 or a fragment thereof, wherein the anti-CD40 is a humanized antibody having three heavy chain CDRs comprising the amino acid sequences of SEQ ID NO:31 (CDR1), SEQ ID NO:32 (CDR2), and SEQ ID NO:33 (CDR3) and three light chain CDRs comprising the amino acid sequences of SEQ ID NO:37 (CDR1), SEQ ID NO:38 (CDR2), and SEQ ID NO:39 (CDR3). [This invention 1131] A pharmaceutical composition comprising an anti-DCIR antibody functionally linked to IL-10 or a fragment thereof, wherein the anti-DCIR is a humanized antibody having three heavy chain CDRs derived from the anti-DCIR 9E8 heavy chain variable region (SEQ ID NO: 17) and three light chain CDRs derived from the anti-DCIR 9E8 light chain variable region (SEQ ID NO: 23). [This invention 1132] 20. The pharmaceutical composition of any of claims 1076 to 1131 for use in a method for preventing or treating an autoimmune disease or inflammatory condition. [This invention 1133] Use of any of the pharmaceutical compositions of inventions 1076 to 1131 in the preparation of a medicament for treating or preventing an autoimmune or inflammatory disorder. [This invention 1134] A method for inducing immune tolerance in a subject in need thereof, comprising the step of administering to the subject any one of the compositions of the present inventions 1076 to 1131. [This invention 1135] A method for generating anti-pathogen antigen-specific regulatory T cells in a subject in need thereof, comprising administering to the subject an anti-DC-ASGPR antibody or an antigen-binding fragment thereof. [This invention 1136] A method for reducing a pathogenic T cell response in a patient in need thereof, comprising administering to the patient an anti-DC-ASGPR antibody or an antigen-binding fragment thereof. [This invention 1137] A method for preventing or treating GVHD in a subject in need thereof, comprising administering to the subject an anti-DC-ASGPR antibody or an antigen-binding fragment thereof. [This invention 1138] A method for preventing or treating transplant rejection in a subject in need thereof, comprising administering to the subject an anti-DC-ASGPR antibody or an antigen-binding fragment thereof. [This invention 1139] The method of any one of claims 1135 to 1138, wherein the antibody or the antigen-binding fragment specifically binds to DC-ASGPR and activates DC-ASGPR. [This invention 1140] 1139. The method of claim 1139, wherein said antibody or antigen-binding fragment thereof binds to human DC-ASGPR. [This invention 1141] 1140. The method of any of claims 1135 to 1140, wherein said antibody is a human antibody, a humanized antibody, a recombinant antibody, a bispecific antibody, a chimeric antibody, a nanobody, a DARPin, an antibody derivative, a veneered antibody, a diabody, a monoclonal antibody, or a polyclonal antibody. [This invention 1142] 1141. The method of claim 1141, wherein said antibody is a monoclonal antibody. [This invention 1143] 1141. The method of claim 1141, wherein said antibody is a humanized antibody. [This invention 1144] 1141. The method of claim 1141, wherein said antibody is a mouse / human chimeric antibody. [Invention 1145] The method of any of claims 1135 to 1144, wherein the antibody comprises a variable region comprising an amino acid sequence selected from the sequences of SEQ ID NOs: 3, 8, 58, 60, 62, 64, 66, and 68. [Invention 1146] The method of any of claims 1135 to 1145, wherein the antibody comprises one or more CDRs of a variable region having an amino acid sequence corresponding to any one of SEQ ID NOs: 3, 8, 58, 60, 62, 64, 66, and 68. [This invention 1147] 1135-1146. The method of any of claims 1135-1146, wherein the antibody comprises a heavy chain or a light chain having an amino acid sequence selected from the sequences of SEQ ID NOs: 2, 7, 57, 59, 61, 63, 65, 67, and 69-72. [Invention 1148] 8. The method of any of claims 1135 to 1147, wherein the antibody comprises one or more CDRs from a heavy chain or a light chain having an amino acid sequence selected from the sequences of SEQ ID NOs: 2, 7, 57, 59, 61, 63, 65, 67, and 69 to 72. [This invention 1149] The method of any of claims 1135 to 1148, wherein the antibody comprises a γ4 constant region. [This invention 1150] 1149. The method of claim 1149, wherein said gamma 4 constant region comprises a leucine to glutamic acid substitution at residue 235. [This invention 1151] 1150. The method of any one of claims 1149 to 1150, wherein said gamma 4 constant region comprises a serine to proline substitution at residue 228 in the hinge region. [This invention 1152] The method of any of claims 1135 to 1151, wherein the antibody comprises a human κ chain. [This invention 1153] 1153. The method of any one of claims 1135 to 1152, wherein said subject is a human subject. [This invention 1154] The method of claim 1153, wherein said subject is at risk of developing a disease mediated by a pathogenic T cell response. [Invention 1155] The method of any of claims 1135 to 1154, wherein the subject has an autoimmune disease or an autoinflammatory disease. [Invention 1156] 1155. The method of claim 1155, wherein said autoimmune disease or said autoinflammatory disease is selected from rheumatoid arthritis, allergy, asthma, systemic juvenile arthritis, inflammatory bowel disease, systemic lupus erythematosus, and Crohn's disease. [This invention 1157] The method of any one of claims 1135 to 1156, wherein the subject is a subject who will receive or has received a transplant. [This invention 1158] 1157. The method of claim 1157, wherein the subject has a complication due to the transplanted tissue, and the complication is transplant rejection. [This invention 1159] The method of claim 1157, wherein the subject has a complication due to the transplanted tissue, and the complication is GVHD. [The present invention 1160] 1159. The method of any of claims 1157 to 1159, wherein the antibody or antigen-binding fragment thereof is administered before tissue transplantation. [This invention 1161] 1160. The method of claim 1160, further comprising the step of preventing complications associated with said transplanted tissue, said complications including GVHD or graft rejection. [This invention 1162] 1159. The method of any of claims 1157 to 1159, wherein said antibody or antigen-binding fragment thereof is administered after tissue transplantation. [This invention 1163] 1163. The method of claim 1162, further comprising treating complications due to said transplanted tissue, said complications including GVHD or graft rejection. [This invention 1164] The method of any one of claims 1157 to 1163, wherein the transplant tissue comprises immune cells. [Invention 1165] The method of any one of claims 1157 to 1163, wherein the transplant tissue comprises stem cells. [Invention 1166] 1165. The method of claim 1165, wherein said tissue comprises hematopoietic stem cells. [This invention 1167] The method of any one of claims 1157 to 1163, wherein the transplant tissue comprises bone marrow. [Invention 1168] The method of any one of claims 1157 to 1163, wherein the transplant tissue comprises blood. [This invention 1169] The method of any one of claims 1157 to 1163, wherein the transplant tissue comprises skin cells. [This invention 1170] The method of any of claims 1135 to 1169, wherein said administering increases the production of IL-10 in said subject. [This invention 1171] The method of any of claims 1135 to 1170, wherein the subject maintains pathogen-specific immunity after administration of the antibody or antigen-binding fragment. [This invention 1172] 1135-1171. The method of any of claims 1135-1171, wherein said antibody is administered by intraperitoneal injection. [This invention 1173] 1135-1171. The method of any one of claims 1135-1171, wherein said antibody is administered by intravenous injection. [This invention 1174] 1174. The method of any of claims 1135 to 1173, wherein said antibody or said antigen-binding fragment further comprises a modification. [This invention 1175] 1175. The method of claim 1174, wherein said modifications are conservative amino acid mutations within the CDR1, CDR2, and / or CDR3 regions of VH and / or VL. [Invention 1176] 1174. The method of claim 1174, wherein said modification is a conservative amino acid mutation within the Fc hinge region. [This invention 1177] 1175. The method of claim 1174, wherein said modification is pegylation. [This invention 1178] 1174. The method of claim 1174, wherein said modification is conjugation with a serum protein. [This invention 1179] 1174. The method of claim 1174, wherein said modification is conjugation with human serum albumin. [This invention 1180] 1175. The method of claim 1174, wherein said modification is conjugation with a detectable label. [This invention 1181] 1174. The method of claim 1174, wherein said modification is conjugation with a diagnostic agent. [This invention 1182] 1174. The method of claim 1174, wherein said modification is conjugation with an enzyme. [This invention 1183] 1175. The method of claim 1174, wherein said modification is conjugation with a fluorescent, luminescent, or bioluminescent substance. [This invention 1184] 1174. The method of claim 1174, wherein said modification is conjugation with a radioactive substance. [This invention 1185] 1174. The method of claim 1174, wherein said modification is conjugation with a therapeutic agent. [Invention 1186] The method of any one of claims 1135 to 1185, wherein the antibody is administered in the form of a pharmaceutical composition. [This invention 1187] 1186. The method of claim 1186, wherein said pharmaceutical composition does not contain an antigen. [This invention 1188] 1186. The method of claim 1186, wherein said pharmaceutical composition consists essentially of an anti-DC-ASGPR antibody. [This invention 1189] The method of any of claims 1135 to 1188, wherein said antibody or antigen-binding fragment thereof is not conjugated to an antigen. [This invention 1190] The method of any of claims 1135 to 1189, wherein the antibody is not conjugated to a dockerin molecule or a cohesin molecule. [This invention 1191] 1190. The method of any of claims 1135 to 1190, wherein said antibody is not covalently or operably linked to an antigen. [Brief explanation of the drawings]

[0065] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present invention. The invention may be more fully understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein. [Figure 1] We demonstrate that a recombinant fusion protein of antibody and IL-10 targets human APCs. [Figure 2] We show that antibody-IL-10 fusion proteins inhibit DC maturation induced by E. coli lipopolysaccharide. [Figure 3] Demonstrating the dose-sparing effect of targeting IL-10 fusion proteins. [Figure 4] Figure 1 shows that administration of anti-DC-ASGPR mAb to PBMCs from healthy donors reduces proliferation of CD4+ and CD8+ T cells from MHC-mismatched donors. Summary of data (mean ± SD) obtained using PBMCs from six pairs of MHC-mismatched healthy donors. [Figure 5]We show that IL-10 blockade partially restores allogeneic CD4+ T cell proliferation induced by anti-DC-ASGPR-activated PBMCs. [Figure 6] These results show that allogeneic CD4+ T cells cultured with anti-DC-ASGPR-activated PBMCs secreted less IFNγ but more IL-10 upon restimulation. [Figure 7] 1 demonstrates the effect of anti-DC-ASGPR mAb on delaying xenogeneic GVHD in NOG mice. [Figure 8] This demonstrates a hypothetical pathway for DC-ASGPR-induced suppression of allogeneic T cell responses. DETAILED DESCRIPTION OF THE INVENTION

[0066] DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS The methods and compositions described herein can be used to treat or prevent inflammatory and / or autoimmune disorders or to induce immune tolerance. It has been shown that delivery of the anti-inflammatory cytokine IL-10 to human antigen-presenting cells (APCs) can suppress and modify the pathophysiological function of APCs in patients. It is anticipated that targeted delivery of anti-inflammatory cytokines to APCs in patients will result in more effective and long-lasting immune tolerance in patients. Delivery of IL-10 to APCs can directly suppress ongoing inflammatory responses in the short term and can also induce regulatory T cells, which can prolong the effectiveness of treatment. Furthermore, the methods described herein also provide a dose-sparing effect, in that targeted delivery of IL-10 requires a smaller amount or dose to achieve the same effect as non-targeted IL-10.

[0067] I. Antibodies The methods and compositions of the present disclosure relate to APC-targeting antibodies and antibody-binding fragments thereof. In some embodiments, the antibodies are functionally linked to IL-10. As used herein, "antibody" includes full-length antibodies and any antigen-binding fragments or single chains thereof. Thus, the term "antibody" includes any protein- or peptide-containing molecule that contains at least a portion of an immunoglobulin molecule. Examples of such include, but are not limited to, the complementarity-determining region (CDR) of a heavy or light chain or their ligand-binding portion, the heavy or light chain variable region, the heavy or light chain constant region, the framework (FR) region or any portion thereof, or at least one portion of a binding protein.

[0068] The antibody may be any of the various antibodies described herein, non-limiting examples of which include a polyclonal antibody, a monoclonal antibody, a chimeric antibody, a recombinant antibody, a human antibody, a veneered antibody, a diabody, a humanized antibody, an antibody derivative, a recombinant humanized antibody, or a derivative or fragment of each thereof.

[0069] Antibodies can be produced using conventional techniques known in the art and well documented in the literature. Several methods exist for producing polyclonal antibodies. For example, polyclonal antibodies are typically produced by immunizing suitable mammals, such as, but not limited to, chickens, goats, guinea pigs, hamsters, horses, mice, rats, and rabbits. Antigens are injected into the mammal to induce B lymphocytes to produce immunoglobulins specific to the antigen. The immunoglobulins are purified from the mammal's serum. Common variations on this method include altering the adjuvant, route and site of administration, injection volume per site, and number of sites per animal for optimal production and humane animal treatment. For example, adjuvants are typically used to improve or enhance the immune response to antigens. Most adjuvants create an antigen depot at the injection site, allowing for the sustained release of antigens into the draining lymph nodes. Other adjuvants include surfactants, which promote the concentration of protein antigen molecules and immunostimulatory molecules over a large surface area. Non-limiting examples of adjuvants for producing polyclonal antibody include Freund's adjuvant, Ribi adjuvant system and Titermax.Polyclonal antibody can be produced by the method described in U.S. Patent No. 7,279,559; U.S. Patent No. 7,119,179; U.S. Patent No. 7,060,800; U.S. Patent No. 6,709,659; U.S. Patent No. 6,656,746; U.S. Patent No. 6,322,788; U.S. Patent No. 5,686,073; and U.S. Patent No. 5,670,153.

[0070] Unless otherwise specified, antibodies may be polyclonal or monoclonal and may be isolated from any suitable biological source, such as murine, rat, sheep, or canine.

[0071] In one specific embodiment, the antibody is a monoclonal antibody. As used herein, "monoclonal antibody" refers to an antibody obtained from a substantially homogeneous antibody population. Monoclonal antibodies are highly specific because each monoclonal antibody is generated against a single determinant on an antigen. Antibodies can be detectably labeled, for example, with a radioisotope, an enzyme that generates a detectable product, a fluorescent protein, etc. Antibodies can also be conjugated with other moieties, such as members of specific binding pairs, for example, biotin (a member of the biotin-avidin specific binding pair). Antibodies can also be bound to solid supports, including, but not limited to, polystyrene plates or beads.

[0072] Monoclonal antibodies can be produced using conventional hybridoma techniques known in the art and well documented in the literature. For example, hybridomas can be produced using a suitable immortal cell line (e.g., a myeloma cell line, including but not limited to, Sp2 / 0, Sp2 / 0-AG14, NSO, NS1, NS2, AE-1, L.5, P3X63Ag8,653, Sp2 SA3, Sp2 MAI, Sp2 SS1, Sp2 SA5, U397, MIA 144, ACT IV, MOLT4, DA-1, JURKAT, WEHI, K-562, COS, RAJI, NIH 313, HL-60, MLA 144, NAMAIWA, NEURO, etc.). 2A, CHO, PerC.6, YB2 / O, etc.), or heteromyelomas, their fusion products, or any cells or fusion cells derived therefrom, or any other suitable cell line known in the art, can be fused with antibody-producing cells, including but not limited to, isolated or cloned spleen, peripheral blood, tonsil, or other immune cells or B cells, or can be fused with recombinant or endogenous viruses, bacteria, algae, prokaryotes, amphibians, insects, or other cells, as endogenous or heterologous nucleic acids. Antibody-producing cells can be produced by fusing with any other cell expressing heavy or light chain constant or variable or framework or CDR sequences, such as genomic DNA, cDNA, rDNA, mitochondrial DNA or RNA, chloroplast DNA or RNA, hmRNA, mRNA, tRNA, single-stranded, double-stranded, or triple-stranded, hybridizable, or any combination thereof, from insects, reptiles, fish, mammals, rodents, horses, ovine, goats, sheep, primates, or eukaryotes. Antibody-producing cells can also be obtained from the peripheral blood, or preferably the spleen or lymph nodes, of humans or other suitable animals immunized with the antigen of interest. Any other suitable host cells can also be used to express heterologous or endogenous nucleic acids encoding antibodies, specific fragments, or variants thereof. The fused cells (hybridomas) or recombinant cells can be isolated using selective culture conditions or other suitable known methods and then cloned using limiting dilution, cell sorting, or other known methods.

[0073] Other suitable methods for producing or isolating antibodies with the required specificity can also be used, including, but not limited to, selecting recombinant antibodies from peptide or protein libraries (e.g., but not limited to, bacteriophage, ribosomal, oligonucleotide, cDNA, etc. display libraries; available from various commercial sources, e.g., MorphoSys (Martinsreid / Planegg, Del.), Biolnvent (Lund, Sweden), Affitech (Oslo, Norway)) using methods known in the art. Methods known in the art are described in the patent literature, some of which include U.S. Patent Nos. 4,704,692; 5,723,323; 5,763,192; 5,814,476; 5,817,483; 5,824,514; and 5,976,862. An alternative method relies on immunization of transgenic animals capable of producing a repertoire of human antibodies (e.g., SCID mice, Nguyen et al. (1977) Microbiol. Immunol. 41:901-907 (1997); Sandhu et al. (1996) Crit. Rev. Biotechnol. 16:95-118; Eren et al. (1998) Mumma 93:154-161), as known in the art and / or described herein.Such techniques include ribosome display (Wanes et al. (1997) Proc. Natl. Acad. Sci. USA, 94:4937-4942; Hanes et al, (1998) Proc. Natl. Acad. Sci. USA 95: 14130-14135); single-cell antibody production techniques (e.g., selected lymphocyte antibody method ("SLAM") (U.S. Patent No. 5,627,052, Wen et al, (1987) J. Immunol 17:887-892; Babcook et al. (1996) Proc. Natl. Acad. Sci. USA 93:7843-7848); gel microdroplets and flow cytometry (Powell et al. (1990) Biotechnol. 8:333-337; One Cell Systems (Cambridge, Mass.); Gray et al. (1995) J. Imm. Meth. 182:155-163; and Kenny et al, (1995) Bio. Technol. 13:787-790); B cell selection (Steenbakkers et al. (1994) Molec. Biol. Reports 19:125-134).

[0074] As used herein, the term "polyclonal antibody" or "polyclonal antibody composition" refers to a preparation of antibodies derived from different B-cell lines, which are a mixture of immunoglobulin molecules secreted against a specific antigen, each recognizing a different epitope.

[0075] The term "murine antibody", as used herein, is intended to include antibodies having variable and constant regions derived from mouse germline immunoglobulin sequences.

[0076] As used herein, a chimeric antibody refers to an antibody whose light and heavy chain genes have been constructed, typically by genetic engineering, from antibody variable and constant region genes belonging to different species. In one embodiment, the antibody is a mouse / human chimeric antibody.

[0077] In further embodiments, the antibody contains modifications and is an "antibody derivative." The term "antibody derivative" includes post-translational modifications to the linear polypeptide sequence of an antibody or fragment. For example, U.S. Patent No. 6,602,684 B1 describes methods for producing modified glycoforms of antibodies, including full-length antibody molecules, antibody fragments, or fusion proteins, that contain a region equivalent to the Fc region of an immunoglobulin and have enhanced Fe-mediated cytotoxicity, and the glycoproteins thus produced.

[0078] The antibodies provided herein also include derivatives that have been modified by the covalent attachment of any type of molecule to the antibody, provided that the covalent attachment does not prevent the antibody from generating an anti-idiotypic response. Antibody derivatives include, but are not limited to, antibodies modified by glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization with known protecting / blocking groups, proteolytic cleavage, linkage to intracellular ligands or other proteins, etc. In addition, derivatives may contain one or more non-classical amino acids.

[0079] Antibody derivatives can also be prepared by delivering a polynucleotide encoding the antibody to a suitable host to produce a transgenic animal or mammal, such as a goat, cow, horse, sheep, etc., that produces such antibodies in its milk. These methods are known in the art and are described, for example, in U.S. Patent Nos. 5,827,690; 5,849,992; 4,873,316; 5,849,992; 5,994,616; 5,565,362; and 5,304,489.

[0080] Antibody derivatives can also be prepared by delivering polynucleotides to obtain transgenic plants and cultured plant cells (such as, but not limited to, tobacco, corn, and duckweed) that produce such antibodies, specific portions, or variants in plant parts or cells cultured therefrom. Antibody derivatives have also been produced in large quantities from transgenic plant seeds, including tobacco seeds and potato tubers, that contain antibody fragments such as single-chain antibodies (scFv). See, for example, Conrad et al. (1998) Plant Mol. Biol. 38:101-109 and the references cited therein. Thus, antibodies can also be produced using transgenic plants according to known methods.

[0081] Antibody derivatives can also be generated by adding exogenous sequences to, for example, modify immunogenicity or to reduce, enhance, or modify binding, affinity, on-rate, off-rate, avidity, specificity, half-life, or any other suitable characteristic. Generally, some or all of the non-human or human CDR sequences are maintained, while the non-human sequences in the variable and constant regions are replaced with human or other amino acids.

[0082] The term "variable region" refers to the portion of an antibody that confers its specificity for binding to an antigen. Variable regions are typically located at the ends of the heavy and light chains. The variable loops of the three beta chains on each of the light (VL) and heavy (VH) chains are responsible for binding to the antigen. These loops are called "complementarity-determining regions" (CDRs).

[0083] In general, the CDR residues are directly and most substantially involved in influencing antigen binding. Antibody humanization or engineering can be performed using any known method, including, but not limited to, those described in U.S. Pat. Nos. 5,723,323; 5,976,862; 5,824,514; 5,817,483; 5,814,476; 5,763,192; 5,723,323; 5,766,886; 5,714,352; 6,204,023; 6,180,370; 5,693,762; 5,530,101; 5,585,089; 5,225,539; and 4,816,567.

[0084] The term "constant region" refers to the portion of an antibody that is identical in all antibodies of the same isotype. The constant region differs in antibodies of different isotypes.

[0085] In one embodiment, the antibody is a humanized antibody. As used herein, the term "humanized antibody" or "humanized immunoglobulin" refers to a human / non-human chimeric antibody that contains minimal sequence derived from non-human immunoglobulin. In most cases, humanized antibodies are human immunoglobulins (recipient antibodies) in which residues from the recipient's variable region are replaced with residues from the variable region of a non-human species (donor antibody) such as a mouse, rat, rabbit, or non-human primate having the desired specificity, affinity, and capacity. Humanized antibodies may contain residues that are not found in the recipient or donor antibody. Humanized antibodies may also optionally comprise at least a portion of an immunoglobulin constant region (Fc), typically of a human immunoglobulin. The non-human antibody contains one or more amino acids in the framework regions, constant regions, or CDRs that are substituted for similarly positioned amino acids from a human antibody. In general, humanized antibodies are expected to generate a reduced immune response in a human host compared to non-humanized versions of the same antibody. Humanized antibodies may have conservative amino acid substitutions that have substantially no effect on antigen binding or other antibody functions. Conservative substitution groupings include: glycine-alanine, valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, serine-threonine, and asparagine-glutamine.

[0086] Chimeric antibodies, humanized antibodies, or primatized antibodies can be prepared based on the sequence of a reference monoclonal antibody prepared using standard molecular biology techniques.The DNA encoding heavy and light chain immunoglobulins can be obtained from the hybridoma of interest, and can be manipulated to include non-reference (e.g., human) immunoglobulin sequences using standard molecular biology techniques.For example, to produce chimeric antibodies, the mouse variable region can be linked with human constant region using methods known in the art (U.S. Patent No. 4,816,567).To produce humanized antibodies, the mouse CDR region can be inserted into a human framework using methods known in the art (U.S. Patent No. 5,225,539 and U.S. Patent No. 5,530,101; U.S. Patent No. 5,585,089; U.S. Patent No. 5,693,762 and U.S. Patent No. 6,180,370). Similarly, to generate primatized antibodies, mouse CDR regions can be inserted into a primate framework using methods known in the art (WO 93 / 02108 and WO 99 / 55369). Methods for determining CDRs from variable region sequences are known in the art (see, for example, Zhao and Lu, "A germline knowledge-based computational approach for determining antibody complementarity determining regions," Mol. Immunol., (2010) 47(4):694-700, which is incorporated herein by reference).

[0087] Techniques for producing partially to fully human antibodies are known in the art, and any such techniques can be used. According to one embodiment, fully human antibody sequences are produced in transgenic mice engineered to express human heavy chain antibody genes and human light chain antibody genes. Several such transgenic mouse strains have been produced that can produce various classes of antibodies. B cells from transgenic mice producing the desired antibody can be fused to generate hybridoma cell lines for sustained production of the desired antibody (see, e.g., Russell et al. (2000) Infection and Immunity April 2000:1820-1826; Gallo et al. (2000) European J. of Immun. 30:534-540; Green (1999) J. of Immun. Methods 231: 11-23; Yang et al. (1999A) J. of Leukocyte Biology 66:401-410; Yang (1999B) Cancer Research 59(6): 1236-1243; Jakobovits (1998) Advanced Drug Reviews 31:33-42; Green and Jakobovits (1998) J. Exp. Med. 188(3):483-495;Jakobovits (1998) Exp. Opin. Invest. Drugs 7(4):607-614;Tsuda et al. (1997) Genomics 42:413-421;Sherman-Gold (1997) Genetic Engineering News 17(14);Mendez et al. (1997) Nature Genetics 15:146-156;Jakobovits (1996) Weir's Handbook of Experimental Immunology, The Integrated Immune System Vol. IV, 194.1-194.7; Jakobovits (1995) Current Opinion in Biotechnology 6:561-566; Mendez et al. (1995) Genomics 26:294-307; Jakobovits (1994) Current Biology 4(8):761-763; Arbones et al. (1994) Immunity 1(4):247-260; Jakobovits (1993) Nature 362(6417):255-258; Jakobovits et al. (1993) Proc. Natl. Acad. Sci. USA 90(6):2551-2555; and U.S. Patent No. 6,075,181.

[0088] Antibodies can also be engineered to create chimeric antibodies, which are antibodies in which the various domains of the antibody's heavy and light chains are encoded by DNA from multiple species. See, e.g., U.S. Patent No. 4,816,567.

[0089] Alternatively, antibodies can also be modified to create veneered antibodies. A veneered antibody is one in which exterior amino acid residues of an antibody from one species have been carefully replaced, or "veneered," with exterior amino acid residues from a second species, such that the antibody from the first species is not immunogenic in the second species, thereby reducing the immunogenicity of the antibody. Because the immunogenicity of a protein depends primarily on the nature of its surface, it is believed that replacing exposed residues that differ from those normally found in antibodies from another mammalian species can reduce the immunogenicity of an antibody. Such careful replacement of exterior residues should have little or no effect on internal domains or interdomain junctions. Therefore, changes limited to framework residues in the variable regions should not affect the binding properties of ligands. This process is referred to as "veneering" because only the outer surface or skin of the antibody is altered, leaving supporting residues unperturbed.

[0090] The "veneering" procedure uses available sequence data for human antibody variable domains compiled by Kabat et al. (1987) Sequences of Proteins of Immunological Interest, 4th ed., Bethesda, Md., National Institutes of Health, updated versions of this database, and other available databases (both nucleic acid and protein) in the United States and abroad. Non-limiting examples of methods used to generate veneered antibodies include those described in EP 519596; U.S. Patent No. 6,797,492; and Padlan et al. (1991) Mol. Immunol. 28(4-5):489-498.

[0091] The term "antibody derivative" also includes "diabodies," which are small antibody fragments having two antigen-binding sites, in which the fragments comprise a heavy-chain variable domain (VH) linked to a light-chain variable domain (VL) in the same polypeptide chain (see, e.g., EP 404,097; WO 93 / 11161; and Hollinger et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448). By using a linker that is too short to allow pairing between the two domains on the same chain, these domains are forced to pair with complementary domains on another chain to generate two antigen-binding sites (see also U.S. Pat. No. 6,632,926 to Chen et al., which discloses antibody mutants in which one or more amino acids have been inserted into the hypervariable regions of the parent antibody, resulting in antibody mutants with binding affinity for a target antigen that is at least about two-fold stronger than that of the parent antibody).

[0092] The term "antibody derivatives" also includes engineered antibody molecules, fragments, and single domains, such as scFvs, dAbs, nanobodies, minibodies, unibodies, and affibodies. Hudson (2005) Nature Biotech 23(9): 1126-36; U.S. Patent Publication US 2006 / 0211088; PCT Publication WO2007 / 059782; U.S. Patent No. 5,831,012).

[0093] The term "antibody derivative" further includes "linear antibodies." Procedures for generating linear antibodies are known in the art and are described in Zapata et al. (1995) Protein Eng. 8(10): 1057-1062. Briefly, these antibodies comprise a pair of tandem Ed segments (V) that form a pair of antigen-binding regions. H -C H1 -VH-C H1 ) Linear antibodies can be bispecific or monospecific.

[0094] Antibodies can be recovered and purified from recombinant cell culture by known methods, including, but not limited to, Protein A purification, ammonium sulfate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography, and lectin chromatography. High performance liquid chromatography ("HPLC") can also be used for purification.

[0095] Whether an antibody has the same specificity as the antibodies contemplated herein can be determined without undue experimentation by determining whether the test antibody prevents the antibody from binding to a protein or polypeptide with which the antibody is normally reactive. If the test antibody competes with the antibody used in the embodiments described herein, as indicated by reduced binding by the monoclonal antibody, the two antibodies likely bind to the same epitope or a similar epitope. Alternatively, the antibody for use in the embodiments can be preincubated with the protein with which it is normally reactive to determine whether its ability to bind to the antigen is inhibited. If the test antibody is inhibited, then it is highly likely that the antibody has the same or a similar epitope specificity as the antibody for use in the embodiments described herein.

[0096] The term "antibody" is also intended to include antibodies of all immunoglobulin isotypes and immunoglobulin subclasses. Isotype refers to the genetic variation or differences in the constant regions of the heavy and light chains of an antibody. In humans, there are five heavy chain isotypes: IgA, IgD, IgG, IgE, and IgM, and two light chain isotypes: kappa and lambda. The IgG class is divided into four isotypes: IgG1, IgG2, IgG3, and IgG4 in humans, and IgG1, IgG2a, IgG2b, and IgG3 in mice. They share over 95% homology in the amino acid sequence of the Fc region, but show significant differences in the amino acid composition and structure of the hinge region. Specific isotypes of monoclonal antibodies can be prepared directly by selection from the initial fusion, or can be subsequently prepared from parent hybridomas secreting monoclonal antibodies of different isotypes by using sib selection methods to isolate class-switched variants using the procedures described in Steplewski et al. (1985) Proc. Natl. Acad. Sci. USA 82:8653 or Spira et al. (1984) J. Immunol. Methods 74:307. Alternatively, recombinant DNA methods can be used.

[0097] Isolation of other monoclonal antibodies having the specificity of the monoclonal antibodies described herein can also be achieved by one skilled in the art by raising anti-idiotypic antibodies. Herlyn et al. (1986) Science 232:100. Anti-idiotypic antibodies are antibodies that recognize unique determinants present on the monoclonal antibody of interest.

[0098] In some aspects, it may be useful to detectably or therapeutically label an antibody.Methods for conjugating antibodies with these agents are known in the art.For illustrative purposes only, antibodies can be labeled with detectable moieties such as radioactive atoms, chromophores, fluorophores, etc.Such labeled antibodies can be used in diagnostic procedures in vivo or in isolated test samples.

[0099] In certain embodiments, the antibody or antigen-binding fragment further comprises a modification, which may be a conservative amino acid mutation in the CDR1, CDR2, and / or CDR3 regions of the VH and / or VL, a conservative amino acid mutation in the Fc hinge region, pegylation, conjugation with a serum protein, conjugation with human serum albumin, conjugation with a detectable label, conjugation with a diagnostic agent, conjugation with an enzyme, conjugation with a fluorescent, luminescent, or bioluminescent substance, conjugation with a radioactive substance, or conjugation with a therapeutic agent.

[0100] As used herein, the term "label" refers to a directly or indirectly detectable compound or composition that is conjugated directly or indirectly to a composition to be detected, e.g., a protein such as a polynucleotide or an antibody, to produce a "labeled" composition. The term also includes sequences conjugated to a polynucleotide that provide a signal when the inserted sequence is expressed, such as green fluorescent protein (GFP). The label may be detectable itself (e.g., a radioisotope label or a fluorescent label) or, in the case of an enzyme label, may catalyze a chemical change in a substrate compound or composition that is detectable. The label may be suitable for small-scale detection or may be more suitable for high-throughput screening. Thus, suitable labels include, but are not limited to, radioisotopes, fluorescent dyes, chemiluminescent compounds, dyes, and proteins, including enzymes. The label may be simply detected or quantified. A simply detected response generally includes a response that merely confirms its presence, while a quantified response generally includes a response that has a quantifiable (e.g., numerically reportable) value, such as intensity, polarization, and / or other property. In luminescent or fluorescent assays, the detectable response can occur directly, using a luminophore or fluorophore associated with the assay component actually responsible for binding, or indirectly, using a luminophore or fluorophore associated with another (e.g., reporter or indicator) component.

[0101] Examples of luminescent labels that produce a signal include, but are not limited to, bioluminescence and chemiluminescence. A detectable luminescent response generally involves a change in, or the generation of, a luminescent signal. Suitable methods and luminophores for luminescently labeling assay components are known in the art and are described, for example, in Haugland, Richard P. (1996) Handbook of Fluorescent Probes and Research Chemicals (6 th (ed.) Examples of luminescent probes include, but are not limited to, aequorin and luciferase.

[0102] Examples of suitable fluorescent labels include fluorescein, rhodamine, tetramethylrhodamine, eosin, erythrosine, coumarin, methylcoumarin, pyrene, malacite green, stilbene, Lucifer Yellow, Cascade Blue™, and Texas Red. Other suitable optical dyes are described in Haugland, Richard P. (1996) Handbook of Fluorescent Probes and Research Chemicals (6 th (ed.).

[0103] In another aspect, the fluorescent label is functionalized to facilitate covalent binding with cellular components present in or on the surface of cells or tissues, such as cell surface markers. Suitable functional groups include, but are not limited to, isothiocyanate groups, amino groups, haloacetyl groups, maleimides, succinimidyl esters, and sulfonyl halides, all of which can be used to bind the fluorescent label to a second molecule. The choice of functional group of the fluorescent label depends on the binding site with either a linker, an agent, a marker, or a second labeling agent.

[0104] Attachment of the fluorescent label can be direct to the cellular component or compound, or alternatively via a linker. Suitable binding pairs for indirectly linking the fluorescent label to an intermediate include, but are not limited to, antigen / antibody, e.g., rhodamine / anti-rhodamine, biotin / avidin, and biotin / streptavidin.

[0105] Coupling of an antibody to a low molecular weight hapten can increase the sensitivity of the antibody in an assay. The hapten can then be specifically detected by a second reaction. For example, it is common to use haptens such as biotin, which reacts with avidin, or dinitrophenol, pyridoxal, and fluorescein, which can react with specific anti-hapten antibodies. See Harlow and Lane (1988), supra.

[0106] The variable regions of antibodies can be modified by mutating amino acid residues in the CDR1, CDR2, and / or CDR3 regions of VH and / or VL to improve one or more binding characteristics (e.g., affinity) of the antibody. Mutations can be introduced by site-directed mutagenesis or PCR-mediated mutagenesis, and their effect on antibody binding or other functional properties of interest can be evaluated using appropriate in vitro or in vivo assays. Conservative modifications are preferably introduced, typically changing no more than one, two, three, four, or five residues in the CDR regions. Mutations can be amino acid substitutions, additions, or deletions.

[0107] Framework modifications can be made to antibodies to reduce immunogenicity, for example, by "backmutating" one or more framework residues to the corresponding germline sequence.

[0108] Additionally, antibodies can be engineered to contain modifications in the Fc region to alter one or more functional properties of the antibody, such as serum half-life, complement fixation, Fc receptor binding, and / or antigen-dependent cellular cytotoxicity. Such modifications include, but are not limited to, altering the number of cysteine ​​residues in the hinge region to facilitate assembly of the light and heavy chains or to increase or decrease antibody stability (U.S. Patent No. 5,677,425), and mutating amino acids in the Fc hinge region to decrease the biological half-life of the antibody (U.S. Patent No. 6,165,745).

[0109] Additionally, one or more antibodies can be chemically modified. For example, the glycosylation of an antibody can be altered by modifying one or more glycosylation sites in the antibody sequence to increase the affinity of the antibody for the antigen (U.S. Patent Nos. 5,714,350 and 6,350,861). Alternatively, to enhance antibody-dependent cell-mediated cytotoxicity, an antibody can be expressed in a host cell with an altered glycosylation machinery to obtain a hypofucosylated antibody with reduced amounts of fucosyl residues or an increased number of bisecting GlcNac structures (Shields, RL et al., 2002 J. Biol. Chem. 277:26733-26740; Umana et al., 1999 Nat. Biotech. 17:176-180).

[0110] To extend biological half-life, antibodies or fragments thereof can be pegylated by reacting them with polyethylene glycol (PEG) or a reactive ester or aldehyde derivative of PEG under conditions that result in the attachment of one or more PEG groups to the antibody or antibody fragment. Pegylation of antibodies can be carried out by an acylation reaction or an alkylation reaction with a reactive PEG molecule (or an analogous reactive water-soluble polymer). As used herein, the term "polyethylene glycol" is intended to encompass any of the forms of PEG used to derivatize other proteins, such as mono(C1-C10)alkoxypolyethyleneglycol or aryloxypolyethyleneglycol, or polyethyleneglycolmaleimide. The antibody to be pegylated can be an aglycosylated antibody. Methods for pegylation of proteins are known in the art and can be applied to one or more antibodies (EP 0 154 316 and EP 0 401 384).

[0111] Additionally, antibodies can be chemically modified to increase the half-life of the resulting molecule by conjugating or fusing the antigen-binding region of the antibody to a serum protein, such as human serum albumin. Such techniques are described, for example, in EP 0322094 and EP 0 486 525.

[0112] Antibodies or fragments thereof can also be conjugated with diagnostic agents for diagnostic use, for example, to monitor the onset or progression of disease and to determine the effectiveness of a given treatment regimen. Examples of diagnostic agents include enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, radioactive materials, positron-emitting metals using various positron emission tomography methods, and non-radioactive paramagnetic metal ions. The detectable substance can be directly linked or conjugated to the antibody or fragment thereof, or indirectly linked or conjugated via a linker using techniques known in the art. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, β-galactosidase, or acetylcholinesterase. Examples of suitable prosthetic group complexes include streptavidin / biotin and avidin / biotin. Examples of suitable fluorescent substances include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride, or phycoerythrin. Examples of luminescent substances include luminol. Examples of bioluminescent substances include luciferase, luciferin, and aequorin. Examples of suitable radioactive substances include 125I, 131I, indium-111, lutetium-171, bismuth-212, bismuth-213, astatine-211, copper-62, copper-64, copper-67, yttrium-90, iodine-125, iodine-131, phosphorus-32, phosphorus-33, scandium-47, silver-111, gallium-67, praseodymium-142, samarium-153, terbium-161, and dysprosium-16. Radioactive metal ions include 6, holmium-166, rhenium-186, rhenium-188, rhenium-189, lead-212, radium-223, actinium-225, iron-59, selenium-75, arsenic-77, strontium-89, molybdenum-99, rhodium-1105, palladium-109, praseodymium-143, promethium-149, erbium-169, iridium-194, gold-198, gold-199, and lead-211. Monoclonal antibodies can be indirectly conjugated to radioactive metal ions by using bifunctional chelating agents that are covalently linked to the antibodies.Chelating agents can be attached via amity (Meares et al., 1984 Anal. Biochem. 142: 68-78); sulfhydral groups of amino acid residues (Koyama 1994 Chem. Abstr. 120: 217262t) and carbohydrate groups (Rodwell et al. 1986 PNAS USA 83: 2632-2636; Quadri et al. 1993 Nucl. Med. Biol. 20: 559-570).

[0113] Other suitable conjugated molecules include ribonucleases (RNases), DNase I, antisense nucleic acids, inhibitory RNA molecules such as siRNA molecules, immunostimulatory nucleic acids, aptamers, ribozymes, triplex-forming molecules, and external guide sequences. Aptamers are small nucleic acids ranging from 15 to 50 bases in length that fold into defined secondary and tertiary structures such as stem-loops or G-quartets. They can bind small molecules such as ATP (U.S. Pat. No. 5,631,146) and theophylline (U.S. Pat. No. 5,580,737), as well as macromolecules such as reverse transcriptase (U.S. Pat. No. 5,786,462) and thrombin (U.S. Pat. No. 5,543,293). Ribozymes are nucleic acid molecules that can catalyze chemical reactions, either intramolecularly or intermolecularly. Ribozymes typically cleave nucleic acid substrates by recognizing and binding to the target substrate to be subsequently cleaved. Nucleic acid molecules with triplex-forming function can interact with double-stranded and single-stranded nucleic acids by forming triplexes, in which the three strands of DNA form a complex relying on both Watson-Crick and Hoogsteen base pairing. The triplex molecules can bind to target regions with high affinity and specificity.

[0114] Functional nucleic acid molecules may act as effectors, inhibitors, modulators, and stimulators of a specific activity possessed by a target molecule, or functional nucleic acid molecules may possess de novo activity that is independent of any other molecule. In one embodiment, antibodies are stimulators of dendritic cells.

[0115] The conjugated agent can be linked to the antibody directly or indirectly using any of a number of available methods. For example, an agent can be attached to the hinge region of a reduced antibody component via disulfide bond formation using a cross-linking agent such as N-succinyl-3-(2-pyridyldithio)propionate (SPDP), or via carbohydrate moieties within the Fc region of the antibody (Yu et al. 1994 Int. J. Cancer 56: 244; Upeslacis et al., "Modification of Antibodies by Chemical Methods," in Monoclonal antibodies: principles and applications, Birch et al. (eds.), pages 187-230 (Wiley-Liss, Inc. 1995); Price, "Production and Characterization of Synthetic Peptide-Derived Antibodies," in Monoclonal antibodies: Production, engineering and clinical application, Ritter et al. (eds.), pages 60-84 (Cambridge University Press 1995)).

[0116] Techniques for conjugating agents to antibodies are well known (Amon et al., "Monoclonal Antibodies For Immunotargeting Of Drugs In Cancer Therapy," in Monoclonal Antibodies And Cancer Therapy, Reisfeld et al. (eds.), pp. 243-56 (Alan R. Liss, Inc. 1985); Hellstrom et al., "Antibodies For Drug Delivery," in Controlled Drug Delivery (2nd Ed.), Robinson et al. (eds.), pp. 623-53 (Marcel Dekker, Inc. 1987); Thorpe, "Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A Review," in Monoclonal Antibodies '84: Biological And Clinical Applications, Pinchera et al. (eds.), pp. 475-506 (1985); "Analysis, Results, And Future Prospects Of The Therapeutic Use Of Radiolabeted Antibody in Cancer Therapy", in Monoclonal Antibodies For Cancer Detection And Therapy, Baldwin et al. (eds.), pp. 303-16 (Academic Press 1985), and Thorpe et al., The Preparation And Cytotoxic Properties Of Antibody-Toxin Conjugates" 1982 Immunol. Rev. 62: 119-58).

[0117] An antibody, or its antigen-binding region, can be linked to another functional molecule, such as another antibody or a receptor ligand, to generate a bispecific or multispecific molecule that binds to at least two or more different binding sites or target molecules. Linking an antibody to one or more other binding molecules, such as another antibody, antibody fragment, peptide, or binding mimetic, can be achieved, for example, by chemical coupling, genetic fusion, or noncovalent association. A multispecific molecule can further include a third binding specificity in addition to the first and second target epitopes.

[0118] Bispecific and multispecific molecules can be prepared using methods known in the art.For example, each binding unit of a highly specific molecule can be prepared separately, and then they can be conjugated together.When the binding molecule is a protein or peptide, various coupling or cross-linking agents can be used for covalent conjugation. Examples of cross-linking agents include protein A, carbodiimide, N-succinimidyl-S-acetyl-thioacetate (SATA), 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB), o-phenylenedimaleimide (oRDM), N-succinimidyl-3-(2-pyridyldithio)propionate (SPDP), and sulfosuccinimidyl 4-(N-maleimidomethyl)cyclohexane-I-carboxylate (sulfo-SMCC) (Karpovsky et al., 1984 J. Exp. Med. 160: 1686; Liu et al., 1985 Proc. Natl. Acad. Sci. USA 82: 8648). When the binding molecule is an antibody, they can be conjugated by sulfhydryl bonding between the C-terminal hinge regions of the two heavy chains.

[0119] Antibodies or fragments thereof can be linked to moieties that are toxic to cells to which the antibody binds to form "depleting" antibodies. These antibodies are particularly useful for applications in which it is desired to deplete NK cells.

[0120] Antibodies can also be linked to solid supports, which are particularly useful for immunoassays or purification of target antigens. Such solid supports include, but are not limited to, glass, cellulose, polyacrylamide, nylon, polystyrene, polyvinyl chloride, or polypropylene.

[0121] Antibodies can also be bound to various carriers. Thus, compositions containing antibodies and other active or inactive substances are also provided. Examples of well-known carriers include glass, polystyrene, polypropylene, polyethylene, dextran, nylon, amylase, natural and modified cellulose, polyacrylamide, agarose, and magnetite. The nature of the carrier can be soluble or insoluble, depending on the purpose of the embodiments described herein. Those skilled in the art will know of other suitable carriers for binding monoclonal antibodies, or will be able to ascertain such carriers using routine experimentation.

[0122] II. Constructs All of the exemplary heavy chain constructs are typically used for co-transfection of CHO cells with a compatible light chain vector, and in some embodiments, the immunotherapeutic will have humanized variable regions.

[0123] Below are listed APC-targeting antibodies and antibody-IL10 fusion proteins useful in the methods and compositions described herein.

[0124] Anti-ASGPR-49C11-hIL-10 SEQ ID NO:1 shows a fusion protein of the heavy chain of the anti-ASGPR 49C11 antibody fused to human IL-10 via a linker. The linker is underlined and the IL-10 amino acid sequence is in bold italics.

[0125] manti-ASGPR_49C11_7H-LV-hIgG4H-C- Flex-v1-hIL-10] antibody, SEQ ID NO: 1: TIFF0007663616000001.tif87161.

[0126] The heavy chain of the anti-ASGPR 49C11 antibody according to the above is represented by SEQ ID NO:2: TIFF0007663616000002.tif56160

[0127] The heavy chain variable region of anti-ASGPR 49C11 is represented by SEQ ID NO:3: Shown in TIFF0007663616000003.tif20159.

[0128] The linker shown above is SEQ ID NO:4: The file is TIFF0007663616000004.tif5128.

[0129] The hIL-10 amino acid sequence from anti-ASGPR-49C11-hIL-10 is SEQ ID NO:5: Shown in TIFF0007663616000005.tif20160.

[0130] manti-ASGPR_49C11_7H-LV-hIgG4H-C- Flex-v1 - The DNA sequence of the hIL-10 antibody is SEQ ID NO:6: Shown in TIFF0007663616000006.tif245160TIFF0007663616000007.tif20160.

[0131] The corresponding light chain amino acid sequence, mAnti-ASGPR_49C11_7K-LV-hIgGK-C, is SEQ ID NO:7: Shown in TIFF0007663616000008.tif27161.

[0132] The light chain variable region of anti-ASGPR 49C11 is SEQ ID NO:8: Shown in TIFF0007663616000009.tif13160.

[0133] The DNA sequence of mAnti-ASGPR_49C11_7K-LV-hIgGK-C is SEQ ID NO:9: Shown in TIFF0007663616000010.tif100161.

[0134] anti-CD40-24A3-hIL-10 SEQ ID NO:10 shows a fusion protein of the heavy chain of the anti-CD40 24A3 antibody fused to human IL-10 via a linker. The linker is underlined and the IL-10 amino acid sequence is in bold italics.

[0135] manti-hCD40_24A3.3F1_H-LV-hIgG4H-C- Flex-v1 - hIL-10 antibody, SEQ ID NO: 10: TIFF0007663616000011.tif86161.

[0136] The heavy chain of the anti-CD40 24A3 antibody according to above is SEQ ID NO:11: TIFF0007663616000012.tif63160.

[0137] The linker shown above is SEQ ID NO:4, and the IL-10 amino acid sequence is shown as SEQ ID NO:5.

[0138] manti-hCD40_24A3.3F1_H-LV-hIgG4H-C- Flex-v1 - The DNA sequence of the hIL-10 antibody is SEQ ID NO:12: Shown in TIFF0007663616000013.tif245160TIFF0007663616000014.tif20160.

[0139] The corresponding light chain amino acid sequence, manti-hCD40_24A3.3F1_K-LV-hIgGK-C, is SEQ ID NO:13: Shown in TIFF0007663616000015.tif27160.

[0140] The DNA sequence of mAnti-hCD40_24A3.3F1_K-LV-hIgGK-C is SEQ ID NO:14: Shown in TIFF0007663616000016.tif100160.

[0141] Anti-DCIR-9E8-hIL-10 SEQ ID NO:15 shows a fusion protein of the heavy chain of the anti-DCIR 9E8 antibody fused to human IL-10 via a linker, the linker is underlined and the IL-10 amino acid sequence is in bold italics.

[0142] mAnti-DCIR_9E8_H-LV-hIgG4H-C- Flex-v1 - hIL-10 antibody, SEQ ID NO: 15: TIFF0007663616000017.tif86161.

[0143] The heavy chain of the anti-DCIR 9E8 antibody according to above is SEQ ID NO:16: TIFF0007663616000018.tif64161.

[0144] The heavy chain variable region of anti-DCIR 9E8 is SEQ ID NO:17: Shown in TIFF0007663616000019.tif19160.

[0145] The linker shown above is SEQ ID NO:18: The file is TIFF0007663616000020.tif5128.

[0146] The IL-10 amino acid sequence is SEQ ID NO:19: Shown as TIFF0007663616000021.tif27160.

[0147] The corresponding DNA sequence of the IL-10 gene is SEQ ID NO:20: Shown as TIFF0007663616000022.tif71160.

[0148] mAnti-DCIR_9E8_H-LV-hIgG4H-C- Flex-v1 - The DNA sequence of the hIL-10 antibody is SEQ ID NO:21: Shown in TIFF0007663616000023.tif123161TIFF0007663616000024.tif144159.

[0149] The corresponding light chain amino acid sequence, mAnti-DCIR_9E8_K-LV-hIgGK-C, is SEQ ID NO:22: Shown in TIFF0007663616000025.tif27160.

[0150] The light chain variable region of anti-DCIR 9E8 is SEQ ID NO:23: Shown in TIFF0007663616000026.tif12160.

[0151] The DNA sequence of the light chain variable region of anti-DCIR 9E8 is SEQ ID NO:24: Shown in TIFF0007663616000027.tif50161.

[0152] The leader sequence preceding the light chain amino acid sequence is Contains TIFF0007663616000028.tif5128.

[0153] The corresponding DNA sequence of the leader sequence is Contains TIFF0007663616000029.tif13159.

[0154] The DNA sequence of mAnti-DCIR_9E8_K-LV-hIgGK-C is SEQ ID NO:27: Shown in TIFF0007663616000030.tif100161.

[0155] anti-CD40-12E12-hIL-10 SEQ ID NO:28 shows a fusion protein of the heavy chain of the anti-DCIR 9E8 antibody fused to human IL-10 via a linker, the linker is underlined and the IL-10 amino acid sequence is in bold italics.

[0156] manti-CD40_12E12.3F3_H-LV-hIgG4H-C- Flex-v1 - hIL-10 antibody, SEQ ID NO: 28: TIFF0007663616000031.tif86161.

[0157] The heavy chain of the anti-CD40 12E12 antibody according to above is SEQ ID NO:29: TIFF0007663616000032.tif64161.

[0158] The heavy chain variable region of anti-CD40 12E12 is represented by SEQ ID NO:30: Shown in TIFF0007663616000033.tif19160.

[0159] The CDRs of the heavy chain variable region of anti-CD40 12E12 are CDR1: SASQGISNYLN (SEQ ID NO: 31), CDR2: AYINSGGGSTYYPDTVK (SEQ ID NO: 32), and CDR3: RRGLPFHAMD (SEQ ID NO: 33).

[0160] The linker shown above is SEQ ID NO:4, and the IL-10 amino acid sequence is shown as SEQ ID NO:5.

[0161] manti-CD40_12E12.3F3 H-LV-hIgG4H-C- Flex-v1 - The DNA sequence of the hIL-10 antibody is SEQ ID NO:34: Shown in TIFF0007663616000034.tif230160TIFF0007663616000035.tif34159.

[0162] The corresponding light chain amino acid sequence, manti-CD40_12E12.3F3_K-V-hIgGK-C, is SEQ ID NO:35: Shown in TIFF0007663616000036.tif27160.

[0163] The light chain variable region of anti-CD40 12E12 is represented by SEQ ID NO:36: Shown in TIFF0007663616000037.tif13161.

[0164] The CDRs of the light chain variable region of anti-CD40 12E12 are CDR1: SASQGISNYLN (SEQ ID NO: 37), CDR2: YTSILHS (SEQ ID NO: 38), and CDR3: QQFNKLPPT (SEQ ID NO: 39).

[0165] The DNA sequence of mAnti-CD40_12E12.3F3_K-V-hIgGK-C is SEQ ID NO:40: Shown in TIFF0007663616000038.tif100160.

[0166] IgG-hIL10 control SEQ ID NO:41 shows a fusion protein of the heavy chain of an IgG control antibody fused to human IL-10 via a linker, the linker is underlined and the IL-10 amino acid sequence is in bold italics.

[0167] hIgG4H- Flex-v1 - hIL-10 antibody, SEQ ID NO: 41: TIFF0007663616000039.tif85160.

[0168] The linker shown above is SEQ ID NO:4, and the IL-10 amino acid sequence is shown as SEQ ID NO:5.

[0169] hIgG4H- Flex-v1 - The DNA sequence of the hIL-10 antibody is SEQ ID NO:42: Shown in TIFF0007663616000040.tif62160TIFF0007663616000041.tif202160.

[0170] The corresponding light chain amino acid sequence hIgGK is SEQ ID NO:43: Shown in TIFF0007663616000042.tif27160.

[0171] The DNA sequence of hIgGK is SEQ ID NO:44: Shown in TIFF0007663616000043.tif100160.

[0172] Provided below are further examples of antibodies and antibody fragments useful in the methods and compositions described herein.

[0173] Anti-Dectin-1 mAb mAntiDectin-1-11B6.4-HV-hIgG4H-C]; SEQ ID NO: 45: TIFF0007663616000044.tif63160.

[0174] The above sequence is a chimera of the heavy chain variable region of mAb 11B6.4 and the C region of hIgG4.

[0175] The heavy chain variable region of mAb 11B6.4 is represented by SEQ ID NO:46: Shown in TIFF0007663616000045.tif20160.

[0176] [mAnti-Dectin-1-11B6.4-K-LV-hIgGK-C] is the corresponding L chain chimera; SEQ ID NO:47: The file is TIFF0007663616000046.tif27159.

[0177] The light chain variable region of mAnti-Dectin-1-11B6.4-K-LV-hIgGK-C is SEQ ID NO:48: Shown in TIFF0007663616000047.tif12158.

[0178] mAntiDectin-1-15E2.5-HV-hIgG4H-C]; SEQ ID NO: 49: TIFF0007663616000048.tif64161.

[0179] The above sequence is a chimera of the heavy chain variable region of mAb 15E2.5 and the C region of hIgG4.

[0180] The heavy chain variable region of mAb 15E2.5 is represented by SEQ ID NO:50: Shown in TIFF0007663616000049.tif20160.

[0181] [mAnti-Dectin-1-15E2.5-KV-hIgGK-C] is the corresponding light chain chimera; SEQ ID NO:51: TIFF0007663616000050.tif27160.

[0182] The light chain variable region of mAnti-Dectin-1-15E2.5-KV-hIgGK-C is SEQ ID NO:52: Shown in TIFF0007663616000051.tif12159.

[0183] mAntiDectin-1-2D8.2D4-HV-hIgG4H-C]; SEQ ID NO: 53: TIFF0007663616000052.tif64161.

[0184] The above sequence is a chimera of the heavy chain variable region of mAb 2D8.2D4 and the C region of hIgG4.

[0185] The heavy chain variable region of mAb 2D8.2D4 is represented by SEQ ID NO:54: Shown in TIFF0007663616000053.tif20159.

[0186] [mAntiDectin-1-2D8.2D4-KV-hIgGK-C] is the corresponding light chain chimera; SEQ ID NO:55: The file is TIFF0007663616000054.tif27160.

[0187] The light chain variable region of mAnti-Dectin-1-2D8.2D4-KV-hIgGK-C is SEQ ID NO:56: Shown in TIFF0007663616000055.tif12159.

[0188] Anti-DC ASGPR mAb [manti-ASGPR-4G2.2-Hv-V-hIgG4H-C];SEQ ID NO:57: TIFF0007663616000056.tif64161.

[0189] The above sequence is a chimera of the heavy chain variable region of mAb 4G2.2 and the C region of hIgG4.

[0190] The heavy chain variable region of mAb 4G2.2 is represented by SEQ ID NO:58: Shown in TIFF0007663616000057.tif20160.

[0191] [mAnti-ASGPR-4G2.2-Kv-V-hIgGK-C] is the corresponding light chain chimera; SEQ ID NO:59: The file is TIFF0007663616000058.tif27160.

[0192] The light chain variable region of mAnti-ASGPR-4G2.2-Kv-V-hIgGK-C is SEQ ID NO:60: Shown in TIFF0007663616000059.tif20159.

[0193] [manti-ASGPR-5F10H-LV-hIgG4H-C](SEQ ID NO:61): TIFF0007663616000060.tif63160.

[0194] The above sequence is a chimera of the heavy chain variable region of mAb 5F10 and the C region of hIgG4.

[0195] The heavy chain variable region of mAb 5F10 is SEQ ID NO:62: Shown in TIFF0007663616000061.tif20160.

[0196] [mAnti-ASGPR-5F10K-LV-hIgGK-C] is the corresponding light chain chimera; SEQ ID NO:63: The file is TIFF0007663616000062.tif27160.

[0197] The light chain variable region of mAnti-ASGPR-5F10K-LV-hIgGK-C is SEQ ID NO:64: Shown in TIFF0007663616000063.tif20160.

[0198] [manti-ASGPR-1H11H-V-hIgG4H-C](SEQ ID NO:65): TIFF0007663616000064.tif64160.

[0199] The above sequence is a chimera of the heavy chain variable region of mAb 1H11 and the C region of hIgG4.

[0200] The heavy chain variable region of mAb 1H11 is represented by SEQ ID NO:66: Shown in TIFF0007663616000065.tif20159.

[0201] [mAnti-ASGPR-1H11K-LV-hIgGK-C] is the corresponding light chain chimera, SEQ ID NO:67: TIFF0007663616000066.tif27160.

[0202] The light chain variable region of mAnti-ASGPR-1H11K-LV-hIgGK-C is SEQ ID NO:68: Shown in TIFF0007663616000067.tif19159.

[0203] mAnti-hASGPR-6.3H9.1D11H (heavy chain) SEQ ID NO:69: TIFF0007663616000068.tif64160.

[0204] mAnti-hASGPR_6.3H9.1D11K (light chain) SEQ ID NO:70: TIFF0007663616000069.tif34160.

[0205] mAnti-hASGPR-5H8.1D4H (heavy chain) SEQ ID NO:71: TIFF0007663616000070.tif56161.

[0206] mAnti-hASGPR-5H8.1D4K (light chain) SEQ ID NO:72: TIFF0007663616000071.tif34161.

[0207] Anti-CD40 mAb Anti-CD40-12B4.2C10, heavy chain, SEQ ID NO:73: TIFF0007663616000072.tif27160.

[0208] Anti-CD40-12B4.2C10, light chain, SEQ ID NO:74: TIFF0007663616000073.tif35160.

[0209] Anti-CD40-12B4.2C10, light chain-alternative clone (17K6), SEQ ID NO:75: TIFF0007663616000074.tif34160.

[0210] Anti-CD40_11B6.1C3, heavy chain, SEQ ID NO:76: TIFF0007663616000075.tif27160.

[0211] Anti-CD40_11B6.1C3, light chain, SEQ ID NO:77: TIFF0007663616000076.tif34161.

[0212] Anti-LOX-1 Ab [manti-LOX-1-11C8H-LV-hIgG4H-C], heavy chain, SEQ ID NO:78: TIFF0007663616000077.tif64161.

[0213] The heavy chain variable region of Ab 11C8 is SEQ ID NO:79: Shown in TIFF0007663616000078.tif20160.

[0214] [manti-LOX-1-11C8K-LV-hIgGK-C], light chain, SEQ ID NO:80: TIFF0007663616000079.tif34160.

[0215] The light chain variable region of Ab 11C8 is SEQ ID NO:81: Shown in TIFF0007663616000080.tif20159.

[0216] [mAnti-LOX-1-10F9H-LV-hIgG4H-C], heavy chain, SEQ ID NO:82: TIFF0007663616000081.tif56160.

[0217] The heavy chain variable region of Ab 10F9 is SEQ ID NO:83: Shown in TIFF0007663616000082.tif20160.

[0218] [mAnti-LOX_1-10F9K-LV-hIgGK-C], light chain, SEQ ID NO:84: TIFF0007663616000083.tif27160.

[0219] The light chain variable region of Ab 10F9 is SEQ ID NO:85: Shown in TIFF0007663616000084.tif20160.

[0220] [manti-LOX-1-15C4H-LV-hIgG4H-C], heavy chain, SEQ ID NO:86: TIFF0007663616000085.tif63161.

[0221] The heavy chain variable region of Ab 15C4 is SEQ ID NO:87: Shown in TIFF0007663616000086.tif20160.

[0222] [manti-LOX-1-15C4K-LV-hIgGK-C], light chain, SEQ ID NO:88: TIFF0007663616000087.tif27160.

[0223] The light chain variable region of Ab 15C4 is SEQ ID NO:89: Shown in TIFF0007663616000088.tif20160.

[0224] Anti-DCIR Ab Anti-DCIR_24A5.4A5_H-V-hIgG4H-C, heavy chain, SEQ ID NO:90: TIFF0007663616000089.tif71161.

[0225] Anti-DCIR_24A5.4A5_K-V-hIgGK-C, light chain, SEQ ID N0:91: TIFF0007663616000090.tif34161.

[0226] Anti-DCIR_24E7.3H9_H-V-hIgG4H-C, heavy chain, SEQ ID NO:92: TIFF0007663616000091.tif64160。

[0227] Anti-DCIR_24E7.3H9_K-V-hIgGK-C, light chain, SEQ ID NO:93: TIFF0007663616000092.tif34161。

[0228] Anti-DCIR_29E9.2E2_H-VhIgG4H-C, heavy chain, SEQ ID NO:94: TIFF0007663616000093.tif71161。

[0229] Anti-DCIR_29E9.2E2_K-V-hIgGK-C, light chain, SEQ ID NO:95: TIFF0007663616000094.tif34161。

[0230] Anti-DCIR_29G10.3D9_H-V-hIgG4H-C, heavy chain, SEQ ID NO:96: TIFF0007663616000095.tif64161。

[0231] Anti-DCIR_29G10.3D9_K-Var1-V-hIgGK-C, light chain, SEQ ID NO:97: TIFF0007663616000096.tif34161。

[0232] Anti-DCIR_29G10.3D9_K-Var2-V-hIgGK-C, light chain, SEQ ID NO:98: TIFF0007663616000097.tif34160。

[0233] Anti-DCIR_31A6.1F5_H-var2-V-hIgG4H-C, heavy chain, SEQ ID NO:99: TIFF0007663616000098.tif64161.

[0234] Anti-DCIR_31A6.1F5_K-var2-V-hIgGK-C, light chain, SEQ ID NO:100: TIFF0007663616000099.tif34161.

[0235] Anti-DCIR_3C2.2D9_H-LV-hIgG4H-C, heavy chain, SEQ ID NO:101: TIFF0007663616000100.tif71161.

[0236] Anti-DCIR_3C2.2D9_K-LV-hIgGK-C, light chain, SEQ ID NO:102: TIFF0007663616000101.tif34160.

[0237] Anti-DCIR_6C8.1G9_H-V-hIgG4H-C, heavy chain, SEQ ID NO:103: TIFF0007663616000102.tif63161.

[0238] Anti-DCIR_6C8.1G9_K-V-hIgGK-C, light chain, SEQ ID NO:104: TIFF0007663616000103.tif41161.

[0239] Anti-DCIR2C9H-LV-hIgG4H-V-hIgG4H-C, heavy chain, SEQ ID NO: 105: TIFF0007663616000104.tif64160.

[0240] Anti-DCIR_2C9K-V-hIgGK-C, light chain, SEQ ID NO:106: TIFF0007663616000105.tif34160.

[0241] Anti-Langerin Ab Anti-Langerin-15B10H-LV-hIgG4H-C, heavy chain, SEQ ID NO:107: TIFF0007663616000106.tif64160.

[0242] The heavy chain variable region of Ab 15B10 is SEQ ID NO:108: Shown in TIFF0007663616000107.tif13159.

[0243] Anti-Langerin-15B10K-LV-hIgGK-C, light chain, SEQ ID NO: 109: TIFF0007663616000108.tif34161.

[0244] The light chain variable region of Ab 15B10 is SEQ ID NO:110: Shown in TIFF0007663616000109.tif12159.

[0245] Anti-Langerin-2G3H-LV-hIgG4H-C, heavy chain, SEQ ID NO:111: TIFF0007663616000110.tif64161.

[0246] The heavy chain variable region of Ab 2G3 is SEQ ID NO:112: Shown in TIFF0007663616000111.tif12160.

[0247] Anti-Langerin-2G3L-LV-hIgGK-C, light chain, SEQ ID NO:113: TIFF0007663616000112.tif35161.

[0248] The light chain variable region of Ab 2G3 is SEQ ID NO:114: Shown in TIFF0007663616000113.tif12160.

[0249] III. Interleukin 10 (IL-10) Interleukin-10 (IL-10), also known as human cytokine suppressor factor (CSIF), is an anti-inflammatory cytokine. In humans, IL-10 is encoded by the IL10 gene. The mRNA sequence of human IL-10 is represented by accession number NM_000572.2. The amino acid sequence of human IL-10 is represented by accession number NP_000563.1 and SEQ ID NO: 5. Sequences associated with these accession numbers are incorporated by reference for any purpose.

[0250] In some embodiments, the APC targeting antibody or fragment thereof is operably linked to an IL-10 polypeptide comprising a sequence corresponding to the protein sequence of NCBI Accession No. NP_000563.1. In some embodiments, the IL-10 polypeptide comprises the amino acid sequence of SEQ ID NO:5 or a fragment thereof.

[0251] IV. Antigen Certain aspects of the present disclosure include methods and compositions relating to antigenic components, generally referred to as antigens, including segments, fragments, or epitopes of polypeptides, peptides, nucleic acids, carbohydrates, lipids, and other molecules that induce or induce an antigenic response.In one embodiment, the antigen is a peptide.In particular, antigens that induce cell destruction through an immune response, or antigenic segments or fragments of such antigens, can be identified and used in the methods and compositions described herein.

[0252] Antigens related to various diseases and disorders are known in the art.It is envisioned that any antigen can be used in the methods and compositions described herein.In certain aspects, antigen is involved in the pathogenesis of autoimmune disease, allergic disease or inflammatory disease known in the art and / or described herein.

[0253] In certain aspects, the antigen is one known in the art to be involved in rheumatoid arthritis, allergies, asthma, systemic juvenile arthritis, inflammatory bowel disease, systemic lupus erythematosus, type 1 diabetes, and Crohn's disease.

[0254] V. Peptide Components and Proteinaceous Compositions Polypeptides and peptides can be modified by various amino acid deletions, insertions, and / or substitutions. In certain embodiments, modified polypeptides and / or peptides can modulate immune responses in subjects. As used herein, "protein" or "polypeptide" or "peptide" refers to a molecule containing at least five amino acid residues. In some embodiments, wild-type versions of proteins or peptides are used, but in many embodiments, modified proteins or polypeptides are used to generate the antibody conjugates described herein. "Modified protein" or "modified polypeptide" or "modified peptide" refers to a protein or polypeptide whose chemical structure, particularly its amino acid sequence, has been modified compared to that of a wild-type protein or polypeptide.

[0255] Peptides include those known to be specific to cancer cells or precancerous cells in the body. These peptides may be associated with the APC-targeting antibodies described herein. Administration of these peptide combinations includes administering a population of antibody conjugates to which multiple peptides are attached, and / or administering a population of multiple conjugates, each with a specific peptide attached, or a combination of such conjugates, including nanoparticles to which one, two, three, four, five, six, or more peptides are attached, to an APC-targeting antibody, its antigen-binding fragment, or IL-10 protein.

[0256] Proteinaceous compositions can be produced by any method known to those skilled in the art, including (i) expression of proteins, polypeptides, or peptides through standard molecular biology techniques, (ii) isolation of proteinaceous compounds from natural sources, or (iii) chemical synthesis of proteinaceous substances. Nucleotide as well as protein, polypeptide, and peptide sequences for various genes have been previously disclosed and can be found in generally recognized electronic databases. One such database is the GenBank and GenPept databases of the National Center for Biotechnology Information (available on the World Wide Web at ncbi.nlm.nih.gov / ). The coding regions of these genes, in whole or in part, can be amplified and / or expressed using the techniques disclosed herein or as would be known to those skilled in the art.

[0257] The amino acid sequence variants of the antigenic epitopes and other polypeptides of these compositions can be substitutional, insertional or deletion variants. Modifications in a polypeptide can result in a change in the amino acid sequence of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69 of a peptide or polypeptide compared to the wild type. , 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135 , 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 1 94, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252,253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346、347、348、349、350、351、352、353、354、355、356、357、358、359、360、361、362、363、364、365、366、367、368、369、370、371、372、373、374、375、376、 377, 378, 379, 380, 381, 382, ​​383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500,The amino acid sequence may affect one or more non-contiguous or contiguous amino acids. Peptides or polypeptides that produce an immune response are contemplated for use in the embodiments.

[0258] Deletion mutants typically lack one or more residues of the native or wild-type amino acid sequence. Individual residues may be deleted, or several consecutive amino acids may be deleted. A stop codon may be introduced (by substitution or insertion) into the encoding nucleic acid sequence, resulting in a truncated protein. Insertion mutants typically involve the addition of material at a non-terminal position in the polypeptide. This may involve the insertion of one or more residues. Terminal additions, called fusion proteins, may also occur.

[0259] Substitutional variants typically involve the exchange of one amino acid for another at one or more sites in the protein and can be designed to modulate one or more properties of the polypeptide, with or without loss of other functions or properties. Substitutions can be conservative, i.e., one amino acid is replaced with one of similar shape and charge. Conservative substitutions are well known in the art and include, for example, the following changes: alanine to serine; arginine to lysine; asparagine to glutamine or histidine; aspartic acid to glutamic acid; cysteine ​​to serine; glutamine to asparagine; glutamic acid to aspartic acid; glycine to proline; histidine to asparagine or glutamine; isoleucine to leucine or valine; leucine to valine or isoleucine; lysine to arginine; methionine to leucine or isoleucine; phenylalanine to tyrosine, leucine, or methionine; serine to threonine; threonine to serine; tryptophan to tyrosine; tyrosine to tryptophan or phenylalanine; and valine to isoleucine or leucine. Alternatively, substitutions may be non-conservative, such that the function or activity of the polypeptide or peptide, such as binding strength or affinity for a cellular receptor, is affected. Non-conservative changes typically involve substituting a residue with a chemically dissimilar residue, such as substituting a polar or charged amino acid for a nonpolar or uncharged amino acid, or vice versa.

[0260] The proteins may be recombinant or synthesized in vitro, or the recombinant proteins may be isolated from bacteria or other host cells.

[0261] The term "functionally equivalent codon" is used herein to refer to codons that encode the same amino acid, such as the six codons for arginine or serine, and also refers to codons that encode biologically equivalent amino acids.

[0262] It will also be understood that the amino acid and nucleic acid sequences may contain additional residues, such as additional N- or C-terminal amino acids or 5' or 3' nucleic acid sequences, respectively, and still be essentially as set forth in one of the sequences disclosed herein, so long as the sequence meets the above criteria, including maintenance of biological protein activity (e.g., immunogenicity). The addition of terminal sequences particularly applies to nucleic acid sequences, which may include various non-coding sequences adjacent, for example, to either the 5' or 3' portion of the coding region.

[0263] In the composition embodiment, it is contemplated that there is about 0.001 mg to about 10 mg of total protein per ml.Thus, the concentration of protein in the composition may be about 0.001, 0.010, 0.050, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 50, 100 μg / ml or 0.001, 0.010, 0.050, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, 2.0, 2.5 , 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 50, 100 mg / ml or more, at least about 0.001, 0.010, 0.050, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 50, 100 μg / ml or more 1, 0.010, 0.050, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 50, 100 mg / ml or more, or up to about 0.001, 0.010, 0.050, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4. 5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 50, 100 μg / ml or 0.001, 0.010, 0.050, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 50, 100 mg / ml or more (or any range derivable therein).

[0264] An embodiment optionally includes the administration of an APC-targeting antibody. In some embodiments, the method and composition further include an antigen. U.S. Patent No. 4,554,101 (Hopp), incorporated herein by reference, teaches the identification and preparation of epitopes from primary amino acid sequences based on hydrophilicity. The method disclosed in Hopp allows those skilled in the art to identify potential epitopes within amino acid sequences and confirm their immunogenicity. Numerous scientific publications have also addressed the prediction of secondary structure and the identification of epitopes from the analysis of amino acid sequences (Chou & Fasman, 1974a,b; 1978a,b; 1979). Any of these can be used as desired to supplement the teachings of Hopp in U.S. Patent No. 4,554,101.

[0265] VI. Pharmaceutical Compositions Embodiments include methods and compositions for increasing an immune response in a subject in need thereof, including compositions that can be used to induce or modify an immune response to an antigen, e.g., a polypeptide, peptide, carbohydrate, lipid, or other molecule or molecular fragment, and to developing a condition or disease associated with such antigen.

[0266] It is contemplated that the APC-targeting antibody or antigen-binding fragment thereof (and optionally linked to an antigen, and optionally IL-10) may be administered with additional adjuvants known in the art, such as TLR agonists. TLR agonists include agonists for TLR1 (e.g., peptidoglycan or triacyl lipoprotein), TLR2 (e.g., lipoteichoic acid; peptidoglycan from Bacillus subtilis, Escherichia coli 0111:B4, E. coli K12, or Staphylococcus aureus); typical lipopolysaccharides (LPS), such as Leptospirosis LPS and Porphyromonas gingivalis LPS; synthetic diacylated lipoproteins, such as FSL-1 or Pam2CSK4; Mycobacterium smegmatis (M.lipoarabinomannan or lipomannan from P. smegmatis; triacylated lipoproteins, such as Pam3CSK4; lipoproteins, such as MALP-2 and MALP-404 from mycoplasmas; Borrelia burgdorferi OspA; porins from Neisseria meningitidis or Haemophilus influenza; Propionibacterium acnes antigen mixture; Yersinia LcrV; lipomannans from Mycobacterium or Mycobacterium tuberculosis; Trypanosoma cruzi GPI anchor; Schistosoma mansoni lysophosphatidylserine; Leishmania major lipophosphoglycan (LPG); Plasmodium falciparum falciparum glycophosphatidylinositol (GPI); zymosan; antigen mixtures from Aspergillus fumigatus or Candida albicans; and measles hemagglutinin, TLR3 (e.g., double-stranded) RNA, polyadenylic-polyuridylic acid (poly(A:U)); polyinosinic-polycytidylic acid (poly(I:C)); polyinosinic-polycytidylic acid high molecular weight (poly(I:C) HMW); and polyinosinic-polycytidylic acid low molecular weight (poly(I:C) LMW)), TLR4 (e.g., LPS from Escherichia coli and Salmonella species); TLR5 (e.g., Bacillus subtilis, Pseudomonas aeruginosa, or Salmonella typhimurium (S.Typhimurium (Typhimurium) derived flagellin), TLR8 (e.g., single-stranded RNA, e.g., ssRNA with 6UUAU repeats, RNA homopolymer (ssPolyU naked), HIV-1 LTR-derived ssRNA (ssRNA40), or ssRNA with two GUCCUUCAA repeats (ssRNA-DR)), TLR7 (e.g., the imidazoquinoline compounds Imiquimod, Imiquimod VacciGrade™, Gardiquimod VacciGrade™, or Gardiquimod™; the adenine analog CL264; the base analog CL307; the guanosine analog loxoribine; TLR7 / 8 (e.g., the thiazoquinoline compound CL075; the imidazoquinoline compounds CL097, R848, or R848 VacciGrade™), TLR9 (e.g., CpG ODN); and TLR11 (e.g., Toxoplasma gondii profilin). In certain embodiments, the TLR is a specific agonist listed above. In further embodiments, the TLR specifically stimulates either one TLR or two TLRs.

[0267] In certain embodiments, the methods and compositions specifically exclude the administration of TLR ligands and / or agonists.

[0268] Administration of the compositions will typically be via any common route, including oral, parenteral, orthotopic, intradermal, subcutaneous, intramuscular, intraperitoneal, intranasal, inhalation, nebulizer, or intravenous injection. In certain embodiments, vaccine compositions may be inhaled (e.g., U.S. Pat. No. 6,651,655, specifically incorporated by reference). Other formulations suitable for other modes of administration include oral formulations. Oral formulations contain commonly used excipients such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. These compositions take the form of solutions, suspensions, tablets, pills, capsules, sustained-release formulations, or powders and contain about 10% to about 95%, preferably about 25% to about 70%, of the active ingredient.

[0269] Typically, compositions are administered in a manner compatible with the dosage formulation, and in such amount as will be therapeutically effective and immunomodulatory. The amount administered will depend on the subject being treated. Precise amounts of active ingredient required to be administered depend on the judgment of the practitioner.

[0270] The mode of application may vary widely. Any conventional method for administering a vaccine may be applied. These conventional methods may include oral application on a solid physiologically acceptable base or in a physiologically acceptable dispersion, parenterally, by injection, etc. The dosage of the pharmaceutical composition will depend on the route of administration and will vary depending on the size and health of the subject.

[0271] In many cases, multiple administrations are desirable, up to about 3, 4, 5, 6, 7, 8, 9, 10, or more, or at least about 3, 4, 5, 6, 7, 8, 9, 10, or more. Administrations may range from 2 days to 12 weeks apart, more usually 1 to 2 weeks apart. Following the course of administration, assays for reactive immune responses and T cell activity can be performed.

[0272] The phrase "pharmaceutically acceptable" or "pharmacologically acceptable" refers to molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to animals or humans. As used herein, "pharmaceutically acceptable carriers" include any and all solvents, dispersion media, coating agents, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in immunogenic and therapeutic compositions is contemplated.

[0273] Antibody or antigen-binding fragment can be formulated for parenteral administration, for example, can be formulated for injection via intravenous, intradermal, intramuscular, subcutaneous, or even intraperitoneal route.In one specific embodiment, the composition is administered by intradermal injection.In a further embodiment, the composition is administered by intravenous injection.In view of the present disclosure, it is believed that the preparation of aqueous compositions containing APC targeting antibodies that modify the immune status of subjects will be known to those skilled in the art.Typically, such compositions can be prepared as injections either as liquid solutions or suspensions; they can also be prepared as solid forms suitable for preparing solutions or suspensions by adding liquid before injection; and the preparations can also be emulsified.

[0274] Pharmaceutical dosage forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations containing sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the dosage form must be sterile and fluid to the extent that it can be easily syrup-injected. It must also be stable under the conditions of manufacture and storage and preserved against the contaminating action of microorganisms such as bacteria and fungi.

[0275] The compositions can be formulated in neutral or salt form. Pharmaceutically acceptable salts include acid addition salts (formed with the free amino groups of the protein) and are formed with inorganic acids such as hydrochloric acid or phosphoric acid, or organic acids such as acetic acid, oxalic acid, tartaric acid, mandelic acid, etc. Salts formed with free carboxyl groups can also be derived from inorganic bases such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, or ferric hydroxide, and organic bases such as isopropylamine, trimethylamine, histidine, procaine, etc.

[0276] The carrier may also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. Prevention of microbial activity can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it is preferable to include an isotonic agent, for example, sugar or sodium chloride. Prolonged absorption of injectable compositions can be achieved by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0277] Sterile injectable solution can be prepared by incorporating the required amount of active compound in a suitable solvent with various other ingredients as listed above, and then sterilizing as needed.Generally, dispersion is prepared by incorporating various sterilized active ingredients into a sterile vehicle containing a basic dispersion medium and the other required ingredients listed above.For sterile powders for preparing sterile injectable solution, the preferred preparation method is vacuum drying and freeze-drying, which can obtain a powder of active ingredient and any additional desired ingredients from the solution that has been previously sterile-filtered.

[0278] The effective amount of a therapeutic or prophylactic composition is determined based on the intended goal. The term "unit dose" or "dosage" refers to a physically discrete unit suitable for use in a subject, each unit containing a predetermined amount of the composition calculated to produce the desired response discussed above in conjunction with its administration, i.e., an appropriate route and administration regimen. The amount administered, both according to the number of treatments and the unit dose, depends on the desired outcome and / or protection. The precise amount of the composition also depends on the judgment of the physician and is unique to each individual. Factors affecting the dosage include the subject's physical and clinical condition, the route of administration, the intended goal of treatment (alleviation of symptoms or cure), and the efficacy, stability, and toxicity of the particular composition. Upon formulation, a solution will be administered in a manner compatible with the dosage formulation and in an amount that will be therapeutically or prophylactically effective. The formulations are easily administered in a variety of dosage forms, such as the types of injection solutions described above.

[0279] VII. In Vitro or Ex Vivo Administration As used herein, the term in vitro administration refers to manipulations performed on cells removed from or outside a subject, including, but not limited to, cells in culture. The term ex vivo administration refers to cells that are manipulated in vitro and then administered to a subject. The term in vivo administration includes all manipulations performed within a subject, including administration.

[0280] In certain aspects, the composition can be administered in vitro, ex vivo, or in vivo. In certain in vitro embodiments, isolated immune cells are incubated with the compositions described herein. For example, isolated APCs can be incubated with the antibodies or antibody conjugates described herein. These cells can then be used for in vitro analysis, or alternatively for ex vivo administration.

[0281] VIII. Therapeutic applications The methods include the treatment of inflammatory and autoimmune disorders, and may be used on individuals who have tested positive for such disorders or who are considered to be at risk for developing such conditions or related conditions.

[0282] The antibodies or antigen-binding fragments of the present disclosure (in some embodiments, conjugated to IL-10) can be administered to induce or modify immune responses in individuals who have, are suspected of having, or are at risk for developing an allograft-associated autoimmune condition or autoimmune complication. These methods may be used on individuals who have tested positive for autoreactivity or alloreactivity or who are considered to be at risk for developing such conditions or related conditions.

[0283] The methods described herein are particularly useful for treating or preventing disorders for which antigenic determinants have not been fully characterized. Such disorders include, for example, rheumatoid arthritis, allergies, asthma, systemic juvenile arthritis, inflammatory bowel disease, and Crohn's disease. The methods described herein are also particularly useful for disorders such as GVHD and transplant rejection, because the antigenic determinants for such diseases are unknown or may vary depending on the tissue and / or the individual from which the tissue is obtained.

[0284] It is postulated that targeting dendritic cells (eg, with anti-DC-ASGPR antibodies) will inhibit autoimmune disease but not prevent pathogen-specific T cell responses.

[0285] Embodiments can be used to treat or ameliorate numerous immune-mediated, inflammatory, or autoimmune-inflammatory diseases, such as allergies, asthma, diabetes (e.g., type 1 diabetes), transplant rejection, etc. Examples of such diseases or disorders also include, but are not limited to, arthritis (rheumatoid arthritis, such as acute arthritis, chronic rheumatoid arthritis, gout or gouty arthritis, acute gouty arthritis, acute immunological arthritis, chronic inflammatory arthritis, osteoarthritis, type II collagen-induced arthritis, infectious arthritis, Lyme arthritis, proliferative arthritis, psoriatic arthritis, Still's disease, spondyloarthritis, and juvenile-onset rheumatoid arthritis, osteoarthritis, progressive chronic arthritis, osteoarthritis, primary chronic polyarthritis, reactive arthritis, and ankylosing spondylitis), inflammatory hyperproliferative skin diseases, psoriasis, such as plaque psoriasis,psoriasis), guttate psoriasis, pustular psoriasis, and nail psoriasis; atopy, including atopic diseases such as hay fever and Job's syndrome; contact dermatitis, chronic contact dermatitis, exfoliative dermatitis, allergic dermatitis, allergic contact dermatitis, dermatitis herpetiformis, nummular dermatitis, seborrheic dermatitis, nonspecific dermatitis, primary irritant contact dermatitis, and atopic dermatitis; x-linked hyper-IgM syndrome; allergies allergic intraocular inflammatory disease, urticaria, such as chronic allergic urticaria and chronic idiopathic urticaria including chronic autoimmune urticaria, myositis, polymyositis / dermatomyositis, juvenile dermatomyositis, toxic epidermal necrolysis, scleroderma (including systemic sclerosis), sclerosis, such as systemic sclerosis, multiple sclerosis (MS), such as spino-optical MS, primary progressive MS (PPMS) and relapsing MS and autoimmune diseases such as remitting multiple sclerosis (RRMS), progressive systemic sclerosis, atherosclerosis, arteriosclerosis, disseminated sclerosis, ataxic sclerosis, neuromyelitis optica (NMO), inflammatory bowel disease (IBD) (e.g., Crohn's disease), autoimmune-mediated gastrointestinal diseases, colitis, such as ulcerative colitis, colonic ulcer, microscopic colitis, collagenous colitis, polypoid colitis, necrotizing enterocolitis, and transmural colitis, and autoimmune diseases such as ulcerative colitis, colonic ulcer, microscopic colitis, collagenous colitis, polypoid colitis, necrotizing enterocolitis, and transmural colitis. Infectious inflammatory bowel disease), enteritis, pyoderma gangrenosum, erythema nodosum, primary sclerosing cholangitis, respiratory distress syndromes including adult or acute respiratory distress syndrome (ARDS), meningitis, inflammation of all or part of the uvea, iritis, choroiditis, autoimmune blood disorders, rheumatoid spondylitis, rheumatoid synovitis, hereditary angioedema, cranial nerve damage such as in meningitis, herpes gestationis, pemphigoid of gestationis, scrotal pruritus (pruritis)scroti), autoimmune premature ovarian failure, sudden hearing loss due to autoimmune conditions, IgE-mediated diseases such as anaphylaxis and allergic and atopic rhinitis, encephalitis such as Rasmussen encephalitis and limbic and / or brainstem encephalitis, uveitis such as anterior uveitis, acute anterior uveitis, granulomatous uveitis, non-granulomatous uveitis, phacoantigenic uveitis, posterior uveitis, or autoimmune uveitis, nephrotic uveitis, Glomerulonephritis (GN) with or without leucocerebellar syndrome, e.g., chronic or acute glomerulonephritis, e.g., primary GN, immune-mediated GN, membranous GN (membranous nephropathy), idiopathic membranous GN or idiopathic membranous nephropathy, membranous or membranous proliferative GN (MPGN), including types I and II, and rapidly progressive GN, proliferative nephritis, autoimmune polyendocrine deficiency, balanitis, including plasma cell balanitis, balanoposthitis, erythema annulare centrifugally, erythema dyschromicus perstans, erythema multiforme (erythema multiforme), multiform), granuloma annulare, lichen nitidus, lichen sclerosus and atrophicus, lichen simplex chronicus, lichen spinous, lichen planus, ichthyosis lamellar, epidermolytic hyperkeratosis, premalignant keratosis, pyoderma gangrenosum, allergic conditions and responses, allergic reactions, eczema including allergic or atopic eczema, asteatotic eczema, dyshidrotic eczema, and vesicular palmoplantar eczema, asthma, e.g., asthma bronchitisconditions involving T cell infiltration and chronic inflammatory responses, such as bronchial asthma, bronchial asthma, and autoimmune asthma; immune responses to foreign antigens, such as fetal ABO blood group during pregnancy; chronic pulmonary inflammatory disease; autoimmune myocarditis; leukocyte adhesion deficiency; lupus nephritis; lupus encephalitis; pediatric lupus; non-renal lupus; extrarenal lupus; discoid lupus; and discoid lupus erythematosus; lupus alopecia; systemic lupus erythematosus (SLE), including cutaneous SLE, or subacute cutaneous SLE, neonatal lupus syndrome (NLE), and disseminated lupus erythematosus; pediatric insulin-dependent diabetes mellitus (IDDM), and juvenile-onset (type I) diabetes mellitus, including adult-onset diabetes mellitus (type II diabetes) and autoimmune diabetes. Also contemplated are immune responses associated with acute and delayed hypersensitivity mediated by cytokines and T lymphocytes, granulomatous diseases including lymphomatoid granulomatosis, Wegener's granulomatosis, agranulocytosis, vasculitis, including large vasculitis (including polymyalgia rheumatica and giant cell (Takayasu) arteritis), medium vasculitis (including Kawasaki disease and polyarteritis nodosa / periarteritis nodosa), microscopic polyarteritis, immunovasculitis, CNS vasculitis, cutaneous vasculitis, hypersensitivity vasculitis, necrotizing vasculitis, such as systemic necrotizing vasculitis, and ANCA-associated vasculitis, such as Churg-Strauss vasculitis or syndrome (CSS) and ANCA-associated small vasculitis, temporal arteritis, aplastic anemia, autoimmune aplastic anemia, Coombs' Hemolytic anemia or immune hemolytic anemia including autoimmune hemolytic anemia (AIHA), Addison's disease, immune neutropenia, pancytopenia, leukopenia, diseases with leukocyte leakage, CNS inflammatory disorders, Alzheimer's disease, Parkinson's disease, multiple organ injury syndromes such as those secondary to sepsis, trauma or hemorrhage, antigen-antibody complex mediated diseases, antiglomerular basement membrane disease, antiphospholipid antibody syndrome, allergic neuritis, Behcet's disease / syndrome, Castleman syndrome, Goodpasture's syndrome, Raynaud's syndrome, Sjögren's syndrome, Stevens-Johnson syndrome, pemphigoid such as bullous pemphigoid and cutaneous pemphigoid, pemphigus (pemphigus vulgaris, pemphigus foliaceus, pemphigus mucous membrane pemphigoid)mucusmembrane pemphigoid, and pemphigus erythematosus), autoimmune polyendocrinopathy, Reiter's disease or syndrome, burns, pre-eclampsia, immune complex disorders such as immune complex nephritis, antibody-mediated nephritis, polyneuropathy, chronic neuropathy such as IgM polyneuropathy or IgM-mediated neuropathy, autoimmune or immune-mediated thrombocytopenia such as idiopathic thrombocytopenic purpura (ITP) including chronic or acute ITP, scleritis such as idiopathic keratoscleritis, episcleritis, autoimmune diseases of the testes and ovaries including autoimmune orchitis and oophoritis, primary hypothyroidism, hypoparathyroidism, thyroid adenitis, such as autoimmune thyroiditis, Hashimoto's disease, chronic thyroiditis (Hashimoto's thyroiditis), or subacute thyroiditis; autoimmune thyroid diseases, idiopathic hypothyroidism, autoimmune endocrine diseases including Graves' disease; polyglandular syndromes, such as autoimmune polyglandular syndrome (or polyendocrinopathy syndrome); paraneoplastic syndromes, such as neurological paraneoplastic syndromes, such as Lambert-Eaton myasthenic syndrome or Eaton-Lambert syndrome, stiff-man or stiff-person syndrome; encephalomyelitis, such as allergic encephalomyelitis or allergic encephalomyelitis allergic amyloidosis) and experimental allergic encephalomyelitis (EAE), myasthenia gravis, e.g., thymoma-associated myasthenia gravis, cerebellar degeneration, neuromyotonia, opsoclonus or opsoclonus-myoclonus syndrome (OMS), and sensory neuropathy, multifocal motor neuropathy, Sheehan's syndrome, autoimmune hepatitis, chronic hepatitis, lupoid hepatitis, giant cell hepatitis, chronic active hepatitis or autoimmune chronic active hepatitis, lymphocytic interstitial pneumonia (LIP), bronchiolitis obliterans (non-graft) vs.NSIP, Guillain-Barré syndrome, Berger's disease (IgA nephropathy), idiopathic IgA nephropathy, linear IgA dermatosis, acute febrile neutrophilic dermatosis, subcorneal pustular dermatitis, transient acantholytic dermatosis, liver cirrhosis, e.g., primary biliary cirrhosis and pneumonocirrhosis, autoimmune enteropathy syndrome, celiac disease or coeliac disease, celiac sprue (gluten-induced enteropathy) , refractory sprue, idiopathic sprue, cryoglobulinemia, amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease), coronary artery disease, autoimmune ear diseases such as autoimmune inner ear disease (AIED), autoimmune hearing loss, polychondritis such as refractory or relapsing or relapsing polychondritis, pulmonary alveolar proteinosis, Cogan's syndrome / non-syphilitic interstitial keratitis, Bell's palsy, Sweet's disease / syndrome, autoimmune rosacea, varicella zoster rash-related pain, amyloidosis, non-cancerous lymphocytosis, primary lymphocytosis, such as monoclonal B-cell lymphocytosis (e.g., benign monoclonal gammopathy and monoclonal gammopathy of undetermined significance, MGUS), peripheral neuropathies, paraneoplastic syndromes, channelopathies, such as epilepsy, migraine, cardiac arrhythmias, muscle disorders, hearing loss, blindness, periodic paralysis, and CNS disorders Channelopathies, etc., autism, inflammatory myopathies, focal or segmental glomerulosclerosis (FSGS), endocrine ophthalmopathy, uveoretinitis, chorioretinitis, autoimmune liver disorders, fibromyalgia, polyendocrine glandular deficiency, Schmidt's syndrome, adrenal inflammation, gastrotrophy, presenile dementia, demyelinating diseases, such as autoimmune demyelinating diseases and chronic inflammatory demyelinating polyneuropathy, Dressler's syndrome, alopecia areatagreata), alopecia totalis, CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia), male and female autoimmune infertility due to antisperm antibodies, mixed connective tissue disease, Chagas' disease, rheumatic fever, recurrent miscarriage, farmer's lung, erythema multiforme, postcardiotomy syndrome, Cushing's syndrome, bird breeder's lung, allergic granulomatous vasculitis, benign lymphocytic vasculitis, Alport's syndrome, alveolitis, e.g., allergic alveolitis and and fibrosing alveolitis, interstitial lung disease, transfusion reactions, leprosy, malaria, parasitic diseases such as leishmaniasis, kypanosomiasis, schistosomiasis, ascariasis, aspergillosis, Sumpter's syndrome, Caplan's syndrome, dengue fever, endocarditis, endomyocardial fibrosis, diffuse interstitial pulmonary fibrosis, interstitial pulmonary fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, endophthalmitis, erythema elevatum (erythema elevata) elevatum et diutinum, erythroblastosis fetalis, eosinophilic fasciitis, Charmant's syndrome, Felty's syndrome, filariasis, cyclitis, such as chronic cyclitis, heterochronic cyclitis, iridocyclitis (acute or chronic), or Fuchs' cyclitis, Henoch-Schönlein purpura, human immunodeficiency virus (HIV) infection, SCID, acquired immune deficiency syndrome (AIDS), echovirus infection, sepsis, endotoxemia, pancreatitis, thyrotoxicosis, parvovirus infection, rubella virus infection, post-vaccination syndrome, congenital rubella infection, Epstein-Barr virus infection, mumps, Evans' syndrome, autoimmune dysgonadism, Sydenham's chorea, post-streptococcal nephritis, thromboangitis obliterans ubiterans), thyrotoxicosis, spinal cord aplasia, choroiditis, giant cell polymyalgia (gianT cellpolymyalgia, chronic hypersensitivity pneumonitis, keratoconjunctivitis sicca, epidemic keratoconjunctivitis, idiopathic nephritic syndrome, minimal change nephropathy, benign familial and ischemia-reperfusion injury, transplanted organ reperfusion, retinal autoimmunity, joint inflammation, bronchitis, chronic obstructive airway / pulmonary disease, silicosis, aphthous stomatitis, atherosclerotic disorders, asperniogenese, autoimmune hemolysis, Beck's disease, cryoglobulinemia, Dupuytren's contracture, endophthalmia phacoanaphylactica, allergic enterocolitis, erythema nodosum leprosum, idiopathic facial nerve palsy, chronic fatigue syndrome, rheumatic fever (febris rheumatica), Hammann-Rich disease, sensorineural hearing loss, hemoglobinuria attacks (haemoglobinuria paroxysmatica), hypogonadism, regional ileitis, leukopenia, infectious monocytosis, lateral myelitis, primary idiopathic myxedema, nephrosis, sympathetic ophthalmia (ophthalmia)symphatica), orchitis granulomatosis, pancreatitis, acute polyradiculoneuritis, pyoderma gangrenosum, Quervain's thyroiditis, acquired splenic atrophy, nonmalignant thymoma, vitiligo, toxic shock syndrome, food poisoning, conditions with T-cell infiltration, leukocyte adhesion deficiency, acute and delayed hypersensitivity-related immune responses mediated by cytokines and T lymphocytes, diseases with leukocyte extravasation, multiorgan injury syndrome, antigen-antibody complex-mediated diseases, anti-glomerular basement membrane disease, allergic neuritis, autoimmune polyendocrinopathy, oophoritis, primary myxedema, autoimmune atrophic gastritis, sympathetic ophthalmia, rheumatic diseases Diseases, mixed connective tissue disease, nephrotic syndrome, insulitis, polyendocrine deficiency, autoimmune polyglandular syndrome type I, adult-onset idiopathic hypoparathyroidism (AOIH), cardiomyopathy, e.g., dilated cardiomyopathy, epidermolysis bullosa acquisita (EBA), hemochromatosis, myocarditis, nephrotic syndrome, primary sclerosing cholangitis, suppurative or non-suppurative sinusitis, acute or chronic sinusitis, ethmoid, frontal, maxillary or sphenoid sinusitis, eosinophil-related diseases, e.g., eosinophilia, pulmonary infiltrate eosinophilia, eosinophilia-myalgia syndrome, Löffler's syndrome, chronic eosinophilic pneumonia, tropical pulmonary eosinophilia Bronchopneumonia, aspergillosis, aspergilloma, or eosinophilic-containing granulomas, anaphylaxis, seronegative spondyloarthritis, polyendocrine autoimmune diseases, sclerosing cholangitis, scleral, episcleral, chronic mucocutaneous candidiasis, Bratton syndrome, transient hypogammaglobulinemia of infancy, Wiskott-Aldrich syndrome, ataxia-telangiectasia syndrome, vascular ectasia, autoimmune disorders associated with connective tissue diseases, rheumatism, neurological disorders, lymphadenitis, decreased blood pressure response, vascular insufficiency, tissue damage, cardiovascular ischemia, hyperalgesia, renal ischemia, cerebral ischemia, and diseases with vascularization , allergic hypersensitivity disorders, glomerulonephritis, reperfusion injury, ischemic reperfusion injury, reperfusion injury of the myocardium or other tissues, lymphoma, tracheobronchitis, inflammatory skin diseases, skin diseases with an acute inflammatory component, acute purulent meningitis, multiple organ failure, bullous disease, renal cortical necrosis, acute purulent meningitis or other central nervous system inflammatory disorders, ocular and orbital inflammatory disorders, granulocyte transfusion-associated syndrome, cytokine-induced toxicity, narcolepsy, acute severe inflammation, chronic refractory inflammation, pyelitis, intra-arterial hyperplasia, peptic ulcer, valvulitis, graft-versus-host disease, contact hypersensitivity, asthmatic airway hyperresponsiveness, and endometriosis.

[0286] Embodiments can be used to prevent, treat, or ameliorate numerous allergic disorders, non-limiting examples of which include asthma, type 1 diabetes, chronic obstructive pulmonary disease, interstitial lung disease, chronic obstructive pulmonary disease, chronic bronchitis, eosinophilic bronchitis, eosinophilic pneumonia, pneumonia, inflammatory bowel disease, atopic dermatitis, atopy, allergy, allergic rhinitis, idiopathic pulmonary fibrosis, scleroderma, emphysema, breast cancer, and ulcerative colitis. Non-limiting examples of allergic disorders include allergic atopy and dermatitis, allergic rhinitis, allergic asthma, allergic reactions to foods (e.g., milk, eggs, wheat, nuts, fish, shellfish, sulfites, soy, and casein), environmental allergens (e.g., plant and animal allergens, such as dander, house dust mites, pollen, cedar, poison ivy, poison oak, sumac, etc.), insect bites (e.g., bee, wasp, wood wasp, hornet, or fire ant stings), hay fever, allergic conjunctivitis, hives, mold, drug allergies (e.g., aspirin and penicillin), and cosmetic allergies.

[0287] In some embodiments, the compositions and methods described herein are used to treat the inflammatory component of the disorders listed herein and / or known in the art.Therefore, the methods and compositions described herein can be used to treat subjects suffering from inflammation.In some embodiments, the inflammation is acute.In other embodiments, the inflammation is chronic.In further embodiments, the compositions and methods described herein are used to treat or prevent cancer by treating or preventing the inflammatory component associated with cancer.In some embodiments, the cancer is breast cancer.

[0288] IX. Combination Therapy The compositions and related methods disclosed herein, particularly the administration of APC targeting antibody or antigen-binding fragment, can also be used in combination with the administration of conventional therapy.These include, but are not limited to, the application of immunosuppressive or immunomodulatory therapy or treatment.Non-limiting examples of existing immunosuppressive therapy include the administration of immunosuppressive compounds, such as cyclosporin A, cyclophosphamide, FK506, tacrolimus, corticosteroids, azathioprine, mycophenolate mofetil, sirolimus, rapamycin, rapamycin analogs, deoxyspergualin, and prednisone.

[0289] In one aspect, the APC-targeting antibody or antigen-binding fragment is contemplated for use in conjunction with cytokine therapy. Alternatively, antibody administration may precede or follow the other treatment by intervals ranging from a few minutes to several weeks. In embodiments in which the other agent is administered separately, it is generally ensured that no significant time elapses between delivery times, so that the agent and antibody can still exert their beneficially combined effect on the subject. In such cases, it is contemplated that both modalities may be administered within about 12 to 24 hours of each other, more preferably within about 6 to 12 hours of each other. However, in some situations, it may be desirable to extend the period of administration significantly, ranging from several days (2, 3, 4, 5, 6, or 7 days) to several weeks (1, 2, 3, 4, 5, 6, 7, or 8 weeks) between each administration.

[0290] Administration of the anti-DC-ASGPR antibody or antigen-binding fragment composition to patients / subjects will follow standard protocols for administering such compounds, taking into account toxicity, if any. It is anticipated that treatment cycles will be repeated as necessary. It is also anticipated that various standard therapies, such as hydration, may be applied in combination with the described treatments. [Example]

[0291] X. Example The following examples are included to demonstrate certain particular embodiments. It should be recognized by those of skill in the art that the procedures disclosed in the examples which follow represent techniques found by the inventors to function well in the practice of the invention and, therefore, can be considered preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, recognize that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.

[0292] Example 1: Targeting IL-10 to antigen-presenting cells Targeted in vivo delivery of IL-10 to APCs subsequently alters the pathogenic functions of APCs and enhances regulatory T cell responses, making this treatment strategy more effective and durable than non-targeted anti-inflammatory cytokines. Compared with non-targeted methods, the targeted methods described herein require much lower amounts of IL-10 to achieve the same or similar effects. Due to the dose-sparing effect associated with delivering IL-10 to a subset of a patient's APCs, this strategy is expected to significantly reduce the side effects of anti-inflammatory cytokine treatment while providing superior efficacy.

[0293] To test the efficacy of APC-targeted IL-10, recombinant fusion proteins of antibodies with human IL-10 were generated. Monoclonal antibodies (anti-CD40 clone 12E12, anti-CD40 clone 24A3, anti-DCIR clone 9E8, anti-DC-ASGPR clone 49C11, and control IgG4) and human IL-10 fusion proteins were generated.

[0294] We found that various antibodies fused to human IL-10 could target subsets of human DCs in distinct patterns. The ability of antibody-IL-10 fusion proteins to bind to human DCs was measured. Myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) were purified from human blood. DCs were incubated on ice for 20 minutes in the presence of various concentrations of recombinant antibody-IL-10 fusion proteins (Figure 1). After extensive washing, DCs were further stained with anti-human IL-10 to detect surface-bound antibody-IL-10 fusion proteins using flow cytometry. As shown in Figure 1, all of the recombinant antibody-IL-10 fusion proteins (except for the control IgG4-IL-10) were able to bind to mDCs. However, the binding patterns of individual proteins to mDCs were not identical. For example, anti-DCIR(9E8)-IL-10 bound to mDCs more efficiently than the others. Additionally, anti-CD40(12E12)-IL-10 exhibits superior binding to mDCs compared with anti-CD40(24A3)-IL-10. Although both anti-CD40(12E12)-IL-10 and anti-CD40(24A3)-IL-10 bind to pDCs, anti-DCIR(9E8)-IL-10 exhibits the greatest binding to pDCs.

[0295] Taken together, these data indicate that anti-inflammatory cytokines (including IL-10) fused to various antibodies can target different subsets of human APCs at different levels, leading to different outcomes in terms of immune responses.

[0296] We also found that antibody-IL-10 fusion proteins could inhibit DC maturation. DCs are the primary APCs that can induce and direct host immune responses toward either immunity or tolerance. It is also known that mature DCs induce immunity, while immature DCs induce tolerance. Therefore, we investigated the effectiveness of antibody-IL-10 fusion proteins on DC maturation induced by Escherichia coli lipopolysaccharide (LPS; Toll-like receptor 4 ligand). Purified blood mDCs were cultured overnight with 0, 10, or 100 ng / ml LPS in the presence or absence of 10 μg of the indicated recombinant fusion proteins or the same molar concentration of recombinant IL-10. Subsequently, mDCs were stained with anti-CD83 and anti-CD86, and the expression levels of these two surface molecules (an indicator of DC maturation) were measured using flow cytometry. Figure 2 shows that non-targeting human IL-10 somewhat reduced the expression of CD83 and CD86. Compared with non-targeted IL-10, targeted delivery of IL-10 using a recombinant antibody-IL-10 fusion protein was much more efficient in suppressing LPS-induced DC maturation. Anti-CD40(12E12)-IL-10 was somewhat more efficient than the others in suppressing CD86 expression.

[0297] These data demonstrate that a recombinant antibody-IL-10 fusion protein can efficiently target human DCs and thus effectively suppress DC maturation, indicating that targeted delivery of anti-inflammatory cytokines to human APCs can effectively suppress ongoing inflammatory responses by inhibiting the maturation of APCs, including DCs.

[0298] We next found that targeted delivery of IL-10 to DCs using a recombinant fusion protein of antibody and IL-10 could efficiently suppress T cell responses. The effectiveness of the recombinant fusion protein of antibody and IL-10 on T cell responses (Figure 3) was further evaluated. Purified mDCs were incubated with various concentrations of either recombinant human IL-10 or the fusion protein of antibody and IL-10 for 2 hours. CFSE-labeled allogeneic CD4+ T cells were cocultured for 5 days, and T cell proliferation was assessed by measuring CFSE dilution by flow cytometry. Compared with IL-10 alone, the recombinant fusion protein of antibody and IL-10 was much more effective in suppressing allogeneic CD4+ T cell proliferation. 54 nM of IL-10 was required to produce a 50% inhibition of T cell proliferation, whereas when IL-10 was delivered in a targeted manner to DCs, only 5.4 to 0.054 nM (IL-10) was required to achieve a similar effect on T cell proliferation.

[0299] Taken together, these data (Figures 1, 2, and 3) demonstrate that (1) recombinant fusion proteins of antibodies and anti-inflammatory cytokines can effectively target human APCs (Figure 1) in different patterns depending on the APC subset; (2) they can inhibit the activation and maturation of human APCs (including DCs); and (3) they can effectively suppress T cell responses.

[0300] Example 2: Treatment of GVHD with anti-DC-ASGPR Tolerance to specific antigens is the ultimate goal for successful transplantation. Over the past few decades, numerous immunosuppressive drugs have been developed and administered to patients. However, immunosuppression does not guarantee long-term prevention of alloreactivity in patients receiving organ, tissue, and hematopoietic stem cell (HPSC) transplants. As a result, patients die from graft-versus-host disease (GVHD) and other severe side effects caused by lifelong immunosuppression. T cell depletion also impairs the graft-versus-leukemia (GVL) effect in allogeneic HPSC transplants. Furthermore, nonspecific immunosuppression does not preserve existing memory cells or distinguish between alloreactive and nonalloreactive T cells. Therefore, although immunosuppression can control GVHD to some extent, it comes at the cost of increased incidence of graft failure, leukemia relapse, and immunodeficiency against posttransplant infections such as cytomegalovirus (CMV). Therefore, new therapeutic strategies that can prevent GVHD while preserving host immunity against infection are likely to be of great benefit to patients.

[0301] Dendritic cells (DCs), the primary antigen-presenting cells (APCs), can induce host immune responses. DCs also exhibit functional plasticity in regulating immune responses. The ability of DCs as immunoregulators is due in part to the expression of pattern recognition receptors (PRRs), including lectins. DC-asialoglycoprotein receptor (DC-ASGPR), a lectin expressed on human DCs, was found to exhibit the unique ability to generate regulatory T cells (Tregs) that produce antigen-specific IL-10. This was true for both self-antigens (prostate-specific antigen) and foreign antigens (influenza HA1), as demonstrated in vitro in humans and in vivo in non-human primates. Antigen-specific Tregs induced by DC-ASGPR efficiently suppressed the proliferation of effector T cells and the expression of inflammatory cytokines. It was further discovered that DC-ASGPR-mediated signals induce DCs to express IL-10, which in turn promotes the generation of antigen-specific Tregs. We sought to verify whether DC-ASGPR-mediated DC activation could generate alloantigen-specific Tregs and thus prevent GVHD and allograft rejection. Data have shown that targeting DC-ASGPR with anti-DC-ASGPR antibodies results in a reduction of allogeneic T cell responses. These T cells can also secrete high levels of IL-10 during their reactivation in response to alloantigens. Therefore, we speculate that DC-ASGPR could be a novel therapeutic target for inhibiting such unwanted immune responses in patients undergoing transplant surgery. This strategy focuses on the induction of alloantigen-specific Tregs and therefore is unlikely to interfere with host immunity against posttransplant infection. Therefore, we hypothesized that targeting DC-ASGPR with anti-DC-ASGPR antibodies not fused to antigens would prevent GVHD and allograft rejection without interfering with host immunity against infection.

[0302] Establishing alloantigen-specific immune tolerance is the ultimate goal for successful transplantation. The novel immunotherapeutic strategy described herein ultimately enables the generation of alloantigen-specific Tregs in patients without interfering with host immunity against post-transplant infection. Therefore, this research has great implications for both medicine and immunology.

[0303] The approach to control GVHD and transplant rejection by targeting DC-ASGPR is highly novel and innovative in terms of both basic immunology and medical implications.

[0304] DC-ASGPR has a specialized function in generating antigen-specific Tregs. The scavenger receptor DC-ASGPR (Li, et al., 2012; Valladeau, et al., 2001) is expressed on subsets of human DCs (blood-myeloid DCs (mDCs) and dermal DCs, but not plasmacytoid DCs (pDCs) and Langerhans cells (LCs)), monocytes, macrophages, and B cells (Li, et al., 2012). While epithelial cells express ASGPR, DC-ASGPR does not. DC-ASGPR is expressed in non-human primates (NHPs) (Li, et al., 2012), but not in mice. Mice possess two closely related genes, Mgl-1 and Mgl-2, that are distantly related to human DC-ASGPR, the former of which has a tissue distribution profile that more closely resembles that of this single human gene (not shown).

[0305] A. Anti-DC-ASGPR antibody treatment suppresses proliferation of allogeneic CD4+ and CD8+ T cells To investigate the immunological function of DC-ASGPR, we first generated a mouse monoclonal antibody (mAb) specific for human DC-ASGPR (Li, et al., 2012). To eliminate their nonspecific binding to FcR, we generated a recombinant mAb carrying a mouse variable region chimera with a human κ chain and a human IgG4 carrying two mutations (Reddy, et al., 2000) (Li, et al., 2012). A recombinant control mAb was also generated in the same manner.

[0306] Importantly, note that both DC-ASGPR and dectin-1 (Ni, et al., 2010) possess immunoreceptor tyrosine-based activation motifs (ITAMs) and can induce IL-10 expression in DCs. However, DC-ASGPR is superior to dectin-1 in generating Tregs (data not shown). In addition, anti-DC-ASGPR mAb does not induce DCs to express IL-1β, IL-23, or IL-12, whereas anti-dectin-1 mAb induces these cytokines, as previously described (Ni, et al., 2010).

[0307] Anti-DC-ASGPR mAb can suppress MHC-mismatched allogeneic T cell responses: The effect of anti-DC-ASGPR mAb on MHC-mismatched allogeneic T cell responses was examined (Figure 4). Various numbers of PKH25-labeled PBMCs from healthy donors were incubated overnight in the presence of anti-DC-ASGPR or control mAb, and then cocultured with CFSE-labeled PBMCs from MHC-mismatched donors (a total of six pairs of MHC-mismatched donors) for 5 days. CFSE - CD4 + T cells and CFSE - CD8 + The percentages of CD4 T cells are shown. + T cells and CD8 + Both T cell proliferations correlated with the number of stimulators (PBMCs from other donors). However, anti-DC-ASGPR mAb did not stimulate allogeneic CD4 +T cells and CD8 + significantly reduced T cell proliferation, especially when the number of stimulators (x-axis) was 12.5 × 10 3 This was especially true when the number of cells / well was greater than 1. Interestingly, the CD4 counts calculated at the end of the culture + T cells and CD8 + The total number of T cells was similar in both groups (control group and anti-DC-ASGPR mAb-treated group) (not shown).

[0308] B. IL-10 secreted from anti-DC-ASGPR-activated PBMCs contributes to the suppression of allogeneic CD4+ and CD8+ T cell responses. We further found that the allogeneic T cell proliferation reduced by anti-DC-ASGPR mAb was restored (approximately 60-70%) by neutralizing IL-10 on day 1 (2 hours before adding MHC-mismatched PBMCs to the culture) (Figure 5), suggesting that IL-10 secreted from anti-DC-ASGPR-activated APCs contributes to the reduced proliferation of T cells from MHC-mismatched donors.

[0309] C. Anti-DC-ASGPR antibody treatment reduces IFNg-producing regulatory T cell responses but enhances IL-10-producing regulatory T cell responses. At day 8 of co-culture with PBMCs from an MHC-mismatched healthy donor, CFSE low CD4 + T cells were sorted by FACS and subsequently restimulated with T cell-depleted (from stimulatory factors) PBMCs for 48 hours. The amounts of IL-10 and IFNγ in the supernatant were measured (Figure 6). MHC-mismatched CD4 + For T cells, CD4 T cells co-cultured with the same PBMCs treated with control mAb were +Compared with T cells, the amount of IFNγ secreted was decreased, but the amount of IL-10 secreted was increased, suggesting that treatment of PBMCs with anti-DC-ASGPR mAb promotes the induction of alloantigen-specific Tregs, which may play an important role in inhibiting GVHD and allograft rejection in vivo.

[0310] D. Anti-DC-ASGPR antibody treatment suppresses GVHD in vivo The applicants further evaluated the in vivo effects of anti-DC-ASGPR mAb. - / - (NOG) mice (5 mice / group) were treated with 50 × 10 PBMCs from healthy donors on day 0. 6 Mice were intravenously injected with 100 μg of antibody (250 μg / each dose) or PBS three times on days 0, 2, and 4. Figure 7 shows that administration of anti-DC-ASGPR resulted in improved survival of mice compared with control IgG or PBS (p<0.001).

[0311] Taken together, these data demonstrate that targeting DC-ASGPR with anti-DC-ASGPR mAb promotes antigen-specific Treg responses, which may also be applicable to the in vivo establishment of alloantigen-specific Tregs. The data and methods described herein are useful in the research and development of novel therapeutic agents that can effectively inhibit GVHD and allograft rejection without interfering with the host immune response to infection.

[0312] We have focused on a novel antibody that binds to DC-ASGPR, which can induce DCs to secrete IL-10 and induce alloantigen-specific Tregs that produce IL-10 in the presence of alloantigen. Thus, our strategy for inhibiting GVHD and allograft rejection is based on two distinct but compensatory mechanisms (Figure 8). First, Direct Route), IL-10 secreted from DCs activated by DC-ASGPR appears to directly inhibit allogeneic T cell responses at an early time point, as shown in Figure 5. Second, Indirect route ), IL-10 induced by DC-ASGPR may contribute to the induction of IL-10-producing alloantigen-specific Tregs, as shown in Figure 6. These two pathways result in improved survival of NOG mice transferred with human PBMCs (Figure 7). Such alloantigen-specific Tregs express IL-10 when activated in vivo where alloantigens are available (Sagoo, et al., 2011).

[0313] It is expressly contemplated that embodiments of the present invention may include one or more elements listed throughout this specification, or may exclude one or more elements. For example, a particular embodiment may include one specific listed item (e.g., an antibody framework) as described herein, or an embodiment of the present invention may include a range of multiple items from a particular list, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, or more. The present invention may also exclude one or more listed elements; for example, some embodiments may exclude 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, or more of the listed elements. Moreover, where ranges or values ​​are provided, it is expressly contemplated that the invention may not include a particular range or value. Finally, where the invention is described in terms of including a particular feature, it is expressly contemplated that the invention may not include such feature.

[0314] All of the methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. Although the compositions and methods of the present invention have been described with reference to preferred embodiments, it will be apparent to those skilled in the art that changes can be made to the methods and in the steps or sequence of steps of the methods described herein without departing from the concept, spirit, and scope of the invention. More specifically, it will be apparent that certain agents that are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope, and concept of the invention as defined by the appended claims.

[0315] Sequence information SEQUENCE LISTING <110> Baylor Research Institute <120> METHODS AND COMPOSITIONS FOR TREATING AUTOIMMUNE AND INFLAMMATORY CONDITIONS <150> US 61 / 994,239 <151> 2014-05-16 <150> US 62 / 014,504 <151> 2014-06-19 <160> 114 <170> PatentIn version 3.5 <210> 1 <211> 633 <212> PRT <213> Homo sapiens <400> 1 Val Gln Leu Gln Glu Ser Gly Pro Asp Leu Val Lys Pro Ser Gln Ser 1 5 10 15 Leu Ser Leu Thr Cys Thr Val Thr Gly Tyr Ser Ile Thr Ser Gly Tyr 20 25 30 Ser Trp His Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp Met 35 40 45 Gly Tyr Ile Leu Phe Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe Leu 65 70 75 80 Gln Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala 85 90 95 Arg Ser Asn Tyr Gly Ser Phe Ala Ser Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ala Ala Lys Thr Thr Gly Pro Ser Val Phe Pro Leu Ala 115 120 125 Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu 130 135 140 Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly 145 150 155 160 Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser 165 170 175 Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu 180 185 190 Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr 195 200 205 Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro 210 215 220 Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro 225 230 235 240 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 245 250 255 Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn 260 265 270 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 275 280 285 Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 290 295 300 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 305 310 315 320 Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys 325 330 335 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu 340 345 350 Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 355 360 365 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 370 375 380 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 385 390 395 400 Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly 405 410 415 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 420 425 430 Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Ala Ser Gln Thr Pro 435 440 445 Thr Asn Thr Ile Ser Val Thr Pro Thr Asn Asn Ser Thr Pro Thr Asn 450 455 460 Asn Ser Asn Pro Lys Pro Asn Pro Ala Ser Pro Gly Gln Gly Thr Gln 465 470 475 480 Ser Glu Asn Ser Cys Thr His Phe Pro Gly Asn Leu Pro Asn Met Leu 485,490,495 Arg Asp Leu Arg Asp Ala Phe Ser Arg Val Lys Thr Phe Phe Gln Met 500 505 510 Lys Asp Gln to Asp to Asn to Lys Glu Ser to Glu to Asp 515,520,525 Phe Lys Gly Tyr Leu Gly Cys Gln Ala Leu Serves as Glu Met Ile Gln Phe 530 535 540 Tyr Leu Glu Glu Val Met Pro Gln Ala Glu Asn Gln Asp Pro Asp Ile 545 550 555 560 Lys Ala His Val Asn Ser Leu Gly Glu Asn Leu Lys Thr Leu Arg Leu 565,570,575 Arg Leu Arg Cys Arg Cys Arg Phe Leu Pro Cys Glu Asn Lys Ser Lys 580,585,590 Only Glu Gln Val Lys Asn Only Phe Asn Lys Leu Gln Glu Lys Gly 595,600,605 Ile Tyr Lys Ala Met Ser Glu Phe Asp Ile Phe Ile Asn Ile Tyr Ile Glu 610 615 620 Only Tyr Met Thr Met Lys Ile Arg Asn 625,630 <210> 2 <211> 445 <212> PRT <213> Homo sapiens <400> 2 Val Gln Leu Gln Glu Ser Gly Pro Asp Leu Val Lys Pro Ser Gln Ser 1 5 10 15 Leu Ser Leu Thr Cys Thr Val Thr Gly Tyr Ser Ile Thr Ser Gly Tyr 20 25 30 Ser Trp His Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp Met 35 40 45 Gly Tyr Ile Leu Phe Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe Leu 65 70 75 80 Gln Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala 85 90 95 Arg Ser Asn Tyr Gly Ser Phe Ala Ser Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ala Ala Lys Thr Thr Gly Pro Ser Val Phe Pro Leu Ala 115 120 125 Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu 130 135 140 Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly 145 150 155 160 Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser 165 170 175 Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu 180 185 190 Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr 195 200 205 Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro 210 215 220 Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro 225 230 235 240 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 245 250 255 Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn 260 265 270 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 275 280 285 Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 290 295 300 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 305 310 315 320 Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys 325 330 335 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu 340 345 350 Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 355 360 365 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 370 375 380 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 385 390 395 400 Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly 405 410 415 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 420 425 430 Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Ala Ser 435 440 445 <210> 3 <211> 119 <212> PRT <213> Homo sapiens <400> 3 Gln Leu Gln Glu Ser Gly Pro Asp Leu Val Lys Pro Ser Gln Ser Leu 1 5 10 15 Ser Leu Thr Cys Thr Val Thr Gly Tyr Ser Ile Thr Ser Gly Tyr Ser 20 25 30 Trp His Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp Met Gly 35 40 45 Tyr Ile Leu Phe Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys Ser 50 55 60 Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe Leu Gln 65 70 75 80 Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg 85 90 95 Ser Asn Tyr Gly Ser Phe Ala Ser Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ala Ala Lys Thr Thr 115 <210> 4 <211> 27 <212> PRT <213> Homo sapiens <400> 4 Gln Thr Pro Thr Asn Thr Ile Ser Val Thr Pro Thr Asn Asn Ser Thr 1 5 10 15 Pro Thr Asn Asn Ser Asn Pro Lys Pro Asn Pro 20 25 <210> 5 <211> 161 <212> PRT <213> Homo sapiens <400> 5 Ala Ser Pro Gly Gln Gly Thr Gln Ser Glu Asn Ser Cys Thr His Phe 1 5 10 15 Pro Gly Asn Leu Pro Asn Met Leu Arg Asp Leu Arg Asp Ala Phe Ser 20 25 30 Arg Val Lys Thr Phe Phe Gln Met Lys Asp Gln Leu Asp Asn Leu Leu 35 40 45 Leu Lys Glu Ser Leu Leu Glu Asp Phe Lys Gly Tyr Leu Gly Cys Gln 50 55 60 Ala Leu Ser Glu Met Ile Gln Phe Tyr Leu Glu Glu Val Met Pro Gln 65 70 75 80 Ala Glu Asn Gln Asp Pro Asp Ile Lys Ala His Val Asn Ser Leu Gly 85 90 95 Glu Asn Leu Lys Thr Leu Arg Leu Arg Leu Arg Arg Cys His Arg Phe 100 105 110 Leu Pro Cys Glu Asn Lys Ser Lys Ala Val Glu Gln Val Lys Asn Ala 115 120 125 Phe Asn Lys Leu Gln Glu Lys Gly Ile Tyr Lys Ala Met Ser Glu Phe 130 135 140 Asp Ile Phe Ile Asn Tyr Ile Glu Ala Tyr Met Thr Met Lys Ile Arg 145 150 155 160 Asn <210> 6 <211> 1959 <212> DNA <213> Homo sapiens <400> 6 atgagagcgc tgattctttt gtgcctgttc acagcctttc ctggtatcct gtctgatgtg 60 cagcttcagg agtcaggacc tgacctggtg aaaccttctc agtcactttc actcacctgc 120 actgtcactg gctactccat caccagtggt tatagctggc actggatccg gcagtttcca 180 ggaaacaaac tggaatggat gggctacata ctcttcagtg gtagcactaa ctacaaccca 240 tctctgaaaa gtcgaatctc tatcactcga gacacatcca agaaccagtt cttcctgcag 300 ttgaattctg tgactactga ggacacagcc acatatttct gtgcaagatc taactatggt 360 tccttgctt cctggggcca agggactctg gtcactgtct ctgcagccaa aaacgggc 420 ccatccgtct tccccctggc gccctgctcc aggagcacct ccgagagcac agccgccctg 480 ggctgcctgg tcaggacta cttccccgaa ccggtgacgg tgtcgtggaa ctcaggcgcc 540 ctgaccagcg gcgtgcacac cttcccggct gtcctacagt cctcaggact ctactccctc 600 agcagcgtgg tgaccgtgcc ctccagcagc ttgggcacga agacctacac ctgcaacgta 660 gatcacaagc ccagcacac caggtggac agagagttg agtccaata tggtccccca 720 tgcccaccct gcccagcacc tgagttcga gggggaccat cagtctctcct gttcccccca 780 aaacccaagg acacctcat gatctcccgg acccctgagg tcacgtgcgt gtggtggac 840 gtgagccagg agaccccga ggtccagttc aactggtacg tggatggcgt ggaggtgcat 900 aatgccaaga caaagccgcg ggaggagcag ttcacagca cgtaccgtgt ggtcagcgtc 960 ctcaccgtcc tgcaccagga ctggctgaac ggcaggagt acagtgca ggtctccac 1020 aaaggcctcc cgtcctccat cgagaaacc atctccaag ccaagggca gccccgagag 1080 ccacaggtgt acaccctgcc cccatcccag gaggagatga ccagaacca ggtcagcctg 1140 acctgcctgg tcaaggctt ctaccccagc gatacgccg tggagtggga gagcaatggg 1200 cagccggaga aacaataa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 1260 ctctacagca ggctaaccgt ggacaagagc aggtggcagg agggaatgt cttctcatgc 1320 tccgtgatgc atgaggctct gcacaaccac tacacacaga agagcctctc cctgtctctg 1380 ggtaaagcta gtcagacccc caccaacacc atcagcgtga ccccaccacaa caacagcacc 1440 cccaccaaca acagcaaccc caagcccaac cccgctagcc caggccaggg cacccagtct 1500 gagaacagct gcaccccactt cccaggcaac ctgcctaaca tgcttcgaga tctccgagat 1560 1620 aaggatcct tgctggagga ctttaagggt tacctgggtt gccaagcctt gtctgagatg 1680 1740 gcgcatgtga actccctggg ggagaacctg aagaccctca ggctgaggct acggcgctgt 1800 catcgatttc ttccctgtga aaacaagagc aaggccgtgg agcaggtgaa gaatgccttt 1860 aataagctcc aagagaaagg catctacaaa gccatgagtg agtttgacat cttcatcaac 1920 tacatagaag cctacatgac aatgaagata cgaaactga 1959 <210> 7 <211> 213 <212> PRT <213> Homo sapiens <400> 7 Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser His Met 20 25 30 His Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr 35 40 45 Asp Thr Ser Arg Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser His Pro Trp Ser 85 90 95 Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro 100 105 110 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125 Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu 145 150 155 160 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190 Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205 Asn Arg Gly Glu Cys 210 <210> 8 <211> 104 <212> PRT <213> Homo sapiens <400> 8 Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser His Met 20 25 30 His Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr 35 40 45 Asp Thr Ser Arg Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser His Pro Trp Ser 85 90 95 Phe Gly Gly Gly Thr Lys Leu Glu 100 <210> 9 <211> 708 <212> PRT <213> Homo sapiens <400> 9 Ala Thr Gly Gly Ala Thr Thr Thr Thr Cys Ala Ala Gly Thr Gly Cys 1 5 10 15 Ala Gly Ala Thr Thr Thr Thr Cys Ala Gly Cys Thr Thr Cys Cys Thr 20 25 30 Gly Cys Thr Ala Ala Thr Cys Ala Gly Thr Gly Cys Cys Thr Cys Ala 35 40 45 Gly Thr Cys Ala Thr Ala Ala Thr Ala Thr Cys Cys Ala Gly Ala Gly 50 55 60 Gly Ala Cys Ala Ala Ala Thr Thr Gly Thr Thr Cys Thr Cys Ala Cys 65 70 75 80 Cys Cys Ala Gly Thr Cys Thr Cys Cys Ala Gly Cys Ala Ala Thr Cys 85 90 95 Ala Thr Gly Thr Cys Thr Gly Cys Ala Thr Cys Thr Cys Cys Ala Gly 100 105 110 Gly Gly Gly Ala Gly Ala Ala Gly Gly Thr Cys Ala Cys Cys Ala Thr 115 120 125 Gly Ala Cys Cys Thr Gly Cys Ala Gly Thr Gly Cys Cys Ala Gly Cys 130 135 140 Thr Cys Ala Ala Gly Thr Gly Thr Ala Ala Gly Thr Cys Ala Cys Ala 145 150 155 160 Thr Gly Cys Ala Cys Thr Gly Gly Thr Ala Cys Cys Ala Gly Cys Ala 165 170 175 Gly Ala Ala Gly Thr Cys Ala Gly Gly Cys Ala Cys Thr Thr Cys Cys 180 185 190 Cys Cys Cys Ala Ala Ala Ala Gly Ala Thr Gly Gly Ala Thr Thr Thr 195 200 205 Ala Thr Gly Ala Cys Ala Cys Ala Thr Cys Cys Ala Gly Ala Cys Thr 210 215 220 Gly Gly Cys Thr Thr Cys Thr Gly Gly Ala Gly Thr Cys Cys Cys Thr 225 230 235 240 Gly Cys Thr Cys Gly Cys Thr Thr Cys Ala Gly Thr Gly Gly Cys Ala 245 250 255 Gly Thr Gly Gly Gly Thr Cys Thr Gly Gly Gly Ala Cys Cys Thr Cys 260 265 270 Thr Thr Ala Cys Thr Cys Thr Cys Thr Cys Ala Cys Ala Ala Thr Cys 275 280 285 Ala Gly Cys Ala Gly Cys Ala Thr Gly Gly Ala Gly Gly Cys Thr Gly 290 295 300 Ala Ala Gly Ala Thr Gly Cys Thr Gly Cys Cys Ala Cys Thr Thr Ala 305 310 315 320 Thr Thr Ala Cys Thr Gly Cys Cys Ala Gly Cys Ala Gly Thr Gly Gly 325 330 335 Ala Gly Thr Ala Gly Thr Cys Ala Cys Cys Cys Ala Thr Gly Gly Thr 340 345 350 Cys Gly Thr Thr Cys Gly Gly Thr Gly Gly Ala Gly Gly Cys Ala Cys 355 360 365 Cys Ala Ala Ala Cys Thr Cys Gly Ala Gly Ala Thr Cys Ala Ala Ala 370 375 380 Cys Gly Ala Ala Cys Thr Gly Thr Gly Gly Cys Thr Gly Cys Ala Cys 385 390 395 400 Cys Ala Thr Cys Thr Gly Thr Cys Thr Thr Cys Ala Thr Cys Thr Thr 405 410 415 Cys Cys Cys Gly Cys Cys Ala Thr Cys Thr Gly Ala Thr Gly Ala Gly 420 425 430 Cys Ala Gly Thr Thr Gly Ala Ala Ala Thr Cys Thr Gly Gly Ala Ala 435 440 445 Cys Thr Gly Cys Cys Thr Cys Thr Gly Thr Thr Gly Thr Gly Thr Gly 450 455 460 Cys Cys Thr Gly Cys Thr Gly Ala Ala Thr Ala Ala Cys Thr Thr Cys 465 470 475 480 Thr Ala Thr Cys Cys Cys Ala Gly Ala Gly Ala Gly Gly Cys Cys Ala 485 490 495 Ala Ala Gly Thr Ala Cys Ala Gly Thr Gly Gly Ala Ala Gly Gly Thr 500 505 510 Gly Gly Ala Thr Ala Ala Cys Gly Cys Cys Cys Thr Cys Cys Ala Ala 515 520 525 Thr Cys Gly Gly Gly Thr Ala Ala Cys Thr Cys Cys Cys Ala Gly Gly 530 535 540 Ala Gly Ala Gly Thr Gly Thr Cys Ala Cys Ala Gly Ala Gly Cys Ala 545 550 555 560 Gly Gly Ala Cys Ala Gly Cys Ala Ala Gly Gly Ala Cys Ala Gly Cys 565 570 575 Ala Cys Cys Thr Ala Cys Ala Gly Cys Cys Thr Cys Ala Gly Cys Ala 580 585 590 Gly Cys Ala Cys Cys Cys Thr Gly Ala Cys Gly Cys Thr Gly Ala Gly 595 600 605 Cys Ala Ala Ala Gly Cys Ala Gly Ala Cys Thr Ala Cys Gly Ala Gly 610 615 620 Ala Ala Ala Cys Ala Cys Ala Ala Ala Gly Thr Cys Thr Ala Thr Gly 625 630 635 640 Cys Cys Thr Gly Cys Gly Ala Ala Gly Thr Cys Ala Cys Cys Cys Ala 645 650 655 Thr Cys Ala Gly Gly Gly Cys Cys Thr Gly Ala Gly Cys Thr Cys Gly 660 665 670 Cys Cys Cys Gly Thr Cys Ala Cys Ala Ala Ala Gly Ala Gly Cys Thr 675 680 685 Thr Cys Ala Ala Cys Ala Gly Gly Gly Gly Ala Gly Ala Gly Thr Gly 690 695 700 Thr Thr Ala Gly 705 <210> 10 <211> 635 <212> PRT <213> Homo sapiens <400> 10 Val Gln Leu Gln Glu Ser Gly Pro Asp Leu Val Lys Pro Ser Gln Ser 1 5 10 15 Leu Ser Leu Thr Cys Thr Val Thr Gly Tyr Ser Ile Thr Ser Asp Tyr 20 25 30 Ser Trp His Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp Met 35 40 45 Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe Leu 65 70 75 80 Gln Leu Asn Ser Val Thr Thr Glu Asp Ser Ala Thr Tyr Phe Cys Ala 85 90 95 Arg Phe Tyr Tyr Gly Tyr Ser Phe Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Thr Leu Thr Val Ser Ser Ala Lys Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys 210 215 220 Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu 225 230 235 240 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 245 250 255 Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln 260 265 270 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 275 280 285 Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu 290 295 300 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 305 310 315 320 Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys 325 330 335 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 340 345 350 Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 355 360 365 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 370 375 380 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 385 390 395 400 Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln 405 410 415 Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 420 425 430 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Ala Ser Gln 435 440 445 Thr Pro Thr Asn Thr Ile Ser Val Thr Pro Thr Asn Asn Ser Thr Pro 450 455 460 Thr Asn Asn Ser Asn Pro Lys Pro Asn Pro Ala Ser Pro Gly Gln Gly 465 470 475 480 Thr Gln Ser Glu Asn Ser Cys Thr His Phe Pro Gly Asn Leu Pro Asn 485 490 495 Met Leu Arg Asp Leu Arg Asp Ala Phe Ser Arg Val Lys Thr Phe Phe 500 505 510 Gln Met Lys Asp Gln Leu Asp Asn Leu Leu Leu Lys Glu Ser Leu Leu 515 520 525 Glu Asp Phe Lys Gly Tyr Leu Gly Cys Gln Ala Leu Ser Glu Met Ile 530 535 540 Gln Phe Tyr Leu Glu Glu Val Met Pro Gln Ala Glu Asn Gln Asp Pro 545 550 555 560 Asp Ile Lys Ala His Val Asn Ser Leu Gly Glu Asn Leu Lys Thr Leu 565 570 575 Arg Leu Arg Leu Arg Arg Cys His Arg Phe Leu Pro Cys Glu Asn Lys 580 585 590 Ser Lys Ala Val Glu Gln Val Lys Asn Ala Phe Asn Lys Leu Gln Glu 595 600 605 Lys Gly Ile Tyr Lys Ala Met Ser Glu Phe Asp Ile Phe Ile Asn Tyr 610 615 620 Ile Glu Ala Tyr Met Thr Met Lys Ile Arg Asn 625 630 635 <210> 11 <211> 447 <212> PRT <213> Homo sapiens <400> 11 Val Gln Leu Gln Glu Ser Gly Pro Asp Leu Val Lys Pro Ser Gln Ser 1 5 10 15 Leu Ser Leu Thr Cys Thr Val Thr Gly Tyr Ser Ile Thr Ser Asp Tyr 20 25 30 Ser Trp His Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp Met 35 40 45 Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe Leu 65 70 75 80 Gln Leu Asn Ser Val Thr Thr Glu Asp Ser Ala Thr Tyr Phe Cys Ala 85 90 95 Arg Phe Tyr Tyr Gly Tyr Ser Phe Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Thr Leu Thr Val Ser Ser Ala Lys Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys 210 215 220 Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu 225 230 235 240 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 245 250 255 Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln 260 265 270 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 275 280 285 Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu 290 295 300 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 305 310 315 320 Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys 325 330 335 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 340 345 350 Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 355 360 365 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 370 375 380 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 385 390 395 400 Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln 405 410 415 Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 420 425 430 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Ala Ser 435 440 445 <210> 12 <211> 1965 <212> DNA <213> Homo sapiens <400> 12 atgagagtgc tgattctttt gtgcctgttc acagcctttc ctggtatcct gtctgatgtg 60 cagcttcagg agtcaggacc tgacctggtg aaaccttctc agtcactttc actcacctgc 120 actgtcactg gctactccat caccagtgat tatagctggc actggatccg gcagttccca 180 ggaaacaaac tggaatggat gggctacata tattacagtg gtagcactaa ctacaaccca 240 tctctcaaaa gtcgaatctc tatcactcga gacacatcca agaaccagtt cttcctgcag 300 ttgaattctg tgactactga ggactcagcc acatatttct gtgcaagatt ttactacggt 360 tatagcttct ttgactactg gggccaaggc accactctca cagtctcctc agccaaaaca 420 aagggcccat ccgtcttccc cctggcgccc tgctccagga gcacctccga gagcacagcc 480 gcctgggct gcctggtcaa ggactacttc cccgaaccgg tgacggtgtc gtggaactca 540 ggcgccctga ccagcggcgt gcacaccttc ccggctgtcc tacagtcctc aggactctac 600 tccctcagca gcgtggtgac cgtgccctcc agcagcttgg gcacgaagac ctacacctgc 660 aacgtagatc acaagcccag caacaccaag gtggacaaga gagttgagtc caaatatggt 720 cccccatgcc caccctgccc agcacctgag ttcgaagggg gaccatcagt cttcctgttc 780 cccccaaaac ccaaggacac tctcatgatc tcccggaccc ctgaggtcac gtgcgtggtg 840 gtggacgtga gccaggaaga ccccgaggtc cagttcaact ggtacgtgga tggcgtggag 900 gtgcataatg ccaagacaaa gccgcgggag gagcagttca acagcacgta ccgtgtggtc 960 agcgtcctca ccgtcctgca ccaggactgg ctgaacggca aggagtacaa gtgcaaggtc 1020 tccaacaaag gcctcccgtc ctccatcgag aaaaccatct ccaaagccaa agggcagccc 1080 cgagagccac aggtgtacac cctgccccca tcccaggagg agatgaccaa gaaccaggtc 1140 agcctgacct gcctggtcaa aggcttctac cccagcgaca tcgccgtgga gtgggagagc 1200 aatgggcagc cggagaacaa ctacaagacc acgcctcccg tgctggactc cgacggctcc 1260 ttctcctct acagcaggct aaccgtggac agagcaggt ggcaggaggg gatgtcttc 1320 tcatgctccg tgatgcatga ggctctgcac aaccactaca cacagaagag cctctccctg 1380 tctctgggta aagctagtca gaccccacc aacaccatca gcgtgacccc caccacac 1440 agcacccca ccacacacag agcaccccag cccaccccg ctagcccagg ccaggcccagg 1500 cagtctgaga acagctgcac ccactccca ggcaacctgc ctaacatgct tcgagatctc 1560 cgagatgcct tcagcagt gagactttc ttcaatga aggatcagct ggacaacttg 1620 ttgttaaagg agtccttgct ggaggacttt aagggttacc tggttgcca agccttgtct 1680 gagatgatcc agttttacct gaggaggtg atgccccaag ctgagaacca agacccagac 1740 atcaggcgc atgtgactc cctgggggag aacctgaga ccctcaggct gaggctacgg 1800 cgctgtcatc gatttcttcc ctgtgaaaac agagcaagg ccgtggagca ggtgaagaat 1860 gcctttaata agctccaaga gaaaggcatc tacaagcca tgagtgagtt tgacatctc 1920 atcaactaca taagccta catgacaatg agatacgaa actga 1965 <210> 13 <211> 215 <212> PRT <213> Homo sapiens <400> 13 Gln Ile Val Leu Thr Gln Ser Pro Ala Phe Met Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met 20 25 30 His Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr 35 40 45 Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Leu Thr 85 90 95 Phe Gly Ala Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro 100 105 110 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125 Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140 Gln Val Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu 145 150 155 160 Ser Val Thr Glu Gln Asp Server Lys Asp Server Thr Tyr Ser Leu Ser Ser 165 170 175 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190 Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205 Asn Arg Gly Glu Cys Only Ser 210 215 <210> 14 <211> 714 <212> DNA <213> Homo sapiens <400> 14 atggatttc aagtgcagat ttcagcttc ctgctaatca gtgcctcagt catagtatcc 60 agaggacaaa 120 gtcaccatga cctgcagtgc cagctcaagt gtcagttaca tgcactgta ccagcagaag 180 tcaggcacct cccccaaaag atggattt gandacatcca aactggctc tggagtccct 240 gctcgcttca gtggcagtgg gtctgggacc tcttactc tcacaatcag cagcatggag 300 gctgaagatg ctgccactta ttactgccag cagtggagta gtaacccact cacgttcggt 360 gctgggacca agctcgagat caaacgaact gtggctgcac catctgtctt catcttcccg 420 ccatctgatg agcagttgaa atctggaact gcctctgttg tgtgcctgct gaataacttc 480 tatcccagag aggccaaagt acagtggaag gtggataacg ccctccaatc gggtaactcc 540 caggagagtg tcacagagca ggacagcaag gacagcacct acagcctcag cagcaccctg 600 acgctgagca aagcagacta cgagaaacac aaagtctatg cctgcgaagt cacccatcag 660 ggcctgagct cgcccgtcac aaagagcttc aacaggggag agtgtgctag ctag 714 <210> 15 <211> 642 <212> PRT <213> Homo sapiens <400> 15 Gln Val Thr Leu Lys Glu Ser Gly Pro Gly Ile Leu Gln Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Ser Phe Ser Gly Phe Ser Leu Ser Thr Ser 20 25 30 Gly Met Gly Leu Ser Trp Ile Arg Gln Pro Ser Gly Lys Gly Leu Glu 35 40 45 Trp Leu Ala His Ile Tyr Trp Asp Asp Asp Lys Arg Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Ser Asn Gln Val 65 70 75 80 Phe Leu Lys Ile Thr Ile Val Asp Thr Ala Asp Ala Ala Thr Tyr Tyr 85 90 95 Cys Ala Arg Ser Ser His Tyr Tyr Gly Tyr Gly Tyr Gly Gly Tyr Phe 100 105 110 Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser Ala Lys Thr 115 120 125 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser 130 135 140 Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys 195 200 205 Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu 210 215 220 Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu 225 230 235 240 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 245 250 255 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 260 265 270 Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu 275 280 285 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr 290 295 300 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 305 310 315 320 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser 325 330 335 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 340 345 350 Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val 355 360 365 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 370 375 380 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 385 390 395 400 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr 405 410 415 Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val 420 425 430 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 435 440 445 Ser Leu Gly Lys Ala Ser Gln Thr Pro Thr Asn Thr Ile Ser Val Thr 450 455 460 Pro Thr Asn Asn Ser Thr Pro Thr Asn Asn Ser Asn Pro Lys Pro Asn 465 470 475 480 Pro Ala Ser Pro Gly Gln Gly Thr Gln Ser Glu Asn Ser Cys Thr His 485 490 495 Phe Pro Gly Asn Leu Pro Asn Met Leu Arg Asp Leu Arg Asp Ala Phe 500 505 510 Ser Arg Val Lys Thr Phe Phe Gln Met Lys Asp Gln Leu Asp Asn Leu 515 520 525 Leu Leu Lys Glu Ser Leu Leu Glu Asp Phe Lys Gly Tyr Leu Gly Cys 530 535 540 Gln Ala Leu Ser Glu Met Ile Gln Phe Tyr Leu Glu Glu Val Met Pro 545 550 555 560 Gln Ala Glu Asn Gln Asp Pro Asp Ile Lys Ala His Val Asn Ser Leu 565 570 575 Gly Glu Asn Leu Lys Thr Leu Arg Leu Arg Leu Arg Arg Cys His Arg 580 585 590 Phe Leu Pro Cys Glu Asn Lys Ser Lys Ala Val Glu Gln Val Lys Asn 595 600 605 Ala Phe Asn Lys Leu Gln Glu Lys Gly Ile Tyr Lys Ala Met Ser Glu 610 615 620 Phe Asp Ile Phe Ile Asn Tyr Ile Glu Ala Tyr Met Thr Met Lys Ile 625 630 635 640 Arg Asn <210> 16 <211> 454 <212> PRT <213> Homo sapiens <400> 16 Gln Val Thr Leu Lys Glu Ser Gly Pro Gly Ile Leu Gln Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Ser Phe Ser Gly Phe Ser Leu Ser Thr Ser 20 25 30 Gly Met Gly Leu Ser Trp Ile Arg Gln Pro Ser Gly Lys Gly Leu Glu 35 40 45 Trp Leu Ala His Ile Tyr Trp Asp Asp Asp Lys Arg Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Ser Asn Gln Val 65 70 75 80 Phe Leu Lys Ile Thr Ile Val Asp Thr Ala Asp Ala Ala Thr Tyr Tyr 85 90 95 Cys Ala Arg Ser Ser His Tyr Tyr Gly Tyr Gly Tyr Gly Gly Tyr Phe 100 105 110 Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser Ala Lys Thr 115 120 125 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser 130 135 140 Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys 195 200 205 Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu 210 215 220 Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu 225 230 235 240 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 245 250 255 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 260 265 270 Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu 275 280 285 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr 290 295 300 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 305 310 315 320 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser 325 330 335 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 340 345 350 Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val 355 360 365 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 370 375 380 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 385 390 395 400 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr 405 410 415 Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val 420 425 430 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 435 440 445 Ser Leu Gly Lys Ala Ser 450 <210> 17 <211> 124 <212> PRT <213> Homo sapiens <400> 17 Gln Val Thr Leu Lys Glu Ser Gly Pro Gly Ile Leu Gln Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Ser Phe Ser Gly Phe Ser Leu Ser Thr Ser 20 25 30 Gly Met Gly Leu Ser Trp Ile Arg Gln Pro Ser Gly Lys Gly Leu Glu 35 40 45 Trp Leu Ala His Ile Tyr Trp Asp Asp Asp Lys Arg Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Ser Asn Gln Val 65 70 75 80 Phe Leu Lys Ile Thr Ile Val Asp Thr Ala Asp Ala Ala Thr Tyr Tyr 85 90 95 Cys Ala Arg Ser Ser His Tyr Tyr Gly Tyr Gly Tyr Gly Gly Tyr Phe 100 105 110 Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser 115 120 <210> 18 <211> 27 <212> PRT <213> Homo sapiens <400> 18 Gln Thr Pro Thr Asn Thr Ile Ser Val Thr Pro Thr Asn Asn Ser Thr 1 5 10 15 Pro Thr Asn Asn Ser Asn Pro Lys Pro Asn Pro 20 25 <210> 19 <211> 161 <212> PRT <213> Homo sapiens <400> 19 Ala Ser Pro Gly Gln Gly Thr Gln Ser Glu Asn Ser Cys Thr His Phe 1 5 10 15 Pro Gly Asn Leu Pro Asn Met Leu Arg Asp Leu Arg Asp Ala Phe Ser 20 25 30 Arg Val Lys Thr Phe Phe Gln Met Lys Asp Gln Leu Asp Asn Leu Leu 35 40 45 Leu Lys Glu Ser Leu Leu Glu Asp Phe Lys Gly Tyr Leu Gly Cys Gln 50 55 60 Ala Leu Ser Glu Met Ile Gln Phe Tyr Leu Glu Glu Val Met Pro Gln 65 70 75 80 Ala Glu Asn Gln Asp Pro Asp Ile Lys Ala His Val Asn Ser Leu Gly 85 90 95 Glu Asn Leu Lys Thr Leu Arg Leu Arg Leu Arg Arg Cys His Arg Phe 100 105 110 Leu Pro Cys Glu Asn Lys Ser Lys Ala Val Glu Gln Val Lys Asn Ala 115 120 125 Phe Asn Lys Leu Gln Glu Lys Gly Ile Tyr Lys Ala Met Ser Glu Phe 130 135 140 Asp Ile Phe Ile Asn Tyr Ile Glu Ala Tyr Met Thr Met Lys Ile Arg 145 150 155 160 Asn <210> 20 <211> 487 <212> DNA <213> Homo sapiens <400> 20 cgctagccca ggccagggca cccagtctga gaacagctgc acccacttcc caggcaacct 60 gcctaacatg cttcgagatc tccgagatgc cttcagcaga gtgaagactt tctttcaaat 120 gaaggatcag ctggacaact tgttgttaaa ggagtccttg ctggaggact ttaagggtta 180 cctgggttgc caagccttgt ctgagatgat ccagttttac ctggaggagg tgatgcccca 240 agctgagaac caagacccag acatcaaggc gcatgtgaac tccctggggg agaacctgaa 300 gaccctcagg ctgaggctac ggcgctgtca tcgatttctt ccctgtgaaa acaagagcaa 360 ggccgtggag caggtgaaga atgcctttaa taagctccaa gagaaaggca tctacaaagc 420 catgagtgag tttgacatct tcatcaacta catagaagcc tacatgacaa tgaagatacg 480 aaactga 487 <210> 21 <211> 1986 <212> DNA <213> Homo sapiens <400> 21 atgaacaggc ttacttcctc attgctgctg ctgattgtcc ctgcatatgt cctgtcccag 60 gttactctga aagagtctgg ccctgggata ttgcagccct cccagaccct cagtctgact 120 tgttctttct ctgggttttc actgagcact tctggtatgg gtctgagctg gattcgtcag 180 ccttcaggaa agggtctgga gtggctggca cacatttact gggatgatga caagcgctat 240 aacccatccc tgaagagccg gctcacaatc tccaaggata cctccagcaa ccaggttttc 300 ctcaagatca ccattgtgga cactgcagat gctgccacat actactgtgc tcgaagctcc 360 cattactacg gttatggcta cgggggatac ttcgatgtct ggggcgcagg gaccacggtc 420 accgtctcct cagccaaaac gaagggccca tccgtcttcc ccctggcgcc ctgctccagg 480 agcacctccg agagcacagc cgccctgggc tgcctggtca aggactactt ccccgaaccg 540 gtgacggtgt cgtggaactc aggcgccctg accagcggcg tgcacacctt cccggctgtc 600 ctacagtcct caggactcta ctccctcagc agcgtggtga ccgtgccctc cagcagcttg 660 ggcacgaaga cctacacctg caactgatag cacaagccca gcaacaccaa ggtggacaag 720 agagttgagt ccaaatatgg tcccccatgc ccaccctgcc cagcacctga gttcgaaggg 780 ggaccatcag tcttcctgtt ccccccaaaaa cccaaggaca ctctcatgat ctcccggacc 840 cctgaggtca cgtgcgtggt ggtggacgtg agccaggaag accccgaggt ccagttcaac 900 tggtacgtgg atggcgtgga ggtgcatat gccaagacaa agccgcggga ggagcagttc 960 aacagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaacggc 1020 aaggagtca agtgcaaggt ctccaacaaa ggcctcccgt cctccatcga gaaaccatc 1080 tccaaagcca aagggcagcc ccgagagcca caggtgtaca ccctgccccc atcccaggag 1140 gagatgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta ccccagcgac 1200 atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac cacgcctccc 1260 gtgctggact ccgacggctc cttcttcctc tacagcaggc taaccgtgga caagagcagg 1320 tggcaggagg ggaatgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac 1380 your acacaga gcctctccct gtctctgggt aaagctagtc agacccccac caacaccatc 1440 agcgtgaccc ccaccaacaa cagcaccccc accaacaaca gcaaccccaa gcccaacccc 1500 gctagcccag gccagggcac ccagtctgag aacagctgca cccacttcc aggcaacctg 1560 cctaacatgc ttcgagatct ccgagatgcc ttcagcagag tgaagaacttt ctttcaaatg 1620 1680 ctgggttgcc aagccttgtc tgagatgatc cagttttacc tggaggggt gatgccccaa 1740 gctgagaacc aagacccaga catcaaggcg catgtgaact ccctggggga gaacctgaag 1800 accctcaggc tgaggctacg gcgctgtcat cgatttcttc cctgtgaaaa caagagcaag 1860 gccgtggagc aggtgaagaa tgcctttaat aagctccaag agaaaggcat ctacaaagcc 1920 atgagtgagt ttgacatctt catcaactac atagaagcct acatgacaat gaagatacga 1980 Act 1986 <210> 22 <211> 218 <212> PRT <213> Homo sapiens <400> 22 Asn Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Ile His Ser Tyr 20 25 30 Gly Asn Ser Phe Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro 35 40 45 Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Ala 50 55 60 Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asp 65 70 75 80 Pro Val Glu Ala Asp Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Asn Asn 85 90 95 Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg 100 105 110 Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln 115 120 125 Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 130 135 140 Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 145 150 155 160 Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 165 170 175 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys 180 185 190 His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 195 200 205 Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 23 <211> 111 <212> PRT <213> Homo sapiens <400> 23 Asn Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Ile His Ser Tyr 20 25 30 Gly Asn Ser Phe Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro 35 40 45 Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Ala 50 55 60 Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asp 65 70 75 80 Pro Val Glu Ala Asp Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Asn Asn 85 90 95 Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 <210> 24 <211> 333 <212> DNA <213> Homo sapiens <400> 24 aacattgtgc tgacccaatc tccagcttct ttggctgtgt ctctagggca gagggccacc 60 atatcctgca gagccagtga aagtattcat agttatggca atagttttct gcactggtac 120 cagcagaaac caggacagcc acccaaactc ctcatctatc ttgcatccaa cctagaatct 180 ggggtccctg ccaggttcag cggcagtggg tctaggacag acttcaccct caccattgat 240 cctgtggagg ctgatgatgc tgcaacctat tactgtcagc aaaataatga ggatccgtgg 300 acgtcggtg gaggcaccaa gctcgagatc aaa 333 <210> 25 <211> 20 <212> PRT <213> Homo sapiens <400> 25 With Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly 20 <210> 26 <211> 60 <212> DNA <213> Homo sapiens <400> 26 atggagacag acacactcct gctatgggtg ctgctgctct gggttccagg ttccacaggt 60 <210> 27 <211> 717 <212> DNA <213> Homo sapiens <400> 27 atggagacag acacactcct gctatgggtg ctgctgctct gggttccagg ttccacaggt 60 aacattgtgc tgacccaatc tccagcttct ttggctgtgt ctctagggca gagggccacc 120 atatcctgca gagccagtga aagtattcat agttatggca atagttttct gcactggtac 180 cagcagaaac caggacagcc acccaaactc ctcatctatc ttgcatccaa cctagaatct 240 ggggtccctg ccaggttcag cggcagtggg tctaggacag acttcaccct caccattgat 300 cctgtggagg ctgatgatgc tgcaacctat tactgtcagc aaaataatga ggatccgtgg 360 acgtcggtg gaggcaccaa gctcgagatc aaacgaactg tggctgcacc atctgtctttc 420 atcttcccgc catctgatga gcagttgaaa tctggaactg cctctgttgt gtgcctgctg 480 aataacttct atcccagaga ggccaaagta cagtggaagg tggataacgc cctccaatcg ggtaactccc aggagagtgt cacagagcag cacagcaagg acagcaccta cagcctcagc agcaccctga cgctgagcaa agcacctc gagaaacaca aagtctatgc ctgcgaagtc acccatcagg gcctgagctc gcccgtcaca aagagcttca acaggggaga gtgttag 717 <210> 28 <211> 636 <212> PRT <213> Homo sapiens <400> 28 Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Thr Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyre Met Tyre Trp Val Arg Gln Thr Pro Glue Light Arg Leu Glue Trp Val 35 40 45 Ala Tyr Ile Asn Ser Gly Gly Gly Ser Thr Tyr Tyr Pro Asp Thr 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 Ser Arg Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Arg Gly Leu Pro Phe His Ala Met Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Ser Val Thr Val Ser Ser Ala Lys Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro 210 215 220 Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe 225 230 235 240 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255 Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val 260 265 270 Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285 Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val 290 295 300 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 305 310 315 320 Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser 325 330 335 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 340 345 350 Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 355 360 365 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 370 375 380 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 385 390 395 400 Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp 405 410 415 Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 420 425 430 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Ala Ser 435 440 445 Gln Thr Pro Thr Asn Thr Ile Ser Val Thr Pro Thr Asn Asn Ser Thr 450 455 460 Pro Thr Asn Asn Ser Asn Pro Lys Pro Asn Pro Ala Ser Pro Gly Gln 465 470 475 480 Gly Thr Gln Ser Glu Asn Ser Cys Thr His Phe Pro Gly Asn Leu Pro 485 490 495 Asn Met Leu Arg Asp Leu Arg Asp Ala Phe Ser Arg Val Lys Thr Phe 500 505 510 Phe Gln Met Lys Asp Gln Leu Asp Asn Leu Leu Leu Lys Glu Ser Leu 515 520 525 Leu Glu Asp Phe Lys Gly Tyr Leu Gly Cys Gln Ala Leu Ser Glu Met 530 535 540 Ile Gln Phe Tyr Leu Glu Glu Val Met Pro Gln Ala Glu Asn Gln Asp 545 550 555 560 Pro Asp Ile Lys Ala His Val Asn Ser Leu Gly Glu Asn Leu Lys Thr 565 570 575 Leu Arg Leu Arg Leu Arg Arg Cys His Arg Phe Leu Pro Cys Glu Asn 580 585 590 Lys Ser Lys Ala Val Glu Gln Val Lys Asn Ala Phe Asn Lys Leu Gln 595 600 605 Glu Lys Gly Ile Tyr Lys Ala Met Ser Glu Phe Asp Ile Phe Ile Asn 610 615 620 Tyr Ile Glu Ala Tyr Met Thr Met Lys Ile Arg Asn 625 630 635 <210> 29 <211> 448 <212> PRT <213> Homo sapiens <400> 29 Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Thr Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Tyr Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val 35 40 45 Ala Tyr Ile Asn Ser Gly Gly Gly Ser Thr Tyr Tyr Pro Asp Thr 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 Ser Arg Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Arg Gly Leu Pro Phe His Ala Met Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Ser Val Thr Val Ser Ser Ala Lys Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro 210 215 220 Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe 225 230 235 240 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255 Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val 260 265 270 Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285 Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val 290 295 300 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 305 310 315 320 Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser 325 330 335 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 340 345 350 Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 355 360 365 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 370 375 380 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 385 390 395 400 Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp 405 410 415 Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 420 425 430 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Ala Ser 435 440 445 <210> 30 <211> 118 <212> PRT <213> Homo sapiens <400> 30 Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Thr Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Tyr Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val 35 40 45 Ala Tyr Ile Asn Ser Gly Gly Gly Ser Thr Tyr Tyr Pro Asp Thr 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 Ser Arg Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Arg Gly Leu Pro Phe His Ala Met Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Ser Val Thr Val Ser 115 <210> 31 <211> 11 <212> PRT <213> Homo sapiens <400> 31 Ser Ala Ser Gln Gly Ile Ser Asn Tyr Leu Asn 1 5 10 <210> 32 <211> 17 <212> PRT <213> Homo sapiens <400> 32 Ala Tyr Ile Asn Ser Gly Gly Gly Ser Thr Tyr Tyr Pro Asp Thr Val 1 5 10 15 Lys <210> 33 <211> 10 <212> PRT <213> Homo sapiens <400> 33 Arg Arg Gly Leu Pro Phe His Ala Met Asp 1 5 10 <210> 34 <211> 1968 <212> DNA <213> Homo sapiens <400> 34 atgaacttgg ggctcagctt gattttcctt gtccttgttt taaaaggtgt ccagtgtgaa 60 gtgaagctgg tggagtctgg gggaggctta gtgcagcccg gagggtccct gaaactctcc 120 tgtgcaacct ctggattcac tttcagtgac tattacatgt attgggttcg ccagactcca 180 gagaagaggc tggagtgggt cgcatacatt aattctggtg gtggtagcac ctattatcca 240 gacactgtaa agggccgatt caccatctcc agagacaatg ccaagaacac cctgtacctg 300 caaatgagcc ggctgaagtc tgaggacaca gccatgtatt actgtgcaag acgggggtta 360 ccgttccatg ctatggacta ttggggtcaa ggaacctcag tcaccgtctc ctcagccaaa 420 acgaagggcc catccgtctt cccctggcg ccctgctcca ggagcacctc cgagagcaca 480 gccgccctgg gctgcctggt caaggactac ttccccgaac cggtgacggt gtcgtggaac 540 tcaggcgccc tgaccagcgg cgtgcacacc ttcccggctg tcctacagtc ctcaggactc 600. tactccctca gcagcgtggt gaccgtgccc tccagcagct tgggcacgaa gacctacacc 660 tgcaacgtag atcacaagcc cagcaacacc aaggtggaca agagagttga gtccaaatat ggtcccccat gcccaccctg cccagcacct gagttcgaag ggggaccatc agtcttcctg 780 ttccccccaa aacccaagga cactctcatg atctcccgga cccctgaggt cacgtgcgtg gtggtggacg tgagccagga agaccccgag gtccagttca actggtacgt ggatggcgtg 900 gaggtgcata atgccaagac aaagccgcgg gaggagcagt tcaacagcac gtaccgtgtg gtcagcgtcc tcaccgtcct gcaccaggac tggctgaacg gcaaggagta caagtgcaag 1020 gtctccaaca aaggcctccc gtcctccatc gagaaacca tctccaaagc caaagggcag ccccgagagc cacaggtgta caccctgccc ccatcccagg aggagatgac caagaaccg gtcagcctga cctgcctggt caaaggcttc taccccagcg acatcgccgt ggagtggggag agcaatgggc agccggagaa caactacaag accacgcctc ccgtgctgga ctccgacggc tccttcttcc tctacagcag gctaaccgtg gaagagagca ggtggcagga ggggaatgtc 1320 ttctcatgct ccgtgatgca tgaggctctg caaaccact acacagaga gagcctctcc 1380 ctgtctctgg gtaaagctag tcagacccc accaacacca tcagcgtgac ccccaccaac 1440 aacagcaccc ccaccaacaa cagcaacccc aagcccaacc ccgctagccc aggccagggc 1500 acccagtctg agaacagctg caccacttc ccaggcaacc tgcctaacat gcttcgagat 1560 ctccgagatg ccttcagcag agtgaagaact ttctttcaaa tgaaggatca gctggacaac 1620 ttgttgttaa aggagtcctt gctggaggac tttaagggtt acctgggttg ccaagccttg 1680 tctgagatga tccagtttta cctggaggag gtgatgcccc aagctgagaa ccaagaccca 1740 gacatcaagg cgcatgtgaa ctccctgggg gagaacctga agaccctcag gctgaggcta 1800 1860 aatgccttta ataagctcca agaaaggc atctacaaag ccatgagtga gtttgacatc 1920 1968 <210> 35 <211> 214 <212> PRT <213> Homo sapiens <400> 35 Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Ser Cys Ser Ala Ser Gln Gly Ile Ser Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile 35 40 45 Tyr Tyr Thr Ser Ile Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Gly Asn Leu Glu Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Lys Leu Pro Pro 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 36 <211> 107 <212> PRT <213> Homo sapiens <400> 36 Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Ser Cys Ser Ala Ser Gln Gly Ile Ser Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile 35 40 45 Tyr Tyr Thr Ser Ile Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Gly Asn Leu Glu Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Lys Leu Pro Pro 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 37 <211> 11 <212> PRT <213> Homo sapiens <400> 37 Ser Ala Ser Gln Gly Ile Ser Asn Tyr Leu Asn 1 5 10 <210> 38 <211> 7 <212> PRT <213> Homo sapiens <400> 38 Tyr Thr Ser Ile Leu His Ser 1 5 <210> 39 <211> 9 <212> PRT <213> Homo sapiens <400> 39 Gln Gln Phe Asn Lys Leu Pro Pro Thr 1 5 <210> 40 <211> 705 <212> DNA <213> Homo sapiens <400> 40 atgatgtcct ctgctcagtt ccttggtctc ctgttgctct gttttcaagg taccagatgt 60 gatatccaga tgacacagac tacatcctcc ctgtctgcct ctctaggaga cagagtcacc 120 atcagttgca gtgcaagtca gggcattagc aattatttaa actggtatca gcagaaacca 180 gatggaactg ttaaactcct gatctattac acatcaattt tacactcagg agtcccatca 240 aggttcagtg gcagtgggtc tgggacagat tattctctca ccatcggcaa cctggaacct 300 gaagatattg ccacttacta ttgtcagcag tttaataagc ttcctccgac gttcggtgga 360 ggcaccaaac tcgagatcaa acgaactgtg gctgcaccat ctgtcttcat cttcccgcca 420 tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 480 cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 540 gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 600 ctgagcaaag cagactacga gaaacacaaa gtctatgcct gcgaagtcac ccatcagggc 660 ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gttag 705 <210> 41 <211> 637 <212> PRT <213> Homo sapiens <400> 41 Arg Leu Gln Leu Gln Glu Ser Gly Pro Gly Leu Leu Lys Pro Ser Val 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asp Ser Val Ala Ser Ser 20 25 30 Ser Tyr Tyr Trp Gly Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu 35 40 45 Trp Ile Gly Thr Ile Asn Phe Ser Gly Asn Met Tyr Tyr Ser Pro Ser 50 55 60 Leu Arg Ser Arg Val Thr Met Ser Ala Asp Met Ser Glu Asn Ser Phe 65 70 75 80 Tyr Leu Lys Leu Asp Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95 Cys Ala Ala Gly His Leu Val Met Gly Phe Gly Ala His Trp Gly Gln 100 105 110 Gly Lys Leu Val Ser Val Ser Pro Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Ala 435 440 445 Ser Gln Thr Pro Thr Asn Thr Ile Ser Val Thr Pro Thr Asn Asn Ser 450 455 460 Thr Pro Thr Asn Asn Ser Asn Pro Lys Pro Asn Pro Ala Ser Pro Gly 465 470 475 480 Gln Gly Thr Gln Ser Glu Asn Ser Cys Thr His Phe Pro Gly Asn Leu 485 490 495 Pro Asn Met Leu Arg Asp Leu Arg Asp Ala Phe Ser Arg Val Lys Thr 500 505 510 Phe Phe Gln Met Lys Asp Gln Leu Asp Asn Leu Leu Leu Lys Glu Ser 515 520 525 Leu Leu Glu Asp Phe Lys Gly Tyr Leu Gly Cys Gln Ala Leu Ser Glu 530 535 540 Met Ile Gln Phe Tyr Leu Glu Glu Val Met Pro Gln Ala Glu Asn Gln 545 550 555 560 Asp Pro Asp Ile Lys Ala His Val Asn Ser Leu Gly Glu Asn Leu Lys 565 570 575 Thr Leu Arg Leu Arg Leu Arg Arg Cys His Arg Phe Leu Pro Cys Glu 580 585 590 Asn Lys Ser Lys Ala Val Glu Gln Val Lys Asn Ala Phe Asn Lys Leu 595 600 605 Gln Glu Lys Gly Ile Tyr Lys Ala Met Ser Glu Phe Asp Ile Phe Ile 610 615 620 Asn Tyr Ile Glu Ala Tyr Met Thr Met Lys Ile Arg Asn 625 630 635 <210> 42 <211> 1992 <212> DNA <213> Homo sapiens <400> 42 atggacctcc tgtgcaagaa catgaagcac ctgtggttct tcctcctgct ggtggcggct 60 cccagatggg tcctgtcccg gctgcagctg caggagtcgg gcccaggcct gctgaagcct 120 tcggtgaccc tgtccctcac ctgcactgtc tcgggtgact ccgtcgccag tagttcttat 180 tactggggct gggtccgtca gcccccaggg aagggactcg agtggatagg gactatcaat 240 tttagtggca atatgtatta tagtccgtcc ctcaggagtc gagtgaccat gtcggcagac 300 atgtccgaga actccttcta tctgaaattg gactctgtga ccgcagcaga cacggccgtc 360 tattattgtg cggcaggaca cctcgttatg ggatttgggg cccactgggg acagggaaaa 420 ctggtctccg tctctccagc ttccaccaag ggcccatccg tcttccccct ggcgccctgc 480 tccaggagca cctccgagag cacagccgcc ctgggctgcc tggtcaagga ctacttcccc 540 gaaccggtga cggtgtcgtg gaactcaggc gccctgacca gcggcgtgca caccttcccg 600 gctgtcctac agtcctcagg actctactcc ctcagcagcg tggtgaccgt gccctccagc 660 agcttgggca cgaagaccta cacctgcaac gtagatcaca agcccagcaa caccaaggtg 720 gacaagagag ttgagtccaa atatggtccc ccatgcccac cctgcccagc acctgagttc 780 gaagggggac catcagtctt cctgttcccc ccaaaaccca aggacactct catgatctcc 840 cggacccctg aggtcacgtg cgtggtggtg gacgtgagcc aggaagaccc cgaggtccag 900 ttcaactggt acgtggatgg cgtggaggtg cataatgcca agacaaagcc gcgggaggag 960 cagttcaaca gcacgtaccg tgtggtcagc gtcctcaccg tcctgcacca ggactggctg 1020 aacggcaagg agtacaagtg caaggtctcc aacaaaggcc tcccgtcctc catcgagaaa 1080 accatctcca aagccaaagg gcagccccga gagccacagg tgtacaccct gcccccatcc 1140 caggaggaga tgaccaagaa ccaggtcagc ctgacctgcc tggtcaaagg cttctacccc 1200 agcgacatcg ccgtggagtg ggagagcaat gggcagccgg agaacaacta caagaccacg 1260 cctcccgtgc tggactccga cggctccttc ttcctctaca gcaggctaac cgtggacaag 1320 agcaggtggc aggaggggaa tgtcttctca tgctccgtga tgcatgaggc tctgcacaac 1380 cactacacac agaagagcct ctccctgtct ctgggtaaag ctagtcagac ccccaccaac 1440 accatcagcg tgacccccac caacaacagc acccccacca acaacagcaa cccaagccc 1500 aaccccgcta gcccaggcca gggcacccag tctgagaaca gctgcaccca cttcccaggc 1560 aacctgccta acatgcttcg agatctccga gatgccttca gcagagtgaa gactttcttt 1620 caaatgaagg atcagctgga caacttgttg ttaaaggagt ccttgctgga ggactttaag 1680 ggttacctgg gttgccaagc cttgtctgag atgatccagt tttacctgga ggaggtgatg 1740 ccccaagctg agaaccaaga cccagacatc aaggcgcatg tgaactccct gggggagaac 1800 ctgaagaccc tcaggctgag gctacggcgc tgtcatcgat ttcttccctg tgaaaacaag 1860 agcaaggccg tggagcaggt gaagaatgcc tttaataagc tccaagagaa aggcatctac 1920 aaagccatga gtgagtttga catcttcatc aactacatag aagcctacat gacaatgaag 1980 atacgaaact ga 1992 <210> 43 <211> 214 <212> PRT <213> Homo sapiens <400> 43 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 44 <211> 705 <212> DNA <213> Homo sapiens <400> 44 atgagggtcc cctggggctc ctgctactct ggctccgagg tgccagatgt 60 gataccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 120 atcacttgcc gggcaagtca gagcattagc agctatttaa attggtatca gcagaaacca 180 gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaagtgg ggtcccatca 240 aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctccaacct 300 gaagattttg caacttacta ctgtcaacag agttacagta ccccgtacac ttttggccag 360 gggaccaagc tggagatcaa acgaactgtg gctgcaccat ctgtcttcat cttcccgcca 420 tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 480 ccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 540 gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 600 ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 660 ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gttag 705 <210> 45 <211> 447 <212> PRT <213> Homo sapiens <400> 45 Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Ser Val Ser Gly Phe Ser Leu Ser Asn Tyr 20 25 30 Asp Ile Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Met Trp Thr Gly Gly Gly Ala Asn Tyr Asn Ser Ala Phe Met 50 55 60 Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Leu 65 70 75 80 Lys Met Asn Asn Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Val 85 90 95 Arg Asp Ala Val Arg Tyr Trp Asn Phe Asp Val Trp Gly Ala Gly Thr 100 105 110 Thr Val Thr Val Ser Ser Ala Lys Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys 210 215 220 Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu 225 230 235 240 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 245 250 255 Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln 260 265 270 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 275 280 285 Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu 290 295 300 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 305 310 315 320 Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys 325 330 335 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 340 345 350 Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 355 360 365 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 370 375 380 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 385 390 395 400 Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln 405 410 415 Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 420 425 430 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Ala Ser 435 440 445 <210> 46 <211> 122 <212> PRT <213> Homo sapiens <400> 46 Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Ser Val Ser Gly Phe Ser Leu Ser Asn Tyr 20 25 30 Asp Ile Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Met Trp Thr Gly Gly Gly Ala Asn Tyr Asn Ser Ala Phe Met 50 55 60 Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Leu 65 70 75 80 Lys Met Asn Asn Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Val 85 90 95 Arg Asp Ala Val Arg Tyr Trp Asn Phe Asp Val Trp Gly Ala Gly Thr 100 105 110 Thr Val Thr Val Ser Ser Ala Lys Thr Lys 115 120 <210> 47 <211> 213 <212> PRT <213> Homo sapiens <400> 47 Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr 35 40 45 Ala Thr Ser His Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu 65 70 75 80 Asp Thr Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Phe Thr 85 90 95 Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro 100 105 110 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125 Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu 145 150 155 160 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190 Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205 Asn Arg Gly Glu Cys 210 <210> 48 <211> 102 <212> PRT <213> Homo sapiens <400> 48 Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr 35 40 45 Ala Thr Ser His Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu 65 70 75 80 Asp Thr Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Phe Thr 85 90 95 Phe Gly Ser Gly Thr Lys 100 <210> 49 <211> 450 <212> PRT <213> Homo sapiens <400> 49 Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Thr Tyr 20 25 30 Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Asn Pro Ser Ser Gly Tyr Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Ser 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Arg Ala Val Leu Val Pro Tyr Ala Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Ser Val Thr Val Ser Ser Ala Lys Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly 210 215 220 Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser 225 230 235 240 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 245 250 255 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro 260 265 270 Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val 290 295 300 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320 Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr 325 330 335 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 340 345 350 Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys 355 360 365 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 370 375 380 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 385 390 395 400 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys 435 440 445 Ala Ser 450 <210> 50 <211> 125 <212> PRT <213> Homo sapiens <400> 50 Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Thr Tyr 20 25 30 Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Asn Pro Ser Ser Gly Tyr Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Asp Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Ser 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Arg Ala Val Leu Val Pro Tyr Ala Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Ser Val Thr Val Ser Ser Ala Lys Thr Lys 115 120 125 <210> 51 <211> 213 <212> PRT <213> Homo sapiens <400> 51 Gln Ile Val Leu Thr Gln Ser Pro Ala Val Met Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Ile Thr Cys Thr Ala Ser Ser Ser Leu Ser Tyr Met 20 25 30 His Trp Phe Gln Gln Lys Pro Gly Thr Ser Pro Lys Leu Trp Leu Tyr 35 40 45 Ser Thr Ser Ile Leu Ala Ser Gly Val Pro Thr Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Met Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Arg Ser Ser Ser Pro Phe Thr 85 90 95 Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro 100 105 110 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 115 120 125 Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 130 135 140 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu 145 150 155 160 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 165 170 175 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 180 185 190 Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 195 200 205 Asn Arg Gly Glu Cys 210 <210> 52 <211> 102 <212> PRT <213> Homo sapiens <400> 52 Gln Ile Val Leu Thr Gln Ser Pro Ala Val Met Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Ile Thr Cys Thr Ala Ser Ser Ser Leu Ser Tyr Met 20 25 30 His Trp Phe Gln Gln Lys Pro Gly Thr Ser Pro Lys Leu Trp Leu Tyr 35 40 45 Ser Thr Ser Ile Leu Ala Ser Gly Val Pro Thr Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Met Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Arg Ser Ser Ser Pro Phe Thr 85 90 95 Phe Gly Ser Gly Thr Lys 100 <210> 53 <211> 448 <212> PRT <213> Homo sapiens <400> 53 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Glu Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Asn Met Asn Trp Val Lys Gln Ser Asn Gly Lys Ser Leu Glu Trp Ile 35 40 45 Gly Asn Ile Asp Pro Tyr Tyr Gly Asp Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met His Leu Lys Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Pro Tyr Gly Ser Glu Ala Tyr Phe Ala Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ala Ala Lys Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro 210 215 220 Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe 225 230 235 240 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255 Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val 260 265 270 Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285 Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val 290 295 300 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 305 310 315 320 Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser 325 330 335 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 340 345 350 Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 355 360 365 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 370 375 380 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 385 390 395 400 Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp 405 410 415 Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 420 425 430 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Ala Ser 435 440 445 <210> 54 <211> 123 <212> PRT <213> Homo sapiens <400> 54 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Glu Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr 20 25 30 Asn Met Asn Trp Val Lys Gln Ser Asn Gly Lys Ser Leu Glu Trp Ile 35 40 45 Gly Asn Ile Asp Pro Tyr Tyr Gly Asp Thr Asn Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met His Leu Lys Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Pro Tyr Gly Ser Glu Ala Tyr Phe Ala Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ala Ala Lys Thr Lys 115 120 <210> 55 <211> 214 <212> PRT <213> Homo sapiens <400> 55 Asp Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Thr Pro Gly 1 5 10 15 Asp Arg Val Ser Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Asp Tyr 20 25 30 Leu His Trp Tyr Gln Gln Lys Ser His Glu Ser Pro Arg Leu Leu Ile 35 40 45 Lys Tyr Ala Ala Gln Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Ser Asp Phe Thr Leu Ser Ile Asn Gly Val Glu Pro 65 70 75 80 Glu Asp Val Gly Val Tyr Tyr Cys Gln Asn Gly His Ser Phe Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 56 <211> 103 <212> PRT <213> Homo sapiens <400> 56 Asp Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Thr Pro Gly 1 5 10 15 Asp Arg Val Ser Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Asp Tyr 20 25 30 Leu His Trp Tyr Gln Gln Lys Ser His Glu Ser Pro Arg Leu Leu Ile 35 40 45 Lys Tyr Ala Ala Gln Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Ser Asp Phe Thr Leu Ser Ile Asn Gly Val Glu Pro 65 70 75 80 Glu Asp Val Gly Val Tyr Tyr Cys Gln Asn Gly His Ser Phe Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys 100 <210> 57 <211> 449 <212> PRT <213> Homo sapiens <400> 57 Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Gly Met Asn Trp Val Lys Gln Val Pro Gly Lys Gly Leu Arg Trp Met 35 40 45 Gly Trp Met Asp Thr Phe Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe 50 55 60 Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Leu Gln Ile Asn Ser Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys 85 90 95 Ala Arg Gly Gly Ile Leu Arg Leu Asn Tyr Phe Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Thr Leu Thr Val Ser Ser Ala Lys Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Ala 435 440 445 Ser <210> 58 <211> 124 <212> PRT <213> Homo sapiens <400> 58 Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Gly Met Asn Trp Val Lys Gln Val Pro Gly Lys Gly Leu Arg Trp Met 35 40 45 Gly Trp Met Asp Thr Phe Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe 50 55 60 Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Leu Gln Ile Asn Ser Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys 85 90 95 Ala Arg Gly Gly Ile Leu Arg Leu Asn Tyr Phe Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Thr Leu Thr Val Ser Ser Ala Lys Thr Lys 115 120 <210> 59 <211> 214 <212> PRT <213> Homo sapiens <400> 59 Asp Ile Gln Met Thr Gln Ser Ser Ser Ser Phe Ser Val Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Glu Asp Ile Tyr Asn Arg 20 25 30 Leu Gly Trp Tyr Gln Gln Lys Pro Gly Asn Ala Pro Arg Leu Leu Ile 35 40 45 Ser Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Lys Asp Tyr Ala Leu Ser Ile Thr Ser Leu Gln Thr 65 70 75 80 Glu Asp Leu Ala Thr Tyr Tyr Cys Gln Gln Cys Trp Thr Ser Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 60 <211> 106 <212> PRT <213> Homo sapiens <400> 60 Asp Ile Gln Met Thr Gln Ser Ser Ser Ser Phe Ser Val Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Glu Asp Ile Tyr Asn Arg 20 25 30 Leu Gly Trp Tyr Gln Gln Lys Pro Gly Asn Ala Pro Arg Leu Leu Ile 35 40 45 Ser Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Lys Asp Tyr Ala Leu Ser Ile Thr Ser Leu Gln Thr 65 70 75 80 Glu Asp Leu Ala Thr Tyr Tyr Cys Gln Gln Cys Trp Thr Ser Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile 100 105 <210> 61 <211> 445 <212> PRT <213> Homo sapiens <400> 61 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Tyr Met Lys Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile 35 40 45 Gly Asp Ile Asn Pro Asn Tyr Gly Asp Thr Phe Tyr Asn Gln Lys Phe 50 55 60 Glu Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Arg Thr Ala Tyr 65 70 75 80 Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Gly Arg Gly Asp Tyr Gly Tyr Phe Asp Val Trp Gly Ala Gly Thr Thr 100 105 110 Val Thr Val Ser Ser Ala Lys Thr Lys Gly Pro Ser Val Phe Pro Leu 115 120 125 Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys 130 135 140 Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 145 150 155 160 Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175 Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 180 185 190 Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn 195 200 205 Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro 210 215 220 Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe 225 230 235 240 Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 245 250 255 Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe 260 265 270 Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 275 280 285 Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr 290 295 300 Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 305 310 315 320 Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala 325 330 335 Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln 340 345 350 Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly 355 360 365 Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro 370 375 380 Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser 385 390 395 400 Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu 405 410 415 Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 420 425 430 Tyr Thr Gln Lys Ser Leu Leu Ser Leu Gly Lys Ala Ser 435 440 445 <210> 62 <211> 121 <212> PRT <213> Homo sapiens <400> 62 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Tyr Met Lys Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile 35 40 45 Gly Asp Ile Asn Pro Asn Tyr Gly Asp Thr Phe Tyr Asn Gln Lys Phe 50 55 60 Glu Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Arg Thr Ala Tyr 65 70 75 80 Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Gly Arg Gly Asp Tyr Gly Tyr Phe Asp Val Trp Gly Ala Gly Thr Thr 100 105 110 Val Thr Val Ser Ser Ala Lys Thr Lys 115 120 <210> 63 <211> 214 <212> PRT <213> Homo sapiens <400> 63 Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly 1 5 10 15 Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Gly Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile 35 40 45 Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Asn Val Gln Ser 65 70 75 80 Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln Tyr Ser Ser Asn Pro Tyr 85 90 95 Met Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 64 <211> 106 <212> PRT <213> Homo sapiens <400> 64 Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly 1 5 10 15 Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Gly Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile 35 40 45 Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Asn Val Gln Ser 65 70 75 80 Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln Tyr Ser Ser Asn Pro Tyr 85 90 95 Met Phe Gly Gly Gly Thr Lys Leu Glu Ile 100 105 <210> 65 <211> 447 <212> PRT <213> Homo sapiens <400> 65 Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala Ser Val 1 5 10 15 Lys Ile Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Glu Tyr Thr Met 20 25 30 His Trp Val Arg Gln Ser His Gly Lys Ser Leu Glu Trp Ile Gly Gly 35 40 45 Ile Asn Pro Ile Asn Gly Gly Pro Thr Tyr Asn Gln Lys Phe Lys Gly 50 55 60 Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr Met Glu 65 70 75 80 Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg 85 90 95 Trp Asp Tyr Gly Ser Arg Asp Val Met Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Ser Val Thr Val Ser Ser Ala Lys Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys 210 215 220 Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu 225 230 235 240 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 245 250 255 Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln 260 265 270 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 275 280 285 Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu 290 295 300 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 305 310 315 320 Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys 325 330 335 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 340 345 350 Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 355 360 365 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 370 375 380 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 385 390 395 400 Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln 405 410 415 Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 420 425 430 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys Ala Ser 435 440 445 <210> 66 <211> 122 <212> PRT <213> Homo sapiens <400> 66 Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala Ser Val 1 5 10 15 Lys Ile Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Glu Tyr Thr Met 20 25 30 His Trp Val Arg Gln Ser His Gly Lys Ser Leu Glu Trp Ile Gly Gly 35 40 45 Ile Asn Pro Ile Asn Gly Gly Pro Thr Tyr Asn Gln Lys Phe Lys Gly 50 55 60 Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr Met Glu 65 70 75 80 Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg 85 90 95 Trp Asp Tyr Gly Ser Arg Asp Val Met Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Ser Val Thr Val Ser Ser Ala Lys Thr Lys 115 120 <210> 67 <211> 214 <212> PRT <213> Homo sapiens <400> 67 Asn Ile Val Met Thr Gln Ser Pro Lys Ser Met Ser Met Ser Val Gly 1 5 10 15 Glu Arg Val Thr Leu Ser Cys Lys Ala Ser Glu Asn Val Gly Thr Tyr 20 25 30 Val Ser Trp Tyr Gln Gln Arg Pro Glu Gln Ser Pro Lys Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly 50 55 60 Ser Gly Ser Ala Thr Asp Phe Thr Leu Thr Ile Ser Ser Val Gln Ala 65 70 75 80 Glu Asp Leu Ala Asp Tyr His Cys Gly Gln Thr Tyr Ser Tyr Ile Phe 85 90 95 Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 68 <211> 105 <212> PRT <213> Homo sapiens <400> 68 Asn Ile Val Met Thr Gln Ser Pro Lys Ser Met Ser Met Ser Val Gly 1 5 10 15 Glu Arg Val Thr Leu Ser Cys Lys Ala Ser Glu Asn Val Gly Thr Tyr 20 25 30 Val Ser Trp Tyr Gln Gln Arg Pro Glu Gln Ser Pro Lys Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly 50 55 60 Ser Gly Ser Ala Thr Asp Phe Thr Leu Thr Ile Ser Ser Val Gln Ala 65 70 75 80 Glu Asp Leu Ala Asp Tyr His Cys Gly Gln Thr Tyr Ser Tyr Ile Phe 85 90 95 Thr Phe Gly Ser Gly Thr Lys Leu Glu 100 105 <210> 69 <211> 446 <212> PRT <213> Homo sapiens <400> 69 Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Thr Ser 1 5 10 15 Val Lys Met Ser Cys Glu Ala Ala Arg Phe Thr Phe Ser Asn Tyr Trp 20 25 30 Ile Gly Trp Val Lys Gln Arg Pro Gly His Gly Leu Glu Trp Ile Gly 35 40 45 Asp Ile Phe Pro Gly Gly Asp Tyr Thr Asn Tyr Asn Lys Lys Phe Lys 50 55 60 Asp Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Ser Thr Ala Tyr Met 65 70 75 80 Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg Ser Asp Tyr Gly Gly Tyr Tyr Val Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Thr Leu Thr Val Ser Ser Ala Lys Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro 210 215 220 Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe 225 230 235 240 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255 Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val 260 265 270 Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285 Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val 290 295 300 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 305 310 315 320 Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser 325 330 335 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 340 345 350 Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 355 360 365 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 370 375 380 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 385 390 395 400 Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp 405 410 415 Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 420 425 430 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys 435 440 445 <210> 70 <211> 220 <212> PRT <213> Homo sapiens <400> 70 Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Val Gly 1 5 10 15 Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Asn Leu Leu Tyr Ser 20 25 30 Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Val Lys Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Tyr Tyr Ser Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile 100 105 110 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 145 150 155 160 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 165 170 175 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 195 200 205 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220 <210> 71 <211> 445 <212> PRT <213> Homo sapiens <400> 71 Ala Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly 1 5 10 15 Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp 20 25 30 Tyr Ser Val His Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp 35 40 45 Met Gly Trp Ile Asn Thr Glu Thr Gly Glu Pro Thr Tyr Ala Asp Asp 50 55 60 Leu Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala 65 70 75 80 Tyr Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe 85 90 95 Cys Ala Lys Pro Thr Tyr Arg Phe Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Thr Leu Thr Ala Ser Ser Ala Lys Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys 210 215 220 Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu 225 230 235 240 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 245 250 255 Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln 260 265 270 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 275 280 285 Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu 290 295 300 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 305 310 315 320 Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys 325 330 335 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 340 345 350 Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 355 360 365 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 370 375 380 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 385 390 395 400 Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln 405 410 415 Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 420 425 430 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys 435 440 445 <210> 72 <211> 219 <212> PRT <213> Homo sapiens <400> 72 Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Ala Gly 1 5 10 15 Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser 20 25 30 Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Lys Gln 85 90 95 Ser Tyr Asn Leu Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 145 150 155 160 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 73 <211> 203 <212> PRT <213> Homo sapiens <400> 73 Met Glu Trp Ser Trp Ile Phe Leu Phe Leu Leu Ser Gly Thr Ala Gly 1 5 10 15 Val His Ser Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys 20 25 30 Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe 35 40 45 Thr Asp Tyr Val Leu His Trp Val Lys Gln Lys Pro Gly Gln Gly Leu 50 55 60 Glu Trp Ile Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn 65 70 75 80 Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser 85 90 95 Thr Ala Tyr Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val 100 105 110 Tyr Tyr Cys Ala Arg Gly Tyr Pro Ala Tyr Ser Gly Tyr Ala Met Asp 115 120 125 Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Ala Lys Thr Thr 130 135 140 Pro Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn 145 150 155 160 Ser Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro 165 170 175 Val Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr 180 185 190 Phe Pro Ala Val Leu Gln Lys Gly Glu Phe Val 195 200 <210> 74 <211> 234 <212> PRT <213> Homo sapiens <400> 74 Met Met Ser Ser Ala Gln Phe Leu Gly Leu Leu Leu Leu Cys Phe Gln 1 5 10 15 Gly Thr Arg Cys Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser 20 25 30 Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp 35 40 45 Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly ...

Claims

1. A pharmaceutical composition for preventing or treating graft-versus-host disease (GVHD) in a subject in need thereof, comprising an anti-DC-ASGPR antibody or an antigen-binding fragment thereof, The anti-DC-ASGPR antibody or antigen-binding fragment thereof is not operably linked to an active ingredient; and The anti-DC-ASGPR antibody or antigen-binding fragment thereof comprises three heavy chain CDRs and three light chain CDRs derived from the variable heavy chain (VH) and variable light chain (VL) of an antibody having the amino acid sequences of SEQ ID NO: 3 and SEQ ID NO: 8, respectively; The pharmaceutical composition.

2. 2. The pharmaceutical composition of claim 1, wherein the antibody is a human antibody, a humanized antibody, a recombinant antibody, a bispecific antibody, a chimeric antibody, a nanobody, a DARPin, an antibody derivative, a veneered antibody, a diabody, a monoclonal antibody, or a polyclonal antibody.

3. The pharmaceutical composition of claim 2, wherein the antibody is a humanized antibody or a mouse / human chimeric antibody.

4. The pharmaceutical composition of claim 1 or 2, wherein the antibody comprises a pair of variable regions of an anti-DC-ASGPR heavy chain variable region and an anti-DC-ASGPR light chain variable region comprising SEQ ID NO: 3 and SEQ ID NO: 8, respectively.

5. 3. The pharmaceutical composition of claim 1 or 2, wherein the antibody comprises a heavy and light chain pair comprising SEQ ID NO:2 and SEQ ID NO:

7.

6. The pharmaceutical composition of any one of claims 1 to 5, wherein the antibody comprises a gamma 4 constant region.

7. 7. The pharmaceutical composition of claim 6, wherein the gamma 4 constant region comprises a leucine to glutamic acid substitution at residue 235 and / or a serine to proline substitution at residue 228 in the hinge region.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the subject is a human subject.

9. The pharmaceutical composition of claim 8, wherein the subject is at risk of developing a disease mediated by a pathogenic T cell response.

10. 10. The pharmaceutical composition of claim 9, wherein the disease is selected from rheumatoid arthritis, allergies, asthma, systemic juvenile arthritis, inflammatory bowel disease, systemic lupus erythematosus, and Crohn's disease.

11. The pharmaceutical composition according to any one of claims 1 to 8, wherein the subject is a subject who is going to receive or has received a transplanted tissue.

12. The pharmaceutical composition of claim 11 , which is administered prior to tissue transplantation.

13. The pharmaceutical composition of claim 12, wherein the transplant-related complications are prevented or treated, the complications including GVHD.

14. The pharmaceutical composition of claim 11 , which is administered after tissue transplantation.

15. The pharmaceutical composition of any one of claims 11 to 14, wherein the transplant comprises immune cells, stem cells, hematopoietic stem cells, bone marrow, blood, or skin cells.

16. The pharmaceutical composition according to any one of claims 1 to 15, which is administered by intraperitoneal or intravenous injection.

17. 17. The pharmaceutical composition of any one of claims 1 to 16, wherein the antibody or antigen-binding fragment further comprises a modification, which modification is one or more of the following (i) to (ii): (i) a conservative amino acid mutation in the Fc hinge region; and (ii) PEGylation.

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